Avascular necrosis of bone after allogeneic hematopoietic cell transplantation in children and adolescents.

Science.gov (United States)

Li, Xiaxin; Brazauskas, Ruta; Wang, Zhiwei; Al-Seraihy, Amal; Baker, K Scott; Cahn, Jean-Yves; Frangoul, Haydar A; Gajewski, James L; Hale, Gregory A; Hsu, Jack W; Kamble, Rammurti T; Lazarus, Hillard M; Marks, David I; Maziarz, Richard T; Savani, Bipin N; Shah, Ami J; Shah, Nirali; Sorror, Mohamed L; Wood, William A; Majhail, Navneet S

2014-04-01

We conducted a nested case-control study within a cohort of 6244 patients to assess risk factors for avascular necrosis (AVN) of bone in children and adolescents after allogeneic transplantation. Eligible patients were ≤21 years of age, received their first allogeneic transplant between 1990 and 2008 in the United States, and had survived ≥ 6 months from transplantation. Overall, 160 patients with AVN and 478 control subjects matched by year of transplant, length of follow-up and transplant center were identified. Patients and control subjects were confirmed via central review of radiology, pathology, and/or surgical procedure reports. Median time from transplant to diagnosis of AVN was 14 months. On conditional logistic regression, increasing age at transplant (≥5 years), female gender, and chronic graft-versus-host disease (GVHD) were significantly associated with increased risks of AVN. Compared with patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with nonmalignant diseases and those who had received reduced-intensity conditioning regimens for malignant diseases. Children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to myeloablative conditioning regimens and immunosuppression after hematopoietic cell transplantation for the treatment of GVHD. More research is needed to determine whether screening strategies specifically for patients at high risk for developing AVN with early interventions may mitigate the morbidity associated with this complication. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Financial burden in recipients of allogeneic hematopoietic cell transplantation.

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Khera, Nandita; Chang, Yu-hui; Hashmi, Shahrukh; Slack, James; Beebe, Timothy; Roy, Vivek; Noel, Pierre; Fauble, Veena; Sproat, Lisa; Tilburt, Jon; Leis, Jose F; Mikhael, Joseph

2014-09-01

Although allogeneic hematopoietic cell transplantation (HCT) is an expensive treatment for hematological disorders, little is known about the financial consequences for the patients who undergo this procedure. We analyzed factors associated with its financial burden and its impact on health behaviors of allogeneic HCT recipients. A questionnaire was retrospectively mailed to 482 patients who underwent allogeneic HCT from January 2006 to June 2012 at the Mayo Clinic, to collect information regarding current financial concerns, household income, employment, insurance, out-of-pocket expenses, and health and functional status. A multivariable logistic regression analysis identified factors associated with financial burden and treatment nonadherence. Of the 268 respondents (56% response rate), 73% reported that their sickness had hurt them financially. All patients for whom the insurance information was available (missing, n = 13) were insured. Forty-seven percent of respondents experienced financial burden, such as household income decreased by >50%, selling/mortgaging home, or withdrawing money from retirement accounts. Three percent declared bankruptcy. Younger age and poor current mental and physical functioning increased the likelihood of financial burden. Thirty-five percent of patients reported deleterious health behaviors because of financial constraints. These patients were likely to be younger, have lower education, and with a longer time since HCT. Being employed decreased the likelihood of experiencing financial burden and treatment nonadherence due to concern about costs. A significant proportion of allogeneic HCT survivors experience financial hardship despite insurance coverage. Future research should investigate potential interventions to help at-risk patients and prevent adverse financial outcomes after this life-saving procedure. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Impact of conditioning with TBI in adult patients with T-cell ALL who receive a myeloablative allogeneic stem cell transplantation

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Cahu, X; Labopin, M; Giebel, S

2016-01-01

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a therapeutic option for adult patients with T-cell ALL (T-ALL). Meanwhile, few allo-SCT data specific to adult T-ALL have been described thus far. Specifically, the optimal myeloablative conditioning regimen is unknown...... patients with T-ALL entitled to receive a myeloablative allo-SCT may benefit from TBI-based regimens.Bone Marrow Transplantation advance online publication, 30 November 2015; doi:10.1038/bmt.2015.278....

Acquisition and Cure of Autoimmune Disease Following Allogeneic Hematopoietic Stem Cell Transplantation

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Hsin-An Hou

2007-09-01

Full Text Available Hematopoietic stem cell transplantation (HSCT can either cause or eliminate autoimmune disease. Here, we report two cases. One was a 33-year-old woman with myelodysplastic syndrome (refractory anemia who received bone marrow transplantation from her human leukocyte antigen (HLA-identical sister who had a history of Graves' disease. Antithyroid antibodies, including antimicrosomal antibody and antithy-roglobulin antibody, appeared 4 months after transplantation. Clinical hyperthyroidism appeared 7 months after transplantation, and a hypothyroid state was noted 2 months later. The other case was a 50-year-old woman with Sjögren's syndrome and hypothyroidism who was diagnosed with peripheral T cell non-Hodgkin's lymphoma. She received allogeneic peripheral blood stem cell transplantation (PBSCT from her histocompatible sister owing to only partial response to traditional chemotherapy. Cure of lymphoma and remission of Sjögren's syndrome was noted 4 years after PBSCT. These two illustrative cases, one of acquisition of hyperthyroidism and the other of remission of Sjögren's syndrome after transplantation, highlights that HSCT can induce adoptive autoimmune disease or cure coincidental autoimmune disease. Donor selection and attentive monitoring is required in such circumstances.

Central nervous system infection following allogeneic hematopoietic stem cell transplantation.

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Hanajiri, Ryo; Kobayashi, Takeshi; Yoshioka, Kosuke; Watanabe, Daisuke; Watakabe, Kyoko; Murata, Yutaka; Hagino, Takeshi; Seno, Yasushi; Najima, Yuho; Igarashi, Aiko; Doki, Noriko; Kakihana, Kazuhiko; Sakamaki, Hisashi; Ohashi, Kazuteru

2017-03-01

Here, we described the clinical characteristics and outcomes of central nervous system (CNS) infections occurring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in a single institution over the previous 6 years. Charts of 353 consecutive allogeneic transplant recipients were retrospectively reviewed for CNS infection. A total of 17 cases of CNS infection were identified at a median of 38 days (range, 10-1028 days) after allo-HSCT. Causative pathogens were human herpesvirus-6 (n=6), enterococcus (n=2), staphylococcus (n=2), streptococcus (n=2), varicella zoster virus (n=1), cytomegalovirus (n=1), John Cunningham virus (n=1), adenovirus (n=1), and Toxoplasma gondii (n=1). The cumulative incidence of CNS infection was 4.1% at 1 year and 5.5% at 5 years. Multivariate analysis revealed that high-risk disease status was a risk factor for developing CNS infection (p=.02), and that overall survival at 3 years after allo-HSCT was 33% in patients with CNS infection and 53% in those without CNS infection (p=.04). Copyright © 2016 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.

Immune Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation

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Ogonek, Justyna; Kralj Juric, Mateja; Ghimire, Sakhila; Varanasi, Pavankumar Reddy; Holler, Ernst; Greinix, Hildegard; Weissinger, Eva

2016-01-01

The timely reconstitution and regain of function of a donor-derived immune system is of utmost importance for the recovery and long-term survival of patients after allogeneic hematopoietic stem cell transplantation (HSCT). Of note, new developments such as umbilical cord blood or haploidentical grafts were associated with prolonged immunodeficiency due to delayed immune reconstitution, raising the need for better understanding and enhancing the process of immune reconstitution and finding strategies to further optimize these transplant procedures. Immune reconstitution post-HSCT occurs in several phases, innate immunity being the first to regain function. The slow T cell reconstitution is regarded as primarily responsible for deleterious infections with latent viruses or fungi, occurrence of graft-versus-host disease, and relapse. Here we aim to summarize the major steps of the adaptive immune reconstitution and will discuss the importance of immune balance in patients after HSCT. PMID:27909435

Specific Factors Influence the Success of Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

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Thissiane L. Gonçalves

2009-01-01

Full Text Available Successful hematopoietic stem cell transplantation (HSCT, both autologous and allogeneic, requires a rapid and durable engraftment, with neutrophil (>500/µL and platelet (>20,000/µL reconstitution. Factors influencing engraftment after autologous or allogeneic HSCT were investigated in 65 patients: 25 autologous peripheral stem cell transplantation (PBSCT and 40 allogeneic bone marrow transplantation (BMT patients. The major factor affecting engraftment was the graft source for HSCT. Neutrophil and platelet recovery were more rapid in autologous PBSCT than in allogeneic BMT [neutrophil occurring in median on day 10.00 (09.00/11.00 and 19.00 (16.00/23.00 and platelet on day 11.00 (10.00/13.00 and 21.00 (18.00/25.00, respectively; p < 0.0001]. The type of disease also affected engraftment, where multiple myeloma (MM and lymphoma showed faster engraftment when compared with leukemia, syndrome myelodysplastic (SMD and aplastic anemia (AA and MM presented the best overall survival (OS in a period of 12 months. Other factors included the drug used in the conditioning regimen (CR, where CBV, melphalan (M-200 and FluCy showed faster engraftment and M-200 presented the best OS, in a period of 12 months and age, where 50–59 years demonstrated faster engraftment. Sex did not influence neutrophil and platelet recovery.

Degree of Predicted Minor Histocompatibility Antigen Mismatch Correlates with Poorer Clinical Outcomes of Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation

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Larsen, Malene Erup; Kornblit, B; Larsen, Mette Voldby

2010-01-01

In fully HLA-matched allogeneic hematopoietic cell transplantations (HCT), the main mechanism of the beneficial graft-versus-tumor (GVT) effect and of the detrimental graft-versus-host disease (GVHD) is believed to be caused by donor cytotoxic T cells directed against disparate recipient minor hi...

A comparison of the effect of xinruibai versus filgrastim on hematopoietic reconstruction after allogeneic hematopoietic stem cell transplantation.

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Ye, Qixiang; Jiang, Hebi; Jiang, Hua

2018-05-31

To compare the effect of xinruibai (Pegfilgrastim) and filgrastim injections on white blood cell and platelet (PLT) recovery, adverse events, post-operative complications, and cost effectiveness after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Children who underwent allo-HSCT at our hospital from January 2014 to May 2017 due to thalassemia major, aplastic anemia, leukemia, and mucopolysaccharidosis were included. Among the children, 53 received xinruibai injections and 33 received filgrastim injections. There were no significant differences in the average time to neutrophil and platelet recovery, the incidence of post-operative complications after allo-HSCT, the number of red blood cell and PLT infusions, or the incidence of adverse events related to the injection between two groups (P >  0.05). The pain score was 3.06 (SD 0.41) for the xinruibai group and 25.18 (SD 6.22) for the filgrastim group, indicating significant differences between the two groups (P <  0.001). No difference was found in the hospitalization cost. The cost of the granulocyte-colony stimulating factor (G-CSF) was 257.11 ± 61.87 Euro in the xinruibai group and 214.79 ± 0.00 Euro in the filgrastim group, showing significant difference (P <  0.001). Xinruibai injection was more convenient, simple, effective, and safer than filgrastim.

Nonmyeloablative and reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation: a clinical review.

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Pollack, Seth M; O'Connor, Thomas P; Hashash, Jana; Tabbara, Imad A

2009-12-01

Allogeneic hematopoietic stem cell transplantation provides many patients, with hematological and malignant diseases, hope of remission and in some cases cure. Because the toxicities of this approach are severe, its use has been limited to younger healthier patients. Nonmyeloablative and reduced intensity conditioning regimens depend more on donor cellular immune effects and less on the cytotoxic effects of the conditioning regimen to eradicate the underlying disease. This approach is based on the induction of host tolerance to donor cells followed by the administration of scheduled donor T-lymphocytes infusions. Accumulated clinical data have been encouraging, and prospective studies are underway to compare this approach to conventional myeloablative allogeneic stem cell transplantation with regard to outcome, durability of responses, effects on the immune system, and the consequences of late complications such as chronic graft-versus-host disease.

Granulocyte-colony stimulating factor (G-CSF)-primed, delayed marrow harvests as a source of hematopoietic stem and progenitor cells for allogeneic transplantation.

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Phillips, G L; Davey, D D; Hale, G A; Marshall, K W; Munn, R K; Nath, R; Reece, D E; Van Zant, G

1999-10-01

We evaluated the ability of G-CSF to increase the number of hematopoietic stem cells obtained by "delayed" BM harvest for allogeneic transplantation. Five normal donors received G-CSF @ 10 mcg/kg/day x 5 followed by repeat PB and BM assays at day 6 and 16, and BM harvest at day 16. Stem cells were not increased in the BM at day 16. Five patients underwent BMT and engrafted at +10 to +19 days. While the tested strategy offers no intrinsic advantages, its potential cannot be evaluated fully without alternative timing and/or additional, "early acting" growth factors.

Correlation and Agreement of Handheld Spirometry with Laboratory Spirometry in Allogeneic Hematopoietic Cell Transplant Recipients.

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Cheng, Guang-Shing; Campbell, Angela P; Xie, Hu; Stednick, Zach; Callais, Cheryl; Leisenring, Wendy M; Englund, Janet A; Chien, Jason W; Boeckh, Michael

2016-05-01

Early detection of subclinical lung function decline may help identify allogeneic hematopoietic cell transplant (HCT) recipients who are at increased risk for late noninfectious pulmonary complications, including bronchiolitis obliterans syndrome. We evaluated the use of handheld spirometry in this population. Allogeneic HCT recipients enrolled in a single-center observational trial performed weekly spirometry with a handheld spirometer for 1 year after transplantation. Participants performed pulmonary function tests in an outpatient laboratory setting at 3 time points: before transplantation, at day 80 after transplantation, and at 1 year after transplantation. Correlation between the 2 methods was assessed by Pearson and Spearman correlations; agreement was assessed using Bland-Altman plots. A total of 437 subjects had evaluable pulmonary function tests. Correlation for forced expiratory volume in 1 second (FEV1) was r = .954 (P spirometry correlated well with laboratory spirometry after allogeneic HCT and may be useful for self-monitoring of patients for early identification of airflow obstruction. Copyright © 2016 American Society for Blood and Marrow Transplantation. All rights reserved.

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling.

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Mori, Takehiko; Koh, Hideo; Onishi, Yasushi; Kako, Shinichi; Onizuka, Makoto; Kanamori, Heiwa; Ozawa, Yukiyasu; Kato, Chiaki; Iida, Hiroatsu; Suzuki, Ritsuro; Ichinohe, Tatsuo; Kanda, Yoshinobu; Maeda, Tetsuo; Nakao, Shinji; Yamazaki, Hirohito

2016-04-01

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

Towards effective and safe immunotherapy after allogeneic stem cell transplantation: identification of hematopoietic-specific minor histocompatibility antigen UTA2-1

NARCIS (Netherlands)

Oostvogels, R.; Minnema, M. C.; van Elk, M.; Spaapen, R. M.; te Raa, G. D.; Giovannone, B.; Buijs, A.; van Baarle, D.; Kater, A. P.; Griffioen, M.; Spierings, E.; Lokhorst, H. M.; Mutis, T.

2013-01-01

Donor T cells directed at hematopoietic system-specific minor histoconnpatibility antigens (mHags) are considered important cellular tools to induce therapeutic graft-versus-tumor (GvT) effects with low risk of graft-versus-host disease after allogeneic stem cell transplantation. To enable the

Atovaquone for Prophylaxis of Toxoplasmosis after Allogeneic Hematopoietic Stem Cell Transplantation.

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Mendorf, Alexander; Klyuchnikov, Evgeny; Langebrake, Claudia; Rohde, Holger; Ayuk, Francis; Regier, Marc; Christopeit, Maximilian; Zabelina, Tatjana; Bacher, Adelbert; Stübig, Thomas; Wolschke, Christine; Bacher, Ulrike; Kröger, Nicolaus

2015-01-01

Toxoplasmosis and infections by other opportunistic agents such as Pneumocystis jirovecii constitute life-threatening risks for patients after allogeneic hematopoietic stem cell transplantation. Trimethoprim/sulfamethoxazole (TMP-SMX) has been well established for post-transplant toxoplasmosis and pneumocystis prophylaxis, but treatment may be limited due to toxicity. We explored atovaquone as an alternative and compared it with TMP-SMX regarding toxicity and efficacy during the first 100 days after transplantation in 155 consecutive adult stem cell recipients. Eight patients with a prior history of TMP-SMX intolerance received atovaquone as first-line prophylaxis. TMP-SMX was used for 141 patients as first-line strategy, but 13 patients (9.2%) were later switched to atovaquone due to TMP-SMX toxicity or gastrointestinal symptoms. No active toxoplasmosis or active P. jirovecii infection developed under continued prophylaxis with either TMP-SMX or atovaquone. However, for reasons of TMP-SMX and/or atovaquone toxicity, 7 patients were unable to tolerate any efficacious toxoplasmosis prophylaxis and therefore obtained inhalative pentamidine as P. jirovecii prophylaxis but no toxoplasmosis prophylaxis. Importantly, 2 of these patients developed severe toxoplasmosis. In summary, atovaquone appears as a valid alternative for at least some post-transplant patients who cannot tolerate TMP-SMX. This should be further confirmed by multicenter trials. © 2015 S. Karger AG, Basel.

Allogeneic Hematopoietic Cell Transplantation for Dyskeratosis Congenita: A Report of 3 Cases.

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Tamura, Shinichi; Imamura, Toshihiko; Urata, Takayo; Kobayashi, Miki; Gen, Mari; Tomii, Toshihiro; Do, Junko; Osone, Shinya; Ishida, Hiroyuki; Hosoi, Hajime; Kuroda, Hiroshi

2017-10-01

Although bone marrow failure in patients with dyskeratosis congenita (DKC) can be successfully treated with allogeneic hematopoietic cell transplantation (allo-HCT) using a reduced intensity conditioning (RIC) regimen, the outcome of nonhematological disorders in patients with DKC treated with allo-HCT using RIC has not been fully elucidated. Here, we describe the clinical course of nonhematological disorders after allo-HCT with RIC in 3 consecutive patients with DKC. Allo-HCT with RIC was feasible in all cases; however, patient 1 developed lethal pulmonary disease and patient 2 experienced progression of hepatic fibrosis. Careful follow-up of patient-specific complications is required after allo-HCT in patients with DKC.

Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prognosis.

Science.gov (United States)

Bergeron, A; Godet, C; Chevret, S; Lorillon, G; Peffault de Latour, R; de Revel, T; Robin, M; Ribaud, P; Socié, G; Tazi, A

2013-06-01

Bronchiolitis obliterans syndrome (BOS) after allogeneic hematopoietic SCT (HSCT) is recognized as a new-onset obstructive lung defect (OLD) in pulmonary function testing and is related to pulmonary chronic GVHD. Little is known about the different phenotypes of patients with BOS and their outcomes. We reviewed the data of all allogeneic HSCT recipients referred to our pulmonary department for a non-infectious bronchial disease between 1999 and 2010. We identified 103 patients (BOS (n=77), asthma (n=11) and chronic bronchitis (n=15)). In patients with BOS, we identified two functional phenotypes: a typical OLD, that is, forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) ratio <0.7 (n=53), and an atypical OLD with a concomitant decrease in the FEV1 <80% and FVC <80% predicted with a normal total lung capacity (n=24). The typical OLD was characterized by more severe FEV1 and fewer centrilobular nodules on the computed tomography scan. The FEV1 was not significantly affected during the follow-up, regardless of the phenotype. In addition to acute and extensive chronic GVHD, only the occurrence of BOS soon after transplantation and the intentional treatment of BOS with steroids were associated with a poor survival. The determination of patient subgroups should be explored to improve the management of this condition.

Endocrinopathies after Allogeneic and Autologous Transplantation of Hematopoietic Stem Cells

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Francesco Orio

2014-01-01

Full Text Available Early and late endocrine disorders are among the most common complications in survivors after hematopoietic allogeneic- (allo- and autologous- (auto- stem cell transplant (HSCT. This review summarizes main endocrine disorders reported in literature and observed in our center as consequence of auto- and allo-HSCT and outlines current options for their management. Gonadal impairment has been found early in approximately two-thirds of auto- and allo-HSCT patients: 90–99% of women and 60–90% of men. Dysfunctions of the hypothalamus-pituitary-growth hormone/insulin growth factor-I axis, hypothalamus-pituitary-thyroid axis, and hypothalamus-pituitary-adrenal axis were documented as later complicances, occurring in about 10, 30, and 40–50% of transplanted patients, respectively. Moreover, overt or subclinical thyroid complications (including persistent low-T3 syndrome, chronic thyroiditis, subclinical hypo- or hyperthyroidism, and thyroid carcinoma, gonadal failure, and adrenal insufficiency may persist many years after HSCT. Our analysis further provides evidence that main recognized risk factors for endocrine complications after HSCT are the underlying disease, previous pretransplant therapies, the age at HSCT, gender, total body irradiation, posttransplant derangement of immune system, and in the allogeneic setting, the presence of graft-versus-host disease requiring prolonged steroid treatment. Early identification of endocrine complications can greatly improve the quality of life of long-term survivors after HSCT.

Periodontal status and bacteremia with oral viridans streptococci and coagulase negative staphylococci in allogeneic hematopoietic stem cell transplantation recipients: a prospective observational study

NARCIS (Netherlands)

Raber-Durlacher, Judith E.; Laheij, Alexa M. G. A.; Epstein, Joel B.; Epstein, Matthew; Geerligs, Gerard M.; Wolffe, Gordon N.; Blijlevens, Nicole M. A.; Donnelly, J. Peter

2013-01-01

This study was aimed to investigate whether any association could be found between the presence of an inflamed and infected periodontium (e.g., gingivitis and periodontitis) and the development of bacteremia during neutropenia following allogeneic hematopoietic stem cell transplantation (HSCT).

Kidney dysfunction after allogeneic stem cell transplantation

NARCIS (Netherlands)

Kersting, S.

2008-01-01

Allogeneic stem cell transplantation (SCT) is a widely accepted approach for malignant and nonmalignant hematopoietic diseases. Unfortunately complications can occur because of the treatment, leading to treatment-related mortality. We studied kidney dysfunction after allogeneic SCT in 2 cohorts of

Allogeneic Hematopoietic Cell Transplantation for Older Patients: Prognosis Determined by Disease Risk Index.

Science.gov (United States)

He, Fiona; Cao, Qing; Lazaryan, Aleksandr; Brunstein, Claudio; Holtan, Shernan; Warlick, Erica; Ustun, Celalettin; McClune, Brian; Arora, Mukta; Rashidi, Armin; Eckfeldt, Craig; Weisdorf, Daniel J; Bejanyan, Nelli

2017-09-01

The treatment of elderly patients with advanced hematological malignancies has expanded to include reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT) as a potentially curative option. We studied the association between Disease Risk Index (DRI) and clinical outcomes of 196 elderly patients (median age, 64.8; range, 60 to 75 years) with hematological malignancies receiving RIC alloHCT (2000 to 2014). Donors were related and unrelated adults (n = 100, 51.1%) or umbilical cord blood (n = 96, 48.9%). DRI classified 12 patients (6.1%) as low risk (LR), 146 patients (74.5%) as intermediate risk (IR), and 38 patients (19.4%) as high risk (HR). Two-year overall survival (OS) was 47% (52% for LR/IR versus 29% for HR, P risk of relapse (hazard ratio, 2.07; 95% confidence interval [CI], 1.34 to 3.33; P = .02) and treatment failure (hazard ratio, 2.07; 95% CI, 1.35 to 3.18; P risk of relapse leading to poor survival in HR DRI, participation in clinical trials offering relapse prevention strategies after RIC alloHCT should be encouraged when available. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Endothelial and circulating progenitor cells in hematological diseases and allogeneic hematopoietic stem cell transplantation.

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Ruggeri, Annalisa; Paviglianiti, Annalisa; Volt, Fernanda; Kenzey, Chantal; Rafii, Hanadi; Rocha, Vanderson; Gluckman, Eliane

2017-10-12

Circulating endothelial cells (CECs), originated form endothelial progenitors (EPCs) are mature cells which are not associated with vessel walls, and that are detached from the endothelium. Normally, they are present in insignificant amounts in the peripheral blood of healthy individuals. On the other hand, elevated CECs and EPCs levels have been reported in the peripheral blood of patients with different types of cancers and some other diseases. Consequently, CECs and EPCs represent a potential biomarker in several clinical conditions involving endothelial turnover and remodeling, such as hematological diseases. These cells may be involved in disease progression and the neoplastic angiogenesis process. Moreover, CESs and EPCs are probably involved in endothelial damage that is a marker of several complications following allogeneic hematopoietic stem cell transplantation. This review aims to provide an overview on the characterization of CECs and EPCs, describe isolation methods and to identify the potential role of these cells in hematological diseases and hematopoietic stem cell transplantation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Eosinophils from hematopoietic stem cell recipients suppress allogeneic T cell proliferation.

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Andersson, Jennie; Cromvik, Julia; Ingelsten, Madeleine; Lingblom, Christine; Andersson, Kerstin; Johansson, Jan-Erik; Wennerås, Christine

2014-12-01

Eosinophilia has been associated with less severe graft-versus-host disease (GVHD), but the underlying mechanism is unknown. We hypothesized that eosinophils diminish allogeneic T cell activation in patients with chronic GVHD. The capacity of eosinophils derived from healthy subjects and hematopoietic stem cell (HSC) transplant recipients, with or without chronic GVHD, to reduce allogeneic T cell proliferation was evaluated using a mixed leukocyte reaction. Eosinophil-mediated inhibition of proliferation was observed for the eosinophils of both healthy subjects and patients who underwent HSC transplantation. Eosinophils from patients with and without chronic GVHD were equally suppressive. Healthy eosinophils required cell-to-cell contact for their suppressive capacity, which was directed against CD4(+) T cells and CD8(+) T cells. Neither eosinophilic cationic protein, eosinophil-derived neurotoxin, indoleamine 2,3-dioxygenase, or increased numbers of regulatory T cells could account for the suppressive effect of healthy eosinophils. Real-time quantitative PCR analysis revealed significantly increased mRNA levels of the immunoregulatory protein galectin-10 in the eosinophils of both chronic GVHD patients and patients without GVHD, as compared with those from healthy subjects. The upregulation of galectin-10 expression in eosinophils from patients suggests a stimulatory effect of HSC transplantation in itself on eosinophilic galectin-10 expression, regardless of chronic GVHD status. To conclude, eosinophils from HSC transplant recipients and healthy subjects have a T cell suppressive capacity. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry.

NARCIS (Netherlands)

Michallet, M.; Sobh, M.; Milligan, D.; Morisset, S.; Niederwieser, D.; Koza, V.; Ruutu, T.; Russell, N.H.; Verdonck, L.; Dhedin, N.; Vitek, A.; Boogaerts, M.; Vindelov, L.; Finke, J.; Dubois, V.; Biezen, A. van; Brand, R.; Witte, T.J.M. de; Dreger, P.

2010-01-01

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high

Acyclovir-resistant herpes simplex virus 1 infection early after allogeneic hematopoietic stem cell transplantation with T-cell depletion.

Science.gov (United States)

Akahoshi, Yu; Kanda, Junya; Ohno, Ayumu; Komiya, Yusuke; Gomyo, Ayumi; Hayakawa, Jin; Harada, Naonori; Kameda, Kazuaki; Ugai, Tomotaka; Wada, Hidenori; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Sato, Miki; Terasako-Saito, Kiriko; Kimura, Shun-Ichi; Kikuchi, Misato; Nakasone, Hideki; Kako, Shinichi; Shiraki, Kimiyasu; Kanda, Yoshinobu

2017-07-01

We previously reported that oral low-dose acyclovir (200 mg/day) for the prevention of herpes simplex virus (HSV) infections after allogenic hematopoietic stem cell transplantation (HSCT) is effective without the emergence of acyclovir-resistant HSV infections. However, HSV infections are of significant concern because the number of allogeneic HSCT with T-cell depletion, which is a risk factor of the emergence of drug-resistant HSV infections, has been increasing. We experienced a 25-year-old female who received allogenic HSCT from an unrelated donor with 1-antigen mismatch using anti-thymocyte globulin. Despite acyclovir prophylaxis (200 mg/day), she developed the right palatal ulcer that was positive for HSV-1 specific antigen by fluorescent antibody on day 20 and developed new hypoglossal and tongue ulcers on day 33. Replacement of acyclovir with foscarnet improved her ulcers. We isolated 2 acyclovir-resistant and foscarnet-sensitive strains from the right palatal and hypoglossal ulcers, which had the same frame shift mutation in the thymidine kinase genes. The rate of proliferation of the isolate from the hypoglossal ulcer was faster than that from the right palatal ulcer in the plaque reduction assay. HSV strains that acquired acyclovir-resistant mutations at the right palatal ulcer with larger plaque might spread to the hypoglossal ulcer as the secondary site of infection because of better growth property. Second-line antiviral agents should be considered when we suspect treatment failure of HSV infection, especially in HSCT with T-cell depletion. Further studies are required whether low-dose acyclovir prophylaxis leads to the emergence of virological resistance. Copyright © 2017 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Prognostic Importance of Pretransplant Functional Capacity After Allogeneic Hematopoietic Cell Transplantation.

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Jones, Lee W; Devlin, Sean M; Maloy, Molly A; Wood, William A; Tuohy, Sharlynn; Espiritu, Noel; Aquino, Jennifer; Kendig, Tiffany; Michalski, Meghan G; Gyurkocza, Boglarka; Schaffer, Wendy L; Ali, Benzar; Giralt, Sergio; Jakubowski, Ann A

2015-11-01

The purpose of this study was to investigate the prognostic importance of functional capacity in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for hematological malignancies. Using a retrospective design, 407 patients completed a 6-minute walk distance (6 MWD) test to assess functional capacity before HCT; 193 (47%) completed a 6 MWD test after hospital discharge. Cox proportional hazards regression was used to estimate the risk of nonrelapse mortality (NRM) and overall survival (OS) according to the 6 MWD category (interval, 0.44-0.96) for a 6 MWD ≥ 400 m. A 6 MWD of ≥ 400 m provided incremental information on the prediction of NRM with adjustment for age (p = .032) but not KPS alone (p = .062) or adjustment for other prognostic markers (p = .099). A significant association was found between the 6 MWD and OS (p = .027). A 6 MWD of ≥ 400 m provided incremental information on the prediction of OS with adjustment for age (p = .032) but not for other prognostic markers (p > .05 for all). Patients presenting with a pre-HCT 6 MWD of information beyond that of traditional prognostic markers in HCT. The pretransplant 6-minute walk test is a significant univariate predictor of clinical outcomes in hematological patients beyond age but not beyond that of performance status. On this basis, 6-minute walk distance testing should not be considered part of the standard battery of assessments for risk stratification before hematopoietic cell transplantation. ©AlphaMed Press.

Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors.

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Carnevale-Schianca, Fabrizio; Caravelli, Daniela; Gallo, Susanna; Coha, Valentina; D'Ambrosio, Lorenzo; Vassallo, Elena; Fizzotti, Marco; Nesi, Francesca; Gioeni, Luisa; Berger, Massimo; Polo, Alessandra; Gammaitoni, Loretta; Becco, Paolo; Giraudo, Lidia; Mangioni, Monica; Sangiolo, Dario; Grignani, Giovanni; Rota-Scalabrini, Delia; Sottile, Antonino; Fagioli, Franca; Aglietta, Massimo

2017-03-01

Allogeneic hematopoietic cell transplant (HCT) remains the only curative therapy for many hematologic malignancies but it is limited by high nonrelapse mortality (NRM), primarily from unpredictable control of graft-versus-host disease (GVHD). Recently, post-transplant cyclophosphamide demonstrated improved GVHD control in allogeneic bone marrow HCT. Here we explore cyclophosphamide in allogeneic peripheral blood stem cell transplantation (alloPBSCT). Patients with high-risk hematologic malignancies received alloPBSCT from HLA-matched unrelated/related donors. GVHD prophylaxis included combination post-HCT cyclophosphamide 50 mg/kg (days +3 and +4) and tacrolimus/mofetil mycophenolate (T/MMF) (day +5 forward). The primary objective was the cumulative incidence of acute and chronic GVHD. Between March 2011 and May 2015, 35 consecutive patients received the proposed regimen. MMF was stopped in all patients at day +28; the median discontinuation of tacrolimus was day +113. Acute and chronic GVHD cumulative incidences were 17% and 7%, respectively, with no grade IV GVHD events, only 2 patients requiring chronic GVHD immunosuppression control, and no deaths from GVHD. Two-year NRM, overall survival, event-free survival, and chronic GVHD event-free survival rates were 3%, 77%, 54%, and 49%, respectively. The graft-versus-tumor effect was maintained as 5 of 15 patients (33%) who received HCT with evidence of disease experienced further disease response. A post-transplant cyclophosphamide + T/MMF combination strategy effectively prevented acute and chronic GVHD after alloPBSCT from HLA-matched donors and achieved an unprecedented low NRM without losing efficacy in disease control or impaired development of the graft-versus-tumor effect. This trial is registered at clinicaltrials.gov as NCT02300571. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry

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Michallet, M; Sobh, M; Milligan, D

2010-01-01

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high re...

ACTIVATION OF T. GONDII INFECTION AFTER ALLOGENEIC TRANSPLANTATION OF HEMATOPOIETIC STEM CELLS: DEPENDENCE ON TIME OF TRANSPLANTATION AND SEROLOGICAL STATUS OF THE PATIENTS

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A. B. Chukhlovin

2014-01-01

Full Text Available The article focuses on aspects of T. gondii reactivation/reinfection in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHSCT. We have observed 297 patients who received conditioning therapy and allogeneic grafts due to different oncohematological or lymphoproliferative diseases (1 to 60 years old, at a mediane of 19 years. Conditioning regimens were either myeloablative (35%, or non-myeloablative (65%. DNA diagnostics of T. gondii was performed on a regular basis at 0 to 6 months post-HSCT. IgG and IgM antibodies against T. gondii were determined in 78 patients before HSCT, as well as in their donors. T. gondii DNA post-transplant proved to be positive in 13% of blood specimens, 9% of cerebrospinal liquor samples, 11% of bronchoalveolar cell lavages, and in 5% of urine sediments. In adolescent patients (10 to 14 years old, an increased prevalence of T. gondii was found in patients who received myeloablative treatment (p = 0.01. When assessing posttransplant dynamics of T. gondii, we have revealed distinct increase in the pathogen excretion within 1st month after HSCT (p = 0.03. Finally, initial presence of IgG antibodies against T. gondii in the patients was associated with lower incidence of the pathogen reactivation post-transplant.

Computed Tomography Findings of Human Polyomavirus BK (BKV)-Associated Cystitis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

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Schulze, M.; Beck, R.; Igney, A.; Vogel, M.; Maksimovic, O.; Claussen, C.D.; Faul, C.; Horger, M.

2008-01-01

Background: Over 70% of the general population worldwide is positive for antibodies against polyomavirus hominis type 1 (BKV). Polyomavirus can be reactivated in immunocompromised patients and thereby induce urogenital tract infection, including cystitis. Purpose: To describe the computed tomography (CT) findings of human polyomavirus-induced cystitis in adult patients after allogeneic hematopoietic stem cell transplantation (allogeneic HCT). Material and Methods: The study population was a retrospective cohort of 11 consecutive adult patients (eight men, three women; age range 22-59 years, mean 42.9 years) who received allogeneic HCT between December 2003 and December 2007 and were tested positive for urinary BKV infection. All CT scans were evaluated with regard to bladder wall thickness, mucosal enhancement, distinct layering of thickened bladder wall, and presence of intravesical clots, perivesical stranding as well as attenuation values of intravesical urine. Clinical data concerning transplant and conditioning regimen variables and laboratory parameters were correlated with degree and extent of imaging findings. Results: All patients had clinical signs of cystitis with different degrees of thickening of the urinary bladder wall. Well-delineated urinary bladder layers were present in six patients. Thickening of the urinary bladder wall was continuous in nine of 11 patients. Increased attenuation of intravesical urine was found in seven patients with hemorrhagic cystitis. Four patients had intraluminal clots. Perivesical stranding was not a major CT finding, occurring in a mild fashion in three of 11 patients. The clinical classification of hemorrhagic cystitis did not correlate with the analyzed imaging parameters. Patient outcome was not influenced by this infectious complication. Conclusion: CT findings in patients with polyomavirus BK cystitis consist of different degrees of bladder wall thickening usually with good delineation of all mural layers and

Computed Tomography Findings of Human Polyomavirus BK (BKV)-Associated Cystitis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

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Schulze, M.; Beck, R.; Igney, A.; Vogel, M.; Maksimovic, O.; Claussen, C.D.; Faul, C.; Horger, M. [Dept. of Diagnostic Radiology, Dept. of Internal Medicine-Oncology, and Inst. of Medical Virology, Eberhard-Karls Univ., Tbingen (Germany)

2008-12-15

Background: Over 70% of the general population worldwide is positive for antibodies against polyomavirus hominis type 1 (BKV). Polyomavirus can be reactivated in immunocompromised patients and thereby induce urogenital tract infection, including cystitis. Purpose: To describe the computed tomography (CT) findings of human polyomavirus-induced cystitis in adult patients after allogeneic hematopoietic stem cell transplantation (allogeneic HCT). Material and Methods: The study population was a retrospective cohort of 11 consecutive adult patients (eight men, three women; age range 22-59 years, mean 42.9 years) who received allogeneic HCT between December 2003 and December 2007 and were tested positive for urinary BKV infection. All CT scans were evaluated with regard to bladder wall thickness, mucosal enhancement, distinct layering of thickened bladder wall, and presence of intravesical clots, perivesical stranding as well as attenuation values of intravesical urine. Clinical data concerning transplant and conditioning regimen variables and laboratory parameters were correlated with degree and extent of imaging findings. Results: All patients had clinical signs of cystitis with different degrees of thickening of the urinary bladder wall. Well-delineated urinary bladder layers were present in six patients. Thickening of the urinary bladder wall was continuous in nine of 11 patients. Increased attenuation of intravesical urine was found in seven patients with hemorrhagic cystitis. Four patients had intraluminal clots. Perivesical stranding was not a major CT finding, occurring in a mild fashion in three of 11 patients. The clinical classification of hemorrhagic cystitis did not correlate with the analyzed imaging parameters. Patient outcome was not influenced by this infectious complication. Conclusion: CT findings in patients with polyomavirus BK cystitis consist of different degrees of bladder wall thickening usually with good delineation of all mural layers and

Computed Tomography Findings of Human Polyomavirus BK (BKV)-Associated Cystitis in Allogeneic Hematopoietic Stem Cell Transplant Recipients

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Schulze, M.; Beck, R.; Igney, A.; Vogel, M.; Maksimovic, O.; Claussen, C.D.; Faul, C.; Horger, M. (Dept. of Diagnostic Radiology, Dept. of Internal Medicine-Oncology, and Inst. of Medical Virology, Eberhard-Karls Univ., Tbingen (Germany))

2008-12-15

Background: Over 70% of the general population worldwide is positive for antibodies against polyomavirus hominis type 1 (BKV). Polyomavirus can be reactivated in immunocompromised patients and thereby induce urogenital tract infection, including cystitis. Purpose: To describe the computed tomography (CT) findings of human polyomavirus-induced cystitis in adult patients after allogeneic hematopoietic stem cell transplantation (allogeneic HCT). Material and Methods: The study population was a retrospective cohort of 11 consecutive adult patients (eight men, three women; age range 22-59 years, mean 42.9 years) who received allogeneic HCT between December 2003 and December 2007 and were tested positive for urinary BKV infection. All CT scans were evaluated with regard to bladder wall thickness, mucosal enhancement, distinct layering of thickened bladder wall, and presence of intravesical clots, perivesical stranding as well as attenuation values of intravesical urine. Clinical data concerning transplant and conditioning regimen variables and laboratory parameters were correlated with degree and extent of imaging findings. Results: All patients had clinical signs of cystitis with different degrees of thickening of the urinary bladder wall. Well-delineated urinary bladder layers were present in six patients. Thickening of the urinary bladder wall was continuous in nine of 11 patients. Increased attenuation of intravesical urine was found in seven patients with hemorrhagic cystitis. Four patients had intraluminal clots. Perivesical stranding was not a major CT finding, occurring in a mild fashion in three of 11 patients. The clinical classification of hemorrhagic cystitis did not correlate with the analyzed imaging parameters. Patient outcome was not influenced by this infectious complication. Conclusion: CT findings in patients with polyomavirus BK cystitis consist of different degrees of bladder wall thickening usually with good delineation of all mural layers and

The impact of center experience on results of reduced intensity:allogeneic hematopoietic SCT for AML. An analysis from the Acute Leukemia Working Party of the EBMT

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Giebel, S; Labopin, M; Mohty, M

2013-01-01

Allogeneic hematopoietic SCT with reduced-intensity conditioning (RIC-HSCT) is increasingly adopted for the treatment of older adults with AML. Our goal was to verify for the first time, if center experience influences outcome of RIC-HSCT. Results of 1413 transplantations from HLA-matched related...

Allogeneic hematopoietic stem cell transplantation in Primary Cutaneous T Cell Lymphoma.

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Cudillo, Laura; Cerretti, Raffaella; Picardi, Alessandra; Mariotti, Benedetta; De Angelis, Gottardo; Cantonetti, Maria; Postorino, Massimiliano; Ceresoli, Eleonora; De Santis, Giovanna; Nasso, Daniela; Pisani, Francesco; Scala, Enrico; Di Piazza, Fabio; Lanti, Alessandro

2018-06-01

In our retrospective study, 16 patients affected by advanced cutaneous T cell lymphoma (CTCL) underwent allogeneic hematopoietic stem cell transplantation (HSCT). Two patients (12.5%) were in complete remission (CR), nine (56.3%) in partial remission (PR), and five (31.2%) with active disease. The patients were transplanted from an HLA-identical (n = 7) from a mismatched (n = 1) or haploidentical (n = 1) sibling, from matched unrelated donor (n = 5), or from a single cord blood unit (n = 2). Conditioning regimen was standard myeloablative in 6 patients and at reduced intensity in 10. Seven patients died from non relapse mortality (NRM) and four patients relapsed or progressed, three of them achieved a second CR after donor lymphocyte infusion (DLI) or chemotherapy plus DLI. To date, with a median follow-up of 76 months (range 6-130), nine patients are alive, eight in CR, and one with active disease. Overall survival (OS) and disease-free survival (DFS) at 1 and 10 years are 61% (95% CI 40-91%) and 54% (95% CI 33-86%), 40% (95% CI 22-74%), and 34% (95% CI 16-68%), respectively. The time from diagnosis to transplant seems to influence negatively both OS (log-rank p < 0.04) and DFS (log-rank p < 0.05). Our results confirm on a long follow-up that CTCL appears particularly susceptible to the graft versus lymphoma (GVL) effect, so that allogeneic HSCT represents a possibility of cure for advanced CTCL. The timing of HSCT in the clinical course of disease remains an open issue.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry.

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Michallet, M; Sobh, M; Milligan, D; Morisset, S; Niederwieser, D; Koza, V; Ruutu, T; Russell, N H; Verdonck, L; Dhedin, N; Vitek, A; Boogaerts, M; Vindelov, L; Finke, J; Dubois, V; van Biezen, A; Brand, R; de Witte, T; Dreger, P

2010-10-01

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high resolution ('well matched' unrelated donor, WMUD), and 139 were mismatched (MM), including 30 matched in low resolution; 266 patients (72%) received reduced-intensity conditioning and 102 (28%) received standard. According to the EBMT risk score, 11% were in scores 1-3, 23% in score 4, 40% in score 5, 22% in score 6 and 4% in score 7. There was no difference in overall survival (OS) at 5 years between HLA-identical siblings (55% (48-64)) and WMUD (59% (41-84)), P=0.82. In contrast, OS was significantly worse for MM (37% (29-48) P=0.005) due to a significant excess of transplant-related mortality. Also OS worsened significantly when EBMT risk score increased. HLA matching had no significant impact on relapse (siblings: 24% (21-27); WMUD: 35% (26-44), P=0.11 and MM: 21% (18-24), P=0.81); alemtuzumab T-cell depletion and stem cell source (peripheral blood) were associated with an increased risk. Our findings support the use of WMUD as equivalent alternative to HLA-matched sibling donors for allogeneic HSCT in CLL, and justify the application of EBMT risk score in this disease.

Autoimmune hematological diseases after allogeneic hematopoietic stem cell transplantation in children: an Italian multicenter experience.

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Faraci, Maura; Zecca, Marco; Pillon, Marta; Rovelli, Attilio; Menconi, Maria Cristina; Ripaldi, Mimmo; Fagioli, Franca; Rabusin, Marco; Ziino, Ottavio; Lanino, Edoardo; Locatelli, Franco; Daikeler, Thomas; Prete, Arcangelo

2014-02-01

Autoimmune hematological diseases (AHDs) may occur after allogeneic hematopoietic stem cell transplantation (HSCT), but reports on these complications in large cohorts of pediatric patients are lacking. Between 1998 and 2011, 1574 consecutive children underwent allogeneic HSCT in 9 Italian centers. Thirty-three children (2.1%) developed AHDs: 15 autoimmune hemolytic anemia (45%), 10 immune thrombocytopenia (30%), 5 Evans' syndrome (15%), 2 pure red cell aplasia (6%), and 1 immune neutropenia (3%). The 10-year cumulative incidence of AHDs was 2.5% (95% confidence interval, 1.7 to 3.6). In a multivariate analysis, the use of alternative donor and nonmalignant disease was statistically associated with AHDs. Most patients with AHDs (64%) did not respond to steroids. Sustained complete remission was achieved in 87% of cases with the anti-CD20 monoclonal antibody (rituximab). Four patients (9%) (1 autoimmune hemolytic anemia, 1 Evans' syndrome, 2 immune thrombocytopenia) died at a median of 87 days after AHD diagnosis as a direct or indirect consequence of their disorder. Our data suggest that AHDs are a relatively rare complication occurring after HSCT that usually respond to treatment with rituximab. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

[Pretreatment doses of antithymocyte globubin-fresenius for allogeneic hematopoietic stem cell transplantation for beta-thalassemia major].

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Li, Chunfu; Wang, Yanhua; Wu, Xuedong; Pei, Fuyu; He, Yuelin; Feng, Xiaoqin; Liu, Huaying

2012-05-01

To investigate the effects of different doses of antithymocyte globubin-fresenius (ATG-F) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with beta-thalassemia Major. Sixty-four children with beta-thalassemia major undergoing allo-HSCT were divided into two equal groups to receive ATG-F pretreatments at high (30 mg/kg) or low (15 mg/kg) doses as part of the conditioning regimen including mainly cyclophosphamide, busulfan, fludarabine, and thiotepa. The outcomes of the patients were compared between the two groups. No obvious difference were noted in the time to leukocyte and platelet engraftment between the two groups. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) appeared to be higher in the low-dose group than in the high-dose group (12.5% vs 9.4%). The incidence of grade III-IV aGVHD was also higher in the low dose group (12.5% vs 6.3%), but the difference was not statistically significant. Application of high-dose ATG-F was associated with a higher rate of probable and possible fungal infection (P<0.05). The two doses of ATG-F is feasible as a part of the conditioning regimen for allo-HSCT in children with beta-thalassemia major.

Donor-specific Anti-HLA antibodies in allogeneic hematopoietic stem cell transplantation

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Sarah Morin-Zorman

2016-08-01

Full Text Available Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT is a curative treatment for a wide variety of hematological diseases. In 30% of the cases, a geno-identical donor is available. Any other situation displays some level of Human Leukocyte Antigen (HLA incompatibility between donor and recipient. Deleterious effects of anti-HLA immunization have long been recognized in solid organ transplant recipients. More recently, anti-HLA immunization was shown to increase the risk of Primary Graft Failure (PGF, a severe complication of AHSCT that occurs in 3 to 4% of matched unrelated donor transplantation and up to 15% in cord blood transplantation and T-cell depleted haplo-identical stem cell transplantation. Rates of PGF in patients with DSA were reported to be between 24 to 83% with the highest rates in haplo-identical and cord blood transplantation recipients. This led to the recommendation of anti-HLA antibody screening to detect Donor Specific Antibodies (DSA in recipients prior to AHSCT. In this review, we highlight the role of anti-HLA antibodies in AHSCT and the mechanisms that may lead to PGF in patients with DSA, and discuss current issues in the field.

Establishing an autologous versus allogeneic hematopoietic cell transplant program in nations with emerging economies.

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Chaudhri, Naeem A; Aljurf, Mahmoud; Almohareb, Fahad I; Alzahrani, Hazzaa A; Bashir, Qaiser; Savani, Bipin; Gupta, Vikas; Hashmi, Shahrukh K

2017-12-01

More than 70,000 hematopoietic cell transplants are currently performed each year, and these continue to increase every year. However, there is a significant variation in the number of absolute transplants and transplant rates between centers, countries, and global regions. The prospect for emerging countries to develop a hematopoietic cell transplantation (HCT) program, as well as to decide on whether autologous HCT (auto-HCT) or allogeneic HCT (allo-HCT) should be established to start with, relies heavily on factors that can explain differences between these two procedures. Major factors that will influence a decision about establishing the type of HCT program are macroeconomic factors such as organization of the healthcare network, available resources and infrastructure. Prevalence of specific diseases in the region as well genetic background of donors and recipients will also influence the mandate or priority of the HCT in the national healthcare plan to explain some of the country-specific differences. Furthermore, microeconomic factors play a role, such as center-specific experience in treating various disorders requiring hematopoietic stem cell transplantation, along with accreditation status and patient volume. The objective of the transplant procedure was to improve the survival and quality of life of patients. The regional difference that one notices in emerging countries about the higher number of allo-HCT compared with auto-HCT procedures performed is primarily based on suboptimal healthcare network in treating various malignant disorders that are the primary indication for auto-stem cell transplantation. In this context, nonmalignant disorders such as bone marrow failure syndromes, inherited genetic disorders and hemoglobinopathies have become the major indication for stem cell transplantation. Better understanding of these factors will assist in establishing new transplant centers in the emerging countries to achieve their specific objectives and

Lentiviral hematopoietic cell gene therapy for X-linked adrenoleukodystrophy.

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Cartier, Nathalie; Hacein-Bey-Abina, Salima; Bartholomae, Cynthia C; Bougnères, Pierre; Schmidt, Manfred; Kalle, Christof Von; Fischer, Alain; Cavazzana-Calvo, Marina; Aubourg, Patrick

2012-01-01

X-linked adrenoleukodystrophy (X-ALD) is a severe genetic demyelinating disease caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. When performed at an early stage of the disease, allogeneic hematopoietic stem cell transplantation (HCT) can arrest the progression of cerebral demyelinating lesions. To overcome the limitations of allogeneic HCT, hematopoietic stem cell (HSC) gene therapy strategy aiming to perform autologous transplantation of lentivirally corrected cells was developed. We demonstrated the preclinical feasibility of HSC gene therapy for ALD based on the correction of CD34+ cells from X-ALD patients using an HIV1-derived lentiviral vector. These results prompted us to initiate an HSC gene therapy trial in two X-ALD patients who had developed progressive cerebral demyelination, were candidates for allogeneic HCT, but had no HLA-matched donors or cord blood. Autologous CD34+ cells were purified from the peripheral blood after G-CSF stimulation, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1 cDNA, and then reinfused into the patients after they had received full myeloablative conditioning. Over 3 years of follow-up, the hematopoiesis remained polyclonal in the two patients treated with 7-14% of granulocytes, monocytes, and T and B lymphocytes expressing the lentivirally encoded ALD protein. There was no evidence of clonal dominance or skewing based on the retrieval of lentiviral insertion repertoire in different hematopoietic lineages by deep sequencing. Cerebral demyelination was arrested 14 and 16months, respectively, in the two treated patients, without further progression up to the last follow-up, a clinical outcome that is comparable to that observed after allogeneic HCT. Longer follow-up of these two treated patients and HSC gene therapy performed in additional ALD patients are however needed to evaluate the safety and efficacy of lentiviral HSC

Association between thymic function and allogeneic hematopoietic stem cell transplantation outcome: results of a pediatric study.

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Saglio, Francesco; Cena, Silvia; Berger, Massimo; Quarello, Paola; Boccasavia, Viola; Ferrando, Federica; Pittana, Laura; Bruno, Benedetto; Fagioli, Franca

2015-06-01

Robust T cell function recovery has been shown to be crucial in determining allogeneic hematopoietic stem cell transplantation (HSCT) outcome, and there is growing evidence that the thymus plays a central role in regulating this process. We performed a long-term analysis of the role of thymic activity recovery in a population of pediatric patients undergoing allogeneic HSCT by signal joint T cell receptor excision circle (sjTREC) quantification. In this study, characterized by a long-term follow-up (median, 72 months), we found patients with higher levels of sjTRECs before transplantation had a statistically significant reduced risk of death compared with patients with lower values (relative risk, .31; 95% confidence interval, .30 to .32; P = .02), showing this different outcome was mainly related to a reduction of relapse incidence (14% versus 43%, P = .02). Unlike previous reports, we observed no correlation between sjTREC levels and lymphocyte recovery. Moreover, we confirmed that only graft-versus-host disease influenced thymic activity after transplantation. In conclusion, our results suggest an association between pretransplantation thymic activity and the long-term outcome of pediatric patients undergoing HSCT, mainly through a reduction of relapse opportunities. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Outcome of allogeneic hematopoietic stem cell transplantation for childhood acute lymphoblastic leukemia in second complete remission: a single institution study

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Eun-Jung Lee

2012-03-01

Full Text Available Purpose : The survival rate for childhood acute lymphoblastic leukemia (ALL has improved significantly. However, overall prognosis for the 20 to 25% of patients who relapse is poor, and allogeneic hematopoietic stem cell transplantation (HSCT offers the best chance for cure. In this study, we identified significant prognostic variables by analyzing the outcomes of allogeneic HSCT in ALL patients in second complete remission (CR. Methods : Fifty-three ALL patients (42 men, 79% who received HSCT in second CR from August 1991 to February 2009 were included (26 sibling donor HSCTs, 49%; 42 bone marrow transplantations, 79%. Study endpoints included cumulative incidence of acute and chronic graft-versus-host disease (GVHD, relapse, 1-year transplant-related mortality (TRM, disease-free survival (DFS, and overall survival (OS. Results : Cumulative incidences of acute GVHD (grade 2 or above and chronic GVHD were 45.3% and 28.5%, respectively. The estimated 5-year DFS and OS for the cohort was 45.2¡?#?.8%; and 48.3¡?#?%,; respectively. Only donor type, i.e., sibling versus unrelated, showed significant correlation with DFS in multivariate analysis (P=0.010. The rates of relapse and 1 year TRM were 28.9¡?#?.4%; and 26.4¡?#?.1%;, respectively, and unrelated donor HSCT (P=0.002 and HLA mismatch (P =0.022 were significantly correlated with increased TRM in univariate analysis. Conclusion : In this single institution study spanning more than 17 years, sibling donor HSCT was the only factor predicting a favorable result in multivariate analysis, possibly due to increased TRM resulting from unrelated donor HSCT.

АВ0-INCOMPATIBILITY IN ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: 15-YEARS EXPERIENCE OF R.M. GORBACHEVA MEMORIAL RESEARCH INSTITUTE FOR CHILDREN ONCOLOGY, HEMATOLOGY AND TRANSPLANTATION

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M. A. Kucher

2016-01-01

Full Text Available Introduction. AB0-incompatibility in different types of allogeneic hematopoietic stem cell transplantation (HSCT may be an additional aggravating factor for the development of immunological complications and decrease treatment efficacy.Materials and methods. From May 1999 to December 2015 in R.M. Gorbacheva Memorial Research Institute for Children Oncology, Hematology and Transplantation 1131 patients with malignancies and hereditary diseases were included to the study, which were performed 1428 allogeneic HSCT: allogeneic unrelated – 814 (57.0 %, allogeneic related – 344 (24.1 %, haploidentical – 267 (18.7 %, umbilical cord blood in 3 patients (0.2 %. Age was 0–76 years, median – 25 years.Results. In 54.6 % of cases (n = 780 АВ0-incompatibility was determined: major – 37.8 % (n = 295; minor – 45.4 % (n = 354; combined – 16.8 % (n = 131. АВ0-incompatibility in allogeneic HSCT did not influence overall survival (p = 0.56, frequency of acute graftversus-host disease (GVHD (p = 0.2. There was an increased frequency of acute GVHD in combination with reduced intensity conditioning regimens and АВ0-incompatibility (30.8 % compared with myeloablative regimens (15.3 %; p = 0.002.Conclusion. The presence of АВ0-incompatibility is not a limiting factor to perform allogeneic HSCT, however, it demands high quality prophylaxis and sophisticated transfusion therapy to prevent immune complications.

Acute Fibrinous and Organizing Pneumonia Associated With Allogenic Hematopoietic Stem Cell Transplant Successfully Treated With Corticosteroids

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Lam-Phuong Nguyen DO

2016-04-01

Full Text Available Acute fibrinous and organizing pneumonia (AFOP is an extremely rare, relatively new, and distinct histological pattern of acute lung injury characterized predominately by the presence of intra-alveolar fibrin and associated organizing pneumonia. AFOP may be idiopathic or associated with a wide spectrum of clinical conditions. It has a variable clinical presentation from mild respiratory symptoms to that similar to the acute respiratory distress syndrome. Currently there is no consensus on treatment, and corticosteroids previously were of unclear benefit. To date, there are less than 40 cases of AFOP reported in the literature and only one has been linked to hematopoietic stem cell transplantation. Here we report the first case series of 2 patients who developed AFOP following allogenic stem cell transplant that were successfully treated with high-dose corticosteroids.

l-asparaginase-based regimens followed by allogeneic hematopoietic stem cell transplantation improve outcomes in aggressive natural killer cell leukemia

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Ki Sun Jung

2016-04-01

Full Text Available Abstract Aggressive nature killer cell leukemia (ANKL is a mature NK-T cell lymphoma with worse prognosis, but optimal treatment is unclear. Therefore, we analyzed the efficacy of l-asparaginase-based regimens for ANKL patients. Twenty-one patients who received dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide (SMILE or etoposide, ifosfamide, dexamethasone, and l-asparaginase (VIDL chemotherapy at Samsung Medical Center were selected. The overall response rate for all patients was 33 % (7/21; 38 % (5/13 in SMILE and 40 % (2/5 in VIDL, respectively. The median progression-free survival was 3.9 months (95 % CI 0.0–8.1 months and median overall survival was 7.0 months (95 % CI 2.3–11.7 months. Treatment response (P = 0.001, hematopoietic stem cell transplantation (HSCT (P = 0.007 and negative conversion of Epstein-Barr virus (EBV DNA titer after treatment (P = 0.004 were significantly associated with survival. Thus, l-asparaginase-based regimens followed by allogeneic HSCT seem to improve the outcome for ANKL patients.

Should elderly patients with higher-risk myelodysplastic syndromes undergo allogeneic hematopoietic stem cell transplantation?

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Zeidan, Amer M; Gore, Steven D

2013-10-01

Myelodysplastic syndromes (MDS) include a group of hematopoietic malignancies characterized by dysplastic changes, ineffective hematopoiesis and variable risk of leukemic progression. At diagnosis, 86% of MDS patients are ≥60 years. Azacitidine, the only drug that prolongs life in high-risk (HR)-MDS patients, adds a median of only 9.5 months to life. Allogeneic stem cell transplantation (alloSCT) remains the only potentially curative approach. Despite recent improvements including use of reduced intensity conditioning (RIC) that decrease transplant-related mortality, alloSCT continues to be used rarely in elderly MDS. There is paucity of data regarding outcomes of RIC alloSCT in elderly MDS patients, especially in direct comparison with azanucleosides. In this paper, the authors discuss the recent Markov decision analysis by Koreth et al. in which investigators demonstrated superior survival of patients with HR-MDS aged 60-70 years who underwent RIC alloSCT in comparison with those who were treated with azanucleosides.

Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis.

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Schetelig, Johannes; van Biezen, Anja; Brand, Ronald; Caballero, Dolores; Martino, Rodrigo; Itala, Maija; García-Marco, José A; Volin, Liisa; Schmitz, Norbert; Schwerdtfeger, Rainer; Ganser, Arnold; Onida, Francesco; Mohr, Brigitte; Stilgenbauer, Stephan; Bornhäuser, Martin; de Witte, Theo; Dreger, Peter

2008-11-01

Patients with chronic lymphocytic leukemia (CLL) and 17p deletion (17p-) have a poor prognosis. Although allogeneic hematopoietic stem-cell transplantation (HCT) has the potential to cure patients with advanced CLL, it is not known whether this holds true for patients with 17p-CLL. Baseline data from patients, for whom information on the presence of 17p-CLL was available, were downloaded from the European Group for Blood and Marrow Transplantation database. Additional information on the course of CLL and follow-up was collected with a questionnaire. A total of 44 patients with 17p-CLL received allogeneic HCT between March 1995 and July 2006 from a matched sibling (n = 24) or an alternative donor (n = 20). 17p-CLL had been diagnosed by fluorescent in situ hybridization in 82% of patients and by conventional banding in 18% of patients. The median age was 54 years. Before HCT, a median of three lines of chemotherapy had been administered. At HCT, 53% of patients were in remission. Reduced-intensity conditioning was applied in 89% of patients. Acute, grade 2 to 4 graft-versus-host disease (GVHD) occurred in 43% of patients, and extensive chronic GVHD occurred in 53% of patients. At last follow-up, 19 patients were alive, with a median observation time of 39 months (range, 18 to 101 months). Three-year overall survival and progression-free survival rates were 44% and 37%, respectively. The cumulative incidence of progressive disease at 4 years was 34%. No late relapse occurred in nine patients with a follow-up longer than 4 years. Allogeneic HCT has the potential to induce long-term disease-free survival in patients with 17p-CLL.

Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation.

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Inazawa, Natsuko; Hori, Tsukasa; Hatakeyama, Naoki; Yamamoto, Masaki; Yoto, Yuko; Nojima, Masanori; Suzuki, Nobuhiro; Shimizu, Norio; Tsutsumi, Hiroyuki

2015-08-01

Viral reactivations following hematopoietic stem cell transplantation are thought to result from the breakdown of both cell-mediated and humoral immunity. As a result, many viruses could be reactivated individually or simultaneously. Using a multiplex polymerase chain reaction (PCR), we prospectively examined many kinds of viral DNAs at a time in 105 patients who underwent allogeneic hematopoietic stem cell transplantation. In total, 591 whole blood samples were collected weekly from pre- to 42 days post-transplantation and the following 13 viruses were tested; herpes simplex virus 1 (HSV-1), HSV-2, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpes virus 6 (HHV-6), HHV-7, HHV-8, adenovirus, BK virus (BKV), JC virus (JCV), parvovirus B19, and hepatitis B virus (HBV). Several viral DNAs were detected in 12 patients before hematopoietic stem cell transplantation. The detection rate gradually increased after transplantation and peaked at 21 days. The most frequently detected virus was HHV-6 (n = 63; 60.0%), followed by EBV (n = 11; 10.5%), CMV (n = 11; 10.5%), and HHV-7 (n = 9; 8.6%). Adenovirus and HBV were each detected in one patient (1.0%). Detection of HHV-6 DNA was significantly more common among patients undergoing cord blood transplantation or with steroid treatment. EBV DNA tended to be more common in patients treated with anti-thymocyte globulin. Multiplex PCR was useful for detecting many viral reactivations after hematopoietic stem cell transplantation, simultaneously. Cord blood transplantation, steroid treatment, or anti-thymocyte globulin use was confirmed to be risk factors after transplantation. © 2015 Wiley Periodicals, Inc.

T cells for viral infections after allogeneic hematopoietic stem cell transplant.

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Bollard, Catherine M; Heslop, Helen E

2016-06-30

Despite recent advances in the field of allogeneic hematopoietic stem cell transplantation (HSCT), viral infections are still a major complication during the period of immune suppression that follows the procedure. Adoptive transfer of donor-derived virus-specific cytotoxic T cells (VSTs) is a strategy to rapidly restore virus-specific immunity to prevent or treat viral diseases after HSCT. Early proof of principle studies demonstrated that the administration of donor-derived T cells specific for cytomegalovirus or Epstein-Barr virus (EBV) could effectively restore virus-specific immunity and control viral infections. Subsequent studies using different expansion or direct selection techniques have shown that donor-derived VSTs confer protection in vivo after adoptive transfer in 70% to 90% of recipients. Because a major cause of failure is lack of immunity to the infecting virus in a naïve donor, more recent studies have infused closely matched third-party VSTs and reported response rates of 60% to 70%. Current efforts have focused on broadening the applicability of this approach by: (1) extending the number of viral antigens being targeted, (2) simplifying manufacture, (3) exploring strategies for recipients of virus-naïve donor grafts, and (4) developing and optimizing "off the shelf" approaches. © 2016 by The American Society of Hematology.

The impact of HLA matching on long-term transplant outcome after allogeneic hematopoietic stem cell transplantation for CLL: a retrospective study from the EBMT registry

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Michallet, M; Sobh, M; Milligan, D

2010-01-01

We analyzed 368 chronic lymphocytic leukemia patients who underwent allogeneic hematopoietic stem cell transplantation reported to the EBMT registry between 1995 and 2007. There were 198 human leukocyte antigen (HLA)-identical siblings; among unrelated transplants, 31 were well matched in high...... worsened significantly when EBMT risk score increased. HLA matching had no significant impact on relapse (siblings: 24% (21-27); WMUD: 35% (26-44), P=0.11 and MM: 21% (18-24), P=0.81); alemtuzumab T-cell depletion and stem cell source (peripheral blood) were associated with an increased risk. Our findings...... support the use of WMUD as equivalent alternative to HLA-matched sibling donors for allogeneic HSCT in CLL, and justify the application of EBMT risk score in this disease....

Use of G-CSF-stimulated marrow in allogeneic hematopoietic stem cell transplantation settings: a comprehensive review.

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Chang, Ying-Jun; Huang, Xiao-Jun

2011-01-01

In recent years, several researchers have unraveled the previously unrecognized effects of granulocyte colony-stimulating factor (G-CSF) on hematopoiesis and the immune cell functions of bone marrow in healthy donors. In human leukocyte antigen-matched or haploidentical transplant settings, available data have established the safety of using G-CSF-stimulated bone marrow grafts, as well as the ability of this source to produce rapid and sustained engraftment. Interestingly, G-CSF-primed bone marrow transplants could capture the advantages of blood stem cell transplants, without the increased risk of chronic graft-versus-host disease that is associated with blood stem cell transplants. This review summarizes the growing body of evidence that supports the use of G-CSF-stimulated bone marrow grafts as an alternative stem cell source in allogeneic hematopoietic stem cell transplantation. © 2010 John Wiley & Sons A/S.

Early NK Cell Reconstitution Predicts Overall Survival in T-Cell Replete Allogeneic Hematopoietic Stem Cell Transplantation

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Minculescu, Lia; Marquart, Hanne Vibeke; Friis, Lone Smidstrups

2016-01-01

Early immune reconstitution plays a critical role in clinical outcome after allogeneic hematopoietic stem cell transplantation (HSCT). Natural killer (NK) cells are the first lymphocytes to recover after transplantation and are considered powerful effector cells in HSCT. We aimed to evaluate...... the clinical impact of early NK cell recovery in T-cell replete transplant recipients. Immune reconstitution was studied in 298 adult patients undergoing HSCT for acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and myelodysplastic syndrome (MDS) from 2005 to 2013. In multivariate analysis NK...... cell numbers day 30 (NK30) >150cells/µL were independently associated with superior overall survival (hazard ratio 0.79, 95% confidence interval 0.66-0.95, p=0.01). Cumulative incidence analyses showed that patients with NK30 >150cells/µL had significantly less transplant related mortality (TRM), p=0...

CAR-T cells and allogeneic hematopoietic stem cell transplantation for relapsed/refractory B-cell acute lymphoblastic leukemia.

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Liu, Jun; Zhang, Xi; Zhong, Jiang F; Zhang, Cheng

2017-10-01

Relapsed/refractory acute lymphoblastic leukemia (ALL) has a low remission rate after chemotherapy, a high relapse rate and poor long-term survival even when allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Chimeric antigen receptors redirected T cells (CAR-T cells) can enhance disease remission with a favorable outcome for relapsed/refractory ALL, though some cases quickly relapsed after CAR-T cell treatment. Thus, treatment with CAR-T cells followed by allo-HSCT may be the best way to treat relapsed/refractory ALL. In this review, we first discuss the different types of CAR-T cells. We then discuss the treatment of relapsed/refractory ALL using only CAR-T cells. Finally, we discuss the use of CAR-T cells, followed by allo-HSCT, for the treatment of relapsed/refractory ALL.

Avascular necrosis of bone following allogeneic hematopoietic cell transplantation in children and adolescents

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Li, Xiaxin; Brazauskas, Ruta; Wang, Zhiwei; Al-Seraihy, Amal; Baker, K. Scott; Cahn, Jean-Yves; Frangoul, Haydar A.; Gajewski, James L.; Hale, Gregory A.; Hsu, Jack W.; Kamble, Rammurti T.; Lazarus, Hillard M.; Marks, David I.; Maziarz, Richard T.; Savani, Bipin N.; Shah, Ami J.; Shah, Nirali; Sorror, Mohamed L.; Wood, William A.; Majhail, Navneet S.

2014-01-01

We conducted a nested case-control study within a cohort of 6,244 patients to assess risk factors for avascular necrosis (AVN) of bone in children and adolescents following allogeneic transplantation. Eligible patients were ≤21 years of age, received their first allogeneic transplant between 1990 and 2008 in the United States and had survived ≥ 6 months from transplantation. Overall, 160 cases with AVN and 478 controls matched by year of transplant, length of followup and transplant center were identified. Cases and controls were confirmed via central review of radiology, pathology and/or surgical procedure reports. Median time from transplant to diagnosis of AVN was 14 months. On conditional logistic regression, increasing age at transplant (≥5 years), female gender and chronic graft-versus-host disease (GVHD) were significantly associated with increased risks of AVN. Compared to patients receiving myeloablative regimens for malignant diseases, lower risks of AVN were seen in patients with non-malignant diseases and those who had received reduced intensity conditioning regimens for malignant diseases. Children at high risk for AVN include those within the age group where rapid bone growth occurs as well as those who experience exposure to myeloablative conditioning regimens and immunosuppression post-HCT for the treatment of GVHD. More research is needed to determine whether screening strategies specifically for patients at high risk for developing AVN with early interventions may mitigate the morbidity associated with this complication. PMID:24388803

Conditioning with Treosulfan and Fludarabine Followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

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Nemecek, Eneida R.; Guthrie, Katherine A.; Sorror, Mohamed L.; Wood, Brent L.; Doney, Kristine C.; Hilger, Ralf A.; Scott, Bart L.; Kovacsovics, Tibor J.; Maziarz, Richard T.; Woolfrey, Ann E.; Bedalov, Antonio; Sanders, Jean E.; Pagel, John M.; Sickle, Eileen J.; Witherspoon, Robert; Flowers, Mary E.; Appelbaum, Frederick R.; Deeg, H. Joachim

2010-01-01

In this prospective study 60 patients of median age 46 (range 5–60) years, with acute myeloid leukemia (AML; n=44), acute lymphoblastic leukemia (ALL; n=3), or myelodysplastic syndrome (MDS; n=13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine combination. Most patients were considered at high risk for relapse or non-relapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m2/day (n=5) or 14 g/m2/day (n=55) on days -6 to -4, and fludarabine (30 mg/m2/day) on days -6 to -2, followed by infusion of marrow (n=7) or peripheral blood stem cells (n=53) from HLA-identical siblings (n=30) or unrelated donors (n=30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival for all patients was 58% and 88% for patients without high risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/fludarabine regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/fludarabine to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients. PMID:20685259

Allogeneic hematopoietic stem cell transplantation in children with primary immunodeficiencies: Hospital Israelita Albert Einstein experience

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Juliana Folloni Fernandes

2011-06-01

Full Text Available Objective: To report the experience of a tertiary care hospital withallogeneic hematopoietic stem cell transplantation in children withprimary immunodeficiencies. Methods: Seven patients with primaryimmunodeficiencies (severe combined immunodeficiency: n = 2;combined immunodeficiency: n = 1; chronic granulomatous disease:n = 1; hyper-IgM syndrome: n = 2; and IPEX syndrome: n = 1who underwent eight hematopoietic stem cell transplants (HSCTin a single center, from 2007 to 2010, were studied. Results: Twopatients received transplants from HLA-identical siblings; the othersix transplants were done with unrelated donors (bone marrow: n= 1; cord blood: n = 5. All patients had pre-existing infectionsbefore hematopoietic stem cell transplants. One patient receivedonly anti-thymocyte globulin prior to transplant, three transplantswere done with reduced intensity conditioning regimens and fourtransplants were done after myeloablative therapy. Two patientswere not evaluable for engraftment due to early death. Three patientsengrafted, two had primary graft failure and one received a secondtransplant with posterior engraftment. Two patients died of regimenrelated toxicity (hepatic sinusoidal obstruction syndrome; one patient died of progressive respiratory failure due to Parainfluenza infection diagnosed prior to transplant. Four patients are alive and well from 60 days to 14 months after transplant. Conclusion: Patients’ status prior to transplant is the most important risk factor on the outcome of hematopoietic stem cell transplants in the treatment of these diseases. Early diagnosis and the possibility of a faster referral of these patients for treatment in reference centers may substantially improve their survival and quality of life.

Clostridium difficile infection in Chilean patients submitted to hematopoietic stem cell transplantation

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Javier Pilcante

2015-12-01

Full Text Available ABSTRACT Introduction: Patients submitted to hematopoietic stem cell transplantation have an increased risk of Clostridium difficile infection and multiple risk factors have been identi- fied. Published reports have indicated an incidence from 9% to 30% of transplant patients however to date there is no information about infection in these patients in Chile. Methods: A retrospective analysis was performed of patients who developed C. difficile infection after hematopoietic stem cell transplantations from 2000 to 2013. Statistical analysis used the Statistical Package for the Social Sciences software. Results: Two hundred and fifty patients were studied (mean age: 39 years; range: 17-69, with 147 (59% receiving allogeneic transplants and 103 (41% receiving autologous trans- plants. One hundred and ninety-two (77% patients had diarrhea, with 25 (10% cases of C. difficile infection being confirmed. Twenty infected patients had undergone allogeneic trans- plants, of which ten had acute lymphoblastic leukemia, three had acute myeloid leukemia and seven had other diseases (myelodysplastic syndrome, chronic myeloid leukemia, severe aplastic anemia. In the autologous transplant group, five patients had C. difficile infection; two had multiple myeloma, one had amyloidosis, one had acute myeloid leukemia and one had germinal carcinoma. The overall incidence of C. difficile infection was 4% within the first week, 6.4% in the first month and 10% in one year, with no difference in overall survival between infected and non-infected groups (72.0% vs. 67.6%, respectively; p-value = 0.56. Patients infected after allogeneic transplants had a slower time to neutrophil engraftment compared to non-infected patients (17.5 vs. 14.9 days, respectively; p-value = 0.008. In the autologous transplant group there was no significant difference in the neutrophil engraftment time between infected and non-infected patients (12.5 days vs. 11.8 days, respectively; p

Spontaneous fertility in a male thalassemic patient after allogeneic hematopoietic cell transplantation

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Nicoletta Iacovidou

2017-11-01

Full Text Available Patients with thalassemia major who received allogeneic hematopoietic cell transplantation are at increased risk of gonadal insufficiency and reduced fertility due to the toxicity of both the transfusional iron overload and the gonadotoxic effects of drugs used in the conditioning regimen. We present a case of an ex-thalassemic patient with spontaneous recovery of spermatogenesis that fathered a healthy, term male neonate. Maternal hemoglobin electrophoresis was within normal limits. At the age of 9.5 years the patient underwent hematopoietic cell transplantation. The conditioning therapy included busulfan (16 mg/kg and cyclophosphamide (200 mg/kg. No irradiation was administered. Thirty-two days after the hematopoietic cell transplantation the patient developed acute graft-versus-host disease needing long-term treatment with methylprednisolone, cyclosporine and immunoglobulin. Although consecutive semen analyses after the hematopoietic cell transplantation revealed azoospermia, the last semen analysis before conception, at the age of 33 years, was improved and normal follicle stimulating hormone (FSH, luteinizing hormone (LH and testosterone (Te levels were detected. The current pregnancy was the result of physical conception. In this case, it seems that thalassemia major along with the respective treatment prior to- and posthematopoietic cell transplantation did not irreparably impair spermatogenesis, probably due to the pre-pubertal time frame they were implemented.   对于接受异基因造血细胞移植的重型地中海贫血患者，由于输注性铁过载的毒性和预处理方案中所用药物性腺毒性作用这两方面的原因，都使其面临更大的性腺功能不全风险和更低的生育力。本文报道一例精子发生出现自然恢复的原重型地中海贫血患者，他成功孕育出一个健康的足月男婴。母体血红蛋白电泳在正常范围内。患者在9�

Allogeneic hematopoietic cell transplantation in first remission abrogates poor outcomes associated with high-risk pediatric acute myeloid leukemia.

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Burke, Michael J; Wagner, John E; Cao, Qing; Ustun, Celalettin; Verneris, Michael R

2013-07-01

Despite remission rates of approximately 85% for children diagnosed with acute myeloid leukemia (AML), greater than 40% will die from relapsed disease. Patients with poor-risk molecular/cytogenetics and/or inadequate response to up-front therapy are typically considered high-risk (HR) and historically have poor outcomes with chemotherapy alone. We investigated whether allogeneic hematopoietic cell transplantation (allo-HCT) with best available donor in first remission (CR1) would abrogate the poor outcomes associated with HR AML in children and young adults treated with chemotherapy. We reviewed the outcomes of 50 consecutive children and young adults (ages 0 to 30 years) with AML who received a myeloablative allo-HCT between 2001 and 2010. Thirty-six patients (72%) were HR, defined as having FLT3-ITD mutations, 11q23 MLL rearrangements, chromosome 5 or 7 abnormalities, induction failure, and/or having persistent disease. The majority of patients received cyclophosphamide and total body irradiation conditioning, and graft-versus-host-disease (GVHD) prophylaxis was cyclosporine based. Transplantation outcomes for HR patients were compared to standard-risk patients, with no significant differences observed in overall survival (72% versus 78%, P = .72), leukemia-free survival (69% versus 79%, P = .62), relapse (11% versus 7%, P = .71), or treatment-related mortality (17% versus 14%, P = .89). Children and young adults with HR-AML have comparable outcomes to standard-risk patients following allo-HCT in CR1. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Hematopoietic stem cells from NOD mice exhibit autonomous behavior and a competitive advantage in allogeneic recipients.

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Chilton, Paula M; Rezzoug, Francine; Ratajczak, Mariusz Z; Fugier-Vivier, Isabelle; Ratajczak, Janina; Kucia, Magda; Huang, Yiming; Tanner, Michael K; Ildstad, Suzanne T

2005-03-01

Type 1 diabetes is a systemic autoimmune disease that can be cured by transplantation of hematopoietic stem cells (HSCs) from disease-resistant donors. Nonobese diabetic (NOD) mice have a number of features that distinguish them as bone marrow transplant recipients that must be understood prior to the clinical application of chimerism to induce tolerance. In the present studies, we characterized NOD HSCs, comparing their engraftment characteristics to HSCs from disease-resistant strains. Strikingly, NOD HSCs are significantly enhanced in engraftment potential compared with HSCs from disease-resistant donors. Unlike HSCs from disease-resistant strains, they do not require graft-facilitating cells to engraft in allogeneic recipients. Additionally, they exhibit a competitive advantage when coadministered with increasing numbers of syngeneic HSCs, produce significantly more spleen colony-forming units (CFU-Ss) in vivo in allogeneic recipients, and more granulocyte macrophage-colony-forming units (CFU-GMs) in vitro compared with HSCs from disease-resistant controls. NOD HSCs also exhibit significantly enhanced chemotaxis to a stromal cell-derived factor 1 (SDF-1) gradient and adhere significantly better on primary stroma. This enhanced engraftment potential maps to the insulin-dependent diabetes locus 9 (Idd9) locus, and as such the tumor necrosis factor (TNF) receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSCs. These findings may have important implications to understand the evolution of autoimmune disease and impact on potential strategies for cure.

Natural and adoptive T-cell immunity against herpes family viruses after allogeneic hematopoietic stem cell transplantation.

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Thomas, Simone; Herr, Wolfgang

2011-06-01

Reactivated infections with herpes family-related cytomegalovirus, Epstein-Barr virus and varicella zoster virus are serious and sometimes life-threatening complications for patients undergoing allogeneic hematopoietic stem cell transplantation. The pathogenesis of these infections critically involves the slow and inefficient recovery of antiviral T-cell immunity after transplantation. Although efficient drugs to decrease viral load during this vulnerable period have been developed, long-term control of herpes viruses and protection from associated diseases require the sufficient reconstitution of virus-specific memory T cells. To heal the deficiency by immunotherapeutic means, numerous research groups have developed antiviral vaccines and strategies based on the adoptive transfer of virus-specific T cells. This article summarizes the substantial progress made in this field during the past two decades and gives future perspectives about challenges that need to be addressed before antigen-specific immunotherapy against herpes family viruses can be implemented in general clinical practice.

Transient hemolysis due to anti-D and anti-A1 produced by engrafted donor's lymphocytes after allogeneic unmanipulated haploidentical hematopoietic stem cell transplantation.

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Bailén, Rebeca; Kwon, Mi; Pérez-Corral, Ana María; Pascual, Cristina; Buño, Ismael; Balsalobre, Pascual; Serrano, David; Gayoso, Jorge; Díez-Martín, José Luis; Anguita, Javier

2017-10-01

Development of de novo alloantibodies against recipient's red blood cell (RBC) antigens by engrafted donor's lymphocytes is a known phenomenon in the setting of allogeneic hematopoietic stem cell transplantation (HSCT). This situation is usually clinically insignificant. We report a case of early clinically relevant hemolytic anemia in a blood group A 1 D+ patient, due to a limited production of anti-D and anti-A 1 produced by nonpreviously sensitized newly engrafted donor's immune system. A 31-year-old Caucasian woman, blood group A 1 , D+, with Hodgkin's lymphoma, received an unmanipulated haploidentical allogeneic peripheral blood HSCT after a nonmyeloablative conditioning regimen. Donor blood group was A 2 B, D-. The patient had an uneventful course until Day +34, when she developed clinically significant hemolytic anemia with a positive direct antiglobulin test. Anti-D and anti-A 1 produced by the donor-engrafted lymphocytes were detected both in serum and in eluate. The hemolysis produced an accelerated group change, turning the patient's ABO group into A 2 B 2 weeks after the detection of the alloantibodies. As the residual patient's RBCs progressively disappeared, anti-D and anti-A 1 production decreased and were not detected in serum by Day +41. This case illustrates that de novo alloantibody production against ABO and D antigens by the newly engrafted donor's lymphocytes can occasionally cause clinically significant anemia. To our knowledge, this is the first case reported of clinically significant hemolytic anemia due to a transient anti-D anti-A 1 alloimmunization after T-cell-repleted haploidentical HSCT. © 2017 AABB.

Genetic DNA profile in urine and hair follicles from patients who have undergone allogeneic hematopoietic stem cell transplantation.

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Santurtún, Ana; Riancho, José A; Santurtún, Maite; Richard, Carlos; Colorado, M Mercedes; García Unzueta, Mayte; Zarrabeitia, María T

2017-09-01

Biological samples from patients who have undergone allogeneic hematopoietic stem cell transplantation (HSCT) constitute a challenge for individual identification. In this study we analyzed the genetic profiles (by the amplification of 15 autosomic STRs) of HSCT patients found in different types of samples (blood, hair and urine) that may be the source of DNA in civil or criminal forensic cases. Our results show that while in hair follicles the donor component was not detected in any patient, thus being a reliable source of biological material for forensic identification, mixed chimerism was detected in urine samples from all patient, and no correlation was found between the time elapsed from the transplant and the percentage of chimerism. These results certainly have practical implications if the urine is being considered as a source of DNA for identification purposes in HSTC patients. Moreover, taking into consideration that chimerism was found not only in patients with leukocyturia (given the hematopoietic origin of leukocytes, this was expected), but also in those without observable leukocytes in the sediment, we conclude that an alternative source or sources of donor DNA must be implicated. Copyright © 2017 The Chartered Society of Forensic Sciences. Published by Elsevier B.V. All rights reserved.

A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display

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Baskar, Sivasubramanian; Suschak, Jessica M.; Samija, Ivan; Srinivasan, Ramaprasad; Childs, Richard W.; Pavletic, Steven Z.; Bishop, Michael R.; Rader, Christoph

2009-01-01

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment available for patients with B-cell chronic lymphocytic leukemia (B-CLL). Here, we show that post-alloHSCT antibody repertoires can be mined for the discovery of fully human monoclonal antibodies to B-CLL cell-surface antigens. Sera collected from B-CLL patients at defined times after alloHSCT showed selective binding to primary B-CLL cells. Pre-alloHSCT sera, donor sera, and control sera w...

Cytotect®CP as salvage therapy in patients with CMV infection following allogeneic hematopoietic cell transplantation: a multicenter retrospective study.

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Alsuliman, Tamim; Kitel, Caroline; Dulery, Rémy; Guillaume, Thierry; Larosa, Fabrice; Cornillon, Jérôme; Labussière-Wallet, Helene; Médiavilla, Clémence; Belaiche, Stéphanie; Delage, Jeremy; Alain, Sophie; Yakoub-Agha, Ibrahim

2018-04-13

Cytomegalovirus is one of the main contributing factors to high mortality rates in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). The main factors of treatment failure are both drug resistance and intolerance. In some cases, Cytotect®CP CMV-hyperimmune globulin is used as salvage therapy. This study aims to investigate the safety and efficacy of Cytotect®CP as a salvage therapy in patients with CMV infection after allo-HCT. Twenty-three consecutive patients received Cytotect®CP for CMV infection after prior CMV therapy. At the time of Cytotect®CP introduction, 17 patients (74%) had developed acute GVHD and 15 patients (64%) were receiving steroid treatment; Cytotect®CP was used as monotherapy (n = 7) and in combination (n = 16). Overall, response was observed in 18 patients (78%) with a median time of 15 days (range: 3-51). Of the 18 responders, 4 experienced CMV reactivation, while 5 responders died within 100 days of beginning treatment. Of these 5 deaths, 4 were due to causes unrelated to CMV. Estimated 100-day OS from the introduction of Cytotect®CP was 69.6%. No statistically significant difference was observed in 100-day OS between responders and non-responders (73.7% vs 50.0%, p = 0.258). Cytotect®CP as salvage therapy is effective and well-tolerated. Given its safety profile, early treatment use should be considered.

Is there a role for B lymphocyte chimerism in the monitoring of B-acute lymphoblastic leukemia patients receiving allogeneic stem cell transplantation?

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Yi-Ning Yang

2015-03-01

Full Text Available Objective: To determine the sensitivity and significance of B-cell chimerism for the detection of early engraftment, transplant rejection, and disease relapse. Methods: The dynamic monitoring of lineage-specific cell subtypes (B, T, and NK cells was made in 20 B-cell acute lymphoblastic leukemia (B-ALL patients following allogeneic hematopoietic stem cell transplantation (allo-HSCT. In the early period after allo-HSCT, the latest establishment of B-cell complete chimerism (CC was observed in a majority of patients. Results: The percentage of donor cells of B-cell lineage was lower than the percent of T-cell lineage in most of the mixed chimerism (MC patients. During graft rejection, the frequency of patients with decreasing MC of B-, T- and NK-cell lineage were 5/5, 2/5, and 2/5. When disease relapsed, five patients showed a faster decrease of the donor percent of B-cells than of T- or NK-cells. Only one patient displayed a more rapid decrease in NK-cells than in T- or B-cells. Conclusion: Monitoring of B-cell chimerism after HSCT seems to be valuable for insuring complete engraftment, anticipating graft rejection, and relapse in B-ALL patients. Keywords: B cell acute lymphoblastic leukemia (B-ALL, B-cell, T-cell, Chimerism, Allogeneic hematopoietic stem cell transplantation (allo-HSCT

Present and future of allogeneic natural killer cell therapy

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Okjae eLim

2015-06-01

Full Text Available Natural killer (NK cells are innate lymphocytes that are capable of eliminating tumor cells and are therefore used for cancer therapy. Although many early investigators used autologous NK cells, including lymphokine-activated killer cells, the clinical efficacies were not satisfactory. Meanwhile, human leukocyte antigen (HLA-haploidentical hematopoietic stem cell transplantation revealed the anti-tumor effect of allogeneic NK cells, and HLA-haploidentical, killer cell immunoglobulin-like receptor (KIR ligand-mismatched allogeneic NK cells are currently used for many protocols requiring NK cells. Moreover, allogeneic NK cells from non-HLA-related healthy donors have been recently used in cancer therapy. The use of allogeneic NK cells from non-HLA-related healthy donors allows the selection of donor NK cells with higher flexibility and to prepare expanded, cryopreserved NK cells for instant administration without delay for ex vivo expansion. In cancer therapy with allogeneic NK cells, optimal matching of donors and recipients is important to maximize the efficacy of the therapy. In this review, we summarize the present state of allogeneic NK cell therapy and its future directions.

Steroid-sparing effect of extracorporeal photopheresis in the therapy of graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

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Ussowicz, M; Musiał, J; Mielcarek, M; Tomaszewska, A; Nasiłowska-Adamska, B; Kałwak, K; Gorczyńska, E; Mariańska, B; Chybicka, A

2013-11-01

Steroid-refractory graft-versus-host disease (GVHD) remains a challenging therapeutic problem after allogeneic hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the clinical effect of extracorporeal photopheresis (ECP), and its impact on intensivity of immunosuppresive therapy in allogeneic HSCT patients. In this study 443 Therakos ECP procedures were performed in 21 patients after allogeneic HSCT with acute (aGVHD, 8 patients) or chronic (cGVHD, 13 patients) therapy-refractory GVHD. The median age at ECP onset was 20.5 years (range, 10-55). Venous access was provided by a nontunelized central venous catheter (12 patients) or 9.6-French portacath (9 patients). In the cGVHD group 9/13 patients were improved with a 4-year overall survival rate of 67.7%. ECP led to steroid discontinuation in 6 and substantial dose reduction in 5 patients. The prednisone dose equivalent per kilogram body weight decreased from 0.32 mg to 0.07 mg after therapy. Therapy of aGVHD led to complete or partial symptom remission in 3/9 subjects. The change in steroid dose in the aGVHD group was not significant, there were no long-term survivors. Portacath access was well tolerated and provided adequate blood flow rates. The ECP therapy significantly reduced the rates of remissions with steroid discontinuation among cGVHD but not aGVHD patients. Rare ECP-related complications were either catheter related or anticoagulation induced during ECP procedures. Photopheresis was a safe, effective method to treat steroid-resistant cGVHD. Copyright © 2013 Elsevier Inc. All rights reserved.

Hematopoietic Stem Cell Transplantation in Thalassemia and Sickle Cell Anemia

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Lucarelli, Guido; Isgrò, Antonella; Sodani, Pietro; Gaziev, Javid

2012-01-01

The globally widespread single-gene disorders β-thalassemia and sickle cell anemia (SCA) can only be cured by allogeneic hematopoietic stem cell transplantation (HSCT). HSCT treatment of thalassemia has substantially improved over the last two decades, with advancements in preventive strategies, control of transplant-related complications, and preparative regimens. A risk class–based transplantation approach results in disease-free survival probabilities of 90%, 84%, and 78% for class 1, 2, and 3 thalassemia patients, respectively. Because of disease advancement, adult thalassemia patients have a higher risk for transplant-related toxicity and a 65% cure rate. Patients without matched donors could benefit from haploidentical mother-to-child transplantation. There is a high cure rate for children with SCA who receive HSCT following myeloablative conditioning protocols. Novel non-myeloablative transplantation protocols could make HSCT available to adult SCA patients who were previously excluded from allogeneic stem cell transplantation. PMID:22553502

Outcome of children with high-risk acute myeloid leukemia given autologous or allogeneic hematopoietic cell transplantation in the aieop AML-2002/01 study.

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Locatelli, F; Masetti, R; Rondelli, R; Zecca, M; Fagioli, F; Rovelli, A; Messina, C; Lanino, E; Bertaina, A; Favre, C; Giorgiani, G; Ripaldi, M; Ziino, O; Palumbo, G; Pillon, M; Pession, A; Rutella, S; Prete, A

2015-02-01

We analyzed the outcome of 243 children with high-risk (HR) AML in first CR1 enrolled in the AIEOP-2002/01 protocol, who were given either allogeneic (ALLO; n=141) or autologous (AUTO; n=102) hematopoietic SCT (HSCT), depending on the availability of a HLA-compatible sibling. Infants, patients with AML-M7, or complex karyotype or those with FLT3-ITD, were eligible to be transplanted also from alternative donors. All patients received a myeloablative regimen combining busulfan, cyclophosphamide and melphalan; [corrected] AUTO-HSCT patients received BM cells in most cases, while in children given ALLO-HSCT stem cell source was BM in 96, peripheral blood in 19 and cord blood in 26. With a median follow-up of 57 months (range 12-130), the probability of disease-free survival (DFS) was 73% and 63% in patients given either ALLO- or AUTO-HSCT, respectively (P=NS). Although the cumulative incidence (CI) of relapse was lower in ALLO- than in AUTO-HSCT recipients (17% vs 28%, respectively; P=0.043), the CI of TRM was 7% in both groups. Patients transplanted with unrelated donor cord blood had a remarkable 92.3% 8-year DFS probability. Altogether, these data confirm that HSCT is a suitable option for preventing leukemia recurrence in HR children with CR1 AML.

Busulfan and total body irradiation as antihematopoietic stem cell agents in the preparation of patients with congenital bone marrow disorders for allogenic bone marrow transplantation

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Parkman, R.; Rappeport, J.M.; Hellman, S.; Lipton, J.; Smith, B.; Geha, R.; Nathan, D.G.

1984-01-01

The capacity of busulfan and total body irradiation to ablate hematopoietic stem cells as preparation for the allogeneic bone marrow transplantation of patients with congenital bone marrow disorders was studied. Fourteen patients received 18 transplants; busulfan was used in the preparatory regimen of eight transplants and total body irradiation in the regimens of six transplants. Sustained hematopoietic ablation was achieved in six of eight patients prepared with busulfan and in all six patients prepared with total body irradiation. Three patients prepared with total body irradiation died with idiopathic interstitial pneumonitis, whereas no patients receiving busulfan developed interstitial pneumonitis. The optimal antihematopoietic stem cell agent to be used for the preparation of patients with congenital bone marrow disorder for bone marrow transplantation is not certain

Prevalence of dry eye syndrome after allogeneic hematopoietic stem cell transplantation.

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Ivanir, Yair; Shimoni, Avichai; Ezra-Nimni, Orit; Barequet, Irina S

2013-05-01

To evaluate the prevalence, severity, and effect of dry eye in patients after allogeneic hematopoietic stem cell transplantation (aHSCT) and to correlate the findings to the duration after transplantation. A total of 222 eyes of 111 patients after aHSCT at the Department of Bone Marrow Transplantation, Sheba Medical Center, Israel in a consecutive 3-year period. All patients underwent a full ophthalmic examination and filled the ocular surface disease index (OSDI) questionnaire to assess ocular involvement in the form of dry eye syndrome or any other ocular manifestation. The main outcome measures were best-corrected visual acuity, tear break-up time, corneal fluorescein staining, Schirmer test, and OSDI questionnaire. A total of 111 patients were recruited. In 37%, a diagnosis of ocular graft versus host disease was previously made and 46% had no previous ocular examination. Schirmer test was less than 5 mm in 50% of all patients, and in 30% of patients with undiagnosed ocular involvement. The mean OSDI score was 13, and in 28% it was above 20. Correlation was found between visual acuity decrease and high OSDI score to the diagnosis of ocular graft versus host disease and signs of dry eye syndrome. A trend of worsening dry eye was observed up to the second half of the second year posttransplantation. Although many patients are either asymptomatic or do not seek ophthalmic examination, severe dry eye is a common finding after aHSCT. Mandatory follow-up, patient education, and early treatment may improve the quality of life.

Early Pathologic Findings of Bronchiolitis Obliterans after Allogeneic Hematopoietic Stem Cell Transplantation: A Proposal from a Case

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Rie Nakamoto-Matsubara

2012-01-01

Full Text Available Bronchiolitis obliterans (BO is one of the serious, noninfectious pulmonary complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT. Early diagnosis of BO is usually difficult because patients are often asymptomatic at an initial stage of the disease and pathologic findings are available mostly at the late stages. Therefore, the diagnosis of the disease is based on the pulmonary function test using the National Institute of Health consensus criteria. Here, we report a case of slowly progressive BO. A biopsy specimen at an early stage demonstrated alveolar destruction with lymphocyte infiltration in bronchial walls and mild narrowing of bronchioles without fibrosis, those were strongly indicative of initial pathologic changes of BO. Definitive BO followed, which was proven by both clinical course and autopsy. While alloreactive lymphocytes associated with chronic graft-versus-host disease are believed to initiate BO, we present a rare case that directly implies such a scenario.

Control of infectious mortality due to carbapenemase-producing Klebsiella pneumoniae in hematopoietic stem cell transplantation.

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Forcina, A; Baldan, R; Marasco, V; Cichero, P; Bondanza, A; Noviello, M; Piemontese, S; Soliman, C; Greco, R; Lorentino, F; Giglio, F; Messina, C; Carrabba, M; Bernardi, M; Peccatori, J; Moro, M; Biancardi, A; Nizzero, P; Scarpellini, P; Cirillo, D M; Mancini, N; Corti, C; Clementi, M; Ciceri, F

2017-01-01

Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections are an emerging cause of death after hematopoietic stem cell transplantation (HSCT). In allogeneic transplants, mortality rate may rise up to 60%. We retrospectively evaluated 540 patients receiving a transplant from an auto- or an allogeneic source between January 2011 and October 2015. After an Institutional increase in the prevalence of KPC-Kp bloodstream infections (BSI) in June 2012, from July 2012, 366 consecutive patients received the following preventive measures: (i) weekly rectal swabs for surveillance; (ii) contact precautions in carriers (iii) early-targeted therapy in neutropenic febrile carriers. Molecular typing identified KPC-Kp clone ST512 as the main clone responsible for colonization, BSI and outbreaks. After the introduction of these preventive measures, the cumulative incidence of KPC-Kp BSI (P=0.01) and septic shocks (P=0.01) at 1 year after HSCT was significantly reduced. KPC-Kp infection-mortality dropped from 62.5% (pre-intervention) to 16.6% (post-intervention). Day 100 transplant-related mortality and KPC-Kp infection-related mortality after allogeneic HSCT were reduced from 22% to 10% (P=0.001) and from 4% to 1% (P=0.04), respectively. None of the pre-HSCT carriers was excluded from transplant. These results suggest that active surveillance, contact precautions and early-targeted therapies, may efficiently control KPC-Kp spread and related mortality even after allogeneic HSCT.

PARASITIC INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

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Isidro Jarque

2016-07-01

Full Text Available Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However, they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients.

An evidence-based stress management intervention for allogeneic hematopoietic stem cell transplant caregivers: development, feasibility and acceptability.

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Simoneau, Teresa L; Kilbourn, Kristin; Spradley, Janet; Laudenslager, Mark L

2017-08-01

Caregivers of cancer patients face challenges impacting their physical, psychological and social well-being that need attention in the form of well-designed and tested interventions. We created an eight-session individual stress management intervention for caregivers of allogeneic hematopoietic stem cell transplant (Allo-HSCT) recipients. This intervention, tested by randomized control trial, proved effective in decreasing distress. Herein, we describe the intervention including theoretical framework, development, and elements of fidelity. Implementation challenges along with recommendations for refinement in future studies are discussed with the goal of replication and dissemination. Seventy-four of 148 caregivers received stress management training following randomization. The intervention occurred during the 100-day post-transplant period when caregivers are required. The training provided integrated cognitive behavioral strategies, psychoeducation, and problem-solving skills building as well as use of a biofeedback device. Seventy percent of caregivers completed all eight sessions indicating good acceptability for the in-person intervention; however, most caregivers did not reliably use the biofeedback device. The most common reason for drop-out was their patient becoming gravely ill or patient death. Few caregivers dropped out because of study demands. The need for flexibility in providing intervention sessions was key to retention. Our evidence-based stress management intervention for Allo-HSCT caregivers was feasible. Variability in acceptability and challenges in implementation are discussed and suggestions for refinement of the intervention are outlined. Dissemination efforts could improve by using alternative methods for providing caregiver support such as telephone or video chat to accommodate caregivers who are unable to attend in-person sessions.

ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN THE TREATMENT OF CHRONIC LYMPHOCITIC LEUKEMIA : WHY AND WHEN ?

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Maria L. Delioukina

2010-06-01

Full Text Available Chronic lymphocytic leukemia (CLL is the most common hematologic malignancy in adults with an incidence rate of 4.2 per 100,000 per year. CLL frequently takes an indolent course, with some patients not requiring treatment for years, yet is incurable by currently available chemo- and immuno-therapeutic modalities. Despite high initial response rates, particularly to purine analogues, patients invariably relapse and subsequently develop resistance to therapy. The traditional “watchful waiting” approach to CLL is being challenged by data showing that treatments used early in the disease course impact long-term overall and progression-free survivals . The only curative treatment for CLL currently, is allogeneic hematopoeietic cell transplantation (alloHCT. In contrast to autologous transplant, myeloablative alloHCT for CLL patients generates durable remissions with promising survival plateaus; however, significant transplant related mortality (TRM is also observed (25-50% . At present the fact remains that for poor-risk CLL, alloHCT is the only treatment with the potential of providing long-term disease control. Future combinations with emerging low-toxicity therapies may further enhance the curative potential of allogeniec hematopoietic cell transplant. New drugs can also potentially enable refractory patients to attain response as a bridge to more effective stem cell transplantation.

Country-Level Macroeconomic Indicators Predict Early Post-Allogeneic Hematopoietic Cell Transplantation Survival in Acute Lymphoblastic Leukemia: A CIBMTR Analysis.

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Wood, William A; Brazauskas, Ruta; Hu, Zhen-Huan; Abdel-Azim, Hisham; Ahmed, Ibrahim A; Aljurf, Mahmoud; Badawy, Sherif; Beitinjaneh, Amer; George, Biju; Buchbinder, David; Cerny, Jan; Dedeken, Laurence; Diaz, Miguel Angel; Freytes, Cesar O; Ganguly, Siddhartha; Gergis, Usama; Almaguer, David Gomez; Gupta, Ashish; Hale, Gregory; Hashmi, Shahrukh K; Inamoto, Yoshihiro; Kamble, Rammurti T; Adekola, Kehinde; Kindwall-Keller, Tamila; Knight, Jennifer; Kumar, Lalit; Kuwatsuka, Yachiyo; Law, Jason; Lazarus, Hillard M; LeMaistre, Charles; Olsson, Richard F; Pulsipher, Michael A; Savani, Bipin N; Schultz, Kirk R; Saad, Ayman A; Seftel, Matthew; Seo, Sachiko; Shea, Thomas C; Steinberg, Amir; Sullivan, Keith; Szwajcer, David; Wirk, Baldeep; Yared, Jean; Yong, Agnes; Dalal, Jignesh; Hahn, Theresa; Khera, Nandita; Bonfim, Carmem; Atsuta, Yoshiko; Saber, Wael

2018-03-19

For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n = 697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

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Aisa, Yoshinobu; Mori, Takehiko; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Yokoyama, Akihiro; Ikeda, Yasuo; Okamoto, Shinichiro

2005-04-01

The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose melphalan (140 mg/m2) in combination with fludarabine alone or with fludarabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis was graded according to the National Cancer Institute Common Toxicity Criteria. Patients were kept on oral cryotherapy using ice chips and ice-cold water shortly before, during, and for additional 90 min after completion of melphalan administration. Only two of 18 patients (11.1%) developed grade 2 or 3 stomatitis while six of seven patients in the historical control developed it (85.7%; P=0.001). These results suggested that oral cryotherapy could effectively prevent stomatitis caused by high-dose melphalan, and we recommend that it should be incorporated into the conditioning regimen with high-dose melphalan.

Evolution of human cytomegalovirus-seronegative donor/-seropositive recipient high-risk combination frequency in allogeneic hematopoietic stem cell transplantations at Institute of Hematology and Blood Transfusion during 1995-2014.

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Nemeckova, S; Sroller, V; Stastna-Markova, M

2016-04-01

Human cytomegalovirus (HCMV) establishes lifelong latent infection that can result in severe life-threatening disease in immunosuppressed patients after hematopoietic stem cell transplantation (HSCT). An HCMV-seropositive transplant recipient who receives a graft from a seronegative donor (R+/D-) is at high risk of recurrent HCMV reactivation. To assess the incidence of R+/D- combination, we retrospectively evaluated HCMV-seronegative donors for 746 allogeneic HSCT treatments carried out at our center during 1995-2014. In our cohort, 20% HCMV-seronegative HSCT recipients, 21% HCMV-seronegative related graft donors, and 52% HCMV-seronegative unrelated graft donors were included. Analyses of the HCMV serostatus of hematopoietic stem cell donors during 2 consecutive calendar periods (1995-2005 and 2006-2014) showed a significant increase in the proportion of seronegative donors (odds ratio [OR] = 1.947). In addition, the number of HSCT treatments using an unrelated donor increased (OR = 2.376). Finally, the use of grafts from countries with a very low HCMV prevalence increased. This increase in HCMV seronegativity in unrelated donors and the increased proportion of unrelated donors were responsible for the increased occurrence of the high-risk combination R+/D- (OR = 1.680). If the reduction in the rate of HCMV-seropositive graft donors continues, an increased frequency of HCMV reactivation events in our transplant recipients can be expected, because of the increasing occurrence of the high-risk R+/D- combination. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hematopoietic Stem Cell Transplantation—50 Years of Evolution and Future Perspectives

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Israel Henig

2014-10-01

Full Text Available Hematopoietic stem cell transplantation is a highly specialized and unique medical procedure. Autologous transplantation allows the administration of high-dose chemotherapy without prolonged bone marrow aplasia. In allogeneic transplantation, donor-derived stem cells provide alloimmunity that enables a graft-versus-tumor effect to eradicate residual disease and prevent relapse. The first allogeneic transplantation was performed by E. Donnall Thomas in 1957. Since then the field has evolved and expanded worldwide. New indications beside acute leukemia and aplastic anemia have been constantly explored and now include congenital disorders of the hematopoietic system, metabolic disorders, and autoimmune disease. The use of matched unrelated donors, umbilical cord blood units, and partially matched related donors has dramatically extended the availability of allogeneic transplantation. Transplant-related mortality has decreased due to improved supportive care, including better strategies to prevent severe infections and with the incorporation of reduced-intensity conditioning protocols that lowered the toxicity and allowed for transplantation in older patients. However, disease relapse and graft-versus-host disease remain the two major causes of mortality with unsatisfactory progress. Intense research aiming to improve adoptive immunotherapy and increase graft-versus-leukemia response while decreasing graft-versus-host response might bring the next breakthrough in allogeneic transplantation. Strategies of graft manipulation, tumor-associated antigen vaccinations, monoclonal antibodies, and adoptive cellular immunotherapy have already proved clinically efficient. In the following years, allogeneic transplantation is likely to become more complex, more individualized, and more efficient.

Clinical and Microbiological Characteristics of Breakthrough Candidemia in Allogeneic Hematopoietic Stem Cell Transplant Recipients in a Japanese Hospital

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Kimura, Muneyoshi; Yamamoto, Hisashi; Asano-Mori, Yuki; Nakamura, Shigeki; Yamagoe, Satoshi; Ohno, Hideaki; Miyazaki, Yoshitsugu; Abe, Masahiro; Yuasa, Mitsuhiro; Kaji, Daisuke; Kageyama, Kosei; Nishida, Aya; Ishiwata, Kazuya; Takagi, Shinsuke; Yamamoto, Go; Uchida, Naoyuki; Izutsu, Koji; Wake, Atsushi; Taniguchi, Shuichi; Yoneyama, Akiko

2017-01-01

ABSTRACT Few data on breakthrough candidemia (BC), defined as candidemia that develops on administration of antifungal agents (AFAs), in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients are available. The medical and microbiological records of recipients of an allo-HSCT obtained between December 2008 and December 2014 were reviewed. Of 768 allo-HSCT cases, 26 developed BC. Among the 26 causative strains, 22 strains were stored and identified by sequencing. The following species were isolated: Candida parapsilosis (9 strains), C. glabrata (4 strains), C. guilliermondii (3 strains), and other Candida species (6 strains). The AFAs being used when BC developed were micafungin (17 cases), liposomal amphotericin B (5 cases), itraconazole (2 cases), and voriconazole (2 cases). All 17 cases who developed BC during micafungin administration were administered 150 mg/day of micafungin. The susceptibilities of the causative Candida species to the administered AFAs when breakthrough occurred ranged from susceptible to resistant. Especially, 85% of the Candida species that caused BC during micafungin administration were susceptible to micafungin. Additionally, 75% of the strains were wild type for susceptibility to the administered AFAs when breakthrough occurred. Systemic steroid administration and a longer severe neutropenic phase (≥5 days) were independent risk factors for BC (P = 0.016 and P = 0.015, respectively). BC developed in allo-HSCT recipients even when they received a sufficient dose of AFA, including micafungin, to which the causative Candida species were susceptible and/or had wild-type susceptibility in vitro. Systemic steroid administration and a longer severe neutropenic phase were host-based factors associated with BC. PMID:28115352

Peripheral blood stem cell collection for allogeneic hematopoietic stem cell transplantation: Practical implications after 200 consequent transplants.

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Goren Sahin, Deniz; Arat, Mutlu

2017-12-01

Proper stem cell mobilization is one of the most important steps in hematopoietic stem cell transplantation (HSCT). The aim of this paper is to share our 6 years' experience and provide practical clinical approaches particularly for stem cell mobilization and collection within the series of more than 200 successive allogeneic HSCT at our transplant center. Two hundred and seven consecutive patients who underwent allogeneic peripheral blood stem cell transplantation were included in this study. Age, sex, weight, complete blood counts, CD34 + cell counts, total collected amount of CD34 + cells, CD34 + cells per 10l processed, mobilization failure and adverse events were reviewed. Median age was 40.2±12.9 (21-68) years and 46.4±13.4 (17-67) years for donors and patients, respectively. The number of donors who had undergone adequate CD34 + cell harvesting and completed the procedure on the fourth day was 67 (32.8% of all patients). Only 12 patients required cell apheresis both on day 5 and 6. Apheresis was completed on day 4 and/or day 5 in 94.2% of all our donors. There was no significant association between CD34 + stem cell volume and age, gender and weight values of donors. Mobilization failure was not seen in our series. G-CSF is highly effective in 1/3 of the donors on the 4th day in order to collect enough number of stem cells. We propose that peripheral stem cell collection might start on day 4th of G-CSF treatment for avoiding G-CSF related side effects and complications. Copyright © 2017 Elsevier Ltd. All rights reserved.

Longitudinal follow-up of nutritional status and its influencing factors in adults undergoing allogeneic hematopoietic cell transplantation.

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Urbain, P; Birlinger, J; Lambert, C; Finke, J; Bertz, H; Biesalski, H-K

2013-03-01

There are few longitudinal data on nutritional status and body composition of patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). We assessed nutritional status of 105 patients before alloHCT and its course during the early post-transplant period to day +30 and day +100 via weight history, body mass index (BMI) normalized for gender and age, Subjective Global Assessment, phase angle normalized for gender, age, and BMI, and fat-free and body fat masses. Furthermore, we present a multivariate regression model investigating the impact of factors on body weight. At admission, 23.8% reported significant weight losses (>5%) in the previous 6 months, and we noted 31.5% with abnormal age- and sex-adjusted BMI values (10th, 90th percentiles). BMI decreased significantly (Panorexia (parameter estimate 1.07; P=0.058) as independent factors influencing early weight loss. In conclusion, our results show a significant deterioration in nutritional status during the early post-transplant period. Predominant alloHCT-associated complications such as anorexia and acute GVHD became evident as significant factors influencing nutritional status.

Allogeneic hematopoietic stem cell transplant in adult patients with myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap syndromes.

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Sharma, Prashant; Shinde, Shivani S; Damlaj, Moussab; Hefazi Rorghabeh, Mehrdad; Hashmi, Shahrukh K; Litzow, Mark R; Hogan, William J; Gangat, Naseema; Elliott, Michelle A; Al-Kali, Aref; Tefferi, Ayalew; Patnaik, Mrinal M

2017-04-01

MDS/MPN (myelodysplastic syndrome/myeloproliferative neoplasm) overlap syndromes are myeloid malignancies for which allogeneic hematopoietic stem cell transplant (allo-HSCT) is potentially curative. We describe transplant outcomes of 43 patients - 35 with chronic myelomonocytic leukemia, CMML (of which 17 had blast transformation, BT) and eight with MDS/MPN-unclassifiable (MDS/MPN,U). At median follow-up of 21 months, overall survival (OS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 55%, 29%, and 25% respectively in CMML without BT and 47%, 40%, and 34% respectively in CMML with BT. Higher HSCT-comorbidity index (HSCT-CI >3 versus ≤3; p = 0.015) and splenomegaly (p = 0.006) predicted worse OS in CMML without BT. In CMML with BT, engraftment failure (p = 0.006) and higher HSCT-CI (p = 0.03) were associated with inferior OS, while HSCT within 1-year of diagnosis was associated with improved OS (p = 0.045). In MDS/MPN,U, at median follow-up of 15 months, OS, CIR, and NRM were 62%, 30%, and 14%, respectively.

Hypothyroidism following allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia.

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Medinger, Michael; Zeiter, Deborah; Heim, Dominik; Halter, Jörg; Gerull, Sabine; Tichelli, André; Passweg, Jakob; Nigro, Nicole

2017-07-01

Hypothyroidism may complicate allogeneic hematopoietic stem cell transplantation (allo-HSCT); we therefore analyzed risk factors in this study. We studied 229 patients with acute myeloid leukemia (AML) who underwent an allo-HSCT between 2003 and 2013 with different conditioning regimens (myeloablative, reduced-intensity, chemotherapy-based, or total body irradiation-based). Thyroid-stimulating hormone (TSH) and free thyroxine levels (fT4) were available in 104 patients before and after allo-HSCT. The median age at transplantation (n=104) was 47 (IQR 40-59)], 37 (35.6%) patients were female, and the overall mortality was 34.6% (n=36). After a median follow-up period of 47 (IQR 25-84) months, overt hypothyroidism (basal TSH>4.49mIU/l, FT4hypothyroidism (basal TSH>4.49mIU/l, normal fT4) was observed in 20 patients (19.2%). Positive thyroperoxidase (TPO) antibodies were found in 5 (4.8%) patients. A total of 13 patients (12.5%) were treated with thyroid hormone replacement. Acute graft-versus-host disease (aGvHD) ≥grade 2 occurred in 55 (52.9%) and chronic GvHD (cGvHD) in 74 (71.2%) of the patients. The risk of developing hypothyroidism was higher in the patients with repeated allo-HSCTs (P=0.024) and with positive TPO antibodies (P=0.045). Furthermore, the development of overt hypothyroidism was inversely proportional to age (P=0.043). No correlation was found with GvHD, HLA-mismatch, total body irradiation, and gender. After allo-HSCT, a significant number of patients experience thyroid dysfunction, including subclinical and overt hypothyroidism. Long-term and continuous follow-up for thyroid function after HSCT is important to provide timely and appropriate treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Expansion of donor-reactive host T cells in primary graft failure after allogeneic hematopoietic SCT following reduced-intensity conditioning.

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Koyama, M; Hashimoto, D; Nagafuji, K; Eto, T; Ohno, Y; Aoyama, K; Iwasaki, H; Miyamoto, T; Hill, G R; Akashi, K; Teshima, T

2014-01-01

Graft rejection remains a major obstacle in allogeneic hematopoietic SCT following reduced-intensity conditioning (RIC-SCT), particularly after cord blood transplantation (CBT). In a murine MHC-mismatched model of RIC-SCT, primary graft rejection was associated with activation and expansion of donor-reactive host T cells in peripheral blood and BM early after SCT. Donor-derived dendritic cells are at least partly involved in host T-cell activation. We then evaluated if such an expansion of host T cells could be associated with graft rejection after RIC-CBT. Expansion of residual host lymphocytes was observed in 4/7 patients with graft rejection at 3 weeks after CBT, but in none of the 17 patients who achieved engraftment. These results suggest the crucial role of residual host T cells after RIC-SCT in graft rejection and expansion of host T cells could be a marker of graft rejection. Development of more efficient T cell-suppressive conditioning regimens may be necessary in the context of RIC-SCT.

Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

DEFF Research Database (Denmark)

Qasim, Waseem; Cavazzana-Calvo, Marina; Davies, E Graham

2009-01-01

OBJECTIVES: Leukocyte adhesion deficiency is a rare primary immune disorder caused by defects of the CD18 beta-integrin molecule on immune cells. The condition usually presents in early infancy and is characterized by deep tissue infections, leukocytosis with impaired formation of pus, and delayed...... of leukocyte adhesion deficiency who underwent hematopoietic stem-cell transplantation between 1993 and 2007 was retrospectively analyzed. Data were collected by the registries of the European Society for Immunodeficiencies/European Group for Blood and Marrow Transplantation, and the Center for International......, with full donor engraftment in 17 cases, mixed multilineage chimerism in 7 patients, and mononuclear cell-restricted chimerism in an additional 3 cases. CONCLUSIONS: Hematopoietic stem-cell transplantation offers long-term benefit in leukocyte adhesion deficiency and should be considered as an early...

Biosimilar G-CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation.

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Schmitt, Michael; Publicover, Amy; Orchard, Kim H; Görlach, Matthias; Wang, Lei; Schmitt, Anita; Mani, Jiju; Tsirigotis, Panagiotis; Kuriakose, Reeba; Nagler, Arnon

2014-01-01

The use of granulocyte colony stimulating factor (G-CSF) biosimilars for peripheral blood hematopoietic stem cell (PBSC) mobilization has stimulated an ongoing debate regarding their efficacy and safety. However, the use of biosimilar G-CSF was approved by the European Medicines Agency (EMA) for all the registered indications of the originator G-CSF (Neupogen (®) ) including mobilization of stem cells. Here, we performed a comprehensive review of published reports on the use of biosimilar G-CSF covering patients with hematological malignancies as well as healthy donors that underwent stem cell mobilization at multiple centers using site-specific non-randomized regimens with a biosimilar G-CSF in the autologous and allogeneic setting. A total of 904 patients mostly with hematological malignancies as well as healthy donors underwent successful autologous or allogeneic stem cell mobilization, respectively, using a biosimilar G-CSF (520 with Ratiograstim®/Tevagrastim, 384 with Zarzio®). The indication for stem cell mobilization in hematology patients included 326 patients with multiple myeloma, 273 with Non-Hodgkin's lymphoma (NHL), 79 with Hodgkin's lymphoma (HL), and other disease. 156 sibling or volunteer unrelated donors were mobilized using biosimilar G-CSF. Mobilization resulted in good mobilization of CD34+ stem cells with side effects similar to originator G-CSF. Post transplantation engraftment did not significantly differ from results previously documented with the originator G-CSF. The side effects experienced by the patients or donors mobilized by biosimilar G-CSF were minimal and were comparable to those of originator G-CSF. In summary, the efficacy of biosimilar G-CSFs in terms of PBSC yield as well as their toxicity profile are equivalent to historical data with the reference G-CSF.

Herpesvirus-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

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Wu, Meiqing; Huang, Fen; Jiang, Xinmiao; Fan, Zhiping; Zhou, Hongsheng; Liu, Can; Jiang, Qianli; Zhang, Yu; Zhao, Ke; Xuan, Li; Zhai, Xiao; Zhang, Fuhua; Yin, Changxin; Sun, Jing; Feng, Ru; Liu, Qifa

2013-01-01

Herpesvirus infections of the central nervous system (CNS) are associated with encephalitis/myelitis and lymphoproliferative diseases in immunocompromised individuals. As of now, data of herpesvirus-associated CNS diseases in transplant recipients is limited. Hence, in this prospective study, we investigated the incidence of herpesvirus-associated CNS diseases and explored the diagnosis of these diseases in 281 allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Herpesvirus-DNA and cerebrospinal fluid (CSF) cells were sampled from 58 recipients with herpesvirus-associated diseases or with unexplainable CNS manifestations. Results showed that 23 patients were diagnosed as herpesvirus-associated CNS diseases, including 15 Epstein-Barr virus (EBV)-associated diseases (4 encephalitis and 11 lymphoproliferative diseases), 5 herpes simplex virus type 1 encephalitis, 2 cytomegalovirus encephalitis/myelitis and 1 varicella zoster virus encephalitis. The median time of diseases onset was 65 (range 22-542) days post-transplantation. The 3-year cumulative incidence of herpesvirus-associated encephalitis/myelitis and post-transplant lymphoproliferative disorder (PTLD) was 6.3% ± 1.9% and 4.1% ± 1.2%, respectively. Of the evaluable cases, CSF cells mainly consisted of CD19(+)CD20(+) B cells (7/11) and had clonal rearrangement of immunoglobulin genes (3/11) in patients with CNS-PTLD. On the contrary, in patients with encephalitis/myelitis, CSF cells were comprised of different cell populations and none of the gene rearrangement was detected. Herpesvirus-associated CNS diseases are common in the early stages of allo-HSCT, wherein EBV is the most frequent causative virus. The immunophenotypic and clonal analysis of CSF cells might be helpful in the differential diagnosis between encephalitis and lymphoproliferative diseases.

Second hematopoietic SCT for leukemia relapsing after myeloablative T cell-depleted transplants does not prolong survival.

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McIver, Z A; Yin, F; Hughes, T; Battiwalla, M; Ito, S; Koklanaris, E; Haggerty, J; Hensel, N F; Barrett, A John

2013-09-01

Patients with leukemia relapsing after allogeneic hematopoietic SCT have a dismal prognosis. A second SCT offers a further opportunity for cure, but has a high rate of treatment failure. To determine the utility of this option, we analyzed 59 consecutive patients relapsing after a myeloablative HLA-matched sibling T cell-depleted (TCD) SCT. Twenty-five patients (13 relapsing within 6 months and 12 relapsing between 6 and 170 months after the first SCT) received a T-replete second SCT. Thirty-eight patients relapsing early had a shorter survival than the 21 patients relapsing later (median 96 vs 298 days, P=0.0002). In patients relapsing early, the second SCT did not improve OS compared with patients receiving non-SCT treatments (median survival 109 vs 80 days, P=0.41). In patients relapsing late, despite an early trend in favor of second SCT, survival was comparable for patients receiving a second SCT compared with non retransplanted patients (median survival 363.5 vs 162 days, P=0.49). Disappointingly, our results do not demonstrate an important survival benefit for a second T-replete allogeneic SCT to treat relapse following a TCD SCT.

Hematopoietic stem cell transplantation for chronic lymphocytic leukemia.

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Gladstone, Douglas E; Fuchs, Ephraim

2012-03-01

Although hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many aggressive hematologic malignancies, the role of HSCT in chronic lymphocytic leukemia (CLL) has remained controversial. Now in the era of improved conventional treatment and better prognostication of long-term outcome, a review of autologous and allogeneic HSCT in CLL treatment is warranted. Despite an improved disease-free survival in some patients, multiple, prospective, randomized autologous HSCT CLL trials fail to demonstrate an overall survival benefit as compared to conventional therapy. Allogeneic bone marrow transplantation, although limited by donor availability, can successfully eradicate CLL with adverse prognostic features. In the older CLL patients, nonmyeloablative allogeneic transplants are better tolerated than myeloablative transplants. Nonmyeloablative allogeneic transplants are less effective in heavily diseased burdened patients. Outside of a clinical protocol, autologous HSCT for CLL cannot be justified. Nonmyeloablative allogeneic transplantation should be considered in high-risk populations early in the disease process, when disease burden is most easily controlled. Alternative donor selection using haploidentical donors and posttransplantation cyclophosphamide has the potential to vastly increase the availability of curative therapy in CLL while retaining a low treatment-related toxicity.

[Retrospective study of the implementation of the qualitative PCR technique in biological samples for monitoring toxoplasmosis in pediatric patients receiving hematopoietic stem cell transplantation].

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Nigro, Mónica G; Figueroa, Carlos; Ledesma, Bibiana A

2014-01-01

Toxoplasmosis is an opportunistic infection caused by the parasite Toxoplasma gondii. The infection is severe and difficult to diagnose in patients receiving allogeneic hematopoietic stem cell transplantation (HSCT). Twelve patients receiving HSCT were monitored post-transplant, by qualitative PCR at the Children's Hospital S.A.M.I.C. "Prof. Dr. Juan P. Garrahan". The monitoring of these patients was defined by a history of positive serology for toxoplasmosis in the donor or recipient and because their hematologic condition did not allow the use of trimethoprim-sulfamethoxazole for prophylaxis. During the patients' monitoring, two of them with positive PCR results showed signs of illness by T. gondii and were treated with pyrimethamine-clindamycin. In two other patients, toxoplasmosis was the cause of death and an autopsy finding, showing negative PCR results. Four patients without clinical manifestations received treatment for toxoplasmosis because of positive PCR detection. In four patients there were no signs of toxoplasmosis disease and negative PCR results during follow-up. The qualitative PCR technique proved useful for the detection of toxoplasmosis reactivation in HSCT recipients, but has limitations in monitoring and making clinical decisions due to the persistence of positive PCR over time and manifestations of toxicity caused by the treatment. Copyright © 2014 Asociación Argentina de Microbiología. Publicado por Elsevier España. All rights reserved.

Having a sibling as donor: patients' experiences immediately before allogeneic hematopoietic stem cell transplantation.

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Kisch, Annika; Bolmsjö, Ingrid; Lenhoff, Stig; Bengtsson, Mariette

2014-08-01

Allogeneic hematopoietic stem cell transplantation (HSCT) offers a potential cure for a variety of diseases but is also associated with significant risks. With HSCT the donor is either a relative, most often a sibling, or an unrelated registry donor. The aim was to explore patients' experiences, immediately before transplantation, regarding having a sibling as donor. Ten adult patients with sibling donors were interviewed before admission for HSCT. The interviews were digitally recorded, transcribed verbatim and subjected to qualitative content analysis. The main theme Being in no man's land is a metaphor for the patients' complex situation with its mixture of emotions and thoughts prior to transplantation. The three subthemes Trust in the sibling donor, Concern about others and Loss of control cover the various experiences. The patient's experiences are influenced by their personal situation and the quality of the relationship with the sibling donor. While patients feel secure in having a sibling donor, they are dependent for their survival on the cell donation and feel responsible for the donor's safety during donation. These emotions intensify the patients' sense of dependency and loss of control. In caring for HSCT patients the nurses should be aware of the complexity of the patients' situation and keep in mind that having a sibling donor might imply extra pressure, including a sense of responsibility. Caring for both patients and sibling donors optimally is a challenge, which needs further improvement and exploration. Copyright © 2014 Elsevier Ltd. All rights reserved.

Impact of estimated glomerular filtration rate based on plasma cystatin C and serum creatinine levels before allogeneic hematopoietic cell transplantation.

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Wada, Hidenori; Kanda, Junya; Akahoshi, Yu; Nakano, Hirofumi; Ugai, Tomotaka; Yamasaki, Ryoko; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Ashizawa, Masahiro; Sato, Miki; Terasako-Saito, Kiriko; Kimura, Shun-Ichi; Kikuchi, Misato; Nakasone, Hideki; Yamazaki, Rie; Kako, Shinichi; Tanihara, Aki; Nishida, Junji; Kanda, Yoshinobu

2018-06-01

No standard method for measuring renal function has been established in allogeneic hematopoietic cell transplantation (allo-HCT). We retrospectively analyzed 80 patients with hematological diseases who underwent allo-HCT at our center. We assessed renal function using creatinine clearance (Ccr), estimated glomerular filtration rate (eGFR) based on creatinine (eGFRcre), eGFR based on cystatin C (eGFRcys), and the average of eGFRcre and eGFRcys (eGFRave). We then evaluated the impact of pre-transplant renal function on the exacerbation of renal function and non-relapse mortality after transplantation. There was a significant correlation between Ccr and eGFRcre, eGFRcys, and eGFRave. eGFRave best predicted the exacerbation of renal function according to the area under the receiver-operating characteristic curve. The cumulative incidence of renal function exacerbation at 1 year was higher in the lower eGFRave group (<90 ml/min/1.73 m 2 ) than in the higher eGFRave group (≥90 ml/min/1.73 m 2 ; 0.85 vs. 0.39, p < 0.001), which was confirmed by a multivariate analysis (HR 2.75, p = 0.001). A lower eGFRave value was a marginally significant factor for non-relapse mortality (HR 3.29, p = 0.076). Among the four parameters, eGFRave best predicted the exacerbation of renal function in allo-HCT. Further, the marginal association between low eGFRave and high non-relapse mortality warrants further study in a prospective study in allo-HCT.

Childhood Hematopoietic Cell Transplantation (PDQ®)—Health Professional Version

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Hematopoietic cell transplantation involves the infusion of blood stem cells (peripheral/umbilical cord blood, bone marrow) into a patient to reconstitute the blood system. Get detailed information about autologous and allogeneic transplant, including cell selection, HLA matching, and preparative regimens, and the acute complications and late effects of treatment in this summary for clinicians.

Mesenchymal stromal cells in the antimicrobial host response of hematopoietic stem cell recipients with graft-versus-host disease--friends or foes?

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Balan, A; Lucchini, G; Schmidt, S; Schneider, A; Tramsen, L; Kuçi, S; Meisel, R; Bader, P; Lehrnbecher, T

2014-10-01

Mesenchymal stromal cells (MSCs) are multipotent cells, which exhibit broad immunosuppressive activities. Moreover, they may be administered irrespectively of human leukocyte antigen (HLA) compatibility, without inducing life-threatening immunological reactions, as they express no HLA class II and limited HLA class I antigens under resting conditions. These characteristics have made MSC an appealing candidate for cell therapy after hematopoietic stem cell transplantation (HSCT), for example, for treatment of graft-versus-host disease (GvHD) or for graft rejection prevention/treatment in allogeneic HSCT recipients. Unfortunately, information regarding the effect of MSC infusion on the host response to infectious agents is scarce, and study results on infectious complications in patients receiving MSC are conflicting. The present review focuses on the available data from in vitro studies and animal models regarding the interaction of MSC with bacterial, viral and fungal pathogens. In a clinical part, we present the current information on infectious complications in allogeneic HSCT recipients who had received MSCs as prophylaxis or treatment of GvHD disease.

Oral changes in individuals undergoing hematopoietic stem cell transplantation

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Regina Haddad Barrach

2015-04-01

Full Text Available INTRODUCTION: Patients undergoing hematopoietic stem cell transplantation receive high doses of chemotherapy and radiotherapy, which cause severe immunosuppression.OBJECTIVE: To report an oral disease management protocol before and after hematopoietic stem cell transplantation.METHODS: A prospective study was carried out with 65 patients aged > 18 years, with hematological diseases, who were allocated into two groups: A (allogeneic transplant, 34 patients; B (autologous transplant, 31 patients. A total of three dental status assessments were performed: in the pre-transplantation period (moment 1, one week after stem cell infusion (moment 2, and 100 days after transplantation (moment 3. In each moment, oral changes were assigned scores and classified as mild, moderate, and severe risks.RESULTS: The most frequent pathological conditions were gingivitis, pericoronitis in the third molar region, and ulcers at the third moment assessments. However, at moments 2 and 3, the most common disease was mucositis associated with toxicity from the drugs used in the immunosuppression.CONCLUSION: Mucositis accounted for the increased score and potential risk of clinical complications. Gingivitis, ulcers, and pericoronitis were other changes identified as potential risk factors for clinical complications.

Allogeneic hematopoietic stem-cell transplantation for acute myeloid leukemia in remission

DEFF Research Database (Denmark)

Nagler, Arnon; Rocha, Vanderson; Labopin, Myriam

2013-01-01

Cyclophosphamide (Cy) combined with total-body irradiation (TBI) or with busulfan (Bu) are currently the most common myeloablative regimens used in allogeneic stem-cell transplantation (alloSCT) in adults with acute myelogenous leukemia (AML). Intravenous (IV) Bu has more predictable...

Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually.

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Passweg, J R; Baldomero, H; Bader, P; Bonini, C; Cesaro, S; Dreger, P; Duarte, R F; Dufour, C; Kuball, J; Farge-Bancel, D; Gennery, A; Kröger, N; Lanza, F; Nagler, A; Sureda, A; Mohty, M

2016-06-01

A record number of 40 829 hematopoietic stem cell transplantation (HSCT) in 36 469 patients (15 765 allogeneic (43%), 20 704 autologous (57%)) were reported by 656 centers in 47 countries to the 2014 survey. Trends include: continued growth in transplant activity, more so in Eastern European countries than in the west; a continued increase in the use of haploidentical family donors (by 25%) and slower growth for unrelated donor HSCT. The use of cord blood as a stem cell source has decreased again in 2014. Main indications for HSCT were leukemias: 11 853 (33%; 96% allogeneic); lymphoid neoplasias; 20 802 (57%; 11% allogeneic); solid tumors; 1458 (4%; 3% allogeneic) and non-malignant disorders; 2203 (6%; 88% allogeneic). Changes in transplant activity include more allogeneic HSCT for AML in CR1, myeloproliferative neoplasm (MPN) and aplastic anemia and decreasing use in CLL; and more autologous HSCT for plasma cell disorders and in particular for amyloidosis. In addition, data on numbers of teams doing alternative donor transplants, allogeneic after autologous HSCT, autologous cord blood transplants are presented.

Risk factors for Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation.

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Uhlin, Michael; Wikell, Helena; Sundin, Mikael; Blennow, Ola; Maeurer, Markus; Ringden, Olle; Winiarski, Jacek; Ljungman, Per; Remberger, Mats; Mattsson, Jonas

2014-02-01

Allogeneic hematopoietic stem cell transplantation is a successful treatment for hematologic malignancies and a variety of genetic and metabolic disorders. In the period following stem cell transplantation, the immune-compromised milieu allows opportunistic pathogens to thrive. Epstein-Barr virus-associated post-transplant lymphoproliferative disease can be a life-threatening complication for transplanted patients because of suppressed T-cell-mediated immunity. We analyzed possible risk factors associated with post-transplant lymphoproliferative disease in a cohort of over 1,000 patients. The incidence of post-transplant lymphoproliferative disease was 4%. Significant risk factors identified by multivariate analysis were: human leukocyte antigen-mismatch (PEpstein-Barr virus mismatch recipient-/donor+ (Pdisease grade II to IV (P=0.006), pre-transplant splenectomy (P=0.008) and infusion of mesenchymal stromal cells (P=0.015). The risk of post-transplant lymphoproliferative disease has increased in more recent years, from less than 2% before 1998 to more than 6% after 2011. Additionally, we show that long-term survival of patients with post-transplant lymphoproliferative disease is poor despite initial successful treatment. The 3-year survival rate among the 40 patients with post-transplant lymphoproliferative disease was 20% as opposed to 62% among patients without post-transplant lymphoproliferative disease (Pdisease after transplantation in need of pre-emptive measures.

Mesenchymal Stem Cells May Ameliorate Nephrotic Syndrome Post-Allogeneic Hematopoietic Stem Cell Transplantation-Case Report

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Xin Zhang

2017-08-01

Full Text Available IntroductionBecause of their immunomodulatory and anti-inflammatory effects, mesenchymal stem cells (MSCs have been considered as potential therapeutic agents for treating immune-related or autoimmune diseases, such as graft-versus-host disease (GVHD. Nephrotic syndrome (NS after allogeneic hematopoietic stem cell transplantation (allo-HSCT is an uncommon complication with unclear etiology and pathogenesis. It may be an immune disorder involving immune complex deposition, B cells, regulatory T cells (Tregs, and Th1 cytokines and be a manifestation of chronic GVHD. Corticosteroids and calcium antagonists, alone or in combination, are the most common therapeutic agents in this setting. Rituximab is commonly administered as salvage treatment. However, treatment failure and progressive renal function deterioration has been reported to occur in approximately 20% of patients in a particular cohort.Case presentationWe present a patient who developed NS 10 months after allo-HSCT. After treatment failure with cyclosporine A, prednisone, and rituximab, she achieved a complete response with MSC treatment. The clinical improvement of this patient was accompanied by a decreased B cell population together with an increased frequency of regulatory B cells (Bregs and Tregs after MSC treatment.ConclusionMSCs could modulate NS after allo-HSCT by suppressing B cell proliferation, inducing Tregs and Bregs, and inhibiting inflammatory cytokine production by monocytes and NK cells. Among all these, Bregs might play an important role in ameliorating the NS of this patient.

[A comparative study of unrelated donor and matched-sibling donor allogeneic hematopoietic stem cell transplantation in children and adolescents with acquired severe aplastic anemia].

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Zhou, J; Fu, Y W; Liang, L J; Wang, Q; Han, L J; Zu, Y L; Zhang, Yanli; Zhu, X H; Yu, F K; Fang, B J; Wei, X D; Song, Y P

2016-12-01

Objective: To evaluate the efficacy of unrelated donor allogeneic hematopoietic stem cell transplantation(URD allo-HSCT) for children and adolescents with severe aplastic anemia (SAA). Methods: Clinical data of 34 SAA children and adolescents undergoing allo-HSCT were retrospectively analyzed from October 2001 to October 2015. According to the source of donor, the patients were divided into matched sibling donor allo-HSCT group (MSD group) and unrelated donor group (URD group). The clinical outcome of SAA children and adolescents receiving URD allo-HSCT was assessed, and patients in MSD allo-HSCT group were enrolled as control at the same period. Results: The rate of hematopoietic reconstitution, the time of neutrophil and platelet engraftment, incidence of chimerism and graft rejection between two groups were not statistically different.The incidence of acute graft-versus-host disease (GVHD) in URD group was significantly higher than that in MSD group [42.9%(6/14) vs 10.5%(2/19), P =0.047]. The incidence of grade Ⅱ-Ⅳ acute GVHD and chronic GVHD in URD were higher than those in MSD group [21.4%(3/14) vs 5.3%(1/19), P =0.288; 35.7%(5/14) vs 5.3%(1/19), P =0.062, respectively], yet without significant difference between two groups. Other transplant-related complications including pulmonary complications, hemorrhagic cystitis, incidence of EBV and CMV reactivation and venous occlusive disease were comparable with two regimens. Estimated 5-years overall survival (OS) rate and disease free survival (DFS) rate were not statistically significant between URD group and MSD group [(84.4±6.6)% vs (89.4±7.1)%, (82.5±5.4)% vs (82.1±4.3)%; P =0.766, P =0.884, respectively]. Conclusions: By multivariate analysis, the outcome of URD allo-HSCT in SAA children and adolescent is similar to MSD allo-HSCT. It could be an alternative option as the first-line treatment for SAA children and adolescents without HLA matched sibling donors.

Clinical impact of pre-transplant gut microbial diversity on outcomes of allogeneic hematopoietic stem cell transplantation.

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Doki, Noriko; Suyama, Masahiro; Sasajima, Satoshi; Ota, Junko; Igarashi, Aiko; Mimura, Iyo; Morita, Hidetoshi; Fujioka, Yuki; Sugiyama, Daisuke; Nishikawa, Hiroyoshi; Shimazu, Yutaka; Suda, Wataru; Takeshita, Kozue; Atarashi, Koji; Hattori, Masahira; Sato, Eiichi; Watakabe-Inamoto, Kyoko; Yoshioka, Kosuke; Najima, Yuho; Kobayashi, Takeshi; Kakihana, Kazuhiko; Takahashi, Naoto; Sakamaki, Hisashi; Honda, Kenya; Ohashi, Kazuteru

2017-09-01

Post-transplant microbial diversity in the gastrointestinal tract is closely associated with clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, little is known about the impact of the fecal microbiota before allo-HSCT. We analyzed fecal samples approximately 2 weeks before conditioning among 107 allo-HSCT recipients between 2013 and 2015. Microbial analysis was performed using 16S rRNA gene sequencing. Operational taxonomic unit-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into three groups based on the diversity index: low (3) diversity (18 (16.8%), 48 (44.9%), and 41 (38.3%) patients, respectively). There were no significant differences in the 20-month overall survival, cumulative incidence of relapse, and non-relapse mortality among three groups. The cumulative incidence of grade II to IV acute graft-versus-host disease (aGVHD) was similar among the three groups (low 55.6%; intermediate 35.4%; high 48.8%, p = 0.339, at day 100). Furthermore, we found no differences in the cumulative incidence of grade II to IV acute gastrointestinal GVHD among the three groups (low 38.9%; intermediate 21.3%; high 24.4%, p = 0.778, at day 100). Regarding the composition of microbiota before allo-HSCT, aGVHD patients showed a significantly higher abundance of phylum Firmicutes (p strategy to prevent aGVHD.

Prolonged Survival of a Refractory Acute Myeloid Leukemia Patient after a Third Hematopoietic Stem Cell Transplantation with Umbilical Cord Blood following a Second Relapse

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Suk-young Lee

2014-01-01

Full Text Available Although hematopoietic stem cell transplantation (HSCT has been considered to be the only way for potential cure of relapsed acute myeloid leukemia (AML, there has been no report on a third HSCT in patients with multiple relapsed AML. Here, we report a case of 53-year-old female who received a successful third allogeneic HSCT after relapse of AML following a second allogeneic HSCT. She was treated with a toxicity reduced conditioning regimen and received direct intrabone cord blood transplantation (CBT using a single unit of 5/6 HLA-matched cord blood as a graft source. Graft-versus-host disease prophylaxis was performed with a single agent of tacrolimus to increase graft-versus-leukemia effect. She is in remission for 8 months since the direct intrabone CBT. This report highlights not only the importance of individually adjusted approach but also the need for further investigation on the role of HSCT as a treatment modality in patients with refractory or multiple relapsed AML.

Antifungal prophylaxis with fluconazole in allogeneic stem cell transplantation recipients who had prior invasive aspergillosis with subsequent complete resolution by computed tomography.

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Akahoshi, Yu; Kimura, Shun-Ichi; Gomyo, Ayumi; Hayakawa, Jin; Tamaki, Masaharu; Harada, Naonori; Kusuda, Machiko; Kameda, Kazuaki; Ugai, Tomotaka; Wada, Hidenori; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Sato, Miki; Terasako-Saito, Kiriko; Kikuchi, Misato; Nakasone, Hideki; Kako, Shinichi; Kanda, Yoshinobu

2018-04-01

Consensus has yet to be reached regarding secondary prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT) with a complete resolution of invasive aspergillosis (IA) confirmed by chest computed tomography (CT). We retrospectively evaluated the feasibility of antifungal prophylaxis with fluconazole in allogeneic HSCT recipients who had previously developed IA which showed complete resolution as confirmed by chest CT before HSCT. Consecutive adult patients who underwent allogeneic HSCT at our institution and who had received fluconazole as systemic antifungal prophylaxis from June 2007 to January 2015 were included. We compared the clinical outcomes between patients with a past history of IA who showed a complete resolution of chest CT abnormalities (n = 13) and those without a previous history of IA (n = 137). The cumulative incidence of proven or probable IA was 8.8% in the group without a past history of IA and 0.0% in the group with a past history of IA (p = .268). The cumulative incidence of proven or probable invasive fungal disease (IFD) within 100 days after allogeneic HSCT was 10.9% in the group without a past history of IA and 15.4% in the group with a past history of IA (p = .647). Fluconazole was switched to anti-mould agents in two-thirds of the patients in each group by day 100 after HSCT. Fluconazole was confirmed to be an acceptable prophylactic agent early after allogeneic HSCT in appropriately selected patients.

Posaconazole plasma exposure correlated to intestinal mucositis in allogeneic stem cell transplant patients.

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Vanstraelen, Kim; Prattes, Juergen; Maertens, Johan; Lagrou, Katrien; Schoemans, Hélène; Peersman, Nele; Vermeersch, Pieter; Theunissen, Koen; Mols, Raf; Augustijns, Patrick; Annaert, Pieter; Hoenigl, Martin; Spriet, Isabel

2016-08-01

Low posaconazole plasma concentrations (PPCs) are frequently encountered in allogeneic hematopoietic stem cell transplant (HSCT) patients, due to variable gastrointestinal absorption. In this study, the impact of intestinal mucositis on posaconazole exposure is investigated. A prospective pharmacokinetic study was performed including allogeneic HSCT patients receiving posaconazole prophylaxis with the oral suspension or tablets. Steady state PPCs were determined using high-performance liquid chromatography-fluorescence detection at the day of transplantation (=day 0), day +7, and +14. Citrulline was measured using liquid chromatography-tandem mass spectrometry to evaluate severity of mucositis, at baseline (day -7 or -6), and at day 0, +7 and +14. Additionally, citrulline plasma concentrations and steady state trough PPCs were determined in hematological patients without HSCT or mucositis. Thirty-four HSCT patients received posaconazole oral suspension together with 25 cL of Coca Cola, 6 HSCT patients received posaconazole tablets and 33 hematological patients not receiving HSCT received posaconazole oral suspension. The median (interquartile range) average PPC was 0.26 mg/L (0.17-0.43), 0.67 mg/L (0.27-1.38), and 1.08 mg/L (0.96-1.38), with suspension in HSCT patients, suspension in hematological patients and tablets in HSCT patients, respectively. A higher trough PPC was encountered with the oral suspension when citrulline plasma concentrations were above 10 μmol/L compared to values below 10 μmol/L (p < 0.001), whereas for tablets, average PPCs remained high with citrulline plasma concentrations below or above 10 μmol/L (p = 0.64). Posaconazole tablets should be preferred to suspension in HSCT patients immediately after transplantation to prevent insufficient plasma exposure due to intestinal mucositis.

The Association of Combined GSTM1 and CYP2C9 Genotype Status with the Occurrence of Hemorrhagic Cystitis in Pediatric Patients Receiving Myeloablative Conditioning Regimen Prior to Allogeneic Hematopoietic Stem Cell Transplantation

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Chakradhara Rao S. Uppugunduri

2017-07-01

Full Text Available Hemorrhagic cystitis (HC is one of the complications of busulfan-cyclophosphamide (BU-CY conditioning regimen during allogeneic hematopoietic stem cell transplantation (HSCT in children. Identifying children at high risk of developing HC in a HSCT setting could facilitate the evaluation and implementation of effective prophylactic measures. In this retrospective analysis genotyping of selected candidate gene variants was performed in 72 children and plasma Sulfolane (Su, water soluble metabolite of BU levels were measured in 39 children following treatment with BU-CY regimen. The cytotoxic effects of Su and acrolein (Ac, water soluble metabolite of CY were tested on human urothelial cells (HUCs. The effect of Su was also tested on cytochrome P 450 (CYP function in HepaRG hepatic cells. Cumulative incidences of HC before day 30 post HSCT were estimated using Kaplan–Meier curves and log-rank test was used to compare the difference between groups in a univariate analysis. Multivariate Cox regression was used to estimate hazard ratios with 95% confidence intervals (CIs. Multivariate analysis included co-variables that were significantly associated with HC in a univariate analysis. Cumulative incidence of HC was 15.3%. In the univariate analysis, HC incidence was significantly (p < 0.05 higher in children older than 10 years (28.6 vs. 6.8% or in children with higher Su levels (>40 vs. <11% or in carriers of both functional GSTM1 and CYP2C9 (33.3 vs. 6.3% compared to the other group. In a multivariate analysis, combined GSTM1 and CYP2C9 genotype status was associated with HC occurrence with a hazards ratio of 4.8 (95% CI: 1.3–18.4; p = 0.02. Ac was found to be toxic to HUC cells at lower concentrations (33 μM, Su was not toxic to HUC cells at concentrations below 1 mM and did not affect CYP function in HepaRG cells. Our observations suggest that pre-emptive genotyping of CYP2C9 and GSTM1 may aid in selection of more effective prophylaxis to

Rhizomucor and Scedosporium Infection Post Hematopoietic Stem-Cell Transplant

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Dânia Sofia Marques

2011-01-01

Full Text Available Hematopoietic stem-cell transplant recipients are at increased risk of developing invasive fungal infections. This is a major cause of morbidity and mortality. We report a case of a 17-year-old male patient diagnosed with severe idiopathic acquired aplastic anemia who developed fungal pneumonitis due to Rhizomucor sp. and rhinoencephalitis due to Scedosporium apiospermum 6 and 8 months after undergoing allogeneic hematopoietic stem-cell transplant from an HLA-matched unrelated donor. Discussion highlights risk factors for invasive fungal infections (i.e., mucormycosis and scedosporiosis, its clinical features, and the factors that must be taken into account to successfully treat them (early diagnosis, correction of predisposing factors, aggressive surgical debridement, and antifungal and adjunctive therapies.

Lung function after allogeneic hematopoietic stem cell transplantation in children

DEFF Research Database (Denmark)

Uhlving, Hilde Hylland; Larsen Bang, Cæcilie; Christensen, Ib Jarle

2013-01-01

Reduction in pulmonary function (PF) has been reported in up to 85% of pediatric patients during the first year after hematopoietic stem cell transplantation (HSCT). Our understanding of the etiology for this decrease in lung function is, however, sparse. The aim of this study was to describe PF...

Autologous or reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chemotherapy-sensitive mantle-cell lymphoma: analysis of transplantation timing and modality.

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Fenske, Timothy S; Zhang, Mei-Jie; Carreras, Jeanette; Ayala, Ernesto; Burns, Linda J; Cashen, Amanda; Costa, Luciano J; Freytes, César O; Gale, Robert P; Hamadani, Mehdi; Holmberg, Leona A; Inwards, David J; Lazarus, Hillard M; Maziarz, Richard T; Munker, Reinhold; Perales, Miguel-Angel; Rizzieri, David A; Schouten, Harry C; Smith, Sonali M; Waller, Edmund K; Wirk, Baldeep M; Laport, Ginna G; Maloney, David G; Montoto, Silvia; Hari, Parameswaran N

2014-02-01

To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT. For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

Spectrum of Epstein-Barr virus-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation.

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Xuan, Li; Jiang, Xinmiao; Sun, Jing; Zhang, Yu; Huang, Fen; Fan, Zhiping; Guo, Xutao; Dai, Min; Liu, Can; Yu, Guopan; Zhang, Xian; Wu, Meiqing; Huang, Xiaojun; Liu, Qifa

2013-09-01

Epstein-Barr virus (EBV) infection may result in a spectrum of diseases in recipients of transplant. The aim of this study is to investigate the incidence, clinical characteristics, and prognosis of the spectrum of EBV-associated diseases in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). A total of 263 recipients undergoing allo-HSCT were prospectively enrolled. The blood EBV-DNA loads were regularly monitored by quantitative real-time polymerase chain reaction. The 3-year cumulative incidence of total EBV-associated diseases, posttransplantation lymphoproliferative diseases (PTLD), EBV fever, and EBV end-organ diseases (pneumonia, encephalitis/myelitis, and hepatitis) were 15.6%±2.5%, 9.9%±2.0%, 3.3%±1.3%, and 3.3%±1.2% (2.2%±1.0%, 1.6%±0.8%, and 0.9%±0.6%), respectively. Fever was the most common symptom of EBV-associated diseases. Patients with PTLD had better response rate to rituximab-based treatments compared with those with EBV end-organ diseases (including PTLD accompanied by EBV end-organ diseases) (P=0.014). The 3-year overall survival was 37.3%±13.7%, 100.0%, and 0.0%±0.0% in patients with PTLD, EBV fever, and EBV end-organ diseases (P=0.001). EBV-associated diseases other than PTLD are not rare in the recipients of allo-HSCT. The clinical manifestations of EBV end-organ diseases are similar to PTLD. EBV end-organ diseases had poorer response to rituximab-based therapy compared with PTLD.

Prospective assessment of bone turnover and clinical bone diseases after allogeneic hematopoietic stem-cell transplantation.

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Petropoulou, Anna D; Porcher, Raphael; Herr, Andrée-Laure; Devergie, Agnès; Brentano, Thomas Funck; Ribaud, Patricia; Pinto, Fernando O; Rocha, Vanderson; Peffault de Latour, Régis; Orcel, Philippe; Socié, Gérard; Robin, Marie

2010-06-15

Bone complications after hematopoietic stem-cell transplantation (HSCT) are relatively frequent. Evaluation of biomarkers of bone turnover and dual energy x-ray absorptiometry (DEXA) are not known in this context. We prospectively evaluated bone mineral density, biomarkers of bone turnover, and the cumulative incidence of bone complications after allogeneic HSCT. One hundred forty-six patients were included. Bone mineral density was measured by DEXA 2-month and 1-year post-HSCT. The markers of bone turnover were serum C-telopeptide (C-TP), 5 tartrate-resistant acid phosphatase (bone resorption), and osteocalcin (bone formation) determined pre-HSCT and 2 months and 1 year thereafter. Potential association between osteoporosis at 2 months, osteoporotic fracture or avascular necrosis and, individual patient's characteristics and biologic markers were tested. C-TP was high before and 2 months after transplant. At 2 months, DEXA detected osteoporosis in more than half the patients tested. Male sex, median age less than or equal to 15 years, and abnormal C-TP before HSCT were risk factors significantly associated with osteoporosis. Three-year cumulative incidences of fractures and avascular necrosis were 8% and 11%, respectively. Children were at higher risk of fracture, whereas corticosteroid treatment duration was a significant risk factor for developing a clinical bone complication post-HSCT. Bone complications and osteoporosis are frequent after HSCT. Bone biologic markers and DEXA showed that subclinical bone abnormalities appeared early post-HSCT. The risk factors, age, gender, and C-TP easily available at the time of transplantation were identified. Biphosphonates should probably be given to patients with those risk factors.

Outcomes of Children with Hemophagocytic Lymphohistiocytosis Given Allogeneic Hematopoietic Stem Cell Transplantation in Italy.

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Messina, Chiara; Zecca, Marco; Fagioli, Franca; Rovelli, Attilio; Giardino, Stefano; Merli, Pietro; Porta, Fulvio; Aricò, Maurizio; Sieni, Elena; Basso, Giuseppe; Ripaldi, Mimmo; Favre, Claudio; Pillon, Marta; Marzollo, Antonio; Rabusin, Marco; Cesaro, Simone; Algeri, Mattia; Caniglia, Maurizio; Di Bartolomeo, Paolo; Ziino, Ottavio; Saglio, Francesco; Prete, Arcangelo; Locatelli, Franco

2018-06-01

We report on 109 patients with hemophagocytic lymphohistiocytosis (HLH) undergoing 126 procedures of allogeneic hematopoietic stem cell transplantation (HSCT) between 2000 and 2014 in centers associated with the Italian Pediatric Hematology Oncology Association. Genetic diagnosis was FHL2 (32%), FHL3 (33%), or other defined disorders known to cause HLH (15%); in the remaining patients no genetic abnormality was found. Donor for first transplant was an HLA-matched sibling for 25 patients (23%), an unrelated donor for 73 (67%), and an HLA-partially matched family donor for 11 children (10%). Conditioning regimen was busulfan-based for 61 patients (56%), treosulfan-based for 21 (20%), and fludarabine-based for 26 children (24%). The 5-year probabilities of overall survival (OS) and event-free survival (EFS) were 71% and 60%, respectively. Twenty-six patients (24%) died due to transplant-related causes, whereas 14 (13%) and 10 (9%) patients experienced graft rejection and/or relapse, respectively. Twelve of 14 children given a second HSCT after graft failure/relapse are alive and disease-free. Use of HLA-partially matched family donors was associated with higher risk of graft failure and thus with lower EFS (but not with lower OS) in multivariable analysis. Active disease at transplantation did not significantly affect prognosis. These data confirm that HSCT can cure most HLH patients, active disease not precluding successful transplantation. Because in HLH patients HLA-haploidentical HSCT performed through CD34 + cell positive selection was found to be associated with poor sustained engraftment of donor cells, innovative approaches able to guarantee a more robust engraftment are warranted in patients given this type of allograft. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia who had central nervous system involvement: a study from the Adult ALL Working Group of the Japan Society for Hematopoietic Cell Transplantation.

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Shigematsu, Akio; Kako, Shinichi; Mitsuhashi, Kenjiro; Iwato, Koji; Uchida, Naoyuki; Kanda, Yoshinobu; Fukuda, Takahiro; Sawa, Masashi; Senoo, Yasushi; Ogawa, Hiroyasu; Miyamura, Koichi; Takada, Satoru; Nagamura-Inoue, Tokiko; Morishima, Yasuo; Ichinohe, Tatsuo; Atsuta, Yoshiko; Mizuta, Shuichi; Tanaka, Junji

2017-06-01

The prognosis for adult acute lymphoblastic leukemia (ALL) patients with central nervous system (CNS) involvement (CNS+) who received allogeneic hematopoietic stem cell transplantation (allo-SCT) remains unclear. We retrospectively compared the outcomes of allo-SCT for patients with CNS involvement and for patients without CNS involvement (CNS-) using a database in Japan. The eligibility criteria for this study were as follows: diagnosis of ALL, aged more than 16 years, allo-SCT between 2005 and 2012, and first SCT. Data for 2582 patients including 136 CNS+ patients and 2446 CNS- patients were used for analyses. As compared with CNS- patients, CNS+ patients were younger, had worse disease status at SCT and had poorer performance status (PS) at SCT (P < 0.01). Incidence of relapse was higher in CNS+ patients (P = 0.02), and incidence of CNS relapse was also higher (P < 0.01). The probability of 3-year overall survival (OS) was better in CNS- patients (P < 0.01) by univariate analysis. However, in patients who received SCT in CR, there was no difference in the probability of OS between CNS+ and CNS- patients (P = 0.38) and CNS involvement did not have an unfavorable effect on OS by multivariate analysis. CNS+ patients who achieved CR showed OS comparable to that of CNS- patients.

Astrovirus infection in hospitalized infants with severe combined immunodeficiency after allogeneic hematopoietic stem cell transplantation.

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Werner Wunderli

Full Text Available Infants with severe primary combined immunodeficiency (SCID and children post-allogeneic hematopoietic stem cell transplantation (HSCT are extremely susceptible to unusual infections. The lack of generic tools to detect disease-causing viruses among more than 200 potential human viral pathogens represents a major challenge to clinicians and virologists. We investigated retrospectively the causes of a fatal disseminated viral infection with meningoencephalitis in an infant with gamma C-SCID and of chronic gastroenteritis in 2 other infants admitted for HSCT during the same time period. Analysis was undertaken by combining cell culture, electron microscopy and sequence-independent single primer amplification (SISPA techniques. Caco-2 cells inoculated with fecal samples developed a cytopathic effect and non-enveloped viral particles in infected cells were detected by electron microscopy. SISPA led to the identification of astrovirus as the pathogen. Both sequencing of the capsid gene and the pattern of infection suggested nosocomial transmission from a chronically excreting index case to 2 other patients leading to fatal infection in 1 and to transient disease in the others. Virus-specific, real-time reverse transcription polymerase chain reaction was then performed on different stored samples to assess the extent of infection. Infection was associated with viremia in 2 cases and contributed to death in 1. At autopsy, viral RNA was detected in the brain and different other organs, while immunochemistry confirmed infection of gastrointestinal tissues. This report illustrates the usefulness of the combined use of classical virology procedures and modern molecular tools for the diagnosis of unexpected infections. It illustrates that astrovirus has the potential to cause severe disseminated lethal infection in highly immunocompromised pediatric patients.

Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study.

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Cruz, Conrad Russell Y; Micklethwaite, Kenneth P; Savoldo, Barbara; Ramos, Carlos A; Lam, Sharon; Ku, Stephanie; Diouf, Oumar; Liu, Enli; Barrett, A John; Ito, Sawa; Shpall, Elizabeth J; Krance, Robert A; Kamble, Rammurti T; Carrum, George; Hosing, Chitra M; Gee, Adrian P; Mei, Zhuyong; Grilley, Bambi J; Heslop, Helen E; Rooney, Cliona M; Brenner, Malcolm K; Bollard, Catherine M; Dotti, Gianpietro

2013-10-24

Autologous T cells expressing a CD19-specific chimeric antigen receptor (CD19.CAR) are active against B-cell malignancies, but it is unknown whether allogeneic CD19.CAR T cells are safe or effective. After allogeneic hematopoietic stem cell transplantation (HSCT), infused donor-derived virus-specific T cells (VSTs) expand in vivo, persist long term, and display antiviral activity without inducing graft-vs-host disease; therefore, we determined whether donor VSTs, engineered to express CD19.CAR, retained the characteristics of nonmanipulated allogeneic VSTs while gaining antitumor activity. We treated 8 patients with allogeneic (donor-derived) CD19.CAR-VSTs 3 months to 13 years after HSCT. There were no infusion-related toxicities. VSTs persisted for a median of 8 weeks in blood and up to 9 weeks at disease sites. Objective antitumor activity was evident in 2 of 6 patients with relapsed disease during the period of CD19.CAR-VST persistence, whereas 2 patients who received cells while in remission remain disease free. In 2 of 3 patients with viral reactivation, donor CD19.CAR-VSTs expanded concomitantly with VSTs. Hence CD19.CAR-VSTs display antitumor activity and, because their number may be increased in the presence of viral stimuli, earlier treatment post-HSCT (when lymphodepletion is greater and the incidence of viral infection is higher) or planned vaccination with viral antigens may enhance disease control.

Characteristics and risk of chronic graft-versus-host disease of liver in allogeneic hematopoietic stem cell transplant recipients.

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Chien-Ting Chen

Full Text Available Chronic graft-versus-host-disease (cGvHD is a serious complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT. Among various organ-specific cGvHD, the cGvHD of liver is less well-characterized. In this study, we applied the National Institutes of Health 2014 scoring criteria of cGvHD to analyze a retrospective cohort of 362 allo-HSCT recipients focusing on cGvHD of liver. The overall incidence of liver cGvHD with a score of 3 by 1.5 years post-transplant was 5.8% (21/362. Poor outcome, in terms of overall survival (OS, were observed in patients with scores of 3 liver cGvHD, comparing to those with scores less than 3 (hazard ratio [HR] 2.037, 95% confidence interval [CI] 1.123-3.696, P = 0.019. In multivariate analysis, male gender (HR 4.004, P = 0.042 and chronic hepatitis C virus (HCV infection status (HR 19.087, P < 0.001 were statistically significant risk factors for scores of 3 liver cGvHD. Our results indicate that liver cGvHD with scores of 3 has a grave prognosis following allo-HSCT, and that HCV carrier status and male are risk factors. Early recognition of this devastating complication might help in prompt immunosuppressive therapy and reducing late poor outcome.

Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

Science.gov (United States)

Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Angiopoietin-like protein 3 promotes preservation of stemness during Ex Vivo expansion of murine hematopoietic stem cells

NARCIS (Netherlands)

E. Farahbakhshian (Elnaz); M.M.A. Verstegen (Monique); T.P. Visser (Trudi); S. Kheradmandkia (Sima); D. Geerts (Dirk); S. Arshad (Shazia); N. Riaz (Noveen); F.G. Grosveld (Frank); N.P. van Til (Niek); J.P.P. Meijerink (Jules)

2014-01-01

textabstractAllogeneic hematopoietic stem cell (HSC) transplantations from umbilical cord blood or autologous HSCs for gene therapy purposes are hampered by limited number of stem cells. To test the ability to expand HSCs in vitro prior to transplantation, two growth factor cocktails containing stem

Salvaged allogeneic hematopoietic stem cell transplantation for pediatric chemotherapy refractory acute leukemia.

Science.gov (United States)

Wang, Jingbo; Yuan, Lei; Cheng, Haoyu; Fei, Xinhong; Yin, Yumin; Gu, Jiangying; Xue, Song; He, Junbao; Yang, Fan; Wang, Xiaocan; Yang, Yixin; Zhang, Weijie

2018-01-09

There is an ongoing debate concerning the performance of salvaged allogeneic hematopoietic stem cell transplantation (allo-HSCT) in pediatric patients with acute refractory leukemia, in whom the prognosis is quite dismal. Few studies have ever been conducted on this subject. This may be partly due to missed opportunities by majority of the patients in such situations. To investigate the feasibility, evaluate the efficiency, and identify the prognostic factors of allo-HSCT in this sub-setting, the authors performed a single institution-based retrospective analysis. A total of 44 patients, of whom 28 had acute myeloid leukemia (AML), 13 had acute lymphocytic leukemia (ALL), and 3 had mixed phenotype leukemia (MPL), were enrolled in this study. With a median follow-up of 19 months, the estimated 2-year overall survival (OS) and progression free survival (PFS) were 34.3% (95% CI, 17.9-51.4%) and 33.6% (95% CI, 18.0-50.1%), respectively. The estimated 2-year incidence rates of relapse and non-relapse mortality (NRM) were 43.8% (95% CI 26.4-60.0%) and 19.6% (95% CI 9.1-32.9%), respectively. The estimated 100-day cumulative incidence of acute graft versus host disease (aGvHD) was 43.6% (95% CI 28.7-57.5%), and the 1-year cumulative incidence of chronic GvHD (cGvHD) was 45.5% (95% CI 30.5-59.3%). Compared with the previous studies, the multivariate analysis in this study additionally identified that female donors and cGvHD were associated with lower relapse and better PFS and OS. Male recipients, age younger than 10 years, a diagnosis of ALL, and the intermediate-adverse cytogenetic risk group were associated with increased relapse. On the contrary, extramedullary disease (EMD) and aGvHD were only linked to worse PFS. These data suggested that although only one-third of the patients would obtain PFS over 2 years, salvaged allo-HSCT is still the most reliable and best therapeutic strategy for refractory pediatric acute leukemia. If probable, choosing a female donor, better

A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant.

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Ronald, John A; Kim, Byung-Su; Gowrishankar, Gayatri; Namavari, Mohammad; Alam, Israt S; D'Souza, Aloma; Nishikii, Hidekazu; Chuang, Hui-Yen; Ilovich, Ohad; Lin, Chih-Feng; Reeves, Robert; Shuhendler, Adam; Hoehne, Aileen; Chan, Carmel T; Baker, Jeanette; Yaghoubi, Shahriar S; VanBrocklin, Henry F; Hawkins, Randall; Franc, Benjamin L; Jivan, Salma; Slater, James B; Verdin, Emily F; Gao, Kenneth T; Benjamin, Jonathan; Negrin, Robert; Gambhir, Sanjiv Sam

2017-06-01

A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2'-deoxy-2'-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893-902. ©2017 AACR . ©2017 American Association for Cancer Research.

Critical care of the hematopoietic stem cell transplant recipient.

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Afessa, Bekele; Azoulay, Elie

2010-01-01

An estimated 50,000 to 60,000 patients undergo hematopoietic stem cell transplantation (HSCT) worldwide annually, of which 15.7% are admitted to the intensive care unit (ICU). The most common reason for ICU admission is respiratory failure and almost all develop single or multiorgan failure. Most HSCT recipients admitted to ICU receive invasive mechanical ventilation (MV). The overall short-term mortality rate of HSCT recipients admitted to ICU is 65%, and 86.4% for those receiving MV. Patient outcome has improved over time. Poor prognostic indicators include advanced age, poor functional status, active disease at transplant, allogeneic transplant, the severity of acute illness, and the development of multiorgan failure. ICU resource limitations often lead to triage decisions for admission. For HSCT recipients, the authors recommend (1) ICU admission for full support during their pre-engraftment period and when there is no evidence of disease recurrence; (2) no ICU admission for patients who refuse it and those who are bedridden with disease recurrence and without treatment options except palliation; (3) a trial ICU admission for patients with unknown status of disease recurrence with available treatment options.

Comparison of Cyclophosphamide Combined with Total Body Irradiation, Oral Busulfan, or Intravenous Busulfan for Allogeneic Hematopoietic Cell Transplantation in Adults with Acute Lymphoblastic Leukemia.

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Mitsuhashi, Kenjiro; Kako, Shinichi; Shigematsu, Akio; Atsuta, Yoshiko; Doki, Noriko; Fukuda, Takahiro; Kanamori, Heiwa; Onizuka, Makoto; Takahashi, Satoshi; Ozawa, Yukiyasu; Kurokawa, Mineo; Inoue, Yoshiko; Nagamura-Inoue, Tokiko; Morishima, Yasuo; Mizuta, Shuichi; Tanaka, Junji

2016-12-01

We conducted a retrospective analysis to compare outcomes in adult patients with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) with conditioning regimens containing cyclophosphamide (CY) in combination with total body irradiation (TBI), oral busulfan (p.o. BU), or intravenous busulfan (i.v. BU). We used data for January 2000 to December 2012 from the Transplant Registry Unified Management Program of the Japan Society of Hematopoietic Cell Transplantation. We identified 2130 patients treated with TBI/CY (n = 2028), p.o. BU/CY (n = 60), or i.v. BU/CY (n = 42). Two-year overall survival (OS) and 2-year relapse-free survival rates were 69.0% and 62.1%, respectively, in the TBI/CY group, 55.9% and 54.2% in the p.o. BU/CY group, and 71.0% and 46.8% in the i.v. BU/CY group. In multivariate analysis, compared with TBI/CY, p.o. BU/CY, but not i.v. BU/CY, was associated with lower OS (hazard ratio [HR], 1.46; P = .047) and a higher incidence of sinusoidal obstruction syndrome (HR, 3.36; P = .030). No between-group differences were seen in the incidence of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), or chronic GVHD. We suggest that i.v. BU/CY might be a possible alternative allo-HCT conditioning regimen for adults with ALL who are not suitable for TBI. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Allogeneic hematopoietic stem cell transplantation for poor-risk CLL: dissecting immune-modulating strategies for disease eradication and treatment of relapse.

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Hahn, M; Böttcher, S; Dietrich, S; Hegenbart, U; Rieger, M; Stadtherr, P; Bondong, A; Schulz, R; Ritgen, M; Schmitt, T; Tran, T H; Görner, M; Herth, I; Luft, T; Schönland, S; Witzens-Harig, M; Zenz, T; Kneba, M; Ho, A D; Dreger, P

2015-10-01

To elucidate factors contributing to the effectiveness of allogeneic hematopoietic stem cell transplantation (alloHCT) in high-risk CLL, immune interventions, GvHD and clinical outcome of 77 consecutive patients allografted for CLL were analyzed. Immune modulation (immunosuppression tapering, rituximab-augmented donor lymphocyte infusions) was guided by minimal residual disease (MRD) monitoring and commenced at a median of 91 (22-273) days after alloHCT, resulting in a probability of being event free and MRD-negative 1 year after transplant of 57% (84% in those encountering chronic GvHD). Patients who were event free and MRD-negative at the 12-month landmark had a 4-year PFS of 77% and largely remained durably MRD-negative if MRD clearance had occurred subsequent to immune modulation. Three-year overall survival, PFS, relapse incidence and non-relapse mortality of all 77 patients were 69, 57, 26 and 24%, respectively. Survival was not affected by EBMT risk category but by active disease at alloHCT, which could not be overcome by intensification of conditioning. Twenty-three patients who experienced relapse post alloHCT had a survival of 56% at 2 years after CLL recurrence. In conclusion, MRD-guided immune modulation after alloHCT for high-risk CLL can provide durable MRD clearance in more than half of the patients.

Selective T-cell Ablation with Bismuth-213 Labeled Anti-TCR Alpha Beta as Nonmyeloablative Conditionaing for Allogeneic Canine Marrow Transplantion

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Bethge, W. A.; Wilbur, D. Scott; Storb, R.; Hamlin, Donald K.; Santos, E. B.; Brechbiel, M. W.; Fisher, Darrell R.; Sandmaier, B. M.

2003-06-15

Two major immunological barriers, the host versus graft (HVG) and the graft versus host (GVH) reaction, must be overcome for successful allogeneic hematopoietic stem cell transplantation. T-cells are involved in these barriers in the major histocompatibility complex-identical settings. We hypothesized that selective ablation of T-cells using radioimmunotherapy, together with postgrafting immunosuppression, would ensure stable allogeneic engraftment. We developed a canine model of nonmyeloablative marrow transplantation in which host immune reactions are impaired by a single dose of 2 Gy total body irradiation (TBI), and where both GVH and residual HVG reactions are controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). We substituted the alpha-emitter bismuth-213 linked to a monoclonal antibody against TCR(alpha,beta)using the metal-binding chelate CHX-A”-DTPA, for 2 Gy TBI. Biodistribution studies using a gamma-emitting indium-111-labeled anti-TCR mAb showed uptake primarily in blood, marrow, lymph nodes, spleen and liver. In a dosimetry study, 4 dogs were treated with 0.13-0.46 mg/kg TCR mAb labeled with 3.7-5.6 mCi/kg (137-207 MBq/kg) Bi-213. The treatment was administered in 6 injections on days -3 and -2 followed by transplantion of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF and CSP. Therapy was well tolerated except for elevations of transaminases, which were transient in all but one dog. No other organ toxicities or signs of graft-versus-host-disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5-55 % with >30 weeks follow up.

Selective T-cell Ablation with Bismuth-213 Labeled Anti-TCR Alpha Beta as Nonmyeloablative Conditioning for Allogeneic Canine Marrow Transplantion

International Nuclear Information System (INIS)

Bethge, W. A.; Wilbur, D. Scott; Storb, R.; Hamlin, Donald K.; Santos, E. B.; Brechbiel, M. W.; Fisher, Darrell R.; Sandmaier, B. M.

2003-01-01

Two major immunological barriers, the host versus graft (HVG) and the graft versus host (GVH) reaction, must be overcome for successful allogeneic hematopoietic stem cell transplantation. T-cells are involved in these barriers in the major histocompatibility complex-identical settings. We hypothesized that selective ablation of T-cells using radioimmunotherapy, together with postgrafting immunosuppression, would ensure stable allogeneic engraftment. We developed a canine model of nonmyeloablative marrow transplantation in which host immune reactions are impaired by a single dose of 2 Gy total body irradiation (TBI), and where both GVH and residual HVG reactions are controlled by postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). We substituted the alpha-emitter bismuth-213 linked to a monoclonal antibody against TCR(alpha,beta)using the metal-binding chelate CHX-A-DTPA, for 2 Gy TBI. Biodistribution studies using a gamma-emitting indium-111-labeled anti-TCR mAb showed uptake primarily in blood, marrow, lymph nodes, spleen and liver. In a dosimetry study, 4 dogs were treated with 0.13-0.46 mg/kg TCR mAb labeled with 3.7-5.6 mCi/kg (137-207 MBq/kg) Bi-213. The treatment was administered in 6 injections on days -3 and -2 followed by transplantion of dog leukocyte antigen-identical marrow on day 0 and postgrafting immunosuppression with MMF and CSP. Therapy was well tolerated except for elevations of transaminases, which were transient in all but one dog. No other organ toxicities or signs of graft-versus-host-disease were noted. The dogs had prompt allogeneic hematopoietic engraftment and achieved stable mixed donor-host hematopoietic chimerism with donor contributions ranging from 5-55 % with >30 weeks follow up

Transformation of human mesenchymal cells and skin fibroblasts into hematopoietic cells.

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David M Harris

Full Text Available Patients with prolonged myelosuppression require frequent platelet and occasional granulocyte transfusions. Multi-donor transfusions induce alloimmunization, thereby increasing morbidity and mortality. Therefore, an autologous or HLA-matched allogeneic source of platelets and granulocytes is needed. To determine whether nonhematopoietic cells can be reprogrammed into hematopoietic cells, human mesenchymal stromal cells (MSCs and skin fibroblasts were incubated with the demethylating agent 5-azacytidine (Aza and the growth factors (GF granulocyte-macrophage colony-stimulating factor and stem cell factor. This treatment transformed MSCs to round, non-adherent cells expressing T-, B-, myeloid-, or stem/progenitor-cell markers. The transformed cells engrafted as hematopoietic cells in bone marrow of immunodeficient mice. DNA methylation and mRNA array analysis suggested that Aza and GF treatment demethylated and activated HOXB genes. Indeed, transfection of MSCs or skin fibroblasts with HOXB4, HOXB5, and HOXB2 genes transformed them into hematopoietic cells. Further studies are needed to determine whether transformed MSCs or skin fibroblasts are suitable for therapy.

Indications of hematopoietic stem cell transplantations and therapeutic strategies of accidental irradiations

International Nuclear Information System (INIS)

2003-01-01

Produced by a group of experts, this document first discusses the issue of accidental irradiations in terms of medical management. They notably outline the peculiar characteristics of these irradiations with respect to therapeutic irradiations. They agreed on general principles regarding casualty sorting criteria and process, and their medical treatment (systematic hematopoiesis stimulation, allogeneic transplantation of hematopoietic stem cells). They discuss some practical aspects of these issues: casualty sorting within a therapeutic perspective (actions to be performed within 48 hours), therapeutic strategies (support therapy, use of cytokines, and therapy by hematopoietic stem cell transplant). They state a set of recommendations regarding the taking into care and diagnosis, therapeutic strategies, research perspectives, and teaching

Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

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Catherine Weber

2012-01-01

Full Text Available Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG, and total body irradiation (TBI followed by an allogeneic hematopoietic stem cell transplant (HSCT for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Safety and Efficacy of Once-Daily Intravenous Busulfan in Allogeneic Transplantation: A Matched-Pair Analysis.

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Kako, Shinichi; Fujiwara, Shinichiro; Sato, Miki; Kimura, Shun-Ichi; Nakasone, Hideki; Ohashi, Kazuteru; Kawakita, Toshiro; Maeda, Tetsuo; Morishita, Takanobu; Suzuki, Ritsuro; Fukuda, Takahiro; Ichinohe, Tatsuo; Kurata, Mio; Atsuta, Yoshiko; Kanda, Yoshinobu

2018-04-19

Compared with 4-times-daily infusion of intravenous busulfan (ivBU4), the safety and efficacy of once-daily infusion of ivBU (ivBU1) has not been fully clarified. We have been routinely using ivBU1 in a conditioning regimen in adult patients with myeloid malignancy who undergo allogeneic hematopoietic stem cell transplantation. In this study, a total of 91 patients who received ivBU1 for 2 days (n = 18) or 4 days (n = 73) in our institutions were compared with 273 control patients who received ivBU4, who were matched for age, sex, performance status, disease risk, conditioning regimen, and donor type, selected from the database of the Japanese Society for Hematopoietic Cell Transplantation using optimal matching algorithms. One-year overall survival (56.8% versus 57.1%, P = .94), disease-free survival (51.6% versus 50.8%, P = .73), relapse rate (28.5% versus 26.2%, P = .94), nonrelapse mortality (19.9% versus 23.0%, P = .71), and the incidence of graft-versus-host disease were not significantly different between the ivBU1 and ivBU4 groups. In patients who received ivBU1, neutrophil recovery was slower (median days: 22 versus 17, P = .001), and the incidence of veno-occlusive disease was lower (2.6% versus 17.4%, P = .04). In conclusion, ivBU1 can be safely administered with clinical outcomes similar to those with ivBU4. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Estimating demand and unmet need for allogeneic hematopoietic cell transplantation in the United States using geographic information systems.

Science.gov (United States)

Besse, Kelsey L; Preussler, Jaime M; Murphy, Elizabeth A; Denzen, Ellen M; Lill, Michael C; Chell, Jeffrey W; Senneka, Mary K; Majhail, Navneet S; Williams, Eric P

2015-03-01

Allogeneic hematopoietic cell transplantation (HCT) is an increasingly used therapy for many patients with hematologic malignancies and other marrow failure or immune system disorders. The purpose of this study was to quantify and visualize both the demand and unmet need for HCT. HCT use for 2012 was described using the Center for International Blood and Marrow Transplant Research registry. Potential demand for HCT was calculated using 2012 SEER data and published literature for HCT-treatable conditions. Point locations of transplant centers were geocoded using geographic information system (GIS) software; Thiessen polygons were created to establish adult (age 20 to 74 years) and pediatric (age 0 to 19 years) market areas. Market-area population estimates were calculated using 2012 population estimates by age aggregated by census block. US market areas for HCTs were identified separately for transplant centers treating adult (n = 62) and pediatric patients (n = 52). Overall HCT demand among adults was 16,096, with an unmet need for HCTs of 10,276 patients. For pediatric patients, the total demand was 4,561, with an unmet need of 3,213 potential recipients. Evaluation of adult and pediatric market areas indicated that the largest unmet needs tended to be in areas with large populations. Market-area maps and statistics developed using GIS will help communicate the unmet need for HCT, inform policy, and assist transplant centers in planning for the anticipated growth in HCT use. Copyright © 2015 by American Society of Clinical Oncology.

Development of tumor-reactive T cells after nonmyeloablative allogeneic hematopoietic stem cell transplant for chronic lymphocytic leukemia.

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Nishida, Tetsuya; Hudecek, Michael; Kostic, Ana; Bleakley, Marie; Warren, Edus H; Maloney, David; Storb, Rainer; Riddell, Stanley R

2009-07-15

Allogeneic nonmyeloablative hematopoietic stem cell transplant (NM-HSCT) can result in durable remission of chronic lymphocytic leukemia (CLL). It is thought that the efficacy of NM-HSCT is mediated by recognition of tumor cells by T cells in the donor stem cell graft. We evaluated the development of CTLs specific for CLL after NM-HSCT to determine if their presence correlated with antitumor efficacy. Peripheral blood mononuclear cells obtained from 12 transplant recipients at intervals after NM-HSCT were stimulated in vitro with CLL cells. Polyclonal T-cell lines and CD8(+) T-cell clones were derived from these cultures and evaluated for lysis of donor and recipient target cells including CLL. The presence and specificity of responses was correlated with clinical outcomes. Eight of the 12 patients achieved remission or a major antitumor response and all 8 developed CD8(+) and CD4(+) T cells specific for antigens expressed by CLL. A clonal analysis of the CD8(+) T-cell response identified T cells specific for multiple minor histocompatibility (H) antigens expressed on CLL in six of the responding patients. A significant fraction of the CD8(+) T-cell response in some patients was also directed against nonshared tumor-specific antigens. By contrast, CLL-reactive T cells were not detected in the four patients who had persistent CLL after NM-HSCT, despite the development of graft-versus-host disease. The development of a diverse T-cell response specific for minor H and tumor-associated antigens expressed by CLL predicts an effective graft-versus-leukemia response after NM-HSCT.

Hematopoietic cell transplantation in Fanconi anemia: current evidence, challenges and recommendations.

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Ebens, Christen L; MacMillan, Margaret L; Wagner, John E

2017-01-01

Hematopoietic cell transplantation for Fanconi Anemia (FA) has improved dramatically over the past 40 years. With an enhanced understanding of the intrinsic DNA-repair defect and pathophysiology of hematopoietic failure and leukemogenesis, sequential changes to conditioning and graft engineering have significantly improved the expectation of survival after allogeneic hematopoietic cell transplantation (alloHCT) with incidence of graft failure decreased from 35% to 40% to <10%. Today, five-year overall survival exceeds 90% in younger FA patients with bone marrow failure but remains about 50% in those with hematologic malignancy. Areas covered: We review the evolution of alloHCT contributing to decreased rates of transplant related complications; highlight current challenges including poorer outcomes in cases of clonal hematologic disorders, alloHCT impact on endocrine function and intrinsic FA risk of epithelial malignancies; and describe investigational therapies for prevention and treatment of the hematologic manifestations of FA. Expert commentary: Current methods allow for excellent survival following alloHCT for FA associated BMF irrespective of donor hematopoietic cell source. Alternative curative approaches, such as gene therapy, are being explored to eliminate the risks of GVHD and minimize therapy-related adverse effects.

Busulfan, cyclophosphamide and fractionated total body irradiation as a conditioning regimen for allogeneic bone marrow transplantation in patients with non-lymphocytic hematopoietic malignancies

International Nuclear Information System (INIS)

Watanabe, Hiroshi

1996-01-01

Allogeneic bone marrow transplantation (BMT) with the conditioning regimen of 8 mg/kg of busulfan (BUS), 120 mg/kg of cyclophosphamide (CPM) and 10 Gy of total body irradiation (TBI) was evaluated in the patients with non-lymphocytic hematopoietic malignancies. The disease distribution of the 22 patients was as follows; 14 in the standard risk group (SRG), 8 in the high risk group (HRG). SRG included the patients with acute myeloid leukemia (AML) in the first complete remission, chronic myelogenous leukemia (CML) in chronic phase and myelodysplastic syndrome with refractory anemia, while HRG included the patients with refractory AML and CML in blastic phase. The median age of patients was 33 years old (y.o.), and the median observation period was 34.5 months No relapse occurred, but 8 patients (36%) died of various complications. Ail the patients who died of interstitial pneumonitis (4 cases) were 40 y.o. and more. Acute graft-versus-host disease (GvHD) and chronic GvHD were clinically controllable. The probability of disease-free survival rate at 5 years (5y-DFS) was 50.0% in overall patients. The 5y-DFS was 57.1% in HRG (7 cases), while 54.3% in SRG (13 cases) donated from the HLA identical siblings (20 cases). In these 13 patients in SRG, the 5y-DFS was 100% in patients under 40 y.o. (6 cases), while the probability of disease-free survival rate at 3 years was 68.6% and the 5y-DFS was 0% in patients over 40 y.o. (7 cases). Our data indicate that the conditioning regimen combining BUS, CPM and TBI for allogeneic BMT is promising for the treatment of the patients of HRG and the patients under 40 y.o. in SRG. (author)

Busulfan, cyclophosphamide and fractionated total body irradiation as a conditioning regimen for allogeneic bone marrow transplantation in patients with non-lymphocytic hematopoietic malignancies

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Watanabe, Hiroshi [Jikei Univ., Tokyo (Japan). School of Medicine

1996-11-01

Allogeneic bone marrow transplantation (BMT) with the conditioning regimen of 8 mg/kg of busulfan (BUS), 120 mg/kg of cyclophosphamide (CPM) and 10 Gy of total body irradiation (TBI) was evaluated in the patients with non-lymphocytic hematopoietic malignancies. The disease distribution of the 22 patients was as follows; 14 in the standard risk group (SRG), 8 in the high risk group (HRG). SRG included the patients with acute myeloid leukemia (AML) in the first complete remission, chronic myelogenous leukemia (CML) in chronic phase and myelodysplastic syndrome with refractory anemia, while HRG included the patients with refractory AML and CML in blastic phase. The median age of patients was 33 years old (y.o.), and the median observation period was 34.5 months No relapse occurred, but 8 patients (36%) died of various complications. Ail the patients who died of interstitial pneumonitis (4 cases) were 40 y.o. and more. Acute graft-versus-host disease (GvHD) and chronic GvHD were clinically controllable. The probability of disease-free survival rate at 5 years (5y-DFS) was 50.0% in overall patients. The 5y-DFS was 57.1% in HRG (7 cases), while 54.3% in SRG (13 cases) donated from the HLA identical siblings (20 cases). In these 13 patients in SRG, the 5y-DFS was 100% in patients under 40 y.o. (6 cases), while the probability of disease-free survival rate at 3 years was 68.6% and the 5y-DFS was 0% in patients over 40 y.o. (7 cases). Our data indicate that the conditioning regimen combining BUS, CPM and TBI for allogeneic BMT is promising for the treatment of the patients of HRG and the patients under 40 y.o. in SRG. (author)

Hematopoietic stem cell transplantation for isolated extramedullary relapse of acute lymphoblastic leukemia in children.

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Gabelli, Maria; Zecca, Marco; Messina, Chiara; Carraro, Elisa; Buldini, Barbara; Rovelli, Attilio Maria; Fagioli, Franca; Bertaina, Alice; Lanino, Edoardo; Favre, Claudio; Rabusin, Marco; Prete, Arcangelo; Ripaldi, Mimmo; Barberi, Walter; Porta, Fulvio; Caniglia, Maurizio; Santarone, Stella; D'Angelo, Paolo; Basso, Giuseppe; Locatelli, Franco

2018-06-13

Relapse of acute lymphoblastic leukemia (ALL) may occur in extramedullary sites, mainly central nervous system (CNS) and testis. Optimal post-remissional treatment for isolated extramedullary relapse (IEMR) is still controversial. We collected data of children treated with hematopoietic stem cell transplantation (HSCT) for ALL IEMR from 1990 to 2015 in Italy. Among 281 patients, 167 had a relapse confined to CNS, 73 to testis, 14 to mediastinum, and 27 to other organs. Ninety-seven patients underwent autologous HSCT, 79 received allogeneic HSCT from a matched family donor, 75 from a matched unrelated donor, and 30 from an HLA-haploidentical donor. The 10-year overall survival was 56% and was not influenced by gender, ALL blast immune-phenotype, age, site of relapse, duration of first remission, and type of HSCT. In multivariable analysis, the only prognostic factors were disease status at HSCT and year of transplantation. Patients transplanted in third or subsequent complete remission (CR) had a risk of death 2.3 times greater than those in CR2. Children treated after 2000 had half the risk of death than those treated before that year. Our results suggest that both autologous and allogeneic HSCT may be considered for the treatment of pediatric ALL IEMR after the achievement of CR2.

A randomized trial on the effect of a multimodal intervention on physical capacity, functional performance and quality of life in adult patients undergoing allogeneic SCT

DEFF Research Database (Denmark)

Jarden, M; Baadsgaard, M T; Hovgaard, D J

2009-01-01

The aim of this randomized controlled trial was to investigate the effect of a 4- to 6-week multimodal program of exercise, relaxation and psychoeducation on physical capacity, functional performance and quality of life (QOL) in allogeneic hematopoietic cell transplantation (allo-HSCT) adult...

Maternal T cells limit engraftment after in utero hematopoietic cell transplantation in mice

OpenAIRE

Nijagal, Amar; Wegorzewska, Marta; Jarvis, Erin; Le, Tom; Tang, Qizhi; MacKenzie, Tippi C.

2011-01-01

Transplantation of allogeneic stem cells into the early gestational fetus, a treatment termed in utero hematopoietic cell transplantation (IUHCTx), could potentially overcome the limitations of bone marrow transplants, including graft rejection and the chronic immunosuppression required to prevent rejection. However, clinical use of IUHCTx has been hampered by poor engraftment, possibly due to a host immune response against the graft. Since the fetal immune system is relatively immature, we h...

Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype.

Science.gov (United States)

Hsieh, Matthew M; Fitzhugh, Courtney D; Weitzel, R Patrick; Link, Mary E; Coles, Wynona A; Zhao, Xiongce; Rodgers, Griffin P; Powell, Jonathan D; Tisdale, John F

2014-07-02

Myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) is curative for children with severe sickle cell disease, but toxicity may be prohibitive for adults. Nonmyeloablative transplantation has been attempted with degrees of preparative regimen intensity, but graft rejection and graft-vs-host disease remain significant. To determine the efficacy, safety, and outcome on end-organ function with this low-intensity regimen for sickle cell phenotype with or without thalassemia. From July 16, 2004, to October 25, 2013, 30 patients aged 16-65 years with severe disease enrolled in this nonmyeloablative transplant study, consisting of alemtuzumab (1 mg/kg in divided doses), total-body irradiation (300 cGy), sirolimus, and infusion of unmanipulated filgrastim mobilized peripheral blood stem cells (5.5-31.7 × 10(6) cells/kg) from human leukocyte antigen-matched siblings. The primary end point was treatment success at 1 year after the transplant, defined as a full donor-type hemoglobin for patients with sickle cell disease and transfusion independence for patients with thalassemia. The secondary end points were the level of donor leukocyte chimerism; incidence of acute and chronic graft-vs-host disease; and sickle cell-thalassemia disease-free survival, immunologic recovery, and changes in organ function, assessed by annual brain imaging, pulmonary function, echocardiographic image, and laboratory testing. Twenty-nine patients survived a median 3.4 years (range, 1-8.6), with no nonrelapse mortality. One patient died from intracranial bleeding after relapse. As of October 25, 2013, 26 patients (87%) had long-term stable donor engraftment without acute or chronic graft-vs-host disease. The mean donor T-cell level was 48% (95% CI, 34%-62%); the myeloid chimerism levels, 86% (95% CI, 70%-100%). Fifteen engrafted patients discontinued immunosuppression medication with continued stable donor chimerism and no graft-vs-host disease. The normalized hemoglobin and

[Reduced intensity conditioning allogeneic hematopoietic stem cell transplantation in chronic lymphocytic leukemia (CLL) patients with the aberration of p53 gene].

Science.gov (United States)

Wang, Li; Miao, Kourong; Fan, Lei; Xu, Ji; Wu, Hanxin; Li, Jianyong; Xu, Wei

2016-04-01

To investigate the effectiveness and safety of reduced intensity conditioning allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT) in ultra high risk chronic lymphocytic leukemia (CLL) patients with the deletion of p53 to deepen the understanding of allo-HSCT in the treatment of CLL. In this retrospective study, a total of 4 ultra high risk CLL patients with the deletion of p53 in our center between July 2012 and Jan 2014 were enrolled. The RIC regimen was administered and the hematopoietic reconstitution, transplantation related mortality (TRM), overall survival (OS), progress free survival (PFS) were evaluated. We registered 4 patients with the median age of 56 years (49-61 years), including 3 males and 1 female. The median mononuclear cells (MNC) and CD34(+) cells were 6.54 (2.85-14.7) × 10(8)/kg (recipient body weight) and 5.81 (2.85-7.79) × 10(6)/kg (recipient body weight), respectively. The median time of the neutrophil recovery was 11 days (range of 9-12 days), and the median time of the platelet recovery 5.5 days (range of 0-11 days). Three patients (75%) attained a full donor chimerism at day 28 after transplantation and one (25%) got a mixed chimerism of donor and recipient. During the follow-up at a median time of 26.5 months (range of 21-39 months), 2 (50%) patients developed acute graft versus host disease (aGVHD) grade I and 2 (50%) patients got CMV infection. One patient got herpes zoster virus and EB virus infections. No transplantation related mortality was found in the 4 patients. One patient who was in partial response status progressed 5 months after transplantation, and the other 3 patients remained in durable remission after allo-HSCT. These results suggested that RIC allo-HSCT showed durable remission, good tolerance and acceptable toxicity, which could be a better option for the treatment of ultra high risk CLL patients with the deletion of p53 and was worth to be investigated and applied widely in future.

Oral Complications in Hematopoietic Stem Cell Recipients: The Role of Inflammation

Directory of Open Access Journals (Sweden)

T. M. Haverman

2014-01-01

Full Text Available Hematopoietic stem cell transplantation (HSCT is widely used as a potentially curative treatment for patients with various hematological malignancies, bone marrow failure syndromes, and congenital immune deficiencies. The prevalence of oral complications in both autologous and allogeneic HSCT recipients remains high, despite advances in transplant medicine and in supportive care. Frequently encountered oral complications include mucositis, infections, oral dryness, taste changes, and graft versus host disease in allogeneic HSCT. Oral complications are associated with substantial morbidity and in some cases with increased mortality and may significantly affect quality of life, even many years after HSCT. Inflammatory processes are key in the pathobiology of most oral complications in HSCT recipients. This review article will discuss frequently encountered oral complications associated with HSCT focusing on the inflammatory pathways and inflammatory mediators involved in their pathogenesis.

Donor genotype in the Interleukin-7 receptor α-chain predicts risk of graft-versus-host disease and cytomegalovirus infection after allogeneic hematopoietic stem cell transplantation

DEFF Research Database (Denmark)

Kielsen, Katrine; Enevold, Christian; Heilmann, Carsten

2018-01-01

The efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) is challenged by acute and chronic graft-versus-host disease (aGVHD and cGVHD) and viral infections due to long-lasting immunodeficiency. Interleukin-7 (IL-7) is a cytokine essential for de novo T cell generation in thymus.......1-3.8, P = 0.034) and with significantly increased risk of extensive cGVHD (HR = 2.0, 95% CI = 1.1-3.6, P = 0.025) after adjustment for potential risk factors. In addition, the TT genotype was associated with a higher risk of cytomegalovirus (CMV) infection post-transplant (HR = 2.4, 95% CI = 1.2-4.3, P.......7, 95% CI = 1.2-2.3, P = 0.0027) and increased treatment-related mortality (HR = 2.3, 95% CI = 1.3-4.0, P = 0.0047), but was not associated with the risk of relapse (P = 0.35). In conclusion, the IL-7Rα rs6897932 genotype of the donor is predictive of aGVHD and cGVHD, CMV infection, and mortality...

Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience.

Science.gov (United States)

Olsson, Richard F; Hagelberg, Stefan; Schiller, Bodil; Ringdén, Olle; Truedsson, Lennart; Åhlin, Anders

2016-06-01

Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

Comparison of survival outcome between donor types or stem cell sources for childhood acute myeloid leukemia after allogenic hematopoietic stem cell transplantation: A multicenter retrospective study of Study Alliance of Yeungnam Pediatric Hematology-oncology.

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Shim, Ye Jee; Lee, Jae Min; Kim, Heung Sik; Jung, Nani; Lim, Young Tak; Yang, Eu Jeen; Hah, Jeong Ok; Lee, Young-Ho; Chueh, Hee Won; Lim, Jae Young; Park, Eun Sil; Park, Jeong A; Park, Ji Kyoung; Park, Sang Kyu

2018-06-19

We compared transplant outcomes between donor types and stem cell sources for childhood acute myeloid leukemia (AML). The medical records of children with AML in the Yeungnam region of Korea from January 2000 to June 2017 were reviewed. In all, 76 children with AML (male-to-female ratio = 46:30) received allogenic hematopoietic stem cell transplantation (allo-HSCT). In total, 29 patients received HSCT from either a matched-related donor or a mismatched-related donor, 32 patients received an unrelated donor, and 15 patients received umbilical cord blood. In term of stem cell sources, bone marrow was used in 15 patients and peripheral blood in 46 patients. For all HSCT cases, the 5-year overall survival (OS) was 73.1% (95% CI: 62.7-83.5) and the 5-year event-free survival (EFS) was 66.1% (95% CI: 54.5-77.7). There was no statistical difference in 5-year OS according to the donor types or stem cell sources (P = .869 and P = .911). There was no statistical difference in 5-year EFS between donor types or stem cell sources (P = .526 and P = .478). For all HSCT cases, the 5-year relapse rate was 16.1% (95% CI: 7.3-24.9) and the 5-year non-relapse mortality (NRM) was 13.3% (95% CI: 5.1-21.5). There was no statistical difference in the 5-year relapse rate according to the donor types or stem cell sources (P = .971 and P = .965). There was no statistical difference in the 5-year NRM between donor types or stem cell sources (P = .461 and P = .470). © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Myositis in Griscelli syndrome type 2 treated with hematopoietic cell transplantation

DEFF Research Database (Denmark)

Born, Alfred Peter; Müller, Klaus; Marquart, Hanne Vibeke

2010-01-01

Griscelli syndrome is an autosomal recessive disorder characterized by pigmentary dilution and is occasionally associated with a hemophagocytic syndrome (type 2). We present a 13-year-old girl with Griscelli syndrome type 2, who developed a hemophagocytic syndrome along with marked muscle weakness...... and elevated plasma creatine kinase. Muscle biopsy showed massive inflammatory changes in some fascicles, while other fascicles were relatively spared. Clinical symptoms and biopsy changes resolved after immunosuppression and allogeneic hematopoietic cell transplantation. Our results suggest that muscle...

Total lymphoid irradiation based conditioning for hematopoietic stem cell transplantation in severe aplastic anemia

International Nuclear Information System (INIS)

Lee, Yun Hee; Kim, Ji Yoon; Choi, Byung Ock; Ryu, Mi Ryeong; Chung, Su Mi

2012-01-01

To retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused. Between 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate. With a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT. In our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.

Total lymphoid irradiation based conditioning for hematopoietic stem cell transplantation in severe aplastic anemia

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Lee, Yun Hee; Kim, Ji Yoon; Choi, Byung Ock; Ryu, Mi Ryeong; Chung, Su Mi [Dept. of Radiation Oncology, The Catholic University of Korea College of Medicine, Seoul (Korea, Republic of)

2012-12-15

To retrospectively evaluate the outcome and toxicity of total lymphoid irradiation (TLI) based conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) patients who experienced an engraftment failure from prior HSCT or were heavily transfused. Between 1995 and 2006, 20 SAA patients received TLI for conditioning of HSCT. All patients were multi-transfused or had long duration of disease. Fifteen (75%) patients had graft failure from prior HSCT. In 18 (90%) patients, the donors were human leukocyte antigen identical siblings. The stem cell source was the peripheral blood stem cell in 15 (75%) patients. The conditioning regimen was composed of antithymocyte globulin plus TLI with a median dose of 750 cGy in 1 fraction. The graft-versus-host disease (GVHD) prophylaxis used cyclosporine with methotrexate. With a median follow-up of 10.8 years, graft failures developed in 6 patients. Among them, 3 patients received their third HSCT to be engrafted finally. The Kaplan-Meier overall survival rate was 85.0% and 83.1% at 5 and 10 years, respectively. The incidence of acute and chronic GVHD was 20% and 20%, respectively. None of the patients have developed a malignancy after HSCT. In our study, TLI based conditioning in allogeneic HSCT was feasible with acceptable rates of GVHD in SAA patients who experienced graft failure from prior HSCT or was at a high risk of graft rejection. We achieved relatively better results of engraftment and survival with a long term follow-up.

Establishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation.

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Marilène Binsfeld

Full Text Available Multiple myeloma (MM is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT remains controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice, with concomitant development of chronic graft-versus-host disease (GvHD.Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received an allogeneic (B10.D2 donor or autologous (Balb/cJ donor transplant 30 days later. We observed a GvM effect in 94% of the allogeneic transplanted mice, as the luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma progression. Lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect. In addition, the treated mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggested the involvement of effector memory CD4 and CD8 T cells associated with the GvM response. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR Vβ spectratyping analysis identified Vβ families within CD4 and CD8 T cells, which were associated with both GvM effects and GvHD, whereas other Vβ families within CD4 T cells were associated exclusively with either GvM or GvHD responses.We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first murine GvM model using immunocompetent mice that develop MM which closely resembles human MM disease and that are treated after disease establishment with an allo-SCT. Importantly, using TCR Vβ spectratyping, we also demonstrated the presence of GvM unique responses

The Fourth Nagoya International Blood and Marrow Transplantation Symposium: new horizons in allogeneic hematopoietic cell transplantation--2001 revolution.

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Sao, Hiroshi; Morishita, Yoshihisa

2002-02-01

In this symposium, we saw new horizons in allogeneic transplantation. Are these truly revolutionary? We do not yet know the answer. However, there is no question about the importance of allogeneic T cells. T cells are much more powerful than any pharmacological drug man has ever generated. The question is, how do we take the most advantage of their potential. Every participant was encouraged to search for good answers to this question until the next meeting.

FIFTY YEARS OF MELPHALAN USE IN HEMATOPOIETIC STEM CELL TRANSPLANTATION

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Bayraktar, Ulas D.; Bashir, Qaiser; Qazilbash, Muzaffar; Champlin, Richard E.; Ciurea, Stefan O.

2015-01-01

Melphalan remains the most widely used agent in preparative regimens for hematopoietic stem-cell transplantation. From its initial discovery more than 50 years ago, it has been gradually incorporated in the conditioning regimens for both autologous and allogeneic transplantation due to its myeloablative properties and broad antitumor effects as a DNA alkylating agent. Melphalan remains the mainstay conditioning for multiple myeloma and lymphomas; and has been used successfully in preparative regimens of a variety of other hematological and non-hematological malignancies. The addition of newer agents to conditioning like bortezomib or lenalidomide for myeloma, or clofarabine for myeloid malignancies, may improve antitumor effects for transplantation, while in combination with alemtuzumab may represent a backbone for future cellular therapy due to reliable engraftment and low toxicity profile. This review summarizes the development and the current use of this remarkable drug in hematopoietic stem-cell transplantation. PMID:22922522

Experimental study on relationship between expression of SDF-1 and homing of hematopoietic cells

International Nuclear Information System (INIS)

Sun Suping; Cai Jianming; Xiang Yingsong; Zhao Fang; Huang Dingde; Gao Jianguo; Yang Rujun

2002-01-01

Objective: To investigate the role of chemo-attractant SDF-1 in of homing hematopoietic cells. Methods: A mouse allogeneic bone marrow transplantation model and double staining of immunohistochemistry were used in this study. Relationship between expression of chemo-attractant SDF-1 and of homing hematopoietic cells was observed. Results: In bone marrow, SDF-1 was mainly expressed at sites near endosteum, in microvessel endothelium, osteocytes and around donor cells. Contrast to non-irradiation group, SDF-1 was significantly expressed by osteocytes, and at sites near endosteum in the irradiation group, suggesting that pretreatment with irradiation might enhance secretion of SDF-1 by bone marrow stromal cells and SDF-1 could have a close relation with homing cells. Conclusion: Pretreatment with irradiation might be one of the stimulating factors significantly increasing the level of SDF-1 produced by bone marrow stromal cells and the chemo-attractant SDF-1 could play an important role in homing of hematopoietic cells

RANTES polymorphisms and the risk of graft-versus-host disease in human leukocyte antigen-matched sibling allogeneic hematopoietic stem cell transplantation.

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Shin, Dong-Yeop; Kim, Inho; Kim, Jin Hee; Lee, Yun-Gyoo; Kang, Eun Joo; Cho, Hyeon Jin; Lee, Kyung-Hun; Kim, Hye Jin; Park, Eun-Hee; Lee, Jong-Eun; Bae, Ji-Yeon; See, Cha Ja; Yoon, Sung-Soo; Park, Sung Sup; Han, Kyou-Sup; Park, Myoung Hee; Hong, Yun-Chul; Park, Seonyang; Kim, Byoung Kook

2013-01-01

We investigated the association between RANTES (regulated upon activation, normal T cell expressed and secreted) polymorphisms and clinical outcomes in patients treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Three RANTES gene polymorphisms, i.e., -403G/A (rs2107538), -28C/G (rs2280788) and In1.1T/C (rs2280789), were genotyped, and the effects of the genotypes and haplotypes of RANTES on clinical outcomes were analyzed. The competing risk regression analysis was used to investigate the relationship between the polymorphisms and the cumulative risk of graft-versus-host disease (GVHD). An AGC haplotype in a recessive model showed significant harmful effects on the cumulative risk of acute GVHD and relapse-free survival (adjusted hazard ratios 2.42 and 2.71, 95% confidence intervals 1.29-4.55 and 1.30-5.64; p = 0.018 and 0.024, respectively), whereas a GCT haplotype did not. RANTES polymorphisms were not significantly associated with overall survival and the risk of chronic GVHD. This study suggests that RANTES polymorphisms might be associated with the occurrence of acute GVHD rather than of chronic GVHD and also of relapse-free survival in the patients treated with allo-HSCT. Further larger prospective investigations are needed to establish the role of RANTES polymorphisms in patients treated with allo-HSCT. Copyright © 2012 S. Karger AG, Basel.

Comparative analysis of autologous blood transfusion and allogeneic blood transfusion in surgical patients

OpenAIRE

Long, Miao-Yun; Liu, Zhong-Han; Zhu, Jian-Guang

2014-01-01

Objective: To investigate application effects of autologous blood transfusion and allogeneic blood transfusion in surgically treated patients receiving spine surgery, abdomen surgery and ectopic pregnancy surgery. Methods: 130 patients who would undergo selective operations were divided into autologous transfusion group and allogeneic transfusion group. Both groups received the same anesthesia, and there was no significant difference in transfusion volume or fluid infusion volume. Results: Th...

Cytogenetic Evolution in Myeloid Neoplasms at Relapse after Allogeneic Hematopoietic Cell Transplantation: Association with Previous Chemotherapy and Effect on Survival.

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Ertz-Archambault, Natalie; Kosiorek, Heidi; Slack, James L; Lonzo, Melissa L; Greipp, Patricia T; Khera, Nandita; Kelemen, Katalin

2017-05-01

Cytogenetic evolution (CGE) in patients with myeloid neoplasms who relapsed after an allogeneic (allo) hematopoietic cell transplantation (HCT) has been evaluated by only few studies. The effect of the CGE on survival of relapsed allo-HCT recipients is not clear. The effect of previously received chemotherapy to induce CGE in this patient population has not been studied. The aims of our study are to (1) characterize the patterns of cytogenetic change in patients with myeloid neoplasms who relapsed after an allo-HCT, (2) evaluate the effect of CGE on survival, and (3) explore the association of CGE with previous chemotherapy (including the lines of salvage therapy, type of induction, and conditioning therapy). Of 49 patients with a myeloid malignancy (27 acute myeloid leukemia [AML], 19 myelodysplastic syndrome [MDS]/myeloproliferative neoplasm [MPN], and 3 chronic myelogenous leukemia) who relapsed after an allo-HCT, CGE was observed in 25 (51%), whereas 24 patients had unchanged cytogenetic findings at relapse. The CGE group carried more cytogenetic abnormalities at original diagnosis. The most frequent cytogenetic change was the acquisition of 3 or more new chromosomal abnormalities followed by acquisition of unbalanced abnormalities, aneuploidy, and emergence of apparently new clones unrelated to the original clone. The CGE cohort had higher proportion of MDS and MPN and fewer patients with de novo AML. Disease risk assessment category showed a trend to higher frequency of high-risk patients in the CGE group, though the difference was not statistically significant. Time from diagnosis to transplantation and time from transplantation to relapse were not different between the CGE and non-CGE groups. CGE and non-CGE cohorts had similar exposures to salvage therapy and to induction chemotherapy, as well as similar conditioning regimens; thus, no particular type of chemotherapy emerged as a predisposing factor to CGE. CGE was associated with significantly shortened

Pilot study of comprehensive geriatric assessment (CGA) in allogeneic transplant: CGA captures a high prevalence of vulnerabilities in older transplant recipients.

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Muffly, Lori S; Boulukos, Melissa; Swanson, Kate; Kocherginsky, Masha; Cerro, Paula Del; Schroeder, Linda; Pape, Lisa; Extermann, Martine; Van Besien, Koen; Artz, Andrew S

2013-03-01

Comprehensive geriatric assessment (CGA) is frequently used in oncology to measure the health status of older adults with cancer, but it has not been studied in allogeneic hematopoietic cell transplantation (HCT). We conducted a prospective pilot study of CGA in allogeneic HCT recipients aged ≥50 years to examine the prevalence of vulnerabilities in this population. Patients aged ≥50 years eligible for HCT were enrolled. CGA consisted mainly of self-reported, performance-based, and chart-extracted measures evaluating domains of comorbidity, physical and mental function, frailty, disability, and nutrition. Of 238 eligible patients, 166 completed CGA and underwent HCT. Only 1% had a Zubrod Performance Status score >1; 44% had high comorbidity defined by the Hematopoietic Cell Transplantation Comorbidity Index, and 66% had high comorbidity defined by the Cumulative Illness Rating Scale-Geriatrics. The presence of additional vulnerability was frequent. Disability was present in 40% by Instrumental Activities of Daily Living. Self-reported physical and mental function were significantly lower than population age group norms, 58% were pre-frail, and 25% were frail. Among those with Zubrod Performance Status score of 0, 28% demonstrated disability, 58% were pre-frail, 15% were frail, 35% reported low physical function, and 55% reported low mental function. CGA uncovers a substantial prevalence of undocumented impairments in functional status, frailty, disability, and mental health in older allogeneic HCT recipients. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

RESULTS OF HEMATOPOIETIC CELL TRANSPLANTATION IN PEDIATRIC LEUKEMIA

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A. Mousavi

2008-05-01

Full Text Available Hematopoietic cell transplantation (HCT is an accepted treatment for acute myeloid leukemia (AML in first remission, the treatment of choice for chronic myeloid leukemia (CML and high risk groups of ALL who relapse with conventional chemotherapy. We assessed results of HCT for pediatric leukemia in our center. A total of 92 children, 63 with diagnose of AML, 23 with ALL and 6 with CML received allogeneic transplantation from HLA full matched siblings (57.6% and autologous transplantation (42.4%. Source of hematopoietic cells were peripheral blood 83.7%, bone marrow 15.2% and cord blood 1.6%. The median transplanted nucleated cells were 6.4 ± 4.7 ×108 /Kg (body weight of patients and mononuclear cells were 5.5 ± 2.9×108/Kg. The most common conditioning regimens were cyclophosphamide + busulfan. Prophylaxis regimen for GVHD was cyclosporin ± methotrexate. GVHD occurred in 50 (54.3% patients. Eighty five of children had engraftment, 26 (28.6% relapsed and 57 (62% are alive. The most common cause of death was relapse (68.6%. Five years overall survival of patients with AML and ALL were 49% and 44% respectively and disease free survival of them were 52% and 49%. One year overall survival and disease free survival of CML was 57%. Overall survival increased with increasing age of patients at transplantation time (P = 0.06. Longer survival significantly related to earlier WBC and platelet recovery (P < 0.0001 and P = 0.006 respectively. Considering acceptable overall and disease free survival of patients after HCT, we concluded that is a good modality in treatment of leukemia of children.

Immune reconstitution after allogeneic hematopoietic stem cell transplantation in children: a single institution study of 59 patients

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Hyun O Kim

2013-01-01

Full Text Available &lt;b&gt;Purpose:&lt;/b&gt; Lymphocyte subset recovery is an important factor that determines the success of hematopoietic stem cell transplantation (HSCT. Temporal differences in the recovery of lymphocyte subsets and the factors influencing this recovery are important variables that affect a patient's posttransplant immune reconstitution, and therefore require investigation. &lt;b&gt;Methods:&lt;/b&gt; The time taken to achieve lymphocyte subset recovery and the factors influencing this recovery were investigated in 59 children who had undergone HSCT at the Department of Pediatrics, The Catholic University of Korea Seoul St. Mary's Hospital, and who had an uneventful follow-up period of at least 1 year. Analyses were carried out at 3 and 12 months post-transplant. An additional study was performed 1 month post-transplant to evaluate natural killer (NK cell recovery. The impact of preand post-transplant variables, including diagnosis of Epstein-Barr virus (EBV DNAemia posttransplant,on lymphocyte recovery was evaluated. &lt;b&gt;Results:&lt;/b&gt; The lymphocyte subsets recovered in the following order: NK cells, cytotoxic T cells, B cells,and helper T cells. At 1 month post-transplant, acute graft-versus-host disease was found to contribute significantly to the delay of CD16+/56+ cell recovery. Younger patients showed delayed recovery of both CD3+/CD8+ and CD19+ cells. EBV DNAemia had a deleterious impact on the recovery of both CD3+ and CD3+/CD4+ lymphocytes at 1 year post-transplant. &lt;b&gt;Conclusion:&lt;/b&gt; In our pediatric allogeneic HSCT cohort, helper T cells were the last subset to recover. Younger age and EBV DNAemia had a negative impact on the post-transplant recovery of T cells and B cells.

Assessment of Impact of HLA Type on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia.

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Hill, Brian T; Ahn, Kwang Woo; Hu, Zhen-Huan; Aljurf, Mahmoud; Beitinjaneh, Amer; Cahn, Jean-Yves; Cerny, Jan; Kharfan-Dabaja, Mohamed A; Ganguly, Siddhartha; Ghosh, Nilanjan; Grunwald, Michael R; Inamoto, Yoshihiro; Kindwall-Keller, Tamila; Nishihori, Taiga; Olsson, Richard F; Saad, Ayman; Seftel, Matthew; Seo, Sachiko; Szer, Jeffrey; Tallman, Martin; Ustun, Celalettin; Wiernik, Peter H; Maziarz, Richard T; Kalaycio, Matt; Alyea, Edwin; Popat, Uday; Sobecks, Ronald; Saber, Wael

2018-03-01

Chronic lymphocytic leukemia (CLL) is a common hematologic malignancy with many highly effective therapies. Chemorefractory disease, often characterized by deletion of chromosome 17p, has historically been associated with very poor outcomes, leading to the application of allogeneic hematopoietic stem cell transplantation (allo-HCT) for medically fit patients. Although the use of allo-HCT has declined since the introduction of novel targeted therapy for the treatment of CLL, there remains significant interest in understanding factors that may influence the efficacy of allo-HCT, the only known curative treatment for CLL. The potential benefit of transplantation is most likely due to the presence of alloreactive donor T cells that mediate the graft-versus-leukemia (GVL) effect. The recognition of potentially tumor-specific antigens in the context of class I and II major histocompatibility complex on malignant B lymphocytes by donor T cells may be influenced by subtle differences in the highly polymorphic HLA locus. Given previous reports of specific HLA alleles impacting the incidence of CLL and the clinical outcomes of allo-HCT for CLL, we sought to study the overall survival and progression-free survival of a large cohort of patients with CLL who underwent allo-HCT from fully HLA-matched related and unrelated donors at Center for International Blood and Marrow Transplant Research transplantation centers. We found no statistically significant association of allo-HCT outcomes in CLL based on previously reported HLA combinations. Additional study is needed to further define the immunologic features that portend a more favorable GVL effect after allo-HCT for CLL. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Characteristic patterns of relapse after allogeneic hematopoietic SCT for adult T-cell leukemia-lymphoma: a comparative study of recurrent lesions after transplantation and chemotherapy by the Nagasaki Transplant Group.

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Itonaga, H; Sawayama, Y; Taguchi, J; Honda, S; Taniguchi, H; Makiyama, J; Matsuo, E; Sato, S; Ando, K; Imanishi, D; Imaizumi, Y; Yoshida, S; Hata, T; Moriuchi, Y; Fukushima, T; Miyazaki, Y

2015-04-01

Allogeneic hematopoietic SCT (allo-SCT) is a promising therapy that may provide long-term durable remission for adult T-cell leukemia-lymphoma (ATL) patients; however, the incidence of relapse associated with ATL remains high. To determine the clinical features of these patients at relapse, we retrospectively analyzed tumor lesions in 30 or 49 patients who relapsed following allo-SCT or chemotherapy (CHT), respectively, at three institutions in Nagasaki prefecture between 1997 and 2011. A multivariate analysis revealed that the development of abnormal lymphocytes in the peripheral blood of patients at relapse was less frequent after allo-SCT than after CHT (PSCT (P=0.014). Lesions were more frequently observed in the central nervous systems of patients who relapsed with new lesions only (P=0.005). Thus, the clinical manifestation of relapsed ATL was slightly complex, especially in post-transplant patients. Our results emphasized the need to develop adoptive modalities for early and accurate diagnoses of relapsed ATL.

Vascular and perivascular niches, but not the osteoblastic niche, are numerically restored following allogeneic hematopoietic stem cell transplantation in patients with aplastic anemia.

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Wu, Liangliang; Mo, Wenjian; Zhang, Yuping; Zhou, Ming; Li, Yumiao; Zhou, Ruiqing; Xu, Shiling; Pan, Shiyi; Deng, Hui; Mao, Ping; Wang, Shunqing

2017-07-01

Bone marrow (BM) niches, including the osteoblastic, vascular, and perivascular niches, are numerically impaired in patients with aplastic anemia (AA). It remains unclear whether these niches are numerically restored in AA patients after allogenic hematopoietic stem cell transplantation (allo-HSCT). To investigate changes in BM niches, we monitored 52 patients with AA who had undergone allo-HSCT and performed immunohistochemical studies of BM niches using antibodies against CD34, CD146, and osteopontin. After allo-HSCT, patients with AA exhibited a remarkable increase in the number of cellular elements in the BM niches, including the vascular and perivascular cells. However, no significant differences in endosteal cells were detected. We explored the cause of this restoration by analyzing the origin of BM mesenchymal stem cells (BM-MSCs) and the expression of cytokines in BM plasma. STR-PCR revealed that the BM-MSCs were derived from the host, not the donor. In addition, significantly elevated levels of vascular endothelial growth factor (VEGF) were found after allo-HSCT. Our data indicates that vascular and perivascular niches are numerically restored, but the endosteal niche remains numerically impaired in patients with AA after allo-HSCT, and that levels of VEGF, but not donor-derived BM-MSCs, may correlate with the restoration of BM niches.

Analysis of the results of allogeneic hematopoietic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair

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Ye. V. Kuzmich

2015-01-01

Full Text Available HLA matching of the donor / recipient pair is a major factor associated with the outcome of allogeneic stem cell transplantation. In the presentstudy we analyzed the risk of severe acute graft-versus-host disease, graft failure, 2.year overall survival of the patients after allogeneic stem cell transplantation depending on HLA matching of the unrelated donor / recipient pair.

Importance of killer immunoglobulin-like receptors in allogeneic hematopoietic stem cell transplantation

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Danilo Santana Alessio Franceschi

2011-01-01

Full Text Available Hematopoietic stem cell transplantation is the treatment of choice for many hematologic diseases, such as multiple myeloma, bone marrow aplasia and leukemia. Human leukocyte antigen (HLA compatibility is an important tool to prevent post-transplant complications such as graft rejection and graft-versus-host disease, but the high rates of relapse limit the survival of transplant patients. Natural Killer cells, a type of lymphocyte that is a key element in the defense against tumor cells, cells infected with viruses and intracellular microbes, have different receptors on their surfaces that regulate their cytotoxicity. Killer immunoglobulin-like receptors are the most important, interacting consistently with human leukocyte antigen class I molecules present in other cells and thus controlling the activation of natural killer cells. Several studies have shown that certain combinations of killer immunoglobulin-like receptors and human leukocyte antigens (in both donors and recipients can affect the chances of survival of transplant patients, particularly in relation to the graft-versusleukemia effect, which may be associated to decreased relapse rates in certain groups. This review aims to shed light on the mechanisms and effects of killer immunoglobulin-like receptors - human leukocyte antigen associations and their implications following hematopoietic stem cell transplantation, and to critically analyze the results obtained by the studies presented herein.

Graft-versus-Leukemia Effect Following Hematopoietic Stem Cell Transplantation for Leukemia

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Anne M. Dickinson

2017-06-01

Full Text Available The success of hematopoietic stem cell transplantation (HSCT lies with the ability of the engrafting immune system to remove residual leukemia cells via a graft-versus-leukemia effect (GvL, caused either spontaneously post-HSCT or via donor lymphocyte infusion. GvL effects can also be initiated by allogenic mismatched natural killer cells, antigen-specific T cells, and activated dendritic cells of leukemic origin. The history and further application of this GvL effect and the main mechanisms will be discussed and reviewed in this chapter.

Hematopoietic chimerism and transplantation tolerance: a role for regulatory T cells

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Lise ePasquet

2011-12-01

Full Text Available The major obstacle in transplantation medicine is rejection of donor tissues by the host’s immune system. Immunosuppressive drugs can delay but not prevent loss of transplants, and their efficiency is strongly impacted by inter-individual pharmacokinetic differences. Moreover, due to the global immunosuppression induced and to the broad distribution of their targets amongst human tissues, these drugs have severe side effects. Induction of donor-specific non-responsiveness (i.e. immunological tolerance to transplants would solve these problems and would substantially ameliorate patients’ quality of life. It is widely believed that bone marrow or hematopoietic stem cell transplantation, and resulting (mixed hematopoietic chimerism, invariably leads to immunological tolerance to organs of the same donor. A careful analysis of the literature, reviewed here, indeed shows that chimerism consistently prolongs allograft survival. However, in absence of additional conditioning leading to the development of active regulatory mechanisms, it does not prevent chronic rejection. A central role for active tolerance in transplantation-tolerance is also supported by recent data showing that genuine immunological tolerance to organ allografts can be achieved by combining induction of hematopoietic chimerism with infusion of regulatory T lymphocytes. Therefore, conditioning regimens that lead to the establishment of hematopoietic chimerism plus active regulatory mechanisms appear required for induction of genuine tolerance to allogeneic grafts.

Intrathymic injection of hematopoietic progenitor cells establishes functional T cell development in a mouse model of severe combined immunodeficiency

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Andrea Z. Tuckett

2017-05-01

Full Text Available Abstract Background Even though hematopoietic stem cell transplantation can be curative in patients with severe combined immunodeficiency, there is a need for additional strategies boosting T cell immunity in individuals suffering from genetic disorders of lymphoid development. Here we show that image-guided intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice is feasible and facilitates the generation of functional T cells conferring protective immunity. Methods Hematopoietic stem and progenitor cells were isolated from the bone marrow of healthy C57BL/6 mice (wild-type, Luciferase+, CD45.1+ and injected intravenously or intrathymically into both male and female, young or aged NOD-scid IL2rγnull recipients. The in vivo fate of injected cells was analyzed by bioluminescence imaging and flow cytometry of thymus- and spleen-derived T cell populations. In addition to T cell reconstitution, we evaluated mice for evidence of immune dysregulation based on diabetes development and graft-versus-host disease. T cell immunity following intrathymic injection of hematopoietic stem and progenitor cells in NOD-scid IL2rγnull mice was assessed in a B cell lymphoma model. Results Despite the small size of the thymic remnant in NOD-scid IL2rγnull mice, we were able to accomplish precise intrathymic delivery of hematopoietic stem and progenitor cells by ultrasound-guided injection. Thymic reconstitution following intrathymic injection of healthy allogeneic hematopoietic cells was most effective in young male recipients, indicating that even in the setting of severe immunodeficiency, sex and age are important variables for thymic function. Allogeneic T cells generated in intrathymically injected NOD-scid IL2rγnull mice displayed anti-lymphoma activity in vivo, but we found no evidence for severe auto/alloreactivity in T cell-producing NOD-scid IL2rγnull mice, suggesting that immune dysregulation is not a major concern

Does defibrotide prophylaxis decrease the risk of acute graft versus host disease following allogeneic hematopoietic cell transplantation?

Science.gov (United States)

Tekgündüz, Emre; Kaya, Ali Hakan; Bozdağ, Sinem Civriz; Koçubaba, Şerife; Kayıkçı, Ömür; Namdaroğlu, Sinem; Uğur, Bilge; Akpınar, Seval; Batgi, Hikmetullah; Bekdemir, Filiz; Altuntaş, Fevzi

2016-02-01

There is some preliminary evidence, that veno-occlusive disease prophylaxis with defibrotide (DF) may also have a role in decreasing risk of acute graft-versus-host disease (aGvHD) by preventing tissue damage. In this study, we aimed to investigate the role of DF prophylaxis on the development of aGvHD at D+180. One hundred ninety-five consecutive adult patients receiving allogeneic HCT were retrospectively evaluated in 3 groups: no DF, DF/post-HCT (DF D+1 to D+14) and DF/pre-HCT (DF for 14 days concurrently with conditioning). The total (p: 0.057) and grades III/IV (p: 0.051) aGvHD rates at D+180 were 46.5%, 40%, 25.5% and 15.5%, 11.2%, 0% in patients on no DF, DF/post-HCT and DF/pre-HCT. DF may have a role in decreasing incidence and severity of aGvHD, especially if used concurrently with conditioning regimen. Copyright © 2016 Elsevier Ltd. All rights reserved.

[Results of hematopoietic stem cell transplantation in hemoglobinopathies: thalassemia major and sickle cell disease].

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Hladun, R; Elorza, I; Olivé, T; Dapena, J L; Llort, A; Sánchez de Toledo, J; Díaz de Heredia, C

2013-08-01

The prevalence of hemoglobinopathies in Spain is increasing as a result of immigration. Thalassemia major presents with chronic hemolytic anemia that requires regular red blood cell transfusions within the first year of life. Patients with sickle cell disease suffer from chronic anemia, vasculopathy and progressive damage in almost any organ. There is decreased life expectancy in both conditions. Allogeneic hematopoietic stem cell transplantation represents the only potentially curative option. Seventeen patients (fourteen thalassemia major, and three sickle cell disease) underwent allogeneic hematopoietic stem cell transplantations. In the thalassemia group, nine donors were HLA-geno-identical siblings, two were partially matched related donors (one HLA allele mismatch), and three unrelated donors. All three patients with sickle cell disease were transplanted from HLA-geno-identical siblings. The source of stem cells was bone marrow in sixteen cases. Median patient age at transplant was six years (range: 1-16) in the thalassemia group, and twelve years (range: 8-15) in the sickle cell disease group. The graft was successful in all patients. Secondary graft rejection was observed in two thalassemia patients rendering them dependent on blood transfusions. Complete chimerism was observed in thirteen patients and, although mixed chimerism occurred in two, with all of them showing normal hemoglobin levels after transplantation and not requiring further transfusion support. Patients affected by sickle cell disease did not present with new vaso-occlusive crises, and stabilization of pulmonary and neurological function was observed. Chronic graft-versus-host disease was detected in three patients affected by thalassemia, and hypogonadotrophic hypogonadism in five patients. We conclude that for thalassemia major and sickle cell disease, allogenic hematopoietic stem cell transplantation from HLA-geno-identical siblings offers a high probability of complication-free survival

Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

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Kim, Ji Hyun [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Stein, Anthony [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Tsai, Nicole [Department of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Schultheiss, Timothy E. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Palmer, Joycelynne [Department of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Liu, An [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Rosenthal, Joseph [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Department of Pediatrics, City of Hope National Medical Center, Duarte, California (United States); Forman, Stephen J. [Department of Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, California (United States); Wong, Jeffrey Y.C., E-mail: jwong@coh.org [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States)

2014-05-01

Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk.

Extramedullary Relapse Following Total Marrow and Lymphoid Irradiation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation

International Nuclear Information System (INIS)

Kim, Ji Hyun; Stein, Anthony; Tsai, Nicole; Schultheiss, Timothy E.; Palmer, Joycelynne; Liu, An; Rosenthal, Joseph; Forman, Stephen J.; Wong, Jeffrey Y.C.

2014-01-01

Purpose: Approximately 5% to 20% of patients who undergo total body irradiation (TBI) in preparation for hematopoietic cell transplantation (HCT) can develop extramedullary (EM) relapse. Whereas total marrow and lymphoid irradiation (TMLI) provides a more conformally targeted radiation therapy for patients, organ sparing has the potential to place the patient at a higher risk for EM relapse than TBI. This study evaluated EM relapse in patients treated with TMLI at our institution. Methods and Materials: Patients eligible for analysis had been enrolled in 1 of 3 prospective TMLI trials between 2006 and 2012. The TMLI targeted bones, major lymph node chains, liver, spleen, testes, and brain, using image-guided tomotherapy with total dose ranging from 12 to 15 Gy. Results: A total of 101 patients with a median age of 47 years were studied. The median follow-up was 12.8 months. Incidence of EM relapse and bone marrow (BM) relapse were 12.9% and 25.7%, respectively. Of the 13 patients who had EM relapse, 4 also had BM relapse, and 7 had EM disease prior to HCT. There were a total of 19 EM relapse sites as the site of initial recurrence: 11 soft tissue, 6 lymph node, 2 skin. Nine of these sites were within the target region and received ≥12 Gy. Ten initial EM relapse sites were outside of the target region: 5 sites received 10.1 to 11.4 Gy while 5 sites received <10 Gy. Pretransplantation EM was the only significant predictor of subsequent EM relapse. The cumulative incidence of EM relapse was 4% at 1 year and 11.4% at 2 years. Conclusions: EM relapse incidence was as frequent in regions receiving ≥10 Gy as those receiving <10 Gy. EM relapse rates following TMLI that included HCT regimens were comparable to published results with regimens including TBI and suggest that TMLI is not associated with an increased EM relapse risk

Evaluation of the efficacy and safety of original filgrastim (Neupogen®), biosimilar filgrastim (Leucostim®) and Lenograstim (Granocyte®) in CD34(+) peripheral hematopoietic stem cell mobilization procedures for allogeneic hematopoietic stem cell transplant donors.

Science.gov (United States)

Sivgin, Serdar; Karakus, Esen; Keklik, Muzaffer; Zararsiz, Gokmen; Solmaz, Musa; Kaynar, Leylagul; Eser, Bulent; Cetin, Mustafa; Unal, Ali

2016-06-01

In this study, we aimed to compare the potency of different G-CSF agents including original filgrastim (Neupogen®), biosimilar filgrastim (Leucostim®) and Lenograstim (Granocyte®) on CD34(+) cell mobilization in patients that underwent allogeneic hematopoietic stem cell transplantation (alloHSCT). The data of 243 donors for alloHSCT recipients diagnosed with mostly acute leukemia and myelodsyplastic syndromes (MDS) were analyzed, retrospectively. Data for stem cell mobilization have been recorded from patients' files. Donors who received Filgrastim (Neupogen®, Group I), biosimilar Filgrastim (Leucostim®, Group II) and Lenograstim (Granocyte®, Group III) were analyzed for total CD34(+) cell count at the end of mobilization procedures. A total of 243 donors and patients for alloHSCT were analyzed retrospectively. The diagnosis of the patients were; acute myeloid leukemia (AML) (110 patients, 45.2%), acute lymphoid leukemia (ALL) (61 patients, 25.1%), aplastic anemia (AA) (38 patients, 15.6%), lymphomas (14 patients, 5.7%) and others (20 patients, 8.4%). The median number of total collected PB CD34(+) cells (×10(6)/kg) was 7.12 (min-max: 5.38-7.90) in the Neupogen® group, 7.27 (min-max: 6.79-7.55) in the Leucostim® group and 7.15 (min-max: 5.34-7.58) in the Granocyte® group. There was no statistically significant difference among groups in terms of total collected PB CD34(+) cells (p = 0.919). The median doses of G-CSF agents (µg/kg/day) in PBSC collection in Neupogen® group was; 11.00 (10.00-12.00) in Leucostim® group10.35 (min-max: 10.00-11.10) and in Granocyte® group11.00 (min-max: 10.00-11.00). There was no statistical significance among groups (p = 0.215). Biosimilar filgrastim (Leucostim®) was found comparable to original Filgrastim (Neupogen®) and Lenograstim (Granocyte®) for PBSC mobilization in donors of the patients that underwent alloHSCT. Copyright © 2016 Elsevier Ltd. All rights reserved.

Risk Factors for Subsequent Central Nervous System Tumors in Pediatric Allogeneic Hematopoietic Cell Transplant

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Gabriel, Melissa; Shaw, Bronwen E; Brazauskas, Ruta

2017-01-01

Survivors of hematopoietic cell transplantation (HCT) are at risk of subsequent solid tumors, including central nervous system (CNS) tumors. The risk of CNS tumors after HCT in pediatric HCT recipients is not known. We evaluated the incidence and risk factors for CNS tumors in pediatric recipients...

Donor-Cell Origin High-Risk Myelodysplastic Syndrome Synchronous with an Intracranial Meningioma-Like Tumor, 8 Years after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia

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G. Brás

2017-01-01

Full Text Available Secondary neoplasias are well known consequences of radiotherapy or chemotherapy for a primary cancer. In this report, we describe two rare secondary neoplasias occurring in the same patient: a meningioma-like intracranial tumor and high-risk myelodysplastic syndrome (MDS of donor-cells origin, both diagnosed simultaneously, 8 years after an allogeneic hematopoietic stem cell transplantation (allo-HSCT for chronic lymphocytic leukemia (CLL. Due to an engraftment failure during the first allo-HSCT of a matched related donor for CLL treatment, the salvage treatment was a second allo-HSCT. At the moment of meningioma-like tumor diagnosis, the patient was pancytopenic due to high-risk MDS, so it was decided to postpone a surgical intervention until hematological improvement. For the high-risk MDS of donor-cells origin the chosen treatment was induction with intensive chemotherapy. Due to refractory disease, the patient was treated with 5-azacitidine and donor-lymphocytes infusion with no response and, finally, a third allo-HSCT of a matched unrelated donor was performed. The patient died 6 months after the third allo-HSCT, in cytogenetic remission but without hematological recovery, due to an intracranial hemorrhage with origin in the meningioma-like tumor.

ALLOGENEIC STEM CELL TRANSPLANTATION FOR ADULT PATIENTS WITH ACUTE LEUKEMIA – 14 YEARS EXPERIENCE

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Jože Pretnar

2004-12-01

Full Text Available Background. This study was designed to evaluate the impact of various prognostic factors on long-term survival and event free survival after allogeneic hematopoietic stem cell transplantation for patients with acute leukemia.Methods and patients. Between years 1989 and 2002 44 patients with acute leukemia (30 with AML and 14 with ALL were transplanted. Survival curves using the Kaplan-Meier method were calculated for patients transplanted with two different sources of stem cells – bone marrow and peripheral blood and separately for patients with female donor.Results. Estimated 10 years survival for AML is 43% and 64% for ALL patients which is not statistically different. There are no significant differences in outcome regarding source of stem cells and in donors’ gender.Conclusions. To conclude, our results show that neither source of stem cells nor donor’s gender has impact on the long-term survival after hematopoietic stem cell transplantation. As published previously patients transplanted beyond the first remission have significantly worse outcome.

Gastroesophageal reflux disease and its association with bronchiolitis obliterans syndrome in allogeneic hematopoietic stem cell transplant recipients.

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Khalid, Mohammed; Aljurf, Mahmoud; Saleemi, Sarfraz; Khan, Mohammed Qaseem; Khan, Basha; Ahmed, Shad; Ibrahim, Khalid El Tayeb; Mobeireek, Abdullah; Al Mohareb, Fahad; Chaudhri, Naeem

2013-06-01

Bronchiolitis obliterans syndrome is a significant postallogeneic hematopoietic stem cell transplant problem. Recent data in lung transplant patients suggest an association with gastroesophageal reflux disease and bronchiolitis obliterans syndrome. We studied posthematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome for gastroesophageal reflux disease and its response to a proton pump inhibitor. Seven postallogeneic hematopoietic stem cell transplant patients with bronchiolitis obliterans syndrome were studied. Gastroesophageal reflux disease was assessed by 24-hour pH monitoring with a Bravo catheter-free radio pH capsule. Patients with positive gastroesophageal reflux disease were started on omeprazole. Pretreatment and posttreatment pulmonary function tests were done at 3-month intervals. Of 7 patients, 5 had positive results for gastroesophageal reflux disease (71%). Omeprazole had a disease-stabilizing effect on the patients' pulmonary function tests. Our study shows a significant association between bronchiolitis obliterans syndrome and gastroesophageal reflux disease in postallogeneic hematopoietic stem cell transplant patients. Use of omeprazole may have a disease-stabilizing effect in short-term follow-up.

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Patients in the Black Sea Region of Turkey

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Alişan Yıldıran

2017-12-01

Full Text Available Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11, Chediak-Higashi syndrome (n=2, leukocyte adhesion deficiency (n=2, MHC class 2 deficiency (n=2, chronic granulomatous syndrome (n=2, hemophagocytic lymphohistiocytosis (n=1, Wiskott-Aldrich syndrome (n=1, and Omenn syndrome (n=1. Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.

Hematopoietic Stem Cell Transplantation in Primary Immunodeficiency Patients in the Black Sea Region of Turkey.

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Yıldıran, Alişan; Çeliksoy, Mehmet Halil; Borte, Stephan; Güner, Şükrü Nail; Elli, Murat; Fışgın, Tunç; Özyürek, Emel; Sancak, Recep; Oğur, Gönül

2017-12-01

Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years) with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11), Chediak-Higashi syndrome (n=2), leukocyte adhesion deficiency (n=2), MHC class 2 deficiency (n=2), chronic granulomatous syndrome (n=2), hemophagocytic lymphohistiocytosis (n=1), Wiskott-Aldrich syndrome (n=1), and Omenn syndrome (n=1). Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.

Allogeneic Mesenchymal Stem Cell Treatment Induces Specific Alloantibodies in Horses

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Sean D. Owens

2016-01-01

Full Text Available Background. It is unknown whether horses that receive allogeneic mesenchymal stem cells (MSCs injections develop specific humoral immune response. Our goal was to develop and validate a flow cytometric MSC crossmatch procedure and to determine if horses that received allogeneic MSCs in a clinical setting developed measurable antibodies following MSC administration. Methods. Serum was collected from a total of 19 horses enrolled in 3 different research projects. Horses in the 3 studies all received unmatched allogeneic MSCs. Bone marrow (BM or adipose tissue derived MSCs (ad-MSCs were administered via intravenous, intra-arterial, intratendon, or intraocular routes. Anti-MSCs and anti-bovine serum albumin antibodies were detected via flow cytometry and ELISA, respectively. Results. Overall, anti-MSC antibodies were detected in 37% of the horses. The majority of horses (89% were positive for anti-bovine serum albumin (BSA antibodies prior to and after MSC injection. Finally, there was no correlation between the amount of anti-BSA antibody and the development of anti-MSC antibodies. Conclusion. Anti allo-MSC antibody development was common; however, the significance of these antibodies is unknown. There was no correlation between either the presence or absence of antibodies and the percent antibody binding to MSCs and any adverse reaction to a MSC injection.

Umbilical cord blood banking in the worldwide hematopoietic stem cell transplantation system: perspectives for Ukraine.

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Kalynychenko, T O

2017-09-01

Significant progress in the promotion of procedural technologies associated with the transplantation of hematopoietic stem cells caused a rapid increase in activity. The exchange of hematopoietic stem cells for unrelated donor transplantations is now much easier due to the relevant international professional structures and organizations established to support cooperation and standard setting, as well as rules for the functioning of both national donor registries and cord blood banks. These processes are increasing every year and are contributing to the outpacing rates of development in this area. Products within their country should be regulated by the competent government authorities. This study analyzes the work of international and national levels of support for transplantation activity in the field of unrelated hematopoietic stem cell transplantation, the standardization order of technologies, as well as data that justify the need to create a network of donated umbilical cord blood banks in Ukraine as a factor in the development of allogeneic transplantation. This will promote the accessibility of international standards for the treatment of serious diseases for Ukrainian citizens.

Genetic modification of hematopoietic stem cells as a therapy for HIV/AIDS.

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Younan, Patrick; Kowalski, John; Kiem, Hans-Peter

2013-11-28

The combination of genetic modification and hematopoietic stem cell (HSC) transplantation may provide the necessary means to develop an alternative treatment option to conventional antiretroviral therapy. As HSCs give rise to all hematopoietic cell types susceptible to HIV infection, modification of HSCs is an ideal strategy for the development of infection-resistant immune cell populations. Although promising results have been obtained in multiple animal models, additional evidence is needed to convincingly demonstrate the feasibility of this approach as a treatment of HIV-1 infected patients. Here, we review the potential of HSC transplantation and the recently identified limitations of this approach. Using the Berlin Patient as a model for a functional cure, we contrast the confines of autologous versus allogeneic transplantation. Finally, we suggest that although autologous, gene-modified HSC-transplantation may significantly reduce plasma viremia, reaching the lower detection limits currently obtainable through daily HAART will remain a challenging endeavor that will require innovative combinatorial therapies.

Genetic Modification of Hematopoietic Stem Cells as a Therapy for HIV/AIDS

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Patrick Younan

2013-11-01

Full Text Available The combination of genetic modification and hematopoietic stem cell (HSC transplantation may provide the necessary means to develop an alternative treatment option to conventional antiretroviral therapy. As HSCs give rise to all hematopoietic cell types susceptible to HIV infection, modification of HSCs is an ideal strategy for the development of infection-resistant immune cell populations. Although promising results have been obtained in multiple animal models, additional evidence is needed to convincingly demonstrate the feasibility of this approach as a treatment of HIV-1 infected patients. Here, we review the potential of HSC transplantation and the recently identified limitations of this approach. Using the Berlin Patient as a model for a functional cure, we contrast the confines of autologous versus allogeneic transplantation. Finally, we suggest that although autologous, gene-modified HSC-transplantation may significantly reduce plasma viremia, reaching the lower detection limits currently obtainable through daily HAART will remain a challenging endeavor that will require innovative combinatorial therapies.

Allogeneic Hematopoietic Stem Cell Transplantation Is an Effective Salvage Therapy for Patients with Chronic Myeloid Leukemia Presenting with Advanced Disease or Failing Treatment with Tyrosine Kinase Inhibitors.

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Nair, Anish P; Barnett, Michael J; Broady, Raewyn C; Hogge, Donna E; Song, Kevin W; Toze, Cynthia L; Nantel, Stephen H; Power, Maryse M; Sutherland, Heather J; Nevill, Thomas J; Abou Mourad, Yasser; Narayanan, Sujaatha; Gerrie, Alina S; Forrest, Donna L

2015-08-01

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only known curative therapy for chronic myeloid leukemia (CML); however, it is rarely utilized given the excellent long-term results with tyrosine kinase inhibitor (TKI) treatment. The purpose of this study is to examine HSCT outcomes for patients with CML who failed TKI therapy or presented in advanced phase and to identify predictors of survival, relapse, and nonrelapse mortality (NRM). Fifty-one patients with CML underwent HSCT for advanced disease at diagnosis (n = 15), TKI resistance as defined by the European LeukemiaNet guidelines (n = 30), TKI intolerance (n = 2), or physician preference (n = 4). At a median follow-up of 71.9 months, the 8-year overall survival (OS), event-free survival (EFS), relapse, and NRM were 68%, 46%, 41%, and 23%, respectively. In univariate analysis, predictors of OS included first chronic phase (CP1) disease status at HSCT (P = .0005), European Society for Blood and Marrow Transplantation score 1 to 4 (P = .04), and complete molecular response (CMR) to HSCT (P treatment to optimize transplantation outcomes. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Pelvic reconstruction with allogeneic bone graft after tumor resection

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Wang, Wei; Bi, Wen Zhi; Yang, Jing; Han, Gang; Jia, Jin Peng

2013-01-01

OBJECTIVES : Pelvic reconstruction after tumor resection is challenging. METHODS: A retrospective study had been preformed to compare the outcomes among patients who received pelvic reconstructive surgery with allogeneic bone graft after en bloc resection of pelvic tumors and patients who received en bloc resection only. RESULTS: Patients without reconstruction had significantly lower functional scores at 3 months (10 vs. 15, P = 0.001) and 6 months after surgery (18.5 vs. 22, P = 0.0024), a shorter duration of hospitalization (16 day vs. 40 days, P 0.05). CONCLUSIONS : Pelvic reconstruction with allogeneic bone graft after surgical management of pelvic tumors is associated with satisfactory surgical and functional outcomes. Further clinical studies are required to explore how to select the best reconstruction method. Level of Evidence IV, Case Series. PMID:24453659

A single exercise bout enhances the manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy

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Guillaume Spielmann; Catherine M. Bollard; Hawley Kunz; Patrick J. Hanley; Richard J. Simpson

2016-01-01

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The adoptive transfer of donor-derived viral-specific cytotoxic T-cells (VSTs) is an effective treatment for controlling CMV and EBV infections after HSCT; however, new practical methods are required to augment the ex vivo manufacture of multi-VSTs from healthy donors. This study investigated the effects of a single exer...

Donor age and C1orf132/MIR29B2C determine age-related methylation signature of blood after allogeneic hematopoietic stem cell transplantation.

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Spólnicka, Magdalena; Piekarska, Renata Zbieć; Jaskuła, Emilia; Basak, Grzegorz W; Jacewicz, Renata; Pięta, Agnieszka; Makowska, Żanetta; Jedrzejczyk, Maciej; Wierzbowska, Agnieszka; Pluta, Agnieszka; Robak, Tadeusz; Berent, Jarosław; Branicki, Wojciech; Jędrzejczak, Wiesław; Lange, Andrzej; Płoski, Rafał

2016-01-01

Our recent study demonstrated that DNA methylation status in a set of CpGs located in ELOVL2, C1orf132, TRIM59, KLF14, and FHL2 can accurately predict calendar age in blood. In the present work, we used these markers to evaluate the effect of allogeneic hematopoietic stem cell transplantation (HSCT) on the age-related methylation signature of human blood. DNA methylation in 32 CpGs was investigated in 16 donor-recipient pairs using pyrosequencing. DNA was isolated from the whole blood collected from recipients 27-360 days (mean 126) after HSCT and from the donors shortly before the HSCT. It was found that in the recipients, the predicted age did not correlate with their calendar age but was correlated with the calendar age (r = 0.94, p = 4 × 10(-8)) and predicted age (r = 0.97, p = 5 × 10(-10)) of a respective donor. Despite this strong correlation, the predicted age of a recipient was consistently lower than the predicted age of a donor by 3.7 years (p = 7.8 × 10(-4)). This shift was caused by hypermethylation of the C1orf132 CpGs, for C1orf132 CpG_1. Intriguingly, the recipient-donor methylation difference correlated with calendar age of the donor (r = 0.76, p = 6 × 10(-4)). This finding could not trivially be explained by shifts of the major cellular factions of blood. We confirm the single previous report that after HSCT, the age of the donor is the major determinant of age-specific methylation signature in recipient's blood. A novel finding is the unique methylation dynamics of C1orf132 which encodes MIR29B2C implicated in the self-renewing of hematopoietic stem cells. This observation suggests that C1orf132 could influence graft function after HSCT.

Comparisons Between Allogeneic Peripheral Blood Stem Cell Transplantation and Allogeneic Bone Marrow Transplantation in Adult Hematologic Disease: A Single Center Experience

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Yi-Chang Liu

2003-11-01

Full Text Available This retrospective study compared the outcomes in 32 adult patients with hematologic diseases (acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, severe aplastic anemia who received allogeneic bone marrow transplantation (BMT, n = 14; median age, 28 years or allogeneic peripheral blood stem cell transplantation (PBSCT, n = 18; median age, 29 years from human leukocyte antigen-identical sibling donors. Median follow-up was 58 months in BMT recipients and 18 months in PBSCT recipients. Neutrophil (median, Day 8 vs Day 13, p < 0.001 and platelet engraftment (median, Day 9 vs Day 17, p < 0.001 was faster in the PBSCT group than in the BMT group. Patients receiving PBSCT required less platelet transfusion than those receiving BMT (median, 54 units vs 144 units, p < 0.001, but there was no significant difference in red cell transfusion. At 100 days, there was no difference in the incidence of acute graft-versus-host disease (GVHD (42.9% vs 33.3%, p = 0.72 or grade II-IV acute GVHD (14.3% vs 5.6%, p = 0.57, and there was no difference in the cumulative incidence of chronic GVHD (20% vs 33.3%, p = 0.67. No chronic GVHD was noted in any relapsed patients (BMT, 5; PBSCT, 3, and no patients with chronic GVHD during follow-up had a relapse. Relapse was the most frequent cause of death in both groups (BMT, 5/9, 55.6%; PBSCT, 3/4, 75%; p = 0.25; all relapses occurred within 1 year after transplantation. Overall survival was significantly better in the PBSCT group (35.7% vs 77.8%, p = 0.029, but this difference was lost if only hematologic malignancies were analyzed (30.8% vs 63.6%, p = 0.20. Our results are similar to those reported previously, with faster neutrophil and platelet engraftment and less severe acute GVHD and extensive chronic GVHD with PBSCT. Allogeneic PBSCT is a feasible and beneficial alternative to allogeneic BMT in adult hematologic disease.

Comparative assessment of prophylactic transfusions of platelet concentrates obtained by the PRP or buffy-coat methods, in patients undergoing allogeneic hematopoietic stem cell transplantation.

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Fernández-Muñoz, Hermógenes; Plaza, Eva M; Rivera-Caravaca, José Miguel; Candela, María José; Romera, Marta; De Arriba, Felipe; Lozano, María L; Vicente, Vicente; Heras, Inmaculada; Castilla-Llorente, Cristina; Rivera, José

2018-03-27

Whole blood-derived platelet concentrates can be obtained by the platelet-rich plasma (PRP-PCs) or the buffy-coat (BC-PCs) method. Few studies have shown that BC-PCs display lower in vitro platelet activation, but scarce information exists regarding transfusion efficacy. We have performed a retrospective study assessing platelet transfusion in patients undergoing allogeneic hematopoietic cell transplantation (AHCT) in our clinic, before and after the implementation of BC-PCs. We reviewed clinical records corresponding to 70 PRP-PCs and 86 BC-PCs prophylactic transfusions, which were performed to 55 AHCT patients. Transfusion efficacy was assessed by the 24-h post-transfusion corrected count increment (24-h CCI) and bleeding events. Clinical factors affecting transfusion outcome were also investigated. Clinical characteristics and the total number of platelet transfusions were similar among groups. Mean donor exposure was 5.8 and 5.0 in each single PRP-PCs and BC-PCs transfusion, respectively (p PRP-PCs (8.3[2.7-13.4] vs. 4.7[1.3-8.1]; p PRP-PCs transfusion (HR 4.54; 95% CI 1.72-12.01; p = 0.002). There were no differences between both groups regarding the bleeding events. In the AHCT setting, we hypothesize that BC-PCs transfusion, when compared to PRP-PCs, results in higher CCI and reduced donor exposure, but provides no significant benefit regarding bleeding outcome.

Factors Influencing Pulmonary Toxicity in Children Undergoing Allogeneic Hematopoietic Stem Cell Transplantation in the Setting of Total Body Irradiation-Based Myeloablative Conditioning

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Abugideiri, Mustafa, E-mail: Mabugid@emory.edu [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Nanda, Ronica H. [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Butker, Charlotte [Emory University, Atlanta, Georgia (United States); Zhang, Chao [Department of Biostatistics, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Kim, Sungjin [Biostatistics and Bioinformatics Research Center, Cedars-Sinai Medical Center, Los Angeles, California (United States); Chiang, Kuang-Yueh [Aflac Cancer Center and Blood Disorders Center, Children' s Healthcare of Atlanta, and Pediatric Hematology, Oncology, Bone Marrow Transplant, Emory University, Atlanta, Georgia (United States); Butker, Elizabeth; Khan, Mohammad K. [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Haight, Ann E. [Aflac Cancer Center and Blood Disorders Center, Children' s Healthcare of Atlanta, and Pediatric Hematology, Oncology, Bone Marrow Transplant, Emory University, Atlanta, Georgia (United States); Chen, Zhengjia [Department of Biostatistics, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Esiashvili, Natia [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States)

2016-02-01

Purpose: This study evaluated factors associated with increased risk of pulmonary toxicity (PT) from any cause in pediatric patients after myeloablative conditioning, using total body irradiation (TBI), followed by allogeneic hematopoietic stem cell transplantation (HSCT). Methods and Materials: The records of 129 consecutive pediatric patients (range: 1-21 years of age) who underwent TBI-based myeloablative conditioning for hematologic malignancies at our institution between January 2003 and May 2014 were reviewed. Although total TBI doses ranged from 10.5 to 14 Gy, lung doses were limited to 10 Gy with partial transmission blocks. TBI dose rates ranged from 5.6 cGy/min to 20.9 cGy/min. PT was classified using clinical symptoms, radiographic evidence, and ventilatory defects on pulmonary function tests. Noninfectious (idiopathic) pneumonia syndrome (IPS) was characterized by patients exhibiting PT while demonstrating no signs of infection throughout the follow-up period. Results: PT from any cause developed in 70.5% of patients and was significantly associated with increased transplantation-related mortality (TRM) (P=.03) and decreased overall survival (OS) (P=.02). IPS developed in 23.3% of patients but was not associated with increased TRM (P=.6) or decreased OS (P=.5). Acute graft-versus-host disease (GVHD) significantly affected PT (P=.001) but did not significantly influence the development of IPS (P=.4). Infection was a leading cause of PT (75.8%). TBI dose rate significantly affected development of overall PT (P=.02) and was the sole factor to significantly influence the incidence of IPS (P=.002). TBI total dose, dose per fraction, disease type, transplantation chemotherapy, age of patient, sex, and donor type did not significantly impact overall PT or IPS. Conclusions: A high incidence of PT was noted in this large series of homogeneously treated pediatric patients undergoing TBI for allogeneic HSCT. TBI dose rates affected overall PT and strongly

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses.

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Kotsiou, Eleni; Okosun, Jessica; Besley, Caroline; Iqbal, Sameena; Matthews, Janet; Fitzgibbon, Jude; Gribben, John G; Davies, Jeffrey K

2016-07-07

Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies. © 2016 by The American Society of Hematology.

The impact of hematopoietic stem cell transplantation on sexuality: a systematic review of the literature

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Thygesen, Kristina Holmegaard; Schiødt, Ida; Jarden, M

2012-01-01

In this paper we review evidence concerning the impact of hematopoietic SCT (HSCT) on sexuality. The aims are to determine: (1) the sexual changes experienced by patients following allogeneic or autologous HSCT, and its consequences; (2) changes in the sexual function over time and (3) the impact...... in sexual dysfunction with specific reliable validated instruments and more adequate sample sizes will be required to definitively evaluate the impact of HSCT on sexuality.Bone Marrow Transplantation advance online publication, 29 August 2011; doi:10.1038/bmt.2011.169....

Changes of hemoglobin and hematocrit in elderly patients receiving lower joint arthroplasty without allogeneic blood transfusion.

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Zhou, Qi; Zhou, Yiqin; Wu, Haishan; Wu, Yuli; Qian, Qirong; Zhao, Hui; Zhu, Yunli; Fu, Peiliang

2015-01-05

It has rarely been reported about the changes of hemoglobin (Hb) and hematocrit (Hct) in elderly patients receiving total knee arthroplasty (TKA) or total hip arthroplasty (THA). This study aimed to evaluate the changes of Hb and Hct after TKA or THA in elderly patients, and analyze its relationship with sex and type of arthroplasty. This is a prospective cohort study, including 107 patients receiving TKA or THA without allogeneic blood transfusion. There were 54 males and 53 females, with a mean age of 69.42 years. Levels of Hb and Hct were examined preoperatively and during the 6 months follow-up after operation. Levels of Hb and Hct decreased postoperatively and reached their minimum points on postoperative day 4. Thereafter, Hb and Hct recovered to their preoperative levels within 6-12 weeks. No significant differences in the levels of Hb and Hct were noticed between different sexes. THA patients showed significantly greater drop in Hb and Hct than TKA patients in the first 4 days postoperatively (P < 0.05). Levels of Hb and Hct decreased during the first 4 days after arthroplasty and gradually returned to their normal levels within 6-12 weeks postoperatively. THA may be associated with higher postoperative blood loss than TKA.

Donor Selection for Allogenic Hemopoietic Stem Cell Transplantation: Clinical and Ethical Considerations

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Irene Riezzo

2017-01-01

Full Text Available Allogenic hematopoietic progenitor cell transplantation (allo-HSCT is an established treatment for many diseases. Stem cells may be obtained from different sources: mobilized peripheral blood stem cells, bone marrow, and umbilical cord blood. The progress in transplantation procedures, the establishment of experienced transplant centres, and the creation of unrelated adult donor registries and cord blood banks gave those without an human leucocyte antigen- (HLA- identical sibling donor the opportunity to find a donor and cord blood units worldwide. HSCT imposes operative cautions so that the entire donation/transplantation procedure is safe for both donors and recipients; it carries with it significant clinical, moral, and ethical concerns, mostly when donors are minors. The following points have been stressed: the donation should be excluded when excessive risks for the donor are reasonable, donors must receive an accurate information regarding eventual adverse events and health burden for the donors themselves, a valid consent is required, and the recipient’s risks must be outweighed by the expected benefits. The issue of conflict of interest, when the same physician has the responsibility for both donor selection and recipient care, is highlighted as well as the need of an adequate insurance protection for all the parties involved.

Allogenic blood transfusion following total hip arthroplasty: results from the nationwide inpatient sample, 2000 to 2009.

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Saleh, Anas; Small, Travis; Chandran Pillai, Aiswarya Lekshmi Pillai; Schiltz, Nicholas K; Klika, Alison K; Barsoum, Wael K

2014-09-17

The large-scale utilization of allogenic blood transfusion and its associated outcomes have been described in critically ill patients and those undergoing high-risk cardiac surgery but not in patients undergoing elective total hip arthroplasty. The objective of this study was to determine the trends in utilization and outcomes of allogenic blood transfusion in patients undergoing primary total hip arthroplasty in the United States from 2000 to 2009. An observational cohort of 2,087,423 patients who underwent primary total hip arthroplasty from 2000 to 2009 was identified in the Nationwide Inpatient Sample. International Classification of Diseases, Ninth Revision, Clinical Modification procedure codes 99.03 and 99.04 were used to identify patients who received allogenic blood products during their hospital stay. Risk factors for allogenic transfusions were identified with use of multivariable logistic regression models. We used propensity score matching to estimate the adjusted association between transfusion and surgical outcomes. The rate of allogenic blood transfusion increased from 11.8% in 2000 to 19.0% in 2009. Patient-related risk factors for receiving an allogenic blood transfusion include an older age, female sex, black race, and Medicaid insurance. Hospital-related risk factors include rural location, smaller size, and non-academic status. After adjusting for confounders, allogenic blood transfusion was associated with a longer hospital stay (0.58 ± 0.02 day; p conservation methods. Copyright © 2014 by The Journal of Bone and Joint Surgery, Incorporated.

Development of a coordinated allo T cell and auto B cell response against autosomal PTK2B after allogeneic hematopoietic stem cell transplantation.

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Kremer, Anita N; van der Griendt, Judith C; van der Meijden, Edith D; Honders, M Willy; Ayoglu, Burcu; Schwenk, Jochen M; Nilsson, Peter; Falkenburg, J H Frederik; Griffioen, Marieke

2014-02-01

It is well known that allo-reactive T cells play a crucial role in graft-versus-leukemia and graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (alloSCT). Allo-reactive CD4(+) T cells can mediate direct cytolysis, but may also stimulate production of IgG antibodies as helper cells. Immune complexes may subsequently be processed and presented by professional antigen presenting cells and stimulate induction of specific CD8(+) T cells. As such, proteins targeted in coordinated T- and B-cell responses may represent a class of immunodominant antigens in clinical responses after alloSCT. We previously identified LB-PTK2B-1T as HLA class II restricted polymorphic antigen in a patient treated with donor lymphocyte infusion for relapsed chronic myeloid leukemia after HLA-matched alloSCT. Since PTK2B has also been described as antibody target, we here investigated whether a coordinated T- and B-cell response against PTK2B was induced. Patient serum before and after alloSCT and donor lymphocyte infusion (DLI) was screened for antibodies, and we indeed observed development of a humoral immune response against PTK2B. Antibodies against PTK2B were only found after DLI and, in contrast to the CD4(+) T cells, recognized a monomorphic region of the protein. To our knowledge, this is the first description of a coordinated allo-reactive CD4(+) T-cell and auto-reactive antibody response against an autosomal antigen.

Photobiomodulation therapy alleviates tissue fibroses associated with chronic Graft-Versus-Host Disease : Two case reports and putative anti-fibrotic roles of TGF-β

NARCIS (Netherlands)

Epstein, J.B.; Raber-Durlacher, J.E.; Huysmans, M.C.; Schoordijk, M.C.E.; Cheng, J.E.; Bensadoun, R.J.; Arany, P.R.

2018-01-01

Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

Photobiomodulation Therapy Alleviates Tissue Fibroses Associated with Chronic Graft-Versus-Host Disease: Two Case Reports and Putative Anti-Fibrotic Roles of TGF-

NARCIS (Netherlands)

Epstein, Joel B.; Raber-Durlacher, Judith E.; Huysmans, Marie-Charlotte; Schoordijk, Maria C. E.; Cheng, Jerry E.; Bensadoun, Rene-Jean; Arany, Praveen R.

2018-01-01

Objective: Patients who receive allogeneic hematopoietic stem cell transplantation may experience oral complications due to chronic graft-versus-host disease (cGVHD). The manifestations may include progressive sclerosis-like changes that may involve various body sites, including the oropharynx.

Allogenic bone grafts in post-traumatic juxta-articular defects: Need for allogenic bone banking.

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Mishra, Anil Kumar; Vikas, Rohit; Agrawal, H S

2017-07-01

Allogenic bone banking provide both structural and granular bone grafts for various orthopaedic, spinal, oncological and dental surgeries. However allogenic bones, presently, are not readily available. This article discusses the clinical applications of the allogenic grafts, the screening criteria and procedure for maintenance of such a bone banking facility. This article demonstrates the effective role of allogenic bone in a case of post-traumatic bone loss situation and discusses the growing need and present situation of bone banking in our country.

[Treatment of Gaucher disease with allogeneic hematopoietic stem cell transplantation: report of three cases and review of literatures].

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Tang, Xiangfeng; Luan, Zuo; Wu, Nanhai; Zhang, Bo; Jing, Yuanfang; Du, Hong; Lu, Wei; Xu, Shixia

2015-11-01

To explore the efficacy of unrelated umbilical cord blood transplantation (UCBT) in the treatment of Gaucher disease. The clinical characteristics of three children with Gaucher disease underwent UCBT in our hospital between April 2013 and September 2014 were retrospectively analyzed. Literature on allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of Gaucher disease was searched at Wanfang and Pubmed databases between 1983 and 2015 and was reviewed and summaried. Three children with Gaucher disease, all were female, received UCBT. These patients' age at receiving transplantation was 3.8 years, 7.1 years and 2.6 years, respectively. The second case received the second transplantation. The first and third case received splenectomy before UCBT. The pretreatment regimen was busulfan (Bu)/fludarabine (Flu)/cyclophosphamide (CTX)/antithymocyte globulin (ATG), and for the patient received the second transplantation melphalan was added to the myeloablative conditioning regimen of Bu/Flu/CTX/ATG. Cyclosporine and mycophenolate mofetil (MMF) wee used for prophylaxis of acute graft versus host disease (aGVHD). The dose of cord blood stem cell nucleated cell counts was 9.7 × 10⁷ /kg,11.9 × 10⁷ /kg and 7.6 × 10⁷/kg respectively. The dose of cord blood stem cell CD34⁺ cell counts was 5.4 × 10⁵/kg , 3.5 × 10⁵/kg and 3.2 × 10⁵/kg respectively. The day of granulocytes exceeding 0.5 × 10⁹/L was day 11, 12 and 19 after transplantation, respectively. The day of platelets exceeding 20 × 10⁹/L was day 14, 33 and 74 after transplantation, respectively. At one month after transplantation the rate of chimerism was over 95% and all patients got donor complete chimerism. The level of β-glucocerebrosidase recovered to normal at one month after transplantation. During transplantation, all patients developed cytomegalovirus (CMV) and Epstein-Barr virus (EBV) viremia. In case 1 immune thrombocytopenia occurred at five month after

How Does Influenza A (H1N1 Infection Proceed in Allogeneic Stem Cell Transplantation Recipients?

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Sinem Civriz Bozdağ

2012-03-01

Full Text Available Clinical course of H1N1 infection in Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT patients is contraversial. We report three AHSCT patients who were infected with Influenza A/H1N1 infection. All of the patients were diagnosed with different hematological diagnosis and were at different stages of transplantation.All of them were treated with oseltamivir,zanamivir was switched with oseltamivir in one patient. All of the three patients were survived without any complication. Swine flu, can display with different courses and progress with bacterial or other viral infections in immunsupressed patients.

Blood management in total hip replacement: an analysis of factors associated with allogenic blood transfusion.

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Wong, Samuel; Tang, Howard; de Steiger, Richard

2015-06-01

The aim of this study was to audit the blood transfusion practice throughout the Epworth Healthcare Hospitals for patients undergoing primary total hip replacement (THR). We determined if blood-saving techniques were having an impact on the risk of allogenic blood transfusion and which patients were at risk of receiving allogenic blood transfusion. This study uses a retrospective audit of 787 patients who had undergone primary THR surgery at three Melbourne hospitals: Epworth Richmond, Epworth Eastern and Epworth Freemasons in 2010. Patient demographics, transfusion requirements and blood-conserving techniques were recorded. One hundred and eighty (23%) patients received allogenic blood transfusion and 18 (2.3%) patients received autologous blood transfusion. On multivariate analysis, preoperative anaemia (odds ratio (OR) 4.7, P blood transfusion. Use of spinal anaesthetic was found to be associated with lower risk of transfusion (OR 0.6, P = 0.0180) compared with general anaesthetic alone. Cell saver, acute normovolaemic haemodilution and re-infusion drain tube usage did not have a significant impact on reducing the risk of allogenic blood transfusion. Identification of patients at risk of blood transfusion, correction of preoperative anaemia and a restrictive transfusion policy are important factors to consider in effective perioperative blood management. © 2015 Royal Australasian College of Surgeons.

ES-cell derived hematopoietic cells induce transplantation tolerance.

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Sabrina Bonde

Full Text Available BACKGROUND: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs. Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells. METHODOLOGY/PRINCIPAL FINDINGS: Here, we derived CD45(+ HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts. CONCLUSIONS: Our data show, for the first time, the efficacy of ES-derived CD45(+ HPCs to engraft in allogenic recipients without the use of immunosuppressive agents, there by protecting cardiac allografts from rejection.

Epidemiologic Profile of Patients Transplanted With Hematopoietic Stem Cells in a Reference Service in the State of Rio Grande do Norte, Brazil.

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Campos de Azevedo, I; Ferreira Júnior, M A; Pereira de Aquino, L A; de Oliveira, A A; Cruz, G K P; de Queiroz Cardoso, A I; Ivo, M L; Santos, V E P

2018-04-01

Hematopoietic stem cell transplantation (HSCT) consists of the intravenous infusion of healthy hematopoietic stem cells to restore the medullary and immunologic function of patients affected by a series of hematologic, oncologic, immunologic, malignant and nonmalignant inherited or acquired diseases, with the possibility of cure or increase of disease-free survival. To characterize the epidemiologic profile and the cases of death of patients who underwent HSCT. This is a cohort quantitative study, nested with a retrospective, descriptive, and analytical study of a hospital-based cohort that included the patients who underwent HSCT at a referral service in the state of Rio Grande do Norte, a region of northeastern Brazil. There was a slight male prevalence (52.94%), the age of the patients ranged from 2 to 73 years old, 18.38% were brown, 47.06% were married, 15.07% were students, 78.31% had a diagnosis of multiple myeloma, 93.38% developed gastrointestinal toxicities, all patients received chemotherapeutic treatment, 54.78% had allogeneic HSCT, and the cause of the most recorded deaths was septic shock (48.19%). This study showed relevant scientific evidence on the clinical and epidemiologic profile of patients who underwent HSCT. In general, sociodemographic data are similar to national and international research results. Copyright © 2018 Elsevier Inc. All rights reserved.

Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients.

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Mori, Takehiko; Yamazaki, Rie; Aisa, Yoshinobu; Nakazato, Tomonori; Kudo, Masumi; Yashima, Tomoko; Kondo, Sakiko; Ikeda, Yasuo; Okamoto, Shinichiro

2006-04-01

We previously reported the efficacy of oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis. The purpose of this study was to evaluate whether the further shortening of the duration of oral cryotherapy could minimize its side effects while sparing its efficacy. Seventeen consecutive recipients of allogeneic hematopoieic stem cell transplant conditioned with high-dose melphalan in combination with fludarabine alone or with fludarabine and additional radiation were enrolled in the study. The severity of stomatitis was graded according to the National Cancer Institute-Common Toxicity Criteria. Patients were kept on oral cryotherapy shortly before, during, and for additional 30 min after the completion of melphalan administration (60-min oral cryotherapy). Patients who were also enrolled in our previous study received the same type of oral cryotherapy but for additional 90 min after the completion of melphalan administration (120-min oral cryotherapy), and they served as controls. Only 2 (11.8%) of 17 patients receiving 60-min oral cryotherapy and 2 (11.1%) of 18 patients receiving 120-min oral cryotherapy developed grade 2 or 3 stomatitis, respectively. The difference between groups was not statistically significant (P = 0.677). The incidence of unpleasant symptoms such as chills and nausea during oral cryotherapy decreased significantly with 60-min oral cryotherapy, as compared with that associated with 120-min oral cryotherapy (P cryotherapy is as effective as 120-min oral cryotherapy at preventing high-dose melphalan-induced stomatitis, and shorter treatment might have contributed to relieve patient discomfort during oral cryotherapy.

Generating autologous hematopoietic cells from human-induced pluripotent stem cells through ectopic expression of transcription factors.

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Hwang, Yongsung; Broxmeyer, Hal E; Lee, Man Ryul

2017-07-01

Hematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells. Advancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells. IPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.

Myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation.

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Kim, Sung-Yong; Le Rademacher, Jennifer; Antin, Joseph H; Anderlini, Paolo; Ayas, Mouhab; Battiwalla, Minoo; Carreras, Jeanette; Kurtzberg, Joanne; Nakamura, Ryotaro; Eapen, Mary; Deeg, H Joachim

2014-12-01

A proportion of patients with aplastic anemia who are treated with immunosuppressive therapy develop clonal hematologic disorders, including post-aplastic anemia myelodysplastic syndrome. Many will proceed to allogeneic hematopoietic stem cell transplantation. We identified 123 patients with post-aplastic anemia myelodysplastic syndrome who from 1991 through 2011 underwent allogeneic hematopoietic stem cell transplantation, and in a matched-pair analysis compared outcome to that in 393 patients with de novo myelodysplastic syndrome. There was no difference in overall survival. There were no significant differences with regard to 5-year probabilities of relapse, non-relapse mortality, relapse-free survival and overall survival; these were 14%, 40%, 46% and 49% for post-aplastic anemia myelodysplastic syndrome, and 20%, 33%, 47% and 49% for de novo myelodysplastic syndrome, respectively. In multivariate analysis, relapse (hazard ratio 0.71; P=0.18), non-relapse mortality (hazard ratio 1.28; P=0.18), relapse-free survival (hazard ratio 0.97; P=0.80) and overall survival (hazard ratio 1.02; P=0.88) of post-aplastic anemia myelodysplastic syndrome were similar to those of patients with de novo myelodysplastic syndrome. Cytogenetic risk was independently associated with overall survival in both groups. Thus, transplant success in patients with post-aplastic anemia myelodysplastic syndrome was similar to that in patients with de novo myelodysplastic syndrome, and cytogenetics was the only significant prognostic factor for post-aplastic anemia myelodysplastic syndrome patients. Copyright© Ferrata Storti Foundation.

Effects of T cell depletion in radiation bone marrow chimeras. I. Evidence for a donor cell population which increases allogeneic chimerism but which lacks the potential to produce GVHD

International Nuclear Information System (INIS)

Sykes, M.; Sheard, M.; Sachs, D.H.

1988-01-01

The opposing problems of graft-vs-host disease (GVHD) and failure of alloengraftment present major obstacles to the application of bone marrow transplantation (BMT) across complete MHC barriers. The addition of syngeneic T-cell-depleted (TCD) bone marrow (BM) to untreated fully allogeneic marrow inocula in lethally irradiated mice has been previously shown to provide protection from GVHD. We have used this model to study the effects of allogeneic T cells on levels of chimerism in recipients of mixed marrow inocula. The results indicate that T cells in allogeneic BM inocula eliminate both coadministered recipient-strain and radioresistant host hematopoietic elements to produce complete allogeneic chimerism without clinical GVHD. To determine the role of GVH reactivity in this phenomenon, we performed similar studies in an F1 into parent combination, in which the genetic potential for GVHD is lacking. The presence of T cells in F1 marrow inocula led to predominant repopulation with F1 lymphocytes in such chimeras, even when coadministered with TCD-recipient-strain BM. These results imply that the ability of allogeneic BM cells removed by T cell depletion to increase levels of allochimerism may be mediated by a population which is distinct from that which produces GVHD. These results may have implications for clinical BM transplantation

Music Therapy for Patients Who Have Undergone Hematopoietic Stem Cell Transplant

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Chelsea G. Ratcliff

2014-01-01

Full Text Available Objectives. This study examines the short- and long-term QOL benefits of a music therapy intervention for patients recovering from hematopoietic stem cell transplantation (HSCT. Methods. Ninety allogeneic HSCT patients, after transplant, were randomized to receive ISO-principle (i.e., mood matching based music therapy (MT; n=29, unstructured music (UM; n=30, or usual care (UC; n=31 for four weeks. The ISO principle posits that patients may shift their mood from one state to another by listening to music that is “equal to” the individual’s initial mood state and subsequently listening to music selections that gradually shift in tempo and mood to match the patient’s desired disposition. Participants in MT and UM groups developed two audio CDs to help them feel more relaxed and energized and were instructed to use the CDs to improve their mood as needed. Short-term effects on mood and long-term effects on QOL were examined. Results. MT and UM participants reported improved mood immediately after listening to CDs; the within-group effect was greater for UM participants compared to MT participants. Participant group was not associated with long-term QOL outcomes. Conclusions. Music listening improves mood acutely but was not associated with long-term benefits in this study.

Music therapy for patients who have undergone hematopoietic stem cell transplant.

Science.gov (United States)

Ratcliff, Chelsea G; Prinsloo, Sarah; Richardson, Michael; Baynham-Fletcher, Laura; Lee, Richard; Chaoul, Alejandro; Cohen, Marlene Z; de Lima, Marcos; Cohen, Lorenzo

2014-01-01

Objectives. This study examines the short- and long-term QOL benefits of a music therapy intervention for patients recovering from hematopoietic stem cell transplantation (HSCT). Methods. Ninety allogeneic HSCT patients, after transplant, were randomized to receive ISO-principle (i.e., mood matching) based music therapy (MT; n = 29), unstructured music (UM; n = 30), or usual care (UC; n = 31) for four weeks. The ISO principle posits that patients may shift their mood from one state to another by listening to music that is "equal to" the individual's initial mood state and subsequently listening to music selections that gradually shift in tempo and mood to match the patient's desired disposition. Participants in MT and UM groups developed two audio CDs to help them feel more relaxed and energized and were instructed to use the CDs to improve their mood as needed. Short-term effects on mood and long-term effects on QOL were examined. Results. MT and UM participants reported improved mood immediately after listening to CDs; the within-group effect was greater for UM participants compared to MT participants. Participant group was not associated with long-term QOL outcomes. Conclusions. Music listening improves mood acutely but was not associated with long-term benefits in this study.

Application of MultiStem® allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft vs host disease

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Bart eVaes

2012-11-01

Full Text Available The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC for treatment of Graft vs Host Disease (GvHD, and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics. This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products per donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

Response to rituximab-based therapy and risk factor analysis in epstein barr virus-related lymphoproliferative disorder after hematopoietic stem cell transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation.

NARCIS (Netherlands)

Styczynski, J.; Gil, L.; Tridello, G.; Ljungman, P.; Donnelly, J.P.; Velden, W. van der; Omar, H.; Martino, R.; Halkes, C.; Faraci, M.; Theunissen, K.; Kalwak, K.; Hubacek, P.; Sica, S.; Nozzoli, C.; Fagioli, F.; Matthes, S.; Diaz, M.A.; Migliavacca, M.; Balduzzi, A.; Tomaszewska, A.; amara Rde, L. C; Biezen, A. van; Hoek, J. van den; Iacobelli, S.; Einsele, H.; Cesaro, S.

2013-01-01

BACKGROUND: The objective of this analysis was to investigate prognostic factors that influence the outcome of Epstein-Barr virus (EBV)-related posttransplant lymphoproliferative disorder (PTLD) after a rituximab-based treatment in the allogeneic hematopoietic stem cell transplant (HSCT) setting.

Incidence of venous thromboembolism in the setting of hematopoietic cell transplantation.

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O'Hara, V J Daphne; Miller, Trent; Mehta, Rakesh; Swartzendruber, Evonne; Kiel, Patrick J

2014-01-01

The underlying risk of venous thromboembolism (VTE) is unclear in patients undergoing hematopoietic cell transplantation (HCT). As such, these patients should still be considered at risk for development of VTE due to factors such as their underlying malignancy and the marked inflammatory state that develops from treatment. The purpose of this study was to characterize the incidence of VTE in patients undergoing HCT. Retrospective chart review of patients from the Indiana University Stem Cell Transplant Unit treated between January 1, 2008, and May 24, 2011. Patients were older than 18 years and had undergone HCT. The primary objective was to analyze the incidence of VTE in patients undergoing autologous HCT versus allogeneic HCT. Secondary objectives included documentation of VTE treatment strategies and time to occurrence of VTE. Of the 567 patients who underwent autologous HCT, 14 developed VTE (2.5%), whereas 5 of the 180 patients who underwent allogeneic HCT developed VTE (2.8%; P = 1.000). The median time to development of VTE from admission for HCT was 12 days in the autologous HCT arm versus 19 days in the allogeneic HCT arm (P = 0.610). The most commonly used VTE treatment strategy was enoxaparin (12 out of 19 VTEs). This study illustrates that VTE does occur rarely in patients who have undergone HCT. The optimal treatment regimen in this population requires further evaluation. Until a reliable protocol for treatment and evidence for risk factors are established, providers should be vigilant for occurrence of VTE in these patients.

Prediction of Allogeneic Hematopoietic Stem-Cell Transplantation Mortality 100 Days After Transplantation Using a Machine Learning Algorithm: A European Group for Blood and Marrow Transplantation Acute Leukemia Working Party Retrospective Data Mining Study.

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Shouval, Roni; Labopin, Myriam; Bondi, Ori; Mishan-Shamay, Hila; Shimoni, Avichai; Ciceri, Fabio; Esteve, Jordi; Giebel, Sebastian; Gorin, Norbert C; Schmid, Christoph; Polge, Emmanuelle; Aljurf, Mahmoud; Kroger, Nicolaus; Craddock, Charles; Bacigalupo, Andrea; Cornelissen, Jan J; Baron, Frederic; Unger, Ron; Nagler, Arnon; Mohty, Mohamad

2015-10-01

Allogeneic hematopoietic stem-cell transplantation (HSCT) is potentially curative for acute leukemia (AL), but carries considerable risk. Machine learning algorithms, which are part of the data mining (DM) approach, may serve for transplantation-related mortality risk prediction. This work is a retrospective DM study on a cohort of 28,236 adult HSCT recipients from the AL registry of the European Group for Blood and Marrow Transplantation. The primary objective was prediction of overall mortality (OM) at 100 days after HSCT. Secondary objectives were estimation of nonrelapse mortality, leukemia-free survival, and overall survival at 2 years. Donor, recipient, and procedural characteristics were analyzed. The alternating decision tree machine learning algorithm was applied for model development on 70% of the data set and validated on the remaining data. OM prevalence at day 100 was 13.9% (n=3,936). Of the 20 variables considered, 10 were selected by the model for OM prediction, and several interactions were discovered. By using a logistic transformation function, the crude score was transformed into individual probabilities for 100-day OM (range, 3% to 68%). The model's discrimination for the primary objective performed better than the European Group for Blood and Marrow Transplantation score (area under the receiver operating characteristics curve, 0.701 v 0.646; Prisk evaluation of patients with AL before HSCT, and is available online (http://bioinfo.lnx.biu.ac.il/∼bondi/web1.html). It is presented as a continuous probabilistic score for the prediction of day 100 OM, extending prediction to 2 years. The DM method has proved useful for clinical prediction in HSCT. © 2015 by American Society of Clinical Oncology.

A human monoclonal antibody drug and target discovery platform for B-cell chronic lymphocytic leukemia based on allogeneic hematopoietic stem cell transplantation and phage display.

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Baskar, Sivasubramanian; Suschak, Jessica M; Samija, Ivan; Srinivasan, Ramaprasad; Childs, Richard W; Pavletic, Steven Z; Bishop, Michael R; Rader, Christoph

2009-11-12

Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potentially curative treatment available for patients with B-cell chronic lymphocytic leukemia (B-CLL). Here, we show that post-alloHSCT antibody repertoires can be mined for the discovery of fully human monoclonal antibodies to B-CLL cell-surface antigens. Sera collected from B-CLL patients at defined times after alloHSCT showed selective binding to primary B-CLL cells. Pre-alloHSCT sera, donor sera, and control sera were negative. To identify post-alloHSCT serum antibodies and subsequently B-CLL cell-surface antigens they recognize, we generated a human antibody-binding fragment (Fab) library from post-alloHSCT peripheral blood mononuclear cells and selected it on primary B-CLL cells by phage display. A panel of Fab with B-CLL cell-surface reactivity was strongly enriched. Selection was dominated by highly homologous Fab predicted to bind the same antigen. One Fab was converted to immunoglobulin G1 and analyzed for reactivity with peripheral blood mononuclear cells from B-CLL patients and healthy volunteers. Cell-surface antigen expression was restricted to primary B cells and up-regulated in primary B-CLL cells. Mining post-alloHSCT antibody repertoires offers a novel route to discover fully human monoclonal antibodies and identify antigens of potential therapeutic relevance to B-CLL and possibly other cancers. Trials described herein were registered at www.clinicaltrials.gov as nos. NCT00055744 and NCT00003838.

Donor cytomegalovirus status influences the outcome of allogeneic stem cell transplant: a study by the European group for blood and marrow transplantation.

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Ljungman, Per; Brand, Ronald; Hoek, Jennifer; de la Camara, Rafael; Cordonnier, Catherine; Einsele, Hermann; Styczynski, Jan; Ward, Katherine N; Cesaro, Simone

2014-08-15

The use of a cytomegalovirus (CMV)-seronegative donor for a CMV-seronegative allogeneic hematopoietic stem cell transplant (HSCT) recipient is generally accepted. However, the importance of donor serostatus in CMV-seropositive patients is controversial. A total of 49 542 HSCT patients, 29 349 seropositive and 20 193 seronegative, were identified from the European Group for Blood and Marrow Transplantation database. Cox multivariate models were fitted to estimate the effect of donor CMV serological status on outcome. Seronegative patients receiving seropositive unrelated-donor grafts had decreased overall survival (hazard ratio [HR], 1.13; 95% confidence interval [CI], 1.06-1.21; P donors, whereas no difference was seen in patients receiving HLA-matched sibling grafts. Seropositive patients receiving grafts from seropositive unrelated donors had improved overall survival (HR, 0.92; 95% CI, .86-.98; P donors, if they had received myeloablative conditioning. This effect was absent when they received reduced-intensity conditioning. No effect was seen in patients grafted from HLA-identical sibling donors. The same association was found if the study was limited to patients receiving transplants from the year 2000 onward. We confirm the negative impact on overall survival if a CMV-seropositive unrelated donor is selected for a CMV-seronegative patient. For a CMV-seropositive patient, our data support selecting a CMV-seropositive donor if the patient receives a myeloablative conditioning regimen. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Outcomes of Hematopoietic Stem Cell Transplantation at a Limited-Resource Center in Mexico Are Comparable to Those in Developed Countries.

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Leon Rodriguez, Eucario; Rivera Franco, Monica M

2017-11-01

The first hematopoietic stem cell transplantation (HSCT) in Mexico was performed at our institution in 1980. Eighteen years later, our HSCT program was restructured to reduce transplantation-related mortality (TRM) and improve overall survival (OS). The aim of this study was to describe outcomes of HSCT at our institution despite limited resources. Consecutive patients undergoing HSCT, from November 1998 to February 2017, were retrospectively analyzed at the National Institute of Medical Sciences and Nutrition Salvador Zubiran in Mexico City. Three hundred nine HSCT (59% autologous) were performed in 275 patients. From 114 patients (41%) undergoing an allogeneic HSCT, acute and chronic graft-versus-host disease developed in 21% and 33%, respectively. From the entire cohort, 98 patients relapsed after HSCT and at the last follow-up, 183 (67%) patients were alive. The 100-day TRM rates were 1.9% and 6.1% for autologous and allogeneic HSCT, respectively. Ten-year relapse/progression-free survival were 54% and 65%, for autologous and allogeneic HSCT, respectively. Ten-year OS rates in autologous and allogeneic HSCT were 61% and 57%, respectively. We highlight that HSCT is feasible in developing countries, despite financial and infrastructure limitations, and conclude that our results are comparable to international literature and probably better in terms of TRM and cost-effectiveness. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Generation of induced pluripotent stem cells as a potential source of hematopoietic stem cells for transplant in PNH patients.

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Phondeechareon, Tanapol; Wattanapanitch, Methichit; U-Pratya, Yaowalak; Damkham, Chanapa; Klincumhom, Nuttha; Lorthongpanich, Chanchao; Kheolamai, Pakpoom; Laowtammathron, Chuti; Issaragrisil, Surapol

2016-10-01

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT. The disease involves only HSCs and their progeny; therefore, other tissues are not affected by the mutation and may be used to produce disease-free autologous HSCs. This study aimed to derive PNH patient-specific iPSCs from human dermal fibroblasts (HDFs), characterize and differentiate to hematopoietic cells using a feeder-free protocol. Analysis of CD55 and CD59 expression was performed before and after reprogramming, and hematopoietic differentiation. Patients' dermal fibroblasts expressed CD55 and CD59 at normal levels and the normal expression remained after reprogramming. The iPSCs derived from PNH patients had typical pluripotent properties and differentiation capacities with normal karyotype. After hematopoietic differentiation, the differentiated cells expressed early hematopoietic markers (CD34 and CD43) with normal CD59 expression. The iPSCs derived from HDFs of PNH patients have normal levels of CD55 and CD59 expression and hold promise as a potential source of HSCs for autologous transplantation to cure PNH patients.

Financial Hardship and Patient-Reported Outcomes after Hematopoietic Cell Transplantation

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Abel, Gregory A.; Albelda, Randy; Khera, Nandita; Hahn, Theresa; Salas Coronado, Diana Y.; Odejide, Oreofe O.; Bona, Kira; Tucker-Seeley, Reginald; Soiffer, Robert

2016-01-01

Although hematopoietic cell transplantation (HCT) is the only curative therapy for many advanced hematologic cancers, little is known about the financial hardship experienced by HCT patients, nor the association of hardship with patient-reported outcomes. We mailed a 43-item survey to adult patients approximately 180 days post first autologous or allogeneic HCT at three high-volume centers. We assessed decreases in household income, difficulty with HCT-related costs such as need to relocate or travel, and two types of hardship: “hardship_1” (reporting one or two of the following: dissatisfaction with present finances, difficulty meeting monthly bill payments, or not having enough money at the end of the month), and “hardship_2” (reporting all three). Patient-reported stress was measured with the Perceived Stress Scale (PSS-4), and seven-point scales were provided for perceptions of overall quality of life (QOL) and health. 325 of 499 surveys (65.1%) were received. The median days since HCT was 173; 47% underwent an allogeneic HCT, 60% were male, 51% were > 60 years old, and 92% were white. Overall, 46% reported income decline post-HCT, 56% reported “hardship_1” and 15% “hardship 2.” In multivariable models controlling for income, those reporting difficulty paying for HCT-related costs were more likely to report financial hardship (OR 6.9 [3.8, 12.3]). “Hardship_1” was associated with QOL below the median (OR 2.9 [1.7, 4.9]), health status below the median (OR 2.2 [1.3, 3.6]), and stress above the median (OR 2.1 [1.3, 3.5]). In this sizable cohort of HCT patients, financial hardship was prevalent, and associated with worse QOL and higher levels of perceived stress. Interventions to address patient financial hardship—especially those that ameliorate HCT-specific costs—are likely to improve patient-reported outcomes. PMID:27184627

Financial Hardship and Patient-Reported Outcomes after Hematopoietic Cell Transplantation.

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Abel, Gregory A; Albelda, Randy; Khera, Nandita; Hahn, Theresa; Salas Coronado, Diana Y; Odejide, Oreofe O; Bona, Kira; Tucker-Seeley, Reginald; Soiffer, Robert

2016-08-01

Although hematopoietic cell transplantation (HCT) is the only curative therapy for many advanced hematologic cancers, little is known about the financial hardship experienced by HCT patients nor the association of hardship with patient-reported outcomes. We mailed a 43-item survey to adult patients approximately 180 days after their first autologous or allogeneic HCT at 3 high-volume centers. We assessed decreases in household income; difficulty with HCT-related costs, such as need to relocate or travel; and 2 types of hardship: hardship_1 (reporting 1 or 2 of the following: dissatisfaction with present finances, difficulty meeting monthly bill payments, or not having enough money at the end of the month) and "hardship_2" (reporting all 3). Patient-reported stress was measured with the Perceived Stress Scale-4, and 7-point scales were provided for perceptions of overall quality of life (QOL) and health. In total, 325 of 499 surveys (65.1%) were received. The median days since HCT was 173; 47% underwent an allogeneic HCT, 60% were male, 51% were > 60 years old, and 92% were white. Overall, 46% reported income decline after HCT, 56% reported hardship_1, and 15% reported hardship_2. In multivariable models controlling for income, those reporting difficulty paying for HCT-related costs were more likely to report financial hardship (odds ratio, 6.9; 95% confidence interval, 3.8 to 12.3). Hardship_1 was associated with QOL below the median (odds ratio, 2.9; 95% confidence interval, 1.7 to 4.9), health status below the median (odds ratio, 2.2; 95% confidence interval, 1.3 to 3.6), and stress above the median (odds ratio, 2.1; 95% confidence interval, 1.3 to 3.5). In this sizable cohort of HCT patients, financial hardship was prevalent and associated with worse QOL and higher levels of perceived stress. Interventions to address patient financial hardship-especially those that ameliorate HCT-specific costs-are likely to improve patient-reported outcomes. Copyright © 2016

Where does allogeneic stem cell transplantation fit in the treatment of chronic lymphocytic leukemia?

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Dreger, Peter; Montserrat, Emili

2015-03-01

Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (CLL) (i.e., refractory to purine analogs, short response (CLL treatment armamentarium. These signal transduction inhibitors (STI) will change the algorithms of high-risk CLL (HR-CLL) management. Despite the limited body of evidence, there is sufficient rationale for withholding alloHSCT in patients with 17p-/TP53mut CLL in first remission. In contrast, the perspectives of patients with relapsed 17p-/TP53mut CLL remain uncertain even if responding to STI. The same accounts for patients with HR-CLL progressing under STI. In both scenarios, it is reasonable to consider alloHSCT, ideally after response to alternative STI regimens.

Scripts for TRUMP data analyses. Part II (HLA-related data): statistical analyses specific for hematopoietic stem cell transplantation.

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Kanda, Junya

2016-01-01

The Transplant Registry Unified Management Program (TRUMP) made it possible for members of the Japan Society for Hematopoietic Cell Transplantation (JSHCT) to analyze large sets of national registry data on autologous and allogeneic hematopoietic stem cell transplantation. However, as the processes used to collect transplantation information are complex and differed over time, the background of these processes should be understood when using TRUMP data. Previously, information on the HLA locus of patients and donors had been collected using a questionnaire-based free-description method, resulting in some input errors. To correct minor but significant errors and provide accurate HLA matching data, the use of a Stata or EZR/R script offered by the JSHCT is strongly recommended when analyzing HLA data in the TRUMP dataset. The HLA mismatch direction, mismatch counting method, and different impacts of HLA mismatches by stem cell source are other important factors in the analysis of HLA data. Additionally, researchers should understand the statistical analyses specific for hematopoietic stem cell transplantation, such as competing risk, landmark analysis, and time-dependent analysis, to correctly analyze transplant data. The data center of the JSHCT can be contacted if statistical assistance is required.

Allogeneic tumor cell vaccines

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Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N; Imasuen, Imade E; He, Sara; Daniels, Danielle; Selvaraj, Periasamy

2014-01-01

The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies. PMID:24064957

Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study.

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Gratwohl, Alois; Sureda, Anna; Baldomero, Helen; Gratwohl, Michael; Dreger, Peter; Kröger, Nicolaus; Ljungman, Per; McGrath, Eoin; Mohty, Mohamad; Nagler, Arnon; Rambaldi, Alessandro; de Elvira, Carmen Ruiz; Snowden, John A; Passweg, Jakob; Apperley, Jane; Niederwieser, Dietger; Stijnen, Theo; Brand, Ronald

2015-12-01

Hematopoietic stem cell transplantation (HSCT) is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37%) or autologous (N = 65,007; 63%) HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84-0·91 per 10 patients; p < 0·0001; HR 0·90;0·85-0·90 per 10 years; p < 0·001) and autologous HSCT (HR 0·91;0·87-0·96 per 10 patients; p < 0·001; HR 0·93;0·87-0·99 per 10 years; p = 0·02). The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R(2) = 18%; for relapse free survival) after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.

Evaluation of Quality of Life and Care Needs of Turkish Patients Undergoing Hematopoietic Stem Cell Transplantation

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Neslisah Yasar

2016-01-01

Full Text Available This descriptive study explored the quality of life and care needs of Turkish patients who underwent hematopoietic stem cell transplantation. The study sample consisted of 100 hematopoietic stem cell transplant patients. Their quality of life was assessed using Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale. The mean patient age was 44.99 ± 13.92 years. Changes in sexual functions, loss of hair, loss of taste, loss of appetite, and sleep disturbances were the most common symptoms. The quality of life of transplant patients was moderately affected; the functional well-being and social/family well-being subscales were the most adversely and least negatively affected (12.13 ± 6.88 dimensions, respectively. Being female, being between 50 and 59 years of age, being single, having a chronic disease, and having a history of hospitalization were associated with lower quality of life scores. Interventions to improve functional status, physical well-being, and emotional status of patients during the transplantation process may help patients cope with treatment-related impairments more effectively. Frequent screening and management of patient symptoms in order to help patients adapt to life following allogeneic hematopoietic stem cell transplantation are crucial for meeting care needs and developing strategies to improve their quality of life.

A New Clinicobiological Scoring System for the Prediction of Infection-Related Mortality and Survival after Allogeneic Hematopoietic Stem Cell Transplantation.

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Forcina, Alessandra; Rancoita, Paola M V; Marcatti, Magda; Greco, Raffaella; Lupo-Stanghellini, Maria Teresa; Carrabba, Matteo; Marasco, Vincenzo; Di Serio, Clelia; Bernardi, Massimo; Peccatori, Jacopo; Corti, Consuelo; Bondanza, Attilio; Ciceri, Fabio

2017-12-01

Infection-related mortality (IRM) is a substantial component of nonrelapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). No scores have been developed to predict IRM before transplantation. Pretransplantation clinical and biochemical data were collected from a study cohort of 607 adult patients undergoing allo-HSCT between January 2009 and February 2017. In a training set of 273 patients, multivariate analysis revealed that age >60 years (P = .003), cytomegalovirus host/donor serostatus different from negative/negative (P < .001), pretransplantation IgA level <1.11 g/L (P = .004), and pretransplantation IgM level <.305 g/L (P = .028) were independent predictors of increased IRM. Based on these results, we developed and subsequently validated a 3-tiered weighted prognostic index for IRM in a retrospective set of patients (n = 219) and a prospective set of patients (n = 115). Patients were assigned to 3 different IRM risk classes based on this index score. The score significantly predicted IRM in the training set, retrospective validation set, and prospective validation set (P < .001, .044, and .011, respectively). In the training set, 100-day IRM was 5% for the low-risk group, 11% for the intermediate-riak group, and 16% for the high-risk groups. In the retrospective validation set, the respective 100-day IRM values were 7%, 17%, and 28%, and in the prospective set, they were 0%, 5%, and 7%. This score predicted also overall survival (P < .001 in the training set, P < 041 in the retrospective validation set, and P < .023 in the prospective validation set). Because pretransplantation levels of IgA/IgM can be modulated by the supplementation of enriched immunoglobulins, these results suggest the possibility of prophylactic interventional studies to improve transplantation outcomes. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All

Murine cytomegalovirus immediate-early 1 gene expression correlates with increased GVHD after allogeneic hematopoietic cell transplantation in recipients reactivating from latent infection.

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Senthilnathan Palaniyandi

Full Text Available The success of allogeneic (allo hematopoietic cell transplantation (HCT is limited by its treatment related complications, mostly graft versus host disease (GVHD and fungal and viral infections. CMV reactivation after HCT has been associated with increased morbidity and mortality, and a causal relation between GVHD, immunosuppressive therapy and vice versa has been postulated. Using a low GVHD severity murine HCT model, we assessed the role of MCMV reactivation and GVHD development. BALB/c mice were infected with either murine CMV (MCMV or mock and monitored for 25 weeks to establish latency, followed by sublethal irradiation conditioning and infusion of bone marrow plus splenocytes from either syngeneic (syn BALB/c or allo B10.D2 donors. Engraftment of allo donor cells was confirmed by PCR for D2Mit265 gene product size. Day+100 mortality and overall GVHD severity in allo MCMV pre-infected recipients was higher than in allo mock controls. Pathologic changes of lung and liver GVHD in immediate-early gene 1 (IE1 positive recipients were significantly increased compared to mock controls, and were only slightly increased in IE1 negative. No significant gut injury was seen in any group. Aggravated lung injury in IE1 positive recipients correlated with higher BAL cell counts both for total cells and for CD4+ T cells when compared with mock controls, and also with protein expression of lung IFN-gamma and liver TNF. No evidence for CMV specific morphologic changes was seen on histopathology in any organ of IE1 positive recipients, suggesting that CMV reactivation is related to increased GVHD severity but does not require active CMV disease, strengthening the concept of a reciprocal relationship between CMV and GVHD.

Pilot experience with opebacan/rBPI21 in myeloablative hematopoietic cell transplantation [version 1; referees: 2 approved

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Eva Guinan

2015-12-01

Full Text Available Bacterial infection and inflammation contribute significantly to the morbidity and mortality of myeloablative allogeneic hematopoietic cell transplantation (HCT. Endotoxin, a component of the outer membrane of Gram-negative bacteria, is a potent inflammatory stimulus in humans. Bactericidal/permeability increasing protein (BPI, a constituent of human neutrophil granules, binds endotoxin thereby precluding endotoxin-induced inflammation and also has direct anti-infective properties against bacteria. As a consequence of myeloablative therapy used in preparation for hematopoietic cell infusion, patients experience gastrointestinal leak of bacteria and bacterial toxins into the systemic circulation and a period of inflammatory cytokine elevation associated with subsequent regimen-related toxicities.  Patients frequently become endotoxemic and febrile as well as BPI-deficient due to sustained neutropenia. To examine whether enhancing endotoxin-neutralizing and anti-infective activity by exogenous administration of a recombinant N-terminal fragment of BPI (rBPI21, generic name opebacan might ameliorate regimen-related toxicities including infection, we recruited patients scheduled to undergo myeloablative HCT to participate in a proof-of-concept prospective phase I/II trial. After the HCT preparative regimen was completed, opebacan was initiated 18-36 hours prior to administration of allogeneic hematopoietic stem cells (defined as Day 0 and continued for 72 hours. The trial was to have included escalation of rBPI21 dose and duration but was stopped prematurely due to lack of further drug availability.  Therefore, to better understand the clinical course of opebacan-treated patients (n=6, we compared their outcomes with a comparable cohort meeting the same eligibility criteria and enrolled in a non-interventional myeloablative HCT observational study (n = 35.  Opebacan-treated participants had earlier platelet engraftment (p=0.005, mirroring

Autologous transplantation versus allogeneic transplantation in patients with follicular lymphoma experiencing early treatment failure.

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Smith, Sonali M; Godfrey, James; Ahn, Kwang Woo; DiGilio, Alyssa; Ahmed, Sairah; Agrawal, Vaibhav; Bachanova, Veronika; Bacher, Ulrike; Bashey, Asad; Bolaños-Meade, Javier; Cairo, Mitchell; Chen, Andy; Chhabra, Saurabh; Copelan, Edward; Dahi, Parastoo B; Aljurf, Mahmoud; Farooq, Umar; Ganguly, Siddhartha; Hertzberg, Mark; Holmberg, Leona; Inwards, David; Kanate, Abraham S; Karmali, Reem; Kenkre, Vaishalee P; Kharfan-Dabaja, Mohamed A; Klein, Andreas; Lazarus, Hillard M; Mei, Matthew; Mussetti, Alberto; Nishihori, Taiga; Ramakrishnan Geethakumari, Praveen; Saad, Ayman; Savani, Bipin N; Schouten, Harry C; Shah, Nirav; Urbano-Ispizua, Alvaro; Vij, Ravi; Vose, Julie; Sureda, Anna; Hamadani, Mehdi

2018-04-12

Early treatment failure (ETF) in follicular lymphoma (FL), defined as relapse or progression within 2 years of frontline chemoimmunotherapy, is a newly recognized marker of poor survival and identifies a high-risk group of patients with an expected 5-year overall survival (OS) rate of approximately 50%. Transplantation is an established option for relapsed FL, but its efficacy in this specific ETF FL population has not been previously evaluated. This study compared autologous hematopoietic stem cell transplantation (auto-HCT) with either matched sibling donor (MSD) or matched unrelated donor (MUD) allogeneic hematopoietic cell transplantation (allo-HCT) as the first transplantation approach for patients with ETF FL (age ≥ 18 years) undergoing auto-HCT or allo-HCT between 2002 and 2014. The primary endpoint was OS. The secondary endpoints were progression-free survival, relapse, and nonrelapse mortality (NRM). Four hundred forty FL patients had ETF (auto-HCT, 240; MSD hematopoietic stem cell transplantation [HCT], 105; and MUD HCT, 95). With a median follow-up of 69 to 73 months, the adjusted probability of 5-year OS was significantly higher after auto-HCT (70%) or MSD HCT (73%) versus MUD HCT (49%; P = .0008). The 5-year adjusted probability of NRM was significantly lower for auto-HCT (5%) versus MSD (17%) or MUD HCT (33%; P ETF, undergoing auto-HCT for FL have low NRM and a promising 5-year OS rate (70%). MSD HCT has lower relapse rates than auto-HCT but similar OS. Cancer 2018. © 2018 American Cancer Society. © 2018 American Cancer Society.

The cumulative burden of double-stranded DNA virus detection after allogeneic HCT is associated with increased mortality.

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Hill, Joshua A; Mayer, Bryan T; Xie, Hu; Leisenring, Wendy M; Huang, Meei-Li; Stevens-Ayers, Terry; Milano, Filippo; Delaney, Colleen; Sorror, Mohamed L; Sandmaier, Brenda M; Nichols, Garrett; Zerr, Danielle M; Jerome, Keith R; Schiffer, Joshua T; Boeckh, Michael

2017-04-20

Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease ( P values < .01). Absolute lymphocyte count of <200 cells/mm 3 was associated with greater virus exposure on the basis of the maximum cumulative viral load area under the curve (AUC) ( P = .054). The maximum cumulative viral load AUC was the best predictor of early (days 0-100) and late (days 101-365) overall mortality (adjusted hazard ratio [aHR] = 1.36, 95% confidence interval [CI] [1.25, 1.49], and aHR = 1.04, 95% CI [1.0, 1.08], respectively) after accounting for immune reconstitution and graft-versus-host disease. In conclusion, detection of multiple dsDNA viruses was frequent after allogeneic HCT and had a dose-dependent association with increased mortality. These data suggest opportunities to improve outcomes with better antiviral strategies. © 2017 by The American Society of Hematology.

F4/80+ Host Macrophages Are a Barrier to Murine Embryonic Stem Cell-Derived Hematopoietic Progenitor Engraftment In Vivo.

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Thompson, Heather L; van Rooijen, Nico; McLelland, Bryce T; Manilay, Jennifer O

2016-01-01

Understanding how embryonic stem cells and their derivatives interact with the adult host immune system is critical to developing their therapeutic potential. Murine embryonic stem cell-derived hematopoietic progenitors (ESHPs) were generated via coculture with the bone marrow stromal cell line, OP9, and then transplanted into NOD.SCID.Common Gamma Chain (NSG) knockout mice, which lack B, T, and natural killer cells. Compared to control mice transplanted with adult lineage-negative bone marrow (Lin - BM) progenitors, ESHP-transplanted mice attained a low but significant level of donor hematopoietic chimerism. Based on our previous studies, we hypothesized that macrophages might contribute to the low engraftment of ESHPs in vivo . Enlarged spleens were observed in ESHP-transplanted mice and found to contain higher numbers of host F4/80 + macrophages compared to BM-transplanted controls. In vivo depletion of host macrophages using clodronate-loaded liposomes improved the ESHP-derived hematopoietic chimerism in the spleen but not in the BM. F4/80 + macrophages demonstrated a striking propensity to phagocytose ESHP targets in vitro . Taken together, these results suggest that macrophages are a barrier to both syngeneic and allogeneic ESHP engraftment in vivo .

131I-Anti-CD45 Antibody Plus Busulfan and Cyclophosphamide before Allogeneic Hematophoietic Cell Transplantation for Treatment of Acute Myeloid Leukemia in First Remission

International Nuclear Information System (INIS)

Pagel, John M.; Appelbaum, Frederick R.; Eary, Janet F.; Rajendran, Joseph G.; Fisher, Darrell R.; Gooley, Ted; Ruffner, Katherine; Nemecek, Eneida; Sickle, Eileen; Durack, Larry; Carreras, Jeanette; Horowitz, Mary; Press, Oliver W.; Gopal, Ajay K.; Martin, Paul J.; Bernstein, Irwin D.; Matthews, Dana C.

2006-01-01

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a Phase I/II study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/ml) and cyclophosphamide (CY; 120 mg/kg). Fifty-two of 59 patients (88%) receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102-298 mCi 131I delivering an estimated 5.3-19 (mean 11.3) Gy to marrow, 17-72 (mean 29.7) Gy to spleen, and 3.5 Gy (n=4) to 5.25 Gy (n=42) to the liver. The estimated 3-year non-relapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared to those from 509 similar International Bone Marrow Transplant Registry patients transplanted using BU/CY alone. After adjusting for differences in age and cytogenetics-risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; p=.09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and Phase II results are sufficiently encouraging to warrant further study

Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation

Energy Technology Data Exchange (ETDEWEB)

Server, Andres [Oslo University Hospital-Rikshospitalet, Section of Neuroradiology, Department of Radiology and Nuclear Medicine, Oslo (Norway); Bargallo, Nuria [Universitat de Barcelona, Section of Neuroradiology, Department of Radiology, Hospital Clinic, Barcelona (Spain); Institut d' investigacions Biomediques August Pi i Sunyer (IDIBARS), Resonance Magnetic Image Core Facility, Barcelona (Spain); Floeisand, Yngvar [Oslo University Hospital-Rikshospitalet, Department of Hematology, Oslo (Norway); Sponheim, Jon [Oslo University Hospital-Rikshospitalet, Section of Gastroenterology, Department of Transplantation Medicine, Oslo (Norway); Graus, Francesc [Universitat de Barcelona, Department of Neurology, Hospital Clinic, Barcelona (Spain); Institut d' investigacions Biomediques August Pi i Sunyer (IDIBARS), Neuroimmunology Program, Barcelona (Spain); Hald, John K. [Oslo University Hospital-Rikshospitalet, Section of Neuroradiology, Department of Radiology and Nuclear Medicine, Oslo (Norway); University of Oslo, Faculty of Medicine, Oslo (Norway)

2017-02-15

Neurologic complications are common after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) and affect 30-60% of transplant recipients. The aim of this article is to provide a practical imaging approach based on the timeline and etiology of CNS abnormalities, and neurologic complications related to transplantation of specific organs. The lesions will be classified based upon the interval from HSCT procedure: pre-engraftment period <30 days, early post-engraftment period 30-100 days, late post-engraftment period >100 days, and the interval from SOT procedure: postoperative phase 1-4 weeks, early posttransplant syndromes 1-6 months, late posttransplant syndromes >6 months. Further differentiation will be based on etiology: infections, drug toxicity, metabolic derangements, cerebrovascular complications, and posttransplantation malignancies. In addition, differentiation will be based on complications specific to the type of transplantation: allogeneic and autologous hematopoietic stem cells (HSC), heart, lung, kidney, pancreas, and liver. Thus, in this article we emphasize the strategic role of neuroradiology in the diagnosis and response to treatment by utilizing a methodical approach in the work up of patients with neurologic complications after transplantation. (orig.)

Imaging spectrum of central nervous system complications of hematopoietic stem cell and solid organ transplantation

International Nuclear Information System (INIS)

Server, Andres; Bargallo, Nuria; Floeisand, Yngvar; Sponheim, Jon; Graus, Francesc; Hald, John K.

2017-01-01

Neurologic complications are common after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT) and affect 30-60% of transplant recipients. The aim of this article is to provide a practical imaging approach based on the timeline and etiology of CNS abnormalities, and neurologic complications related to transplantation of specific organs. The lesions will be classified based upon the interval from HSCT procedure: pre-engraftment period <30 days, early post-engraftment period 30-100 days, late post-engraftment period >100 days, and the interval from SOT procedure: postoperative phase 1-4 weeks, early posttransplant syndromes 1-6 months, late posttransplant syndromes >6 months. Further differentiation will be based on etiology: infections, drug toxicity, metabolic derangements, cerebrovascular complications, and posttransplantation malignancies. In addition, differentiation will be based on complications specific to the type of transplantation: allogeneic and autologous hematopoietic stem cells (HSC), heart, lung, kidney, pancreas, and liver. Thus, in this article we emphasize the strategic role of neuroradiology in the diagnosis and response to treatment by utilizing a methodical approach in the work up of patients with neurologic complications after transplantation. (orig.)

In utero hematopoietic stem cell transfer: current status and future strategies.

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Surbek, D V; Gratwohl, A; Holzgreve, W

1999-07-01

Successful prenatal treatment of severe immunodeficiencies by allogeneic hematopoietic stem cell transplantation in utero has been reported. Though other diseases like hemoglobinopathies or storage diseases are potentially amenable to this novel therapeutic approach, no success has yet been achieved in recipients without severe immunodeficiency. Graft rejection by the developing fetus and/or lack of selective, competitive advantage of donor versus host stem cells preventing stable engraftment seem to be the major obstacles. Several strategies to overcome these hurdles are being explored in preclinical settings, including timing and repeated dosing of stem cell administration to the fetus, ex vivo modification of the transplant, using different fetal compartments as targets for early stem cell transfer, or inducing microchimerism for postnatal transplantation from the same donor. In addition, the exact definition of the basic concept of early fetal immunologic naivete and the understanding of the molecular basics of migration and homing in fetal hematopoiesis system seem mandatory for a successful approach. Gene therapy using ex vivo transduced autologous cord blood cells or direct gene targeting in utero are other potential means to correct hematopoietic and immunologic single gene disorders in utero, though this approach is still away from the stage of clinical trials.

Application of human amniotic mesenchymal cells as an allogeneic transplantation cell source in bone regenerative therapy

International Nuclear Information System (INIS)

Tsuno, Hiroaki; Yoshida, Toshiko; Nogami, Makiko; Koike, Chika; Okabe, Motonori; Noto, Zenko; Arai, Naoya; Noguchi, Makoto; Nikaido, Toshio

2012-01-01

Autogenous mesenchymal stem cells (MSCs) have therapeutic applications in bone regenerative therapy due to their pluripotency. However, the ability of MSCs to proliferate and differentiate varies between donors. Furthermore, alternative sources of MSCs are required for patients with contraindications to autogenous cell therapy. The aim of this study was to evaluate the potential of mesenchymal cells from the human amniotic membrane (HAM) as a source of cells for allogeneic transplantation in bone regenerative therapy. Cells that retained a proliferative capacity of more than 50 population doubling level were distinguished from other HAM cells as HAMα cells and induced to osteogenic status—their in vivo osteogenesis was subsequently investigated in rats. It was found that HAMα cells were spindle shaped and were positive for MSC markers and negative for hematopoietic stem cell markers. Alkaline phosphatase activity and calcium deposition increased with osteogenic status of HAMα cells. The expression of osteocalcin mRNA was increased in HAMα cells cultured on calcium phosphate scaffolds. Moreover, xenografted HAMα cells remained viable and produced extracellular matrix for several weeks. Thus, this study suggests that human amniotic mesenchymal cells possess osteogenic differentiation potential and could be applied to allogeneic transplantation in bone regenerative therapy. - Highlights: ► Human amniotic mesenchymal cells include cells (HAMα cells) that have the properties of MSCs. ► HAMα cells have excellent osteogenic differentiation potential. ► Osteogenic differentiation ability of HAMα was amplified by calcium phosphate scaffolds. ► HAMα cells can be applicable to allogeneic cell transplantation in bone regenerative therapy.

Late non-infectious lung damage in children after allogeneic hematopoietic stem cells transplantation

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Yu. V. Skvortsova

2015-06-01

Full Text Available Hematopoietic stem cells transplantation (HSCT technology currently allows curing a lot of malignant and non-malignant diseases in adults and children. However, HSCT is highly toxic treatment. HSCT complications include the possibility of prolonged immunodeficiency, alloand autoimmune reactions and various organs dysfunction. These conditions require careful monitoring by specialists, early diagnosis and appropriate treatment. This article discusses the clinical features, diagnosis and treatment options of such late complications as non-infectious lung disease. These conditions can lead to disability of patients. Relevance and importance of timely diagnosis of these pathological conditions, including the range of clinical tests available on a residence, with a view to effective treatment can improve the quality of life ofchildren with complications after HSCT. Theoretical issues are illustrated by case report.

Economics and Outcome After Hematopoietic Stem Cell Transplantation: A Retrospective Cohort Study

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Alois Gratwohl

2015-12-01

Full Text Available Hematopoietic stem cell transplantation (HSCT is a lifesaving expensive medical procedure. Hence, more transplants are performed in more affluent countries. The impact of economic factors on patient outcome is less defined. We analyzed retrospectively a defined cohort of 102,549 patients treated with an allogeneic (N = 37,542; 37% or autologous (N = 65,007; 63% HSCT. They were transplanted by one of 404 HSCT centers in 25 European countries between 1999 and 2006. We searched for associations between center-specific microeconomic or country-specific macroeconomic factors and outcome. Center patient-volume and center program-duration were significantly and systematically associated with improved survival after allogeneic HSCT (HR 0·87; 0·84–0·91 per 10 patients; p < 0·0001; HR 0·90;0·85–0·90 per 10 years; p < 0·001 and autologous HSCT (HR 0·91;0·87–0·96 per 10 patients; p < 0·001; HR 0·93;0·87–0·99 per 10 years; p = 0·02. The product of Health Care Expenditures by Gross National Income/capita was significantly associated in multivariate analysis with all endpoints (R2 = 18%; for relapse free survival after allogeneic HSCT. Data indicate that country- and center-specific economic factors are associated with distinct, significant, systematic, and clinically relevant effects on survival after HSCT. They impact on center expertise in long-term disease and complication management. It is likely that these findings apply to other forms of complex treatments.

Hematopoietic Gene Therapies for Metabolic and Neurologic Diseases.

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Biffi, Alessandra

2017-10-01

Increasingly, patients affected by metabolic diseases affecting the central nervous system and neuroinflammatory disorders receive hematopoietic cell transplantation (HCT) in the attempt to slow the course of their disease, delay or attenuate symptoms, and improve pathologic findings. The possible replacement of brain-resident myeloid cells by the transplanted cell progeny contributes to clinical benefit. Genetic engineering of the cells to be transplanted (hematopoietic stem cell) may endow the brain myeloid progeny of these cells with enhanced or novel functions, contributing to therapeutic effects. Copyright © 2017 Elsevier Inc. All rights reserved.

Use of Eltrombopag in Improving Poor Graft Function after Allogeneic Hematopoietic Stem Cell Transplantation

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Samip Master

2018-03-01

Full Text Available Eltrombopag is a thrombopoietin agonist and has been used in aplastic anemia and post-transplantation thrombocytopenia. The c-MPL receptor is present on hematopoietic stem cells. There are no reports of eltrombopag utilization for improving poor graft function in the post-transplant setting. Here were report a case of a young female with post-transplant poor graft function as evident from the low absolute neutrophil count, anemia, and thrombocytopenia on day 60. Eltrombopag was started on day 72 and resulted in improvement in all 3 cell lines. The counts continued to be stable even after eltrombopag was discontinued. The patient tolerated the drug without significant side effects for 1 year.

[Role of long-term follow-up in management of late-onset post-hematopoietic stem cell transplant complications].

Science.gov (United States)

Asano-Mori, Yuki

As the number of long-term survivors after allogeneic hematopoietic stem cell transplantation (HSCT) has increased owing to advances in transplantation and supportive care techniques, the health and welfare of these survivors have come into focus. However, they are still at risks for various complications, including chronic graft-versus-host disease, infectious diseases, and secondary cancers even in the late period, which can not only interfere with the patient's quality of life (QOL) but also lead to death. The importance of long-term follow-up (LTFU) and management have been recently recognized, and nationwide systems to promote LTFU care in patients receiving HSCT, such as medical fee revision, publication of a LTFU guideline unique to Japan, and preparation of patient pocketbook, is under consideration. The number of medical facilities at LTFU outpatient clinic is also increasing; therefore, an optimal comprehensive support system may be established sooner or later. However, self-management by patients is essential to overcome late complications as well as to improve QOL after HSCT. Healthcare professionals should collaborate and continue to make the greatest possible efforts to educate patients regarding the risks of late complications and their prevention.

Hematopoietic Stem Cell Transplantation Activity Worldwide in 2012 and a SWOT Analysis of the Worldwide Network for Blood and Marrow Transplantation Group (WBMT) including the global survey

Science.gov (United States)

Niederwieser, Dietger; Baldomero, Helen; Szer, Jeff; Gratwohl, Michael; Aljurf, Mahmoud; Atsuta, Yoshiko; Bouzas, Luis Fernando; Confer, Dennis; Greinix, Hildegard; Horowitz, Mary; Iida, Minako; Lipton, Jeff; Mohty, Mohamad; Novitzky, Nicolas; Nunez, José; Passweg, Jakob; Pasquini, Marcelo C.; Kodera, Yoshihisa; Apperley, Jane; Seber, Adriana; Gratwohl, Alois

2016-01-01

Data on 68,146 hematopoietic stem cell transplants (HSCT) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCT were registered from unrelated 16,433 than related 15,493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared to 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCT/team). An increase of 67% was noted in mismatched/haploidentical family HSCT. A SWOT analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four WHO regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood. PMID:26901703

Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation

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Aurélie Tormo

2017-06-01

Full Text Available Abstract Background Impaired T cell reconstitution remains a major deterrent in the field of bone marrow (BM transplantation (BMT due to pre-conditioning-induced damages inflicted to the thymi of recipient hosts. Given the previously reported thymo-stimulatory property of interleukin (IL-21, we reasoned that its use post-BMT could have a profound effect on de novo T cell development. Methods To evaluate the effect of IL-21 on de novo T cell development in vivo, BM derived from RAG2p-GFP mice was transplanted into LP/J mice. Lymphocyte reconstitution was first assessed using a hematological analyzer and a flow cytometer on collected blood samples. Detailed flow cytometry analysis was then performed on the BM, thymus, and spleen of transplanted animals. Finally, the effect of human IL-21 on thymopoiesis was validated in humanized mice. Results Using a major histocompatibility complex (MHC-matched allogeneic BMT model, we found that IL-21 administration improves immune reconstitution by triggering the proliferation of BM Lin−Sca1+c-kit+ (LSK subsets. The pharmacological effect of IL-21 also culminates in the recovery of both hematopoietic (thymocytes and non-hematopoietic (stromal cells within the thymi of IL-21-treated recipient animals. Although T cells derived from all transplanted groups proliferate, secrete various cytokines, and express granzyme B similarly in response to T cell receptor (TCR stimulation, full regeneration of peripheral naïve CD4+ and CD8+ T cells and normal TCRvβ distribution could only be detected in IL-21-treated recipient mice. Astonishingly, none of the recipient mice who underwent IL-21 treatment developed graft-versus-host disease (GVHD in the MHC-matched allogeneic setting while the graft-versus-tumor (GVT effect was strongly retained. Inhibition of GVHD onset could also be attributed to the enhanced generation of regulatory B cells (B10 observed in the IL-21, but not PBS, recipient mice. We also tested the

Platelet-rich-plasmapheresis for minimising peri-operative allogeneic blood transfusion.

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Carless, Paul A; Rubens, Fraser D; Anthony, Danielle M; O'Connell, Dianne; Henry, David A

2011-03-16

Concerns regarding the safety of transfused blood have generated considerable enthusiasm for the use of technologies intended to reduce the use of allogeneic blood (blood from an unrelated donor). Platelet-rich plasmapheresis (PRP) offers an alternative approach to blood conservation. To examine the evidence for the efficacy of PRP in reducing peri-operative allogeneic red blood cell (RBC) transfusion, and the evidence for any effect on clinical outcomes such as mortality and re-operation rates. We identified studies by searching MEDLINE (1950 to 2009), EMBASE (1980 to 2009), The Cochrane Library (Issue 1, 2009), the Internet (to March 2009) and the reference lists of published articles, reports, and reviews. Controlled parallel group trials in which adult patients, scheduled for non-urgent surgery, were randomised to PRP, or to a control group which did not receive the intervention. Primary outcomes measured were: the number of patients exposed to allogeneic RBC transfusion, and the amount of RBC transfused. Other outcomes measured were: the number of patients exposed to allogeneic platelet transfusions, fresh frozen plasma, and cryoprecipitate, blood loss, re-operation for bleeding, post-operative complications (thrombosis), mortality, and length of hospital stay. Treatment effects were pooled using a random-effects model. Trial quality was assessed using criteria proposed by Schulz et al (Schulz 1995). Twenty-two trials of PRP were identified that reported data for the number of patients exposed to allogeneic RBC transfusion. These trials evaluated a total of 1589 patients. The relative risk (RR) of exposure to allogeneic blood transfusion in those patients randomised to PRP was 0.73 (95%CI 0.59 to 0.90), equating to a relative risk reduction (RRR) of 27% and a risk difference (RD) of 19% (95%CI 10% to 29%). However, significant heterogeneity of treatment effect was observed (p transfused (weighted mean difference [WMD] -0.69, 95%CI -1.93 to 0.56 units). Trials

Polymorphism in the interleukin-7 receptor-alpha and outcome after allogeneic hematopoietic cell transplantation with matched unrelated donor.

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Shamim, Z; Spellman, S; Haagenson, M; Wang, T; Lee, S J; Ryder, L P; Müller, K

2013-08-01

Interleukin-7 (IL-7) is essential for T cell development in the thymus and maintenance of peripheral T cells. The α-chain of the IL-7R is polymorphic with the existence of SNPs that give rise to non-synonymous amino acid substitutions. We previously found an association between donor genotypes and increased treatment-related mortality (TRM) (rs1494555G) and acute graft versus host disease (aGvHD) (rs1494555G and rs1494558T) after hematopoietic cell transplantation (HCT). Some studies have confirmed an association between rs6897932C and multiple sclerosis. In this study, we evaluated the prognostic significance of IL-7Rα SNP genotypes in 590-recipient/donor pairs that received HLA-matched unrelated donor HCT for haematological malignancies. Consistent with the primary studies, the rs1494555GG and rs1494558TT genotypes of the donor were associated with aGvHD and chronic GvHD in the univariate analysis. The Tallele of rs6897932 was suggestive of an association with increased frequency of relapse by univariate analysis (P = 0.017) and multivariate analysis (P = 0.015). In conclusion, this study provides further evidence of a role of the IL-7 pathway and IL-7Rα SNPs in HCT. © 2013 John Wiley & Sons Ltd.

Outcomes of hematopoietic cell transplantation using donors or recipients with inherited chromosomally integrated HHV-6.

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Hill, Joshua A; Magaret, Amalia S; Hall-Sedlak, Ruth; Mikhaylova, Anna; Huang, Meei-Li; Sandmaier, Brenda M; Hansen, John A; Jerome, Keith R; Zerr, Danielle M; Boeckh, Michael

2017-08-24

Human herpesvirus 6 (HHV-6) species have a unique ability to integrate into chromosomal telomeres. Mendelian inheritance via gametocyte integration results in HHV-6 in every nucleated cell. The epidemiology and clinical effect of inherited chromosomally integrated HHV-6 (iciHHV-6) in hematopoietic cell transplant (HCT) recipients is unclear. We identified 4319 HCT donor-recipient pairs (8638 subjects) who received an allogeneic HCT and had archived pre-HCT peripheral blood mononuclear cell samples. We screened these samples for iciHHV-6 and compared characteristics of HCT recipients and donors with iciHHV-6 with those of recipients and donors without iciHHV-6, respectively. We calculated Kaplan-Meier probability estimates and Cox proportional hazards models for post-HCT outcomes based on recipient and donor iciHHV-6 status. We identified 60 HCT recipients (1.4%) and 40 donors (0.9%) with iciHHV-6; both recipient and donor harbored iciHHV-6 in 13 HCTs. Thus, there were 87 HCTs (2%) in which the recipient, donor, or both harbored iciHHV-6. Acute graft-versus-host disease (GVHD) grades 2-4 was more frequent when recipients or donors had iciHHV-6 (adjusted hazard ratios, 1.7-1.9; P = .004-.001). Cytomegalovirus viremia (any and high-level) was more frequent among recipients with iciHHV-6 (adjusted HRs, 1.7-3.1; P = .001-.040). Inherited ciHHV-6 status did not significantly affect risk for chronic GVHD, hematopoietic cell engraftment, overall mortality, or nonrelapse mortality. Screening for iciHHV-6 could guide donor selection and post-HCT risk stratification and treatment. Further study is needed to replicate these findings and identify potential mechanisms. © 2017 by The American Society of Hematology.

Application of human amniotic mesenchymal cells as an allogeneic transplantation cell source in bone regenerative therapy

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Tsuno, Hiroaki [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Yoshida, Toshiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nogami, Makiko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Orthopedic Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Koike, Chika; Okabe, Motonori [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Noto, Zenko [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Arai, Naoya; Noguchi, Makoto [Department of Oral and Maxillofacial Surgery, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan); Nikaido, Toshio, E-mail: tnikaido@med.u-toyama.ac.jp [Department of Regenerative Medicine, Graduate School of Medicine and Pharmaceutical Sciences for Research, University of Toyama, 2630 Sugitani Toyama, Toyama 930-0194 (Japan)

2012-12-01

Autogenous mesenchymal stem cells (MSCs) have therapeutic applications in bone regenerative therapy due to their pluripotency. However, the ability of MSCs to proliferate and differentiate varies between donors. Furthermore, alternative sources of MSCs are required for patients with contraindications to autogenous cell therapy. The aim of this study was to evaluate the potential of mesenchymal cells from the human amniotic membrane (HAM) as a source of cells for allogeneic transplantation in bone regenerative therapy. Cells that retained a proliferative capacity of more than 50 population doubling level were distinguished from other HAM cells as HAM{alpha} cells and induced to osteogenic status-their in vivo osteogenesis was subsequently investigated in rats. It was found that HAM{alpha} cells were spindle shaped and were positive for MSC markers and negative for hematopoietic stem cell markers. Alkaline phosphatase activity and calcium deposition increased with osteogenic status of HAM{alpha} cells. The expression of osteocalcin mRNA was increased in HAM{alpha} cells cultured on calcium phosphate scaffolds. Moreover, xenografted HAM{alpha} cells remained viable and produced extracellular matrix for several weeks. Thus, this study suggests that human amniotic mesenchymal cells possess osteogenic differentiation potential and could be applied to allogeneic transplantation in bone regenerative therapy. - Highlights: Black-Right-Pointing-Pointer Human amniotic mesenchymal cells include cells (HAM{alpha} cells) that have the properties of MSCs. Black-Right-Pointing-Pointer HAM{alpha} cells have excellent osteogenic differentiation potential. Black-Right-Pointing-Pointer Osteogenic differentiation ability of HAM{alpha} was amplified by calcium phosphate scaffolds. Black-Right-Pointing-Pointer HAM{alpha} cells can be applicable to allogeneic cell transplantation in bone regenerative therapy.

The Impact of Methylenetetrahydrofolate Reductase C677T Polymorphism on Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation with Methotrexate Prophylaxis.

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Ja Min Byun

Full Text Available Pharmacogenomics can explain the inter-individual differences in response to drugs, including methotrexate (MTX used for acute graft-versus-host disease (aGVHD prophylaxis during hematopoietic stem cell transplantation (HSCT. In real-world practice, preplanned MTX dose is arbitrarily modified according to observed toxicity which can lead to unexpected and severe aGVHD development. We aimed to validate the influence of MTHFR C677T polymorphism on the outcomes of allogenic HSCT in a relatively under-represented homogenous Asian population. A total of 177 patients were divided into 677TT group versus 677C-carriers (677CT+677CC, and clinical outcomes along with baseline characteristics were analyzed and compared. Although there was a tendency towards increased peak liver function test results and accordingly greater delta values between the highest and the baseline in 677TT group, we found no associations between genotypes and hepatotoxicity. However, the incidence of acute liver GVHD (≥ grade 2 was significantly higher in the 677TT group than in the 677CC + 677CT group (P = 0.016. A total of 25 patients (14.1% expired due to transplantation related mortality (TRM during the first 180 days after HSCT. Patients carrying 677TT genotype were more likely to experience early TRM than 677C-carriers. The same pattern was observed in the cumulative TRM rate, and 677TT genotype patients were more prone to cumulative TRM (P = 0.010. This translated into shorter OS for patients with 677TT compared to 677C-carriers (P = 0.010. The 3-year survival after HSCT was 29.9% for 677TT cases and 47.1% for 677C-carriers. The multivariate analysis identified 677TT genotype (HR = 1.775. 95% CI 1.122-2.808, P = 0.014 and non-CR state (HR = 2.841. 95% CI 1.627-4.960, P<0.001 as predictors for survival. In conclusion, the MTHFR 677TT genotype appears to be associated with acute liver GVHD, and represent a risk factor for TRM and survival in patients undergoing HSCT with MTX

HLA-mismatched hematopoietic stem cell tranplantation for pediatric solid tumors

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Andrea Pession

2011-06-01

Full Text Available Even if the overall survival of children with cancer is significantly improved over these decades, the cure rate of high-risk pediatric solid tumors such as neuroblastoma, Ewing’s sarcoma family tumors or rhabdomiosarcoma remain challenging. Autologous hematopoietic stem cell transplantation (HSCT allows chemotherapy dose intensification beyond marrow tolerance and has become a fundamental tool in the multimodal therapeutical approach of these patients. Anyway this procedure does not allow to these children an eventfree survival approaching more than 50% at 5 years. New concepts of allogeneic HSCT and in particular HLA-mismatched HSCT for high risk solid tumors do not rely on escalation of chemo therapy intensity and tumor load reduction but rather on a graft-versus-tumor effect. We here report an experimental study design of HLA-mismatched HSCT for the treatment of pediatric solid tumors and the inherent preliminary results.

Increased incidence of murine graft-versus-host disease after allogeneic bone marrow transplantation by previous infusion of syngeneic bone marrow cells

International Nuclear Information System (INIS)

Waer, M.; Ang, K.K.; van der Schueren, E.; Vandeputte, M.

1984-01-01

Different groups of BALB/c mice received supralethal total-body irradiation (TBI; 8.5 Gy, day 0). When 30 x 10(6) allogeneic (C57B1) bone marrow (BM) cells were infused with or without 10 x 10(6) syngeneic (BALB/c) bM cells on day 1, many animals (60%) died from graft-versus-host disease (GVHD). Typing of peripheral blood leukocytes for donor antigens showed that, respectively, 22/22 and 17/21 of the mice in both groups became chimeric. When syngeneic bone marrow was given on day 1 and allogeneic bone marrow on day 2 after TBI, a similar number of animals (21/23) became chimeric, but GVHD occurred more frequently in this group (25/26 mice, P less than 0.01). When the syngeneic bone marrow cells were replaced by spleen cells, or when the transplantation of allogeneic bone marrow was delayed till days 3 or 6 after TBI, almost all mice rejected the allogeneic BM graft and became long-term survivors. BALB/c mice receiving 30 x 10(6) C57B1 BM cells after 17 daily fractions of 0.2 Gy of total lymphoid irradiation (TLI), showed a high incidence of chimerism (15/17) and in none of the latter animals was GVHD observed. Despite the high incidence of GVHD in the mice receiving allogeneic BM after TBI and syngeneic BM transplantation, as compared with mice prepared with TLI which do not develop GVHD, suppressor cells were as easily induced after TBI and syngeneic BM transplantation as after TLI

Successful Reduced Intensity Allogeneic Transplant With Full Donor Chimerism and Good Quality of Life in Adolescent Patient With Wiskott-Aldrich Syndrome.

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Ali, Salah; Gacsadi, Anna; McDougall, Elizabeth; Armstrong, Christine; Krueger, Joerg; Schechter, Tal; Ali, Muhammad

2017-07-01

Wiskott-Aldrich syndrome (WAS) is an X-linked disease characterized by microthrombocytopenia, eczema, immune deficiency, and autoimmune phenomena. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Myeloablative conditioning is the most common regimen used for HSCT in patients with WAS to avoid the risk of mixed donor chimerism and autoimmunity post-HSCT. There is limited data on the use of reduced intensity conditioning for HSCT in patients with WAS. Here, we report a case with severe phenotype of WAS transplanted successfully with reduced intensity conditioning, which is an acceptable conditioning regimen and can be considered in patients with WAS with significantly impaired organ functions.

CRISPR/Cas9 system and its applications in human hematopoietic cells.

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Hu, Xiaotang

2016-11-01

Since 2012, the CRISPR-Cas9 system has been quickly and successfully tested in a broad range of organisms and cells including hematopoietic cells. The application of CRISPR-Cas9 in human hematopoietic cells mainly involves the genes responsible for HIV infection, β-thalassemia and sickle cell disease (SCD). The successful disruption of CCR5 and CXCR4 genes in T cells by CRISPR-Cas9 promotes the prospect of the technology in the functional cure of HIV. More recently, eliminating CCR5 and CXCR4 in induced pluripotent stem cells (iPSCs) derived from patients and targeting the HIV genome have been successfully carried out in several laboratories. The outcome from these approaches bring us closer to the goal of eradicating HIV infection. For hemoglobinopathies the ability to produce iPSC-derived from patients with the correction of hemoglobin (HBB) mutations by CRISPR-Cas9 has been tested in a number of laboratories. These corrected iPSCs also show the potential to differentiate into mature erythrocytes expressing high-level and normal HBB. In light of the initial success of CRESPR-Cas9 in target mutated gene(s) in the iPSCs, a combination of genomic editing and autogenetic stem cell transplantation would be the best strategy for root treatment of the diseases, which could replace traditional allogeneic stem cell transplantation. Copyright © 2016 Elsevier Inc. All rights reserved.

Non-traditional CD4+CD25-CD69+ regulatory T cells are correlated to leukemia relapse after allogeneic hematopoietic stem cell transplantation.

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Zhao, Xiao-su; Wang, Xu-hua; Zhao, Xiang-yu; Chang, Ying-jun; Xu, Lan-ping; Zhang, Xiao-hui; Huang, Xiao-jun

2014-07-01

Non-traditional CD4+CD25-CD69+ T cells were found to be involved in disease progression in tumor-bearing mouse models and cancer patients recently. We attempted to define whether this subset of T cells were related to leukemia relapse after allogeneic hematopoietic cell transplantation (allo-HSCT). The frequency of CD4+CD25-CD69+ T cells among the CD4+ T cell population from the bone marrow of relapsed patients, patients with positive minimal residual disease (MRD+) and healthy donors was examined by flow cytometry. The CD4+CD25-CD69+ T cells were also stained with the intracellular markers to determine the cytokine (TGF-β, IL-2 and IL-10) secretion. The results showed that the frequency of CD4+CD25-CD69 + T cells was markedly increased in patients in the relapsed group and the MRD + group compared to the healthy donor group. The percentage of this subset of T cells was significantly decreased after effective intervention treatment. We also analyzed the reconstitution of CD4+CD25-CD69+ T cells at various time points after allo-HSCT, and the results showed that this subset of T cells reconstituted rapidly and reached a relatively higher level at +60 d in patients compared to controls. The incidence of either MRD+ or relapse in patients with a high frequency of CD4+CD25-CD69+ T cells (>7%) was significantly higher than that of patients with a low frequency of CD4+CD25-CD69+ T cells at +60 d, +90 d and +270 d after transplant. However, our preliminary data indicated that CD4+CD25-CD69+ T cells may not exert immunoregulatory function via cytokine secretion. This study provides the first clinical evidence of a correlation between non-traditional CD4+CD25-CD69+ Tregs and leukemia relapse after allo-HSCT and suggests that exploration of new methods of adoptive immunotherapy may be beneficial. Further research related to regulatory mechanism behind this phenomenon would be necessary.

Transplantation of islet cells across major histocompatibility barriers after total lymphoid irradiation and infusion of allogeneic bone marrow cells

International Nuclear Information System (INIS)

Britt, L.D.; Scharp, D.W.; Lacy, P.E.; Slavin, S.

1982-01-01

Diabetic Lewis rats (AgB1/L) were evaluated as recipients of allogeneic Wistar-Furth (AgB2/2) isolated adult islets without the use of standard recipient immunosuppression. One group was treated with fractionated total lymphoid irradiation (TLI) and Wistar-Furth bone marrow cell reconstitution to proven chimerism prior to islet transplantation. This group returned to a prediabetic state following Wistar-Furth islet transplantation without any evidence of rejection for 100 days posttransplant. A second group of Lewis rats received only TLI without bone marrow treatment. They gave a varying result following islet transplantation with one recipient showing evidence of prolonged islet survival. A third chimeric control group did not receive isolated islets and did not alter their diabetic state. A fourth group was not given TLI nor donor bone marrow cells and uniformly rejected their allogeneic islets by 7 days. Thus, allogeneic adult islets will survive across major rat histocompatibility barriers using TLI and donor bone marrow chimerism as the only form of immunosuppression

Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey.

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Niederwieser, D; Baldomero, H; Szer, J; Gratwohl, M; Aljurf, M; Atsuta, Y; Bouzas, L F; Confer, D; Greinix, H; Horowitz, M; Iida, M; Lipton, J; Mohty, M; Novitzky, N; Nunez, J; Passweg, J; Pasquini, M C; Kodera, Y; Apperley, J; Seber, A; Gratwohl, A

2016-06-01

Data on 68 146 hematopoietic stem cell transplants (HSCTs) (53% autologous and 47% allogeneic) gathered by 1566 teams from 77 countries and reported through their regional transplant organizations were analyzed by main indication, donor type and stem cell source for the year 2012. With transplant rates ranging from 0.1 to 1001 per 10 million inhabitants, more HSCTs were registered from unrelated 16 433 donors than related 15 493 donors. Grafts were collected from peripheral blood (66%), bone marrow (24%; mainly non-malignant disorders) and cord blood (10%). Compared with 2006, an increase of 46% total (57% allogeneic and 38% autologous) was observed. Growth was due to an increase in reporting teams (18%) and median transplant activity/team (from 38 to 48 HSCTs/team). An increase of 167% was noted in mismatched/haploidentical family HSCT. A Strengths, Weaknesses, Opportunities, Threats (SWOT) analysis revealed the global perspective of WBMT to be its major strength and identified potential to be the key professional body for patients and authorities. The limited data collection remains its major weakness and threat. In conclusion, global HSCT grows over the years without plateauing (allogeneic>autologous) and at different rates in the four World Health Organization regions. Major increases were observed in allogeneic, haploidentical HSCT and, to a lesser extent, in cord blood transplantation.

Hematopoietic Stem Cell Transplantation Activity in Pediatric Cancer between 2008 and 2014 in the United States: A Center for International Blood and Marrow Transplant Research Report.

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Khandelwal, Pooja; Millard, Heather R; Thiel, Elizabeth; Abdel-Azim, Hisham; Abraham, Allistair A; Auletta, Jeffery J; Boulad, Farid; Brown, Valerie I; Camitta, Bruce M; Chan, Ka Wah; Chaudhury, Sonali; Cowan, Morton J; Angel-Diaz, Miguel; Gadalla, Shahinaz M; Gale, Robert Peter; Hale, Gregory; Kasow, Kimberly A; Keating, Amy K; Kitko, Carrie L; MacMillan, Margaret L; Olsson, Richard F; Page, Kristin M; Seber, Adriana; Smith, Angela R; Warwick, Anne B; Wirk, Baldeep; Mehta, Parinda A

2017-08-01

This Center for International Blood and Marrow Transplant Research report describes the use of hematopoietic stem cell transplantation (HSCT) in pediatric patients with cancer, 4408 undergoing allogeneic (allo) and3076 undergoing autologous (auto) HSCT in the United States between 2008 and 2014. In both settings, there was a greater proportion of boys (n = 4327; 57%), children reports of transplant practices in the United States. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Beneficial Effect of the Nutritional Support in Children Who Underwent Hematopoietic Stem Cell Transplant.

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Koç, Nevra; Gündüz, Mehmet; Tavil, Betül; Azik, M Fatih; Coşkun, Zeynep; Yardımcı, Hülya; Uçkan, Duygu; Tunç, Bahattin

2017-08-01

The aim of this study was to evaluate nutritional status in children who underwent hematopoietic stem cell transplant compared with a healthy control group. A secondary aim was to utilize mid-upper arm circumference as a measure of nutritional status in these groups of children. Our study group included 40 children (18 girls, 22 boys) with mean age of 9.2 ± 4.6 years (range, 2-17 y) who underwent hematopoietic stem cell transplant. Our control group consisted of 20 healthy children (9 girls, 11 boys). The children were evaluated at admission to the hospital and followed regularly 3, 6, 9, and 12 months after discharge from the hospital. In the study group, 27 of 40 patients (67.5%) received nutritional support during hematopoietic stem cell transplant, with 15 patients (56%) receiving enteral nutrition, 6 (22%) receiving total parenteral nutrition, and 6 (22%) receiving enteral and total parenteral nutrition. Chronic malnutrition rate in the study group was 47.5% on admission to the hospital, with the control group having a rate of 20%. One year after transplant, the rate decreased to 20% in the study group and 5% in the control group. The mid-upper arm circumference was lower in children in the study group versus the control group at the beginning of the study (P groups at follow-up examinations (P > .05). During follow-up, all anthropometric measurements increased significantly in both groups. Monitoring nutritional status and initiating appropriate nutritional support improved the success of hematopoietic stem cell transplant and provided a more comfortable process during the transplant period. Furthermore, mid-upper arm circumference is a more sensitive, useful, and safer parameter that can be used to measure nutritional status of children who undergo hematopoietic stem cell transplant.

Dangers resulting from DNA profiling of biological materials derived from patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT with regard to forensic genetic analysis

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Renata Jacewicz

2016-07-01

Full Text Available The study documents the risk that comes with DNA analysis of materials derived from patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT in forensic genetics. DNA chimerism was studied in 30 patients after allo-HSCT, based on techniques applied in contemporary forensic genetics, i.e. real-time PCR and multiplex PCR-STR with the use of autosomal DNA as well as Y-DNA markers. The results revealed that the DNA profile of the recipient’s blood was identical with the donor’s in the majority of cases. Therefore, blood analysis can lead to false conclusions in personal identification as well as kinship analysis. An investigation of buccal swabs revealed a mixture of DNA in the majority of recipients. Consequently, personal identification on the basis of stain analysis of the same origin may be impossible. The safest (but not ideal material turned out to be the hair root. Its analysis based on autosomal DNA revealed 100% of the recipient’s profile. However, an analysis based on Y-chromosome markers performed in female allo-HSCT recipients with male donors demonstrated the presence of donor DNA in hair cells – similarly to the blood and buccal swabs. In the light of potential risks arising from DNA profiling of biological materials derived from persons after allotransplantation in judicial aspects, certain procedures were proposed to eliminate such dangers. The basic procedures include abandoning the approach based exclusively on blood collection, both for kinship analysis and personal identification; asking persons who are to be tested about their history of allo-HSCT before sample collection and profile entry in the DNA database, and verification of DNA profiling based on hair follicles in uncertain cases.

Human CD134 (OX40) expressed on T cells plays a key role for human herpesvirus 6B replication after allogeneic hematopoietic stem cell transplantation.

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Nagamata, Satoshi; Nagasaka, Miwako; Kawabata, Akiko; Kishimoto, Kenji; Hasegawa, Daiichiro; Kosaka, Yoshiyuki; Mori, Takeshi; Morioka, Ichiro; Nishimura, Noriyuki; Iijima, Kazumoto; Yamada, Hideto; Kawamoto, Shinichiro; Yakushijin, Kimikazu; Matsuoka, Hiroshi; Mori, Yasuko

2018-05-01

CD134 (OX40), which is a cellular receptor for human herpesvirus-6B (HHV-6B) and expresses on activated T cells, may play a key role for HHV-6B replication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, we examined the CD134 expression on T cells and HHV-6B replication after allo-HSCT, and analyzed the correlation between them. Twenty-three patients after allo-HSCT were enrolled. The percentages of CD134-positive cells within the CD4 + and CD8 + cell populations were measured by flow cytometry, and the viral copy number of HHV-6B was simultaneously quantified by real-time PCR. The correlation between CD134 and HHV-6B viral load was then statistically analyzed. HHV-6B reactivation occurred in 11 of 23 patients (47.8%). CD134 expression was seen on T cells and was coincident with the time of peak viral load. The percentage of CD134-positive cells decreased significantly when HHV-6B DNA disappeared (p = .005 in CD4 + T cells, p = .02 in CD8 + T cells). In the 4 patients who underwent umbilical cord blood transplantation (UCBT), the viral load varied with the percentage of CD134-positive cells. In the comparison between the HHV-6B reactivation group and non-reactivation group, maximum percentages of CD134-positive cells among CD4 + T cells in reactivation group were significantly higher than those in non-reactivation group (p = .04). This is the first study to show that a correlation of CD134 expression on T cells with HHV-6B replication after allo-HSCT, especially in UCBT. The results possibly indicate that CD134 on T cells plays a key role for HHV-6B replication after allo-HSCT. Copyright © 2018 Elsevier B.V. All rights reserved.

The implication of follicular lymphoma patients receiving allogeneic stem cell transplantation from donors carrying t(14;18)-positive cells.

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McGregor, D K; Keever-Taylor, C A; Bredeson, C; Schur, B; Vesole, D H; Logan, B; Chang, C-C

2005-06-01

We performed real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood (PB) and/or bone marrow (BM) samples collected pre- and post transplant from 23 recipient-donor pairs receiving allogeneic stem cell transplantation (allo-SCT) for follicular lymphoma (FL). Of 23 donors, 11 had a PB and/or BM sample positive for t(14;18) (BCL2/IGH fusion) at low levels (donors with (n=11) and those without (n=12) detectable t(14:18) cells were similar in age, sex, and disease status pretransplant. No differences in the incidence of graft-versus-host-disease (GVHD), delayed engraftment, relapse rate, disease-free survival and overall survival were identified between the groups. Two recipients without detectable t(14;18) cells pre-transplant showed detectable t(14;18) cells at 2 and 11 years after receiving grafts from donors with t(14:18) cells. Neither patient developed FL 1.5 and 2 years after the emergence of t(14;18) cells. Although the sample size is relatively small, our findings suggest that individuals carrying t(14;18) cells may not be excluded as donors given the lack of an association of t(14;18) detected in donors with adverse clinical outcome. It may be necessary to screen for the donor's t(14;18) status before using t(14;18) for monitoring minimal residual disease by RQ-PCR to exclude the possibility of confounding donor's t(14;18) clone.

Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report

OpenAIRE

Boucher, Alexander A.; Miller, Weston; Shanley, Ryan; Ziegler, Richard; Lund, Troy; Raymond, Gerald; Orchard, Paul J.

2015-01-01

Background Metachromatic Leukodystrophy (MLD) is a rare, fatal demyelinating disorder with limited treatment options. Published outcomes after hematopoietic stem cell transplantation (HSCT) are scant and mixed. We report survival and function following HSCT for a large, single-center MLD cohort. Methods Transplant-related data, survival and serial measures (brain MRI, nerve conduction velocity (NCV), neurologic and neuropsychology evaluations) were reviewed. When possible, parental interviews...

The Use of Intravenous Antibiotics at the Onset of Neutropenia in Patients Receiving Outpatient-Based Hematopoietic Stem Cell Transplants

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Hamadah, Aziz; Schreiber, Yoko; Toye, Baldwin; McDiarmid, Sheryl; Huebsch, Lothar; Bredeson, Christopher; Tay, Jason

2012-01-01

Empirical antibiotics at the onset of febrile neutropenia are one of several strategies for management of bacterial infections in patients undergoing Hematopoietic Stem Cell Transplant (HSCT) (empiric strategy). Our HSCT program aims to perform HSCT in an outpatient setting, where an empiric antibiotic strategy was employed. HSCT recipients began receiving intravenous antibiotics at the onset of neutropenia in the absence of fever as part of our institutional policy from 01 Jan 2009; intravenous Prophylactic strategy. A prospective study was conducted to compare two consecutive cohorts [Year 2008 (Empiric strategy) vs. Year 2009 (Prophylactic strategy)] of patients receiving HSCT. There were 238 HSCTs performed between 01 Jan 2008 and 31 Dec 2009 with 127 and 111 in the earlier and later cohorts respectively. Infection-related mortality pre- engraftment was similar with a prophylactic compared to an empiric strategy (3.6% vs. 7.1%; p = 0.24), but reduced among recipients of autologous HSCT (0% vs. 6.8%; p = 0.03). Microbiologically documented, blood stream infections and clinically documented infections pre-engraftment were reduced in those receiving a prophylactic compared to an empiric strategy, (11.7% vs. 28.3%; p = 0.001), (9.9% vs. 24.4%; p = 0.003) and (18.2% vs. 33.9% p = 0.007) respectively. The prophylactic use of intravenous once-daily ceftriaxone in patients receiving outpatient based HSCT is safe and may be particularly effective in patients receiving autologous HSCT. Further studies are warranted to study the impact of this Prophylactic strategy in an outpatient based HSCT program. PMID:23029441

Allogeneic cell transplant expands bone marrow distribution by colonizing previously abandoned areas: an FDG PET/CT analysis.

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Fiz, Francesco; Marini, Cecilia; Campi, Cristina; Massone, Anna Maria; Podestà, Marina; Bottoni, Gianluca; Piva, Roberta; Bongioanni, Francesca; Bacigalupo, Andrea; Piana, Michele; Sambuceti, Gianmario; Frassoni, Francesco

2015-06-25

Mechanisms of hematopoietic reconstitution after bone marrow (BM) transplantation remain largely unknown. We applied a computational quantification software application to hybrid 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) images to assess activity and distribution of the hematopoietic system throughout the whole skeleton of recently transplanted patients. Thirty-four patients underwent PET/CT 30 days after either adult stem cell transplantation (allogeneic cell transplantation [ACT]; n = 18) or cord blood transplantation (CBT; n = 16). Our software automatically recognized compact bone volume and trabecular bone volume (IBV) in CT slices. Within IBV, coregistered PET data were extracted to identify the active BM (ABM) from the inactive tissue. Patients were compared with 34 matched controls chosen among a published normalcy database. Whole body ABM increased in ACT and CBT when compared with controls (12.4 ± 3 and 12.8 ± 6.8 vs 8.1 ± 2.6 mL/kg of ideal body weight [IBW], P bones, ABM increased three- and sixfold in CBT and ACT, respectively, compared with controls (0.9 ± 0.9 and 1.7 ± 2.5 vs 0.3 ± 0.3 mL/kg IBW, P transplanted BM into previously abandoned BM sites. © 2015 by The American Society of Hematology.

Allogeneic Hematopoietic Cell Transplantation in Multiple Myeloma: Focus on Longitudinal Assessment of Donor Chimerism, Extramedullary Disease, and High-Risk Cytogenetic Features.

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Rasche, Leo; Röllig, Christoph; Stuhler, Gernot; Danhof, Sophia; Mielke, Stephan; Grigoleit, Goetz Ulrich; Dissen, Lea; Schemmel, Lea; Middeke, Jan Moritz; Rücker, Viktoria; Schreder, Martin; Schetelig, Johannes; Bornhäuser, Martin; Einsele, Hermann; Thiede, Christian; Knop, Stefan

2016-11-01

Although generally not applied as first-line treatment of multiple myeloma, allogeneic hematopoietic cell transplantation (allo-SCT) can still be chosen as ultimate escalation approach in high-risk patients, preferentially within the framework of clinical trials. In this study, we investigated whether decreasing donor chimerism (DC) is predictive for relapse. In addition, we comprehensively determined the impact of several other disease- and treatment-related factors on outcome. One hundred fifty-five multiple myeloma patients whose DC status was followed serially by the short tandem repeat-based techniques at a single lab were included in this retrospective study. Outcome variables were studied in univariate and multivariable analyses. Available were 2.324 DC samples (median, 12 per patient). Loss of full DC was associated with shorter progression-free survival (PFS) (HR, 1.7; 95% CI, 1.1 to 2.6) but did not impact overall survival. Two-thirds of patients with International Myeloma Working Group-defined relapses still displayed a full DC in peripheral blood or bone marrow. Extramedullary manifestations were observed in 33% of patients, accounting for the discrepancy between DC analysis and the actual disease status. In multivariable analysis, the 2 most relevant variables for an unfavorable PFS were progressive disease before allo-SCT (HR, 3.0; 95% CI, 1.5 to 5.9) and allo-SCT at least the second relapse (HR, 2.8; 95% CI, 1.5 to 4.9), whereas for overall survival progressive disease or partial response before allo-SCT had the strongest negative effects (HR, 4.2; 95% CI, 1.9 to 9, and HR, 2.0; 95% CI, 1.0 to 3.8, respectively). Adverse cytogenetics such as del17p, t(4,14) or amp(1q21) were not associated with shorter survival after allo-SCT. Extensive DC sampling beyond robust engraftment does not appear to provide additional information helpful for disease management in most patients and is challenged by a significant incidence of extramedullary disease. In our

Results of allogeneic stem cell transplantation in the Spanish MDS registry: prognostic factors for low risk patients.

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Díez Campelo, M; Sánchez-Barba, M; de Soria, V Gómez-García; Martino, R; Sanz, G; Insunza, A; Bernal, T; Duarte, R; Amigo, M L; Xicoy, B; Tormo, M; Iniesta, F; Bailén, A; Benlloch, L; Córdoba, I; López-Villar, O; Del Cañizo, M C

2014-10-01

Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics. Copyright © 2014 Elsevier Ltd. All rights reserved.

Outcomes of allogeneic stem cell transplantation in patients with paroxysmal nocturnal hemoglobinuria with or without aplastic anemia.

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Lee, Sung-Eun; Park, Sung Soo; Jeon, Young-Woo; Yoon, Jae-Ho; Cho, Byung-Sik; Eom, Ki-Sung; Kim, Yoo-Jin; Lee, Seok; Min, Chang-Ki; Kim, Hee-Je; Cho, Seok-Goo; Kim, Dong-Wook; Min, Woo-Sung; Lee, Jong Wook

2017-10-01

The aim of this study was to evaluate the long-term outcomes of allogeneic stem cell transplantation (SCT) in patients with paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia (AA). A total of 33 patients with PNH clones who underwent allogeneic SCT were analyzed. After a median follow-up of 57 months (range, 6.0-151.3), the 5-year estimated overall survival rate was 87.9±5.7%. Four patients died of transplant-related mortality (TRM). With the exception of one patient with early TRM, 32 patients were engrafted. Two patients who had developed delayed GF received a second transplant and recovered. The cumulative incidences of acute graft-vs-host disease (GVHD) (≥grade II) and chronic GVHD (≥moderate) were 27.3±7.9% and 18.7±7.0%, respectively. Twenty-one patients receiving SCT with reduced-intensity conditioning (RIC) had available follow-up data for PNH cell population for the first 6 months post-transplant. Analysis of these data revealed that the PNH clones disappeared within approximately 2 months. RIC regimen was sufficient to eradicate PNH clones with sustained donor-type engraftment after allogeneic SCT. Therefore, application of allogeneic SCT with RIC should be considered in patients with PNH, in accordance with the severity of the underlying bone marrow failure. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Genetic Background of Immune Complications after Allogeneic Hematopoietic Stem Cell Transplantation in Children

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Szymon Skoczen

2016-01-01

Full Text Available Immune reactions are among the most serious complications observed after hematopoietic stem cell transplantation (HSCT in children. Microarray technique allows for simultaneous assessment of expression of nearly all human genes. The objective of the study was to compare the whole genome expression in children before and after HSCT. A total of 33 children referred for HSCT were enrolled in the study. In 70% of the patients HSCT was performed for the treatment of neoplasms. Blood samples were obtained before HSCT and six months after the procedure. Subsequently, the whole genome expression was assessed in leukocytes using GeneChip Human Gene 1.0 ST microarray. The analysis of genomic profiles before and after HSCT revealed altered expression of 124 genes. Pathway enrichment analysis revealed upregulation of five pathways after HSCT: allograft rejection, graft-versus-host disease, type I diabetes mellitus, autoimmune thyroid disease, and viral myocarditis. The activation of those pathways seems to be related to immune reactions commonly observed after HSCT. Our results contribute to better understanding of the genomic background of the immunologic complications of HSCT.

Perioperative allogenic blood transfusion is a poor prognostic factor after hepatocellular carcinoma surgery: a multi-center analysis.

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Wada, Hiroshi; Eguchi, Hidetoshi; Nagano, Hiroaki; Kubo, Shoji; Nakai, Takuya; Kaibori, Masaki; Hayashi, Michihiro; Takemura, Shigekazu; Tanaka, Shogo; Nakata, Yasuyuki; Matsui, Kosuke; Ishizaki, Morihiko; Hirokawa, Fumitoshi; Komeda, Koji; Uchiyama, Kazuhisa; Kon, Masanori; Doki, Yuichiro; Mori, Masaki

2018-01-01

The influence of allogenic blood transfusion on the postoperative outcomes of hepatocellular carcinoma (HCC) surgery remains controversial. This study aims to clarify the clinical impacts of perioperative allogenic blood transfusion on liver resection outcome in HCC patients. We analyzed data collected over 5 years for 642 patients who underwent hepatectomy for HCC at one of the five university hospitals. We investigated the impact of allogenic blood transfusion on postoperative outcome after surgery in all patients and in 74 matched pairs, using a propensity score. Of the 642 patients, 198 (30.8%) received perioperative allogenic blood transfusion (AT group) and 444 (69.2%) did not (non-AT group). Overall survival was lower in the AT group than in the non-AT group in univariate (P blood transfusion was found to be a poor prognostic factor for HCC patients. In this multi-center study, perioperative blood transfusion was an independent factor for poor prognosis after curative surgery for primary HCC in the patient group and in pairs matched by propensity scores.

HLA-C incompatibilities in allogeneic unrelated hematopoietic stem cell transplantation

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Jean-Marie eTIERCY

2014-05-01

Full Text Available An increasingly larger fraction of patients with hematological diseases are treated by hematopoietic stem cells transplantation (HSCT from HLA matched unrelated donors. Polymorphism of HLA genes represent a major barrier to HSCT because HLA-A,B,C and DRB1 incompatibilities confer a higher risk of aGVHD and mortality. Although >22 million volunteer HLA-typed donors are available worldwide, still a significant number of patients do not find a highly matched HSC donor. Because of the large haplotypic diversity in HLA-B-C associations, incompatibilities occur most frequently at HLA-C, so that unrelated donors with a single HLA-C mismatch often represent the only possible choice. The ratio of HLA-C-mismatched HSCT over the total number of transplants varies from 15-30%, as determined in 12 multicenter studies. Six multicenter studies involving >1800 patients have reported a 21-43% increase in mortality risk. By using in vitro cellular assays a large heterogeneity in T-cell allorecognition has been observed. Yet the permissiveness of individual HLA-C mismatches remains poorly defined. It could be linked to the position and nature of the mismatched residues on HLA-C molecules, but also to variability in the expression levels of the mismatched alleles. The permissive C*03:03-03:04 mismatch is caracterized by full compatibility at residues 9, 97, 99, 116, 152, 156 and 163 reported to be key positions influencing T-cell allorecognition. With a single difference in these key residues the C*07:01-07:02 mismatch might also be considered by analogy as permissive. High variability of HLA-C expression as determined by quantitative RT-PCR has been observed within individual allotypes and shows some correlation with A-B-C-DRB1 haplotypes. Thus in addition to the position of mismatched amino acid residues, expression level of patient’s mismatched HLA-C allotype might influence T-cell allorecognition, with patient's low expression-C alleles representing possible

Evaluation of febrile neutropenia in patients undergoing hematopoietic stem cell transplantation.

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Shahideh Amini

2014-01-01

Full Text Available The aim of this study was to determine the incidence and causes of fever as a major problem contributing to transplantation related mortality among patients undergoing hematopoietic stem cell transplantation (HSCT and evaluation of antibiotic use, according to reliable guidelines.We retrospectively reviewed hospital records of 195 adult patients who underwent HSCT between 2009-2011 at hematology-oncology and bone marrow transplantation research center. Baseline information and also data related to fever and neutropenia, patient's outcomes, duration of hospitalization and antibiotic use pattern were documented.A total of 195 patients were analyzed and a total of 268 febrile episodes in 180 patients were recorded (mean 1.5 episodes per patient. About 222 episodes (82% were associated with neutropenia which one-fourth of them were without any documented infection sources. Microbiologic documents showed that the relative frequencies of gram positive and gram negative bacteria were 62.5% and 37.5%, respectively. The hospital stay duration was directly related to the numbers of fever episodes (P<0.0001.The rate of febrile episodes in autologous stem cell transplantation was significantly higher compared to allogeneic type (P<0.05.It is necessary to determine not only the local profile of microbiologic pattern, but also antibiotic sensitivities in febrile neutropenic patients following hematopoietic stem cell transplantation, and reassess response to antibiotic treatment to establish any necessity for modifications to treatment guidelines in order to prevent any fatal complications from infection.

Hematopoietic Stem Cell Transplant in Adolescent and Young Adults With Fanconi Anemia Is Feasible With Acceptable Toxicity, With Those Surviving 100 Days Posttransplant Having Excellent Outcomes.

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Alhuraiji, Ahmad; Alzahrani, Hazza; Al Mohareb, Fahad; Chaudhri, Naeem; Alsharif, Fahad; Mohamed, Said; Rasheed, Walid; Aldawsari, Ghuzayel; Ahmed, Syed Osman; Aljurf, Mahmoud

2016-12-01

Fanconi anemia is a congenital bone marrow failure syndrome that is associated with congenital anomalies and increased risk of cancer. Hematopoietic stem cell transplant is a potentially curative modality for bone marrow failure in Fanconi anemia patients. Here, we report our center's experience regarding adolescent and young adult patients with Fanconi anemia and hematopoietic stem cell transplant. We conducted a retrospective patient record analyses of patients who presented at our center from 1988 to 2014. We included patients greater than 14 years old with confirmed Fanconi anemia based on positive chromosome breakage study and who underwent hematopoietic stem cell transplant at our institution. Our study group comprised 12 patients with Fanconi anemia who underwent hematopoietic stem cell transplant at our institution. The median age was 20 years (range, 14-31 y) with a female predominance of 83%. Low-dose cyclophosphamide (20-80 mg/kg)-based conditioning regimens were used with different combinations that included fludarabine, antithymocyte globulin, or total body irradiation. All patients had HLA-matched sibling grafts. In all patients, stem cell source was the bone marrow. All patients showed engraftment. Four patients (33%) developed acute graft-versus-host disease. Three patients (25%) died early before day 100 after hematopoietic stem cell transplant due to infectious complications, with 1 patient having steroid refractory acute graft-versus-host disease. Overall survival was 75% at a median follow-up of 43 months. All patients who survived are well and remained transfusion independent without evidence of secondary malignancy. Our findings support the feasibility of reduced intensity conditioning allogeneic hematopoietic stem cell transplant in older and more heavily pretreated patients with Fanconi anemia, especially for those who are engrafted.

Non-myeloablative allogeneic stem cell transplantation focusing on immunotherapy of life-threatening malignant and non-malignant diseases.

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Slavin, S; Nagler, A; Shapira, M; Panigrahi, S; Samuel, S; Or, A

2001-01-01

Allogeneic bone marrow transplantation (BMT) represents an important therapeutic tool for treatment of otherwise incurable malignant and non-malignant diseases. Until recently, myeloablative regimens were considered mandatory for eradication of all undesirable host-derived hematopoietic elements. Our preclinical and ongoing clinical studies indicated that much more effective eradication of host immunohematopoietic system cells could be achieved by adoptive allogeneic cell therapy with donor lymphocyte infusion (DLI) following BMT. Thus, eradication of blood cancer cells, especially in patients with CML can be frequently accomplished despite complete resistance of such tumor cells to maximally tolerated doses of chemoradiotherapy. Our cumulative experience suggested that graft versus leukemia (GVL) effects might be a useful tool for eradication of otherwise resistant tumor cells of host origin. The latter working hypothesis suggested that effective BMT procedures may be accomplished without lethal conditioning of the host, using new well tolerated non-myeloablative regimen, thus possibly minimizing immediate and late side effects related to myeloablative procedures considered until recently mandatory for conditioning of BMT recipients. Recent clinical data that will be presented suggests that safe non-myeloablative stem cell transplantation (NST), with no major toxicity can replace the conventional BMT. Thus, NST may provide an option for cure for a large spectrum of clinical indications in children and elderly individuals without lower or upper age limit, while minimizing procedure-related toxicity and mortality.

The Total Body Irradiation Schedule Affects Acute Leukemia Relapse After Matched T Cell–Depleted Hematopoietic Stem Cell Transplantation

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Aristei, Cynthia; Carotti, Alessandra; Palazzari, Elisa; Amico, Lucia; Ruggeri, Loredana; Perrucci, Elisabetta; Falcinelli, Lorenzo; Lancellotta, Valentina; Palumbo, Isabella; Falzetti, Franca; Aversa, Franco; Merluzzi, Mara; Velardi, Andrea; Martelli, Massimo Fabrizio

2016-01-01

Purpose: We sought to determine whether the total body irradiation (TBI) schedule affected outcome in patients with acute leukemia in complete remission who received T cell–depleted allogeneic hematopoietic stem cell transplantation from HLA identical siblings. Methods and Materials: The study recruited 55 patients (median age, 48 years; age range, 20-66 years; 30 men and 25 women; 34 with acute myeloid leukemia and 21 with acute lymphoid leukemia). Hyperfractionated TBI (HTBI) (1.2 Gy thrice daily for 4 days [for a total dose of 14.4 Gy] from day −12 to day −9) was administered to 29 patients. Single-dose TBI (STBI) (8 Gy, at a median dose rate of 10.7 cGy/min on day −9) was given to 26 patients. Results: All patients achieved primary, sustained engraftment with full donor-type chimerism. At 10 years, the overall cumulative incidence of transplant-related mortality was 11% (SE, ±0.1%). It was 7% (SE, ±0.2%) after HTBI and 15% (SE, ±0.5%) after STBI (P=.3). The overall cumulative incidence of relapse was 33% (SE, ±0.5). It was 13% (SE, ±0.5%) after HTBI and 46% (SE, ±1%) after STBI (P=.02). The overall probability of disease-free survival (DFS) was 59% (SE, ±7%). It was 67% (SE, ±0.84%) after HTBI and 37% (SE, ±1.4%) after STBI (P=.01). Multivariate analyses showed the TBI schedule was the only risk factor that significantly affected relapse and DFS (P=.01 and P=.03, respectively). Conclusions: In patients with acute leukemia, HTBI is more efficacious than STBI in eradicating minimal residual disease after HLA-matched T cell–depleted hematopoietic stem cell transplantation, thus affecting DFS.

The Total Body Irradiation Schedule Affects Acute Leukemia Relapse After Matched T Cell–Depleted Hematopoietic Stem Cell Transplantation

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Aristei, Cynthia, E-mail: cynthia.aristei@unipg.it [Radiation Oncology Section, Department of Surgery and Biomedical Sciences, University of Perugia and Perugia General Hospital, Perugia (Italy); Carotti, Alessandra [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Palazzari, Elisa [Radiation Oncology Section, University of Perugia, Perugia (Italy); Amico, Lucia; Ruggeri, Loredana [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Perrucci, Elisabetta; Falcinelli, Lorenzo [Radiation Oncology Division, Perugia General Hospital, Perugia (Italy); Lancellotta, Valentina [Radiation Oncology Section, University of Perugia, Perugia (Italy); Palumbo, Isabella [Radiation Oncology Section, Department of Surgery and Biomedical Sciences, University of Perugia and Perugia General Hospital, Perugia (Italy); Falzetti, Franca [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy); Aversa, Franco [Hematology and Bone Marrow Transplant Unit, Department of Clinical and Experimental Medicine, Parma General Hospital and University, Parma (Italy); Merluzzi, Mara; Velardi, Andrea; Martelli, Massimo Fabrizio [Division of Hematology and Clinical Immunology and Bone Marrow Transplant Program, Department of Medicine, Perugia General Hospital and University, Perugia (Italy)

2016-11-15

Purpose: We sought to determine whether the total body irradiation (TBI) schedule affected outcome in patients with acute leukemia in complete remission who received T cell–depleted allogeneic hematopoietic stem cell transplantation from HLA identical siblings. Methods and Materials: The study recruited 55 patients (median age, 48 years; age range, 20-66 years; 30 men and 25 women; 34 with acute myeloid leukemia and 21 with acute lymphoid leukemia). Hyperfractionated TBI (HTBI) (1.2 Gy thrice daily for 4 days [for a total dose of 14.4 Gy] from day −12 to day −9) was administered to 29 patients. Single-dose TBI (STBI) (8 Gy, at a median dose rate of 10.7 cGy/min on day −9) was given to 26 patients. Results: All patients achieved primary, sustained engraftment with full donor-type chimerism. At 10 years, the overall cumulative incidence of transplant-related mortality was 11% (SE, ±0.1%). It was 7% (SE, ±0.2%) after HTBI and 15% (SE, ±0.5%) after STBI (P=.3). The overall cumulative incidence of relapse was 33% (SE, ±0.5). It was 13% (SE, ±0.5%) after HTBI and 46% (SE, ±1%) after STBI (P=.02). The overall probability of disease-free survival (DFS) was 59% (SE, ±7%). It was 67% (SE, ±0.84%) after HTBI and 37% (SE, ±1.4%) after STBI (P=.01). Multivariate analyses showed the TBI schedule was the only risk factor that significantly affected relapse and DFS (P=.01 and P=.03, respectively). Conclusions: In patients with acute leukemia, HTBI is more efficacious than STBI in eradicating minimal residual disease after HLA-matched T cell–depleted hematopoietic stem cell transplantation, thus affecting DFS.

Use of the quality management system "JACIE" and outcome after hematopoietic stem cell transplantation.

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Gratwohl, Alois; Brand, Ronald; McGrath, Eoin; van Biezen, Anja; Sureda, Anna; Ljungman, Per; Baldomero, Helen; Chabannon, Christian; Apperley, Jane

2014-05-01

Competent authorities, healthcare payers and hospitals devote increasing resources to quality management systems but scientific analyses searching for an impact of these systems on clinical outcome remain scarce. Earlier data indicated a stepwise improvement in outcome after allogeneic hematopoietic stem cell transplantation with each phase of the accreditation process for the quality management system "JACIE". We therefore tested the hypothesis that working towards and achieving "JACIE" accreditation would accelerate improvement in outcome over calendar time. Overall mortality of the entire cohort of 107,904 patients who had a transplant (41,623 allogeneic, 39%; 66,281 autologous, 61%) between 1999 and 2006 decreased over the 14-year observation period by a factor of 0.63 per 10 years (hazard ratio: 0.63; 0.58-0.69). Considering "JACIE"-accredited centers as those with programs having achieved accreditation by November 2012, at the latest, this improvement was significantly faster in "JACIE"-accredited centers than in non-accredited centers (approximately 5.3% per year for 49,459 patients versus approximately 3.5% per year for 58,445 patients, respectively; hazard ratio: 0.83; 0.71-0.97). As a result, relapse-free survival (hazard ratio 0.85; 0.75-0.95) and overall survival (hazard ratio 0.86; 0.76-0.98) were significantly higher at 72 months for those patients transplanted in the 162 "JACIE"-accredited centers. No significant effects were observed after autologous transplants (hazard ratio 1.06; 0.99-1.13). Hence, working towards implementation of a quality management system triggers a dynamic process associated with a steeper reduction in mortality over the years and a significantly improved survival after allogeneic stem cell transplantation. Our data support the use of a quality management system for complex medical procedures.

Are the Polyomaviruses BK and JC Associated with Opportunistic Infections, Graft-versus-Host Disease, or Worse Outcomes in Adult Patients Receiving Their First Allogeneic Stem Cell Transplantation with Low-Dose Alemtuzumab?

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Schneidewind, Laila; Neumann, Thomas; Knoll, Florian; Zimmermann, Kathrin; Smola, Sigrun; Schmidt, Christian Andreas; Krüger, William

2017-01-01

The association of polyomaviruses BK and JC with other opportunistic infections and graft-versus-host disease (GvHD) in allogeneic stem cell transplantation is controversially discussed. We conducted a retrospective study of 64 adult patients who received their first allogeneic stem cell transplantation between March 2010 and December 2014; the follow-up time was 2 years. Acute leukemia was the most frequent underlying disease (45.3%), and conditioning included myeloablative (67.2%) and nonmyeloablative protocols (32.8%). All patients received 10 mg of alemtuzumab on day -2 (20 mg in case of mismatch) as GvHD prophylaxis. Twenty-seven patients (41.5%) developed cytomegalovirus (CMV) reactivation. BKPyV-associated hemorrhagic cystitis was diagnosed in 10 patients (15.6%). Other opportunistic infections caused by viruses or protozoa occurred rarely (reactivation, Epstein-Barr virus reactivation, human herpes virus 6, or parvovirus B19 infection requiring treatment. There was a significant correlation of BKPyV-associated hemorrhagic cystitis with toxoplasmosis (p = 0.013). Additionally, there was a significant link of simultaneous BKPyV and JCPyV viruria with toxoplasmosis (p = 0.047). BKPyV and JCPyV were not associated with GvHD, relapse, or death. We found no association of BKPyV or JCPyV with viral infections or GvHD. Only the correlation of both polyomaviruses with toxoplasmosis was significant. This is a novel and interesting finding. © 2017 S. Karger AG, Basel.

Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort.

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Saeed, Hayder; Yalamanchi, Swati; Liu, Meng; Van Meter, Emily; Gul, Zartash; Monohan, Gregory; Howard, Dianna; Hildebrandt, Gerhard C; Herzig, Roger

2018-02-01

Allogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. A retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier's curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. Of the 114 patients that underwent allogeneic transplant in our institution, 75.4% were ≥40 years old. More than 58% had a DLCO ≤80%. Although scores were positively correlated (correlation coefficient 0.43, p < 0.001), HCT-CI/Age more accurately predicted 2-year overall survival (OS) and non-relapse mortality (NRM) in patients with lower (0-4) and higher (5-7) scores (52% and 36% versus 24% and 76%, p = 0.004, 0.003 respectively). PAM score did not reach statistical significance for difference in OS nor NRM between the low (<24) and high-risk (≥24) groups (p = 0.19 for both). Despite our small sample population, HCT-CI/Age was more discriminative to identify patients with poor outcome that might benefit from intensified management strategies or other therapeutic approaches rather than allogeneic HCT. Copyright © 2018. Published by Elsevier B.V.

Incidence and risk factors for hypogammaglobulinemia in pediatric patients following allo-SCT.

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Frangoul, H; Min, E; Wang, W; Chandrasekhar, R; Calder, C; Evans, M; Manes, B; Bruce, K; Brown, V; Ho, R; Domm, J

2013-11-01

We evaluated the incidence and risk factors for hypogammaglobulinemia after allogeneic hematopoietic SCT (HSCT) in pediatric patients. Ig levels were measured pre-transplant, every 2 weeks until day 100 and then monthly post SCT in 185 patients undergoing myeloablative HSCT. Median age was 9 years; 142 (77%) had malignant disease and 114 (62%) received stem cells from an unrelated source. Hypogammaglobulinemia (IgG SCT. The cumulative incidence of hypogammaglobulinemia at 1 year was higher among patients who developed acute GVHD (97% vs 54%, PSCT (P<0.001) and development of acute GVHD (P<0.001) were all significantly associated with higher risk of hypogammaglobulinemia post HSCT. We conclude that hypogammaglobulinemia is common, following allogeneic HSCT in pediatric patients, especially in those with malignant diseases, those who receive an unrelated transplant or patients who develop GVHD.

RENAL ALLOGENEIC TRANSPLANTATION IN PATIENT WITH HAEMOPHILIA B

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N. V. Purlo

2014-01-01

Full Text Available We report the case of successful renal allogeneic transplantation and treatment in a 56-year-old patient with haemophilia B at Hematology Research Center. He has received replacement therapy by factor IX since 2010. The transplant is marked with good renal function during 13 post-transplant months without episodes of rejection or bleeding complications. The complicated surgical interventions are possible in patients with haemophilia В аnd end-stage chronic renal failure in the presence of replacement therapy of IX factor for the purpose of achievement of optimum hemostasis.

Donor Vδ1+ γδ T cells expand after allogeneic hematopoietic stem cell transplantation and show reactivity against CMV-infected cells but not against progressing B-CLL.

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Prinz, Immo; Thamm, Kristina; Port, Matthias; Weissinger, Eva M; Stadler, Michael; Gabaev, Ildar; Jacobs, Roland; Ganser, Arnold; Koenecke, Christian

2013-05-11

γδ T lymphocytes play an important role in immune reactions towards infections and malignancies. In particular, Vγ9-Vδ1+ T lymphocytes are thought to play protective antiviral roles in human CMV infection. Recently, Vδ1+ T lymphocytes were proposed to also have anti- B-CLL reactivity. Here we report a case of 48-year-old man who received allogeneic stem cell transplantation for progressive B-CLL. Within one year after transplantation, lymphoma relapsed despite a dramatic increase of Vδ1+ T cells in the patient's blood. In vitro killing assays revealed activity of patient's γδ cells against CMV target cells, but not against the relapsing lymphoma-cells. This argues for a contribution of Vδ1+ cells in the immune reaction against CMV reactivation, but does not support a strong correlation of expanded Vδ1+ T cells and favorable disease outcome in B-CLL patients.

Engraftment Efficiency after Intra-Bone Marrow versus Intravenous Transplantation of Bone Marrow Cells in a Canine Nonmyeloablative Dog Leukocyte Antigen-Identical Transplantation Model.

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Lange, Sandra; Steder, Anne; Killian, Doreen; Knuebel, Gudrun; Sekora, Anett; Vogel, Heike; Lindner, Iris; Dunkelmann, Simone; Prall, Friedrich; Murua Escobar, Hugo; Freund, Mathias; Junghanss, Christian

2017-02-01

An intra-bone marrow (IBM) hematopoietic stem cell transplantation (HSCT) is assumed to optimize the homing process and therefore to improve engraftment as well as hematopoietic recovery compared with conventional i.v. HSCT. This study investigated the feasibility and efficacy of IBM HSCT after nonmyeloablative conditioning in an allogeneic canine HSCT model. Two study cohorts received IBM HSCT of either density gradient (IBM-I, n = 7) or buffy coat (IBM-II, n = 6) enriched bone marrow cells. An historical i.v. HSCT cohort served as control. Before allogeneic HSCT experiments were performed, we investigated the feasibility of IBM HSCT by using technetium-99m marked autologous grafts. Scintigraphic analyses confirmed that most IBM-injected autologous cells remained at the injection sites, independent of the applied volume. In addition, cell migration to other bones occurred. The enrichment process led to different allogeneic graft volumes (IBM-I, 2 × 5 mL; IBM-II, 2 × 25 mL) and significantly lower counts of total nucleated cells in IBM-I grafts compared with IBM-II grafts (1.6 × 10 8 /kg versus 3.8 × 10 8 /kg). After allogeneic HSCT, dogs of the IBM-I group showed a delayed engraftment with lower levels of donor chimerism when compared with IBM-II or to i.v. HSCT. Dogs of the IBM-II group tended to reveal slightly faster early leukocyte engraftment kinetics than intravenously transplanted animals. However, thrombocytopenia was significantly prolonged in both IBM groups when compared with i.v. HSCT. In conclusion, IBM HSCT is feasible in a nonmyeloablative HSCT setting but failed to significantly improve engraftment kinetics and hematopoietic recovery in comparison with conventional i.v. HSCT. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Dualism of mixed chimerism between hematopoiesis and stroma in chronic idiopathic myelofibrosis after allogeneic stem cell transplantation.

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Thiele, J; Varus, E; Siebolts, U; Kvasnicka, H M; Wickenhauser, C; Metz, K A; Beelen, D W; Ditschkowski, M; Zander, A; Kröger, N

2007-04-01

Scant knowledge exists concerning lineage-restricted mixed chimerism (mCh) after allogeneic peripheral blood stem cell transplantation (PSCT) in patients with chronic idiopathic myelofibrosis (CIMF). Following a sex-mismatched PSCT, a combined immunopheno- and genotyping by fluorescence in-situ hybridization (FISH) was performed on sequential bone marrow (BM) biopsies at standardized intervals. Results were compared with PCR analysis of corresponding peripheral blood samples in five patients. According to FISH, pretransplant specimens revealed a gender congruence of more than 99%, while in the first three months the total BM exhibited a persistent fraction of host cells (30% to 40%) with a tendency to decline after about one year. It is noteworthy that the majority of endothelial cells maintained a recipient origin, whereas CD34+ progenitors and especially CD61+ megakaryocytes exhibited only very few host-derived cells. In keeping with the prevalence of donor cells in the hematopoietic compartment, PCR analysis of peripheral blood cells displayed a non-significant degree of mCh. In conclusion, according to FISH and PCR analysis, successful PSCT in CIMF results in an almost complete chimeric (donor-derived) state of the hematopoietic cell population. The non-transplantable stromal compartment includes the vascular endothelium with a predominance of recipient cells. The minimal mCh of this population implies probably a donor-derived origin (endothelial progenitor cells).

Allogenic lyophilized cartilage grafts for craniomaxillofacial reconstruction

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Pill Hoon Choung

1999-01-01

Allogenic lyophilized cartilages were made in our clinic after Sailer methods and some modification. In our clinic, we have used allogenic cartilage grafts on 102 defects of craniomaxillofacial area; 1) for defects from cyst or ameloblastoma, 2) for lack of continuity of the mandible, 3) for rhinoplasty, 4) for paranasal augmentation, 5) for augmentation genioplasty, 6) for reconstruction of orbital floor, 7) for oroantral fistula, 8) for temporal augmentation, 9) for TMJ surgery 10) for condyle defect as a costochondral graft, 11) for filling of tooth socket and alveolus augmentation,12) for correction or orbital height and 13) for guided bone regeneration in peripheral implant. The types of lyophilized cartilage used were chip, sheet and block types developed by freeze-dried methods. Some grafts showed change of ossification, in which case we could perform implant on it. We have good results on reconstruction of craniomaxillofacial defects. Allogenic cartilage have advantages such as 1) it has no immune reaction clinically, 2) it is more tolerable to infection than that of autogenous cartilage, 3) it has character of less resorption which require no over correction, 4) it is easy to manipulate contouring, and 5) it has possibility of undergoing ossification. Allogenic cartilage has been considered as good substitutes for bone. The author would like to report the results on 102 allogenic cartilage have

Subsequent vitiligo after hematopoietic stem cell transplantation: A nationwide population-based cohort study from Korea.

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Bae, Jung Min; Choi, Kwang Hyun; Jung, Han Mi; Kim, Sook Young; Kim, Miri; Kim, Gyung Moon; Yu, Dong Soo; Lee, Young Bok

2017-03-01

Subsequent vitiligo after hematopoietic stem cell transplantation (HSCT) has been described sporadically in case series. To investigate the incidence and risk factors of subsequent vitiligo after HSCT. A nationwide, population-based cohort study was performed using the Korean National Health Insurance Claims Database from 2009 to 2013. All HSCT recipients who had undergone HSCT between 2010 and 2011 and not treatment for vitiligo in 2009 (to exclude preexisting active vitiligo) were included in the HSCT recipient group, and an age- and sex-matched control group without HSCT was also established. A total of 2747 HSCT recipients and 8241 controls were enrolled. Newly acquired vitiligo occurred in 1.06% of HSCT recipients between 2010 and 2013, and there was a significant increase (OR 3.130, 95% CI 1.859-5.271) in cases of vitiligo in HSCT recipients compared with controls (0.34%). Allogeneic HSCT (OR 5.593, 95% CI 1.628-19.213) and bone marrow-sourced stem cells (as compared with peripheral blood-sourced stem cells; OR 2.492, 95% CI 1.114-5.576) were independently associated with the development of vitiligo after HSCT. Medical record review was not available. Vitiligo developed at a significantly increased rate after HSCT compared with controls. Allogeneic HSCT and bone marrow-sourced stem cells were independent risk factors. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

Clinical assessment of anti-viral CD8+ T cell immune monitoring using QuantiFERON-CMV® assay to identify high risk allogeneic hematopoietic stem cell transplant patients with CMV infection complications.

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Siok-Keen Tey

Full Text Available The reconstitution of anti-viral cellular immunity following hematopoietic stem cell transplantation (HSCT is crucial in preventing cytomegalovirus (CMV-associated complications. Thus immunological monitoring has emerged as an important tool to better target pre-emptive anti-viral therapies. However, traditional laboratory-based assays are too cumbersome and complicated to implement in a clinical setting. Here we conducted a prospective study of a new whole blood assay (referred to as QuantiFERON-CMV® to determine the clinical utility of measuring CMV-specific CD8+ T-cell responses as a prognostic tool. Forty-one evaluable allogeneic HSCT recipients underwent weekly immunological monitoring from day 21 post-transplant and of these 21 (51.2% showed CMV reactivation and 29 (70.7% developed acute graft-versus-host disease (GvHD. Patients with acute GvHD (grade ≥ 2 within 6 weeks of transplant showed delayed reconstitution of CMV-specific T-cell immunity (p = 0.013 and a higher risk of CMV viremia (p = 0.026. The median time to stable CMV-specific immune reconstitution was 59 days and the incidence of CMV reactivation was lower in patients who developed this than those who did not (27% versus 65%; p = 0.031. Furthermore, a failure to reconstitute CMV-specific immunity soon after the onset of CMV viraemia was associated with higher peak viral loads (5685 copies/ml versus 875 copies/ml; p = 0.002. Hence, QuantiFERON-CMV® testing in the week following CMV viremia can be useful in identifying HSCT recipients at risk of complicated reactivation.

Impact of Donor Epstein-Barr Virus Serostatus on the Incidence of Graft-Versus-Host Disease in Patients With Acute Leukemia After Hematopoietic Stem-Cell Transplantation: A Study From the Acute Leukemia and Infectious Diseases Working Parties of the European Society for Blood and Marrow Transplantation.

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Styczynski, Jan; Tridello, Gloria; Gil, Lidia; Ljungman, Per; Hoek, Jennifer; Iacobelli, Simona; Ward, Katherine N; Cordonnier, Catherine; Einsele, Hermann; Socie, Gerard; Milpied, Noel; Veelken, Hendrik; Chevallier, Patrice; Yakoub-Agha, Ibrahim; Maertens, Johan; Blaise, Didier; Cornelissen, Jan; Michallet, Mauricette; Daguindau, Etienne; Petersen, Eefke; Passweg, Jakob; Greinix, Hildegard; Duarte, Rafael F; Kröger, Nicolaus; Dreger, Peter; Mohty, Mohamad; Nagler, Arnon; Cesaro, Simone

2016-07-01

We investigated the effect of Epstein-Barr virus (EBV) serostatus on the overall outcome of allogeneic hematopoietic stem-cell transplantation (allo-HSCT). The study included 11,364 patients who underwent allogeneic peripheral-blood or bone marrow transplantation for acute leukemia between 1997 and 2012. We analyzed the impact of donor and recipient EBV serologic status on overall survival, relapse-free survival, relapse incidence, nonrelapse mortality, and incidence of graft-versus-host disease (GVHD) after allo-HSCT. Patients receiving grafts from EBV-seropositive donors had the same overall survival as patients who received grafts from EBV-seronegative donors (hazard ratio [HR], 1.05; 95% CI, 0.97 to 1.12; P = .23). Seropositive donors also had no influence on relapse-free survival (HR, 1.04; 95% CI, 0.97 to 1.11; P = 0.31), relapse incidence (HR, 1.03; 95% CI, 0.94 to 1.12; P = .58), and nonrelapse mortality (HR, 1.05; 95% CI, 0.94 to 1.17; P = .37). However, in univariate analysis, recipients receiving grafts from seropositive donors had a higher risk of chronic GVHD than those with seronegative donors (40.8% v 31.0%, respectively; P donors, the HR for chronic GVHD was 1.30 (95% CI, 1.06 to 1.59; P = .039). In seropositive patients with seropositive donors, the HR was 1.24 (95% CI, 1.07 to 1.45; P = .016) for acute GVHD and 1.43 (95% CI, 1.23 to 1.67; P donors did not have an increased risk of GVHD. Our data suggest that donor EBV status significantly influences development of acute and chronic GVHD after allo-HSCT. © 2016 by American Society of Clinical Oncology.

Lyophilized allogeneic bone grafts for cystic and discontinuity defects of the jaws

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Pill Hoon Choung; Eun Seok Kim

1999-01-01

Allogenic bone grafts have been used after various processing in each institute was made by lyophilized allogenic bone and used for maxillofacial reconstruction. Three types of lyophilized allogenic bone grafts as powder, chip and block form were performed to reconstruct the following defects: 1) maxillectomy, 2) mandiblectomy, 3) cystectomy, 4) cleft alveolus, 5) gap in orthognathic osteotomy, 6) peri-implant defect, 7) extraction socket, and 8) facial contouring. Above defects can be classified as cystic and discontinuity defects of the maxilia and the mandible. Because discontinuity defects have more difficult problems to reconstruct considering mechanical strength of the allogenic bone. We performed allogenic bone grafts on 50 cystic defects and 12 discontinuity defects of the jaws. Among them, 3 cases were removed due to infection, and the others had no complications. In reconstruction of cystic defects, the defects were filled with allogenic chip which were made from allogenic block bone at the surgery, which later were changed to host bone. Three cases of them showed tooth eruption through the allogenic bone grafting site, changing the eruption pathway, which was interrupted by the lesion. in reconstruction of discontinuity defects, usually allogenic bone has been used as a tray, in which PMCB or demineralized bone chips were filled. But we tried to reconstruct this discontinuity defect using allogeneic bone block without inside filling of PMCB different from tray type. We will present the results of allogenic bone grafts using cranial bone, costochondral graft, and the mandible

Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation.

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Tzannou, Ifigeneia; Papadopoulou, Anastasia; Naik, Swati; Leung, Kathryn; Martinez, Caridad A; Ramos, Carlos A; Carrum, George; Sasa, Ghadir; Lulla, Premal; Watanabe, Ayumi; Kuvalekar, Manik; Gee, Adrian P; Wu, Meng-Fen; Liu, Hao; Grilley, Bambi J; Krance, Robert A; Gottschalk, Stephen; Brenner, Malcolm K; Rooney, Cliona M; Heslop, Helen E; Leen, Ann M; Omer, Bilal

2017-11-01

Purpose Improvement of cure rates for patients treated with allogeneic hematopoietic stem-cell transplantation (HSCT) will require efforts to decrease treatment-related mortality from severe viral infections. Adoptively transferred virus-specific T cells (VSTs) generated from eligible, third-party donors could provide broad antiviral protection to recipients of HSCT as an immediately available off-the-shelf product. Patient and Methods We generated a bank of VSTs that recognized five common viral pathogens: Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6). The VSTs were administered to 38 patients with 45 infections in a phase II clinical trial. Results A single infusion produced a cumulative complete or partial response rate of 92% (95% CI, 78.1% to 98.3%) overall and the following rates by virus: 100% for BKV (n = 16), 94% for CMV (n = 17), 71% for AdV (n = 7), 100% for EBV (n = 2), and 67% for HHV-6 (n = 3). Clinical benefit was achieved in 31 patients treated for one infection and in seven patients treated for multiple coincident infections. Thirteen of 14 patients treated for BKV-associated hemorrhagic cystitis experienced complete resolution of gross hematuria by week 6. Infusions were safe, and only two occurrences of de novo graft-versus host disease (grade 1) were observed. VST tracking by epitope profiling revealed persistence of functional VSTs of third-party origin for up to 12 weeks. Conclusion The use of banked VSTs is a feasible, safe, and effective approach to treat severe and drug-refractory infections after HSCT, including infections from two viruses (BKV and HHV-6) that had never been targeted previously with an off-the-shelf product. Furthermore, the multispecificity of the VSTs ensures extensive antiviral coverage, which facilitates the treatment of patients with multiple infections.

ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

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Luca Laurenti

2010-08-01

Full Text Available Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment. Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%: A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity. The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients. Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

Hodgkin's disease as unusual presentation of post-transplant lymphoproliferative disorder after autologous hematopoietic cell transplantation for malignant glioma

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Scelsi Mario

2005-08-01

Full Text Available Abstract Background Post-transplant lymphoproliferative disorder (PTLD is a complication of solid organ and allogeneic hematopoietic stem cell transplantation (HSCT; following autologous HSCT only rare cases of PTLD have been reported. Here, a case of Hodgkin's disease (HD, as unusual presentation of PTLD after autologous HSCT for malignant glioma is described. Case presentation 60-years old man affected by cerebral anaplastic astrocytoma underwent subtotal neurosurgical excision and subsequent high-dose chemotherapy followed by autologous HSCT. During the post HSCT course, cranial irradiation and corticosteroids were administered as completion of therapeutic program. At day +105 after HSCT, the patient developed HD, nodular sclerosis type, with polymorphic HD-like skin infiltration. Conclusion The clinical and pathological findings were consistent with the diagnosis of PTLD.

Symptoms after hospital discharge following hematopoietic stem cell transplantation

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Gamze Oguz

2014-01-01

Full Text Available Aims: The purposes of this study were to assess the symptoms of hematopoietic stem cell transplant patients after hospital discharge, and to determine the needs of transplant patients for symptom management. Materials and Methods: The study adopted a descriptive design. The study sample comprised of 66 hematopoietic stem cell transplant patients. The study was conducted in Istanbul. Data were collected using Patient Information Form and Memorial Symptom Assessment Scale (MSAS. Results: The frequency of psychological symptoms in hematopoietic stem cell transplant patients after discharge period (PSYCH subscale score 2.11 (standard deviation (SD = 0.69, range: 0.93-3.80 was higher in hematopoietic stem cell transplant patients than frequency of physical symptoms (PHYS subscale score: 1.59 (SD = 0.49, range: 1.00-3.38. Symptom distress caused by psychological and physical symptoms were at moderate level (Mean = 1.91, SD = 0.60, range: 0.95-3.63 and most distressing symptoms were problems with sexual interest or activity, difficulty sleeping, and diarrhea. Patients who did not have an additional chronic disease obtained higher MSAS scores. University graduates obtained higher Global Distress Index (GDI subscale and total MSAS scores with comparison to primary school graduates. Total MSAS, MSAS-PHYS subscale, and MSAS-PSYCH subscale scores were higher in patients with low level of income (P < 0.05. The patients (98.5% reported to receive education about symptom management after hospital discharge. Conclusions: Hematopoietic stem cell transplant patients continue to experience many distressing physical or psychological symptoms after discharge and need to be supported and educated for the symptom management.

Impact of Pretransplantation Indices in Hematopoietic Stem Cell Transplantation: Knowledge of Center-Specific Outcome Data Is Pivotal before Making Index-Based Decisions.

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Törlén, Johan; Remberger, Mats; Le Blanc, Katarina; Ljungman, Per; Mattsson, Jonas

2017-04-01

Outcome after allogeneic hematopoietic stem cell transplantation is influenced by patient comorbidity, disease type, and status before treatment. We performed a retrospective study involving 521 consecutive adult hematopoietic stem cell transplantation patients who underwent transplantation for hematological malignancy at our center from 2000 to 2012 to compare the predictive value of the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and the disease risk index (DRI) for overall survival and transplantation-related mortality. Patients in the highest HCT-CI risk group (HCT-CI score ≥3) had a lower 5-year overall survival rate (50%) than the low-risk group (63%; P 6 [n = 9]). Five-year overall survival in the highest DRI risk group was significantly poorer (44%) than in the low-risk group (63%; P indices failed to predict differences in transplantation-related mortality (HCT-CI, P = .54; DRI, P = .17). We conclude that HCT-CI and DRI were predictive of overall survival in our patient population. Even so, our data show that different patient groups may have different outcomes despite sharing the same index risk group and that indices should, therefore, be evaluated according to local data before clinical implementation at the single-center level. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Clinical features and outcomes in patients with disseminated toxoplasmosis admitted to intensive care: a multicenter study.

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Schmidt, Matthieu; Sonneville, Romain; Schnell, David; Bigé, Naike; Hamidfar, Rebecca; Mongardon, Nicolas; Castelain, Vincent; Razazi, Keyvan; Marty, Antoine; Vincent, François; Dres, Martin; Gaudry, Stephane; Luyt, Charles Edouard; Das, Vincent; Micol, Jean-Baptiste; Demoule, Alexandre; Mayaux, Julien

2013-12-01

Characteristics and outcomes of adult patients with disseminated toxoplasmosis admitted to the intensive care unit (ICU) have rarely been described. We performed a retrospective study on consecutive adult patients with disseminated toxoplasmosis who were admitted from January 2002 through December 2012 to the ICUs of 14 university-affiliated hospitals in France. Disseminated toxoplasmosis was defined as microbiological or histological evidence of disease affecting >1 organ in immunosuppressed patients. Isolated cases of cerebral toxoplasmosis were excluded. Clinical data on admission and risk factors for 60-day mortality were collected. Thirty-eight patients were identified during the study period. Twenty-two (58%) had received an allogeneic hematopoietic stem cell transplant (median, 61 [interquartile range {IQR}, 43-175] days before ICU admission), 4 (10%) were solid organ transplant recipients, and 10 (27%) were infected with human immunodeficiency virus (median CD4 cell count, 14 [IQR, 6-33] cells/µL). The main indications for ICU admission were acute respiratory failure (89%) and shock (53%). The 60-day mortality rate was 82%. Allogeneic hematopoietic stem cell transplant (hazard ratio [HR] = 2.28; 95% confidence interval [CI], 1.05-5.35; P = .04) and systolic cardiac dysfunction (HR = 3.54; 95% CI, 1.60-8.10; P toxoplasmosis leading to ICU admission has a poor prognosis. Recipients of allogeneic hematopoietic stem cell transplant appear to have the highest risk of mortality. We identified systolic cardiac dysfunction as a major determinant of outcome. Strategies aimed at preventing this fatal opportunistic infection may improve outcomes.

Successful Treatment of Richter Transformation with Ibrutinib in a Patient with Chronic Lymphocytic Leukemia following Allogeneic Hematopoietic Stem Cell Transplant

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Samip Master

2017-06-01

Full Text Available Patients with chronic lymphocytic leukemia (CLL who progress to Richter transformation (RT have a poor prognosis. Multi-agent chemotherapy regimens do not have good response rates. There are few case reports on the use of ibrutinib in RT. Here, we present a patient who was heavily pretreated for CLL, including allogeneic stem cell transplant, and progressed to RT. She had a mixed response to multi-agent chemotherapy and was started on ibrutinib. She had a complete response for 16 months on single-agent ibrutinib with minimal toxicity.

Association of Macroeconomic Factors With Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation for Adults With Acute Lymphoblastic Leukemia: An Analysis From the Acute Leukemia Working Party of the EBMT.

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Giebel, Sebastian; Labopin, Myriam; Ibatici, Adalberto; Browne, Paul; Czerw, Tomasz; Socie, Gerard; Unal, Ali; Kyrcz-Krzemien, Slawomira; Bacigalupo, Andrea; Goker, Hakan; Potter, Mike; Furness, Caroline L; McQuaker, Grant; Beelen, Dietrich; Milpied, Noel; Campos, Antonio; Craddock, Charles; Nagler, Arnon; Mohty, Mohamad

2016-03-01

From a global perspective, the rates of allogeneic hematopoietic cell transplantation (alloHCT) are closely related to the economic status of a country. However, a potential association with outcome has not yet been documented. The goal of this study was to evaluate effects of health care expenditure (HCE), Human Development Index (HDI), team density, and center experience on nonrelapse mortality (NRM) after HLA-matched sibling alloHCT for adults with acute lymphoblastic leukemia (ALL). A total of 983 patients treated with myeloablative alloHCT between 2004 and 2008 in 24 European countries were included. In a univariate analysis, the probability of day 100 NRM was increased for countries with lower current HCE (8% vs. 3%; p = .06), countries with lower HDI (8% vs. 3%; p = .02), and centers with less experience (8% vs. 5%; p = .04). In addition, the overall NRM was increased for countries with lower current HCE (21% vs. 17%; p = .09) and HDI (21% vs. 16%; p = .03) and for centers with lower activity (21% vs. 16%; p = .07). In a multivariate analysis, the strongest predictive model for day 100 NRM included current HCE greater than the median (hazard ratio [HR], 0.39; p = .002). The overall NRM was mostly predicted by HDI greater than the median (HR, 0.65; p = .01). Both lower current HCE and HDI were associated with decreased probability of overall survival. Both macroeconomic factors and the socioeconomic status of a country strongly influence NRM after alloHCT for adults with ALL. Our findings should be considered when clinical studies in the field of alloHCT are interpreted. ©AlphaMed Press.

Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

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Matsuyama, Takaharu; Kato, Koji

2002-01-01

A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 μg/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

Hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia

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Matsuyama, Takaharu; Kato, Koji [Nagoya First Red Cross Hospital (Japan). Children' s Medical Center; Hanada, Ryoji [Saitama Children' s Medical Center, Iwatsuki (Japan)] [and others

2002-07-01

A multicenter comparative study was carried out to investigate the efficacy and safety of hematopoietic stem cell transplantation with conditioning regimens containing melphalan in pediatric patients with acute lymphoblastic leukemia. One hundred twenty three patients at a variety of remission stages were eligible for study participation. Eighty-nine were transplanted with allogeneic grafts and 34 patients with autologous grafts (23 cases with bone marrow and 11 cases with peripheral blood stem cells). Conditioning regimens used were as follows: melphalan and busulfan for 40 patients, melphalan, busulfan and TBI for 44 patients, other regimens for 39 patients. To accelerate engraftment G-CSF (lenograstim) was administered as a 1-hour or 24-hour drip infusion daily at 5 {mu}g/kg from day 5 until hematological recovery. The five year disease free survival (DFS) was 63% for 42 patients at CR1, 41% for 41 patients at CR2 and 33% for 40 patients at other stages. There was no significant difference in the DFS between allogeneic-transplantation and autologous-transplantation in all disease stages. In patients at remission stage for CR1 and CR2, the 5-year DFS by conditioning regimen was 63% for regimen with melphalan and busulfan, 54% for regimen with melphalan, busulfan and TBI and 54% for regimens with melphalan and TBI. There was no significant difference in the DFS between the groups. Serious complications such as renal failure were observed in 11%, veno-occlusive disease in 9%, and interstitial pneumonia in 9%. The most dominating cause of death was relapse in the disease (48% of deaths) which was most commonly observed in autologous transplantation. Contrary to that, treatment related toxic death was the most frequent cause of deaths in allogeneic-transplantation. (author)

Outcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the société Francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

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Roux, C; Tifratene, K; Socié, G; Galambrun, C; Bertrand, Y; Rialland, F; Jubert, C; Pochon, C; Paillard, C; Sirvent, A; Nelken, B; Vannier, J P; Freycon, C; Beguin, Y; Raus, N; Yakoub-Agha, I; Mohty, M; Dalle, J-H; Michel, G; Pradier, C; Peffault de Latour, R; Rohrlich, P-S

2017-05-01

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in the case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent 10-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted of chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and donor lymphocyte infusion (DLI; n=30), or isolated reinfusion of donor lymphocytes (DLI; n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy=385 days, second allograft=391 days, chemotherapy=174 days, DLI alone=140 days, palliative care=43 days. A second SCT or a combination of chemotherapy and DLI yielded similar outcome (hazard ratio (HR)=0.85, P=0.53) unlike chemotherapy alone (HR=1.43 P=0.04), palliative care (HR=4.24, P<0.0001) or isolated DLI (HR=1,94, P<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML.

Milestones of Hematopoietic Stem Cell Transplantation – From First Human Studies to Current Developments

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Juric, Mateja Kralj; Ghimire, Sakhila; Ogonek, Justyna; Weissinger, Eva M.; Holler, Ernst; van Rood, Jon J.; Oudshoorn, Machteld; Dickinson, Anne; Greinix, Hildegard T.

2016-01-01

Since the early beginnings, in the 1950s, hematopoietic stem cell transplantation (HSCT) has become an established curative treatment for an increasing number of patients with life-threatening hematological, oncological, hereditary, and immunological diseases. This has become possible due to worldwide efforts of preclinical and clinical research focusing on issues of transplant immunology, reduction of transplant-associated morbidity, and mortality and efficient malignant disease eradication. The latter has been accomplished by potent graft-versus-leukemia (GvL) effector cells contained in the stem cell graft. Exciting insights into the genetics of the human leukocyte antigen (HLA) system allowed improved donor selection, including HLA-identical related and unrelated donors. Besides bone marrow, other stem cell sources like granulocyte-colony stimulating-mobilized peripheral blood stem cells and cord blood stem cells have been established in clinical routine. Use of reduced-intensity or non-myeloablative conditioning regimens has been associated with a marked reduction of non-hematological toxicities and eventually, non-relapse mortality allowing older patients and individuals with comorbidities to undergo allogeneic HSCT and to benefit from GvL or antitumor effects. Whereas in the early years, malignant disease eradication by high-dose chemotherapy or radiotherapy was the ultimate goal; nowadays, allogeneic HSCT has been recognized as cellular immunotherapy relying prominently on immune mechanisms and to a lesser extent on non-specific direct cellular toxicity. This chapter will summarize the key milestones of HSCT and introduce current developments. PMID:27881982

Hematopoietic stem cell transplantation from unrelated donors in children with DOCK8 deficiency.

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Uygun, Dilara Fatma K; Uygun, Vedat; Reisli, İsmail; Keleş, Sevgi; Özen, Ahmet; Yılmaz, Mustafa; Sayar, Esra H; Daloğlu, Hayriye; Öztürkmen, Seda I; Çakı, Suar; Karasu, Gülsün T; Yeşilipek, Akif

2017-11-01

DIDS is a unique form of combined immune deficiency characterized by an unusual susceptibility to cutaneous viral infections, severe allergies with eosinophilia and elevated immunoglobulin E titers, autoimmunity, and cancer. HSCT is considered the standard of care for this deadly disease. We have retrospectively analyzed the outcome of allogeneic HSCT from unrelated donors in patients with DIDS. Data from four patients, with five transplants, are presented. All patients received transplants from unrelated donors' BM, except for one patient who received a cord blood transplant. The conditioning regimens were based on myeloablative protocols for BM derived transplants; a NM regimen was pursued for the patient who received a cord blood transplant, which resulted in graft rejection. Although recurrent pneumonia and skin infections resolved immediately after transplantation, all patients subsequently developed human herpesvirus infection, including cutaneous herpetic lesions, cytomegalovirus reactivation, and zona zoster, which could be attributed to the use of ATG. Despite the presence of serious morbidities prior to transplantation, all patients recovered successfully. DIDS can be successfully treated with allogeneic HSCT from unrelated donors following a myeloablative conditioning regimen, with a reasonable safety profile. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Radioresistant canine hematopoietic cells

International Nuclear Information System (INIS)

Kawakami, T.G.; Shimizu, J.; Rosenblatt, L.S.; Goldman, M.

1987-01-01

Survival of dogs that are continuously exposed to a moderate dose-rate of gamma radiation (10 cGy/day) is dependent on the age of the dog at the time of exposure. Most dogs exposed postpartum to gamma radiation suffered from suppressed hematopoiesis and died of aplasia. On the other hand, none of the in utero-exposed dogs suffered from suppressed hematopoiesis and most became long-term survivors, tolerating 10-fold greater total dose, but dying of myeloproliferative disease (MPD). Using acute gamma irradiation of hematopoietic cells and colony forming unit cell assay (CFU), they observed that a canine hematopoietic cell line established from a myeloid leukemic dog that was a long-term survivor of continuous irradiation was approximately 4-fold more radioresistant than a hematopoietic cell line established from a dog with nonradiation-induced myeloid leukemia or hematopoietic cells from normal canine bone marrow. In utero dogs that are long-term survivors of continuous irradiation have radioresistant hematopoietic cells, and radioresistance that is a constitutive property of the cells

Spiritual absence and 1-year mortality after hematopoietic stem cell transplant.

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Pereira, Deidre B; Christian, Lisa M; Patidar, Seema; Bishop, Michelle M; Dodd, Stacy M; Athanason, Rebecca; Wingard, John R; Reddy, Vijay S

2010-08-01

Religiosity and spirituality have been associated with better survival in large epidemiologic studies. This study examined the relationship between spiritual absence and 1-year all-cause mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Depression and problematic compliance were examined as possible mediators of a significant spiritual absence-mortality relationship. Eighty-five adults (mean = 46.85 years old, SD = 11.90 years) undergoing evaluation for allogeneic HSCT had routine psychologie evaluation prior to HSCT admission. The Millon Behavioral Medicine Diagnostic was used to assess spiritual absence, depression, and problematic compliance, the psychosocial predictors of interest. Patient status at 1 year and survival time in days were abstracted from medical records. Cox regression analysis was used to examine the relationship between the psychosocial factors of interest and mortality after adjusting for relevant biobehavioral factors. Twenty-nine percent (n = 25) of participants died within 1 year of HSCT. After covarying for disease type, individuals with the highest spiritual absence and problematic compliance scores were significantly more likely to die 1-year post-HSCT (hazard ratio [HR] = 2.49, P = .043 and HR = 3.74, P = .029, respectively), particularly secondary to infection, sepsis, or graft-versus-host disease (GVHD) (HR = 4.56, P = .01 and HR = 5.61, P = .014), relative to those without elevations on these scales. Depression was not associated with 1-year mortality, and problematic compliance did not mediate the relationship between spiritual absence and mortality. These preliminary results suggest that both spiritual absence and problematic compliance may be associated with poorer survival following HSCT. Future research should examine these relations in a larger sample using a more comprehensive assessment of spirituality.

An update on ABO incompatible hematopoietic progenitor cell transplantation.

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Staley, Elizabeth M; Schwartz, Joseph; Pham, Huy P

2016-06-01

Hematopoietic progenitor cell (HPC) transplantation has long been established as the optimal treatment for many hematologic malignancies. In the setting of allogenic HLA matched HPC transplantation, greater than 50% of unrelated donors and 30% of related donors demonstrate some degree of ABO incompatibility (ABOi), which is classified in one of three ways: major, minor, or bidirectional. Major ABOi refers to the presence of recipient isoagglutinins against the donor's A and/or B antigen. Minor ABOi occurs when the HPC product contains the isoagglutinins targeting the recipient's A and/or B antigen. Bidirectional refers to the presence of both major and minor ABOi. Major adverse events associated with ABOi HPC transplantation includes acute and delayed hemolysis, pure red cell aplasia, and delayed engraftment. ABOi HPC transplantation poses a unique challenge to the clinical transplantation unit, the HPC processing lab, and the transfusion medicine service. Therefore, it is essential that these services actively communicate with one another to ensure patient safety. This review will attempt to globally address the challenges related to ABOi HPC transplantation, with an increased focus on aspects related to the laboratory and transfusion medicine services. Copyright © 2016 Elsevier Ltd. All rights reserved.

Importance of Nongovernmental Organizations for the Establishment of a Successful Hematopoietic Stem-Cell Transplantation Program in a Developing Country

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Monica M. Rivera Franco

2018-02-01

Full Text Available Purpose: In low- and middle-income countries with limited resources, the success of a hematopoietic stem-cell transplantation (HSCT program relies directly on its affordability while obtaining similar outcomes to developed regions. The objective of this study was to describe the experience of a tertiary/referral center in Mexico City performing HSCT with the subsidy of a nongovernmental organization (NGO. Patients and Methods: We performed a retrospective analysis including 146 patients who underwent HSCT at the National Institutes of Health Sciences and Nutrition Salvador Zubiran and were subsidized by the NGO Unidos. Results: Seventy-five patients (51% and 71 patients (49% underwent autologous and allogeneic HSCT, respectively. The median age was 30 years, 56% did not obtain a bachelor’s degree, 79% had a low socioeconomic level, and 75% were unemployed. None had any health coverage. According to the real patient out-of-pocket expense, the subsidy by Unidos corresponded to 88% and 72% in autologous and allogeneic HSCT, respectively. Conclusion: Our results highlight that undergoing an HSCT was feasible for vulnerable patients because of the subsidy of medications and chemotherapy by Unidos. Therefore, creating NGOs in developing countries is important to provide complex medical procedures, such as HSCT, at limited-resource centers to underserved populations while obtaining good outcomes.

Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.

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Ryan, Christine E; Sahaf, Bita; Logan, Aaron C; O'Brien, Susan; Byrd, John C; Hillmen, Peter; Brown, Jennifer R; Dyer, Martin J S; Mato, Anthony R; Keating, Michael J; Jaglowski, Samantha; Clow, Fong; Rezvani, Andrew R; Styles, Lori; Coutre, Steven E; Miklos, David B

2016-12-22

Ibrutinib, a potent and irreversible small-molecule inhibitor of both Bruton's tyrosine kinase and interleukin-2 inducible kinase (ITK), has been used to treat relapsed/refractory chronic lymphocytic leukemia (CLL) with prolongation of progression-free and overall survival. Here, we present 27 patients with relapsed CLL following allogeneic hematopoietic cell transplant (HCT) who subsequently received ibrutinib salvage therapy. Sixteen of these patients were part of multi-institutional clinical trials and achieved an overall response rate of 87.5%. An additional 11 patients were treated at Stanford University following US Food and Drug Administration approval of ibrutinib; 7 (64%) achieved a complete response, and 3 (27%) achieved a partial response. Of the 9 patients treated at Stanford who had mixed chimerism-associated CLL relapse, 4 (44%) converted to full donor chimerism following ibrutinib initiation, in association with disease response. Four of 11 (36%) patients evaluated by ClonoSeq achieved minimal residual disease negativity with CLL ibrutinib was discontinued, in 1 case even after 26 months. None of the 27 patients developed graft-versus-host-disease (GVHD) following ibrutinib initiation. We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell-mediated effect, most likely due to ITK inhibition. To investigate the immune modulatory effects of ibrutinib, we completed comprehensive immune phenotype characterization of peripheral B and T cells from treated patients. Our results show that ibrutinib selectively targets pre-germinal B cells and depletes Th2 helper cells. Furthermore, these effects persisted after drug discontinuation. In total, our results provide evidence that ibrutinib effectively augments GVL without causing GVHD. © 2016 by The American Society of Hematology.

Subclinical hypothyroidism in children and adolescents after hematopoietic stem cells transplantation without irradiation

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Milenković Tatjana

2014-01-01

Full Text Available Background/Aim. Although total body irradiation (TBI was considered to be the primary cause of thyroid dysfunction following hematopoietic stem cells transplantation (HSCT, a significant prevalence of subclinical hypothyroidism after HSCT with chemotherapy-only conditioning regimens has been observed in several studies. The aim of this study was to assess changes in thyroid stimulating hormone (TSH levels in children after HSCT, without the use of irradiation at any time in the course of the treatment. Methods. Our cohort consisted of 41 children and adolescents who underwent autologous or allogeneic HSCT and were available for follow-up for at least one year after transplantation. Irradiation was not performed in any of the subjects, neither during pretransplatation therapy, nor during conditioning. The median duration of follow-up was 2.9 years. The indications for HSCT were hematologic malignancy (41.5%, solid malignant tumor (34.1%, and other disorders (24.4%. The thyroid status of all the subjects was assessed prior to HSCT and after follow-up period. Results. Thyroid dysfunction after HSCT was present in 27 (65.8% subjects. Subclinical hypothyroidism was the most common abnormality, presenting in 23 (56.1% patients, primary hypothyroidism was present in one (2.4% patient, while 3 (7.3% subjects had low free T4 with normal TSH values. Significantly (p < 0.01 higher elevations in TSH levels were present in the patients who received chemotherapy for the underlying disease prior to HSCT. Conclusion. Our findings emphasize the need for long-term monitoring of thyroid function following HSCT, regardless of whether or not irradiation was used.

Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era

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Ramadan, Safaa M.; Di Veroli, Ambra; Camboni, Agnese; Breccia, Massimo; Iori, Anna Paola; Aversa, Franco; Cupelli, Luca; Papayannidis, Cristina; Bacigalupo, Andrea; Arcese, William; Lo-Coco, Francesco

2012-01-01

The role of allogeneic stem cell transplant in advanced acute promyelocytic leukemia patients who received standard first- and second-line therapy is still unknown. We report the outcome of 31 acute promyelocytic leukemia patients (median age 39 years) who underwent allogeneic transplant in second remission (n=15) or beyond (n=16). Sixteen patients were real-time polymerase chain reaction positive and 15 negative for PML/RARA pre-transplant. The 4-year overall survival was 62% and 31% for patients transplanted in second remission and beyond, respectively (P=0.05), and 64% and 27% for patients with pre-transplant negative and positive real-time polymerase chain reaction, respectively (P=0.03). The 4-year cumulative incidence of relapse was 32% and 44% for patients transplanted in second remission and beyond, respectively (P=0.37), and 30% and 47% for patients transplanted with negative and positive real-time polymerase chain reaction, respectively (P=0.30). Transplant-related mortality was 19.6%. In conclusion, allogeneic transplant is effective in advanced acute promyelocytic leukemia in the all-trans-retinoic acid and arsenic trioxide era, and should be considered once relapse is diagnosed. PMID:22689684

HEMATOPOIETIC PROGENITOR CELL CONTENT OF VERTEBRAL BODY MARROW USED FOR COMBINED SOLID ORGAN AND BONE MARROW TRANSPLANTATION

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Rybka, Witold B.; Fontes, Paulo A.; Rao, Abdul S.; Winkelstein, Alan; Ricordi, Camillo; Ball, Edward D.; Starzl, Thomas E.

2010-01-01

While cadaveric vertebral bodies (VB) have long been proposed as a suitable source of bone marrow (BM) for transplantation (BMT), they have rarely been used for this purpose. We have infused VB BM immediately following whole organ (WO) transplantation to augment donor cell chimerism. We quantified the hematopoietic progenitor cell (HPC) content of VB BM as well as BM obtained from the iliac crests (IC) of normal allogeneic donors (ALLO) and from patients with malignancy undergoing autologous marrow harvest (AUTO). Patients undergoing WOIBM transplantation also had AUTO BM harvested in the event that subsequent lymphohematopoietic reconstitution was required. Twenty-four VB BM, 24 IC BM-ALLO, 31 IC AUTO, and 24 IC WO-AUTO were harvested. VB BM was tested 12 to 72 hr after procurement and infused after completion ofWO grafting. IC BM was tested and then used or cryopreserved immediately. HPC were quantified by clonal assay measuring CFU-GM, BFU-E, and CFU-GEMM, and by flow cytometry for CD34+ progenitor cells. On an average, 9 VB were processed during each harvest, and despite an extended processing time the number of viable nucleated cells obtained was significantly higher than that from IC. Furthermore, by HPC content, VB BM was equivalent to IC BM, which is routinely used for BMT. We conclude that VB BM is a clinically valuable source of BM for allogeneic transplantation. PMID:7701582

Subsequent donation requests among 2472 unrelated hematopoietic progenitor cell donors are associated with bone marrow harvest

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Lown, Robert N.; Tulpule, Sameer; Russell, Nigel H.; Craddock, Charles F.; Roest, Rochelle; Madrigal, J. Alejandro; Shaw, Bronwen E.

2013-01-01

Approximately 1 in 20 unrelated donors are asked to make a second donation of hematopoietic progenitor cells, the majority for the same patient. Anthony Nolan undertook a study of subsequent hematopoietic progenitor cell donations made by its donors from 2005 to 2011, with the aims of predicting those donors more likely to be called for a second donation, assessing rates of serious adverse reactions and examining harvest yields. This was not a study of factors predictive of second allografts. During the study period 2591 donations were made, of which 120 (4.6%) were subsequent donations. The median time between donations was 179 days (range, 21–4016). Indications for a second allogeneic transplant included primary graft failure (11.7%), secondary graft failure (53.2%), relapse (30.6%) and others (1.8%). On multivariate analysis, bone marrow harvest at first donation was associated with subsequent donation requests (odds ratio 2.00, P=0.001). The rate of serious adverse reactions in donors making a subsequent donation appeared greater than the rate in those making a first donation (relative risk=3.29, P=0.005). Harvest yields per kilogram recipient body weight were equivalent between donations, although females appeared to have a lower yield at the subsequent donation. Knowledge of these factors will help unrelated donor registries to counsel their donors. PMID:23812935

Early Experience With CliniMACS Prodigy CCS (IFN-gamma) System in Selection of Virus-specific T Cells From Third-party Donors for Pediatric Patients With Severe Viral Infections After Hematopoietic Stem Cell Transplantation.

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Kállay, Krisztián; Kassa, Csaba; Réti, Marienn; Karászi, Éva; Sinkó, János; Goda, Vera; Stréhn, Anita; Csordás, Katalin; Horváth, Orsolya; Szederjesi, Attila; Tasnády, Szabolcs; Hardi, Apor; Kriván, Gergely

2018-04-01

Viral reactivation is a frequent complication of allogeneic hematopoietic stem cell transplantation especially in children. For refractory cases, rapid virus-specific T-cell therapy would be ideally implemented within a few days. Over the course of a year in our pediatric cohort of 43 allogeneic transplantation, 9 patients fulfilled criteria for virus-specific T-cell therapy. Viral infections were due to cytomegalovirus (CMV) in 3, Epstein-Barr virus (EBV) in 2, and adenovirus (AdV) in 1 case, whereas >1 virus was detected in 3 cases. Viral diseases necessitating a T-cell therapy were CMV pneumonitis and colitis, AdV enteritis and cystitis, and EBV-induced posttransplantation lymphoproliferative disease. Cells were produced by the CliniMACS Prodigy CCS (IFN-gamma) System within 24 hours after mononuclear leukapheresis. Eight patients became completely asymptomatic, whereas 7 also cleared the virus. Six patients are alive without viral illness or sequelae demonstrating viral DNA clearance in peripheral blood with a median follow-up of 535 (350-786) days. One patient with CMV pneumonitis died of respiratory insufficiency. In 2 cases the viral illness improved or cleared, however, the patients died of invasive aspergillosis. No cases of graft-versus-host disease, rejection, organ toxicity, or recurrent infection were noticed. Virus-specific T-cell therapy implemented by the CliniMACS Prodigy CCS (IFN-gamma) System is an automated, fast, safe, and probably effective way to control resistant viral diseases after pediatric hematopoietic stem cell transplantation.

Kosten van allogene stamceltransplantaties

NARCIS (Netherlands)

M. van Agthoven (Michel); M.T. Groot (Martijn); C.A. Uyl-de Groot (Carin)

2001-01-01

textabstractAllogene stamceltransplantatie is een topspecialistische procedure die met succes kan worden ingezet in de behandeling van (hematologische) maligniteiten, met name bij leukemie. Van oudsher worden transplantaten van verwante donoren gebruikt, maar met de mogelijkheden om transplantaten

Success of an International Learning Health Care System in Hematopoietic Cell Transplantation: The American Society of Blood and Marrow Transplantation Clinical Case Forum.

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Barba, Pere; Burns, Linda J; Litzow, Mark R; Juckett, Mark B; Komanduri, Krishna V; Lee, Stephanie J; Devlin, Sean M; Costa, Luciano J; Khan, Shakila; King, Andrea; Klein, Andreas; Krishnan, Amrita; Malone, Adriana; Mir, Muhammad; Moravec, Carina; Selby, George; Roy, Vivek; Cochran, Melissa; Stricherz, Melisa K; Westmoreland, Michael D; Perales, Miguel-Angel; Wood, William A

2016-03-01

The American Society for Blood and Marrow Transplantation (ASBMT) Clinical Case Forum (CCF) was launched in 2014 as an online secure tool to enhance interaction and communication among hematopoietic cell transplantation (HCT) professionals worldwide through the discussion of challenging clinical care issues. After 14 months, we reviewed clinical and demographical data of cases posted in the CCF from January 29, 2014 to March 18, 2015. A total of 137 cases were posted during the study period. Ninety-two cases (67%) were allogeneic HCT, 29 (21%) were autologous HCT, and in 16 (12%), the type of transplantation (autologous versus allogeneic) was still under consideration. The diseases most frequently discussed included non-Hodgkin lymphoma (NHL; n = 30, 22%), acute myeloid leukemia (n = 23, 17%), and multiple myeloma (MM; n = 20, 15%). When compared with the US transplantation activity reported by the US Department of Health and Human Services, NHL and acute lymphoblastic leukemia cases were over-represented in the CCF, whereas MM was under-represented (P educational and research perspectives. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Comparison of hybrid capture and reverse transcriptase polymerase chain reaction methods in terms of diagnosing human cytomegalovirus infection in patients following hematopoietic stem cell transplantation

International Nuclear Information System (INIS)

Orsal, Arif S.; Ozsan, M.; Dolapci, I.; Tekeli, A.; Becksac, M.

2006-01-01

Human cytomegalovirus (CMV) is a life threatening cause of infection among hematopoietic stem cell recipients. Developing reliable methods in detecting the CMV infection is important to identify the patients at risk of CMV infection and disease. The aim of this study was to compare the 2 tests- hybrid capture test, which is routinely used in the diagnosis of CMV infection among hematopoietic stem cell recipients, and reverse transcriptase polymerase chain reaction (RT-PCR) detecting UL21.5 mRNA transcripts of the active virus. In this prospective study, a total of 178 blood samples obtained 35 patients following allogeneic hematopoietic stem cell transplantation at the Bone Marrow Transplantation Unit of the Hematology Department, Ibn-i-Sina Hospital of Ankara University School of Medicine, Turkey between January 2003 and September 2003 were analyzed. Hybrid capture and RT-PCR using UL21.5 gene transcript method to investigate HCMV in blood samples were performed at the department of Microbiology and Clinic Microbiology, Ankara University School of Medicine, Turkey. When Hybrid capture test was accepted as the golden standard, the sensitivity of Rt-PCR was 3%, specificity 100%, false negativity 67%, false positivity 0%, positive predictive value 100%, negative predictive value 74%, and accuracy was 77%. Improving this test by quantification, and application of additional gene transcripts, primarily the late gene transcripts can help increase the sensitivity and feasibility. (author)

A single exercise bout enhances the manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy.

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Spielmann, Guillaume; Bollard, Catherine M; Kunz, Hawley; Hanley, Patrick J; Simpson, Richard J

2016-05-16

Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infections remain a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). The adoptive transfer of donor-derived viral-specific cytotoxic T-cells (VSTs) is an effective treatment for controlling CMV and EBV infections after HSCT; however, new practical methods are required to augment the ex vivo manufacture of multi-VSTs from healthy donors. This study investigated the effects of a single exercise bout on the ex vivo manufacture of multi-VSTs. PBMCs isolated from healthy CMV/EBV seropositive participants before (PRE) and immediately after (POST) 30-minutes of cycling exercise were stimulated with CMV (pp65 and IE1) and EBV (LMP2A and BMLF1) peptides and expanded over 8 days. The number (fold difference from PRE) of T-cells specific for CMV pp65 (2.6), EBV LMP2A (2.5), and EBV BMLF1 (4.4) was greater among the VSTs expanded POST. VSTs expanded PRE and POST had similar phenotype characteristics and were equally capable of MHC-restricted killing of autologous target cells. We conclude that a single exercise bout enhances the manufacture of multi-VSTs from healthy donors without altering their phenotype or function and may serve as a simple and economical adjuvant to boost the production of multi-VSTs for allogeneic adoptive transfer immunotherapy.

Successful bone marrow transplantation in a patient with Diamond-Blackfan anemia with co-existing Duchenne muscular dystrophy: a case report

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Kaur Jasmeet

2011-06-01

Full Text Available Abstract Introduction Diamond-Blackfan anemia and Duchenne muscular dystrophy are two rare congenital anomalies. Both anomalies occurring in the same child is extremely rare. Allogeneic hematopoietic stem cell transplantation is a well-established therapy for Diamond-Blackfan anemia. However, in patients with Duchenne muscular dystrophy, stem cell therapy still remains experimental. Case presentation We report the case of a nine-year-old boy of north Indian descent with Diamond-Blackfan anemia and Duchenne muscular dystrophy who underwent successful allogeneic hematopoietic stem cell transplantation. He is transfusion-independent, and his Duchenne muscular dystrophy has shown no clinical deterioration over the past 45 months. His creatine phosphokinase levels have significantly decreased to 300 U/L from 14,000 U/L pre-transplant. The patient is 100% donor chimera in the hematopoietic system, and his muscle tissue has shown 8% to 10.4% cells of donor origin. Conclusion Our patient's Diamond-Blackfan anemia was cured by allogeneic hematopoietic stem cell transplantation. The interesting clinical observation of a possible benefit in Duchenne muscular dystrophy cannot be ruled out. However, further clinical follow-up with serial muscle biopsies and molecular studies are needed to establish this finding.

Combination antifungal therapy and surgery for the treatment of invasive pulmonary aspergillosis after hematopoietic stem cell transplantation

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Tiziana Toffolutti

2011-06-01

Full Text Available An 8-year old boy, affected by severe aplastic anemia, developed a probable pulmonary invasive aspergillosis (IA early after a second unrelated allogeneic hematopoietic stem cell transplant (HSCT. He was treated promptly with the combination of liposomal amphotericin B and caspofungin. Despite the initial stabilization, the patient deteriorated and the antifungal therapy was switched to voriconazole and caspofungin. The patient gradually improved and was discharged home on day +29 post-HSCT on oral voriconazole. On day +119, a sudden episode of hemoptysis occurred and a right superior lobectomy was decided to remove the residual aspergilloma. The patient is now alive and well more than 24 months from HSCT. This case demonstrated that antifungal combination therapy and surgery are valid options to cure pulmonary IA even in patients at high-risk and severely immunosuppressed.

What is the role of biosimilar G-CSF agents in hematopoietic stem cell mobilization at present?

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Korkmaz, Serdal; Altuntas, Fevzi

2017-12-01

Mobilization of hematopoietic stem cells, which has largely replaced bone marrow harvesting as a source of hematopoietic stem cells, using recombinant agents such as filgrastim or lenograstim has become a standard procedure in both patients and healthy donors prior to peripheral blood stem cell collection for autologous and allogeneic stem cell transplantation. Published literature data suggest that mobilization with recombinant granulocyte-colony stimulating factor (G-CSF) is safe and mobilization outcomes are satisfactory. In recent years, besides G-CSF originators, biosimilar G-CSF agents have been approved by the regulatory agencies for the same indications. Current data showed that by using the biosimilar G-CSF, similar results regarding safety and efficacy of hematopoietic stem cell mobilization may be achieved compared to the originator G-CSF. Although the issues such as the similarity to a licenced biological medicine, differences in manufacturing processes, the potential to cause immunogenicity, extrapolation and interchangeability of these biosimilar products are still being discussed by the scientific area, however, more experience with these agents now exists in approved endications and there seems to be no reason to expect significant differences between biosimilar G-CSF and originator G-CSF regarding their efficacy and safety in both patients and healthy donors. Also, the significant cost savings of biosimilars in real life setting may enhance the use of these agents in the future. Nonetheless, the collection of long-term follow-up data is mandatory for both patients and healthy donors, and multicentre randomized clinical trials that directly compare biosimilar G-CSF with the originator G-CSF are needed in order to allow the transplant community to make informed decisions regarding the choice of G-CSF. Copyright © 2017 Elsevier Ltd. All rights reserved.

Second myeloablative allogeneic stem cell transplantation (SCT) using cord blood for leukemia relapsed after initial allogeneic SCT.

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Konuma, Takaaki; Ooi, Jun; Takahashi, Satoshi; Tomonari, Akira; Tsukada, Nobuhiro; Kato, Seiko; Sato, Aki; Monma, Fumihiko; Kasahara, Senji; Uchimaru, Kaoru; Iseki, Tohru; Tojo, Arinobu; Asano, Shigetaka

2009-06-01

There are many reports of second allogeneic stem cell transplantation (allo-SCT) using cord blood (CB) for graft failure after initial allo-SCT. However, the efficacy of second allo-SCT using CB for patients with leukemia relapsed after initial allo-SCT is unknown. We report the results of second allo-SCT using CB in seven adult patients with leukemia relapsed after initial allo-SCT. All patients received a myeloablative conditioning regimen including oral busulfan 16 mg/kg, intravenously fludarabine 100mg/m(2) and cyclophosphamide 120 mg/kg. All but one patient had myeloid reconstitution and four patients remain alive at between 4 and 40 months after second SCT. We conclude that second myeloablative allo-SCT using CB may be feasible in selected patients with the relatively younger age, less organ damage and longer time interval between first and second allo-SCT.

ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

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Patrizia Chiusolo

2010-05-01

Full Text Available

Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment.

Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%:

A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity.

The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients.

Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

The Changing Epidemiology of Bloodstream Infections and Resistance in Hematopoietic Stem Cell Transplantation Recipients

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Mücahit Yemişen

2016-08-01

Full Text Available Objective: Patients receiving hematopoietic stem cell transplantation (HSCT are exposed to highly immunosuppressive conditions and bloodstream infections (BSIs are one of the most common major complications within this period. Our aim, in this study, was to evaluate the epidemiology of BSIs in these patients retrospectively. Materials and Methods: The epidemiological properties of 312 patients with HSCT were retrospectively evaluated. Results: A total of 312 patients, followed between 2000 and 2011, who underwent autologous (62% and allogeneic (38% HSCT were included in the study. The most common underlying malignancies were multiple myeloma (28% and Hodgkin lymphoma (21.5%. A total of 142 (45% patients developed at least 1 episode of BSI and 193 separate pathogens were isolated from the blood cultures. There was a trend of increase in the numbers of BSIs in 2005-2008 and a relative increase in the proportion of gram-positive infections in recent years (2009-2011, and central venous catheter-related BSI was found to be most common source. Coagulase-negative staphylococci (49.2% and Acinetobacter baumannii (8.8% were the most common pathogens. Extended-spectrum beta-lactamase-producing strains were 23% and 22% among Escherichia coli and Klebsiella spp. isolates, respectively. Quinolone resistance was detected in 10% of Enterobacteriaceae. Resistance to carbapenems was not detected in Enterobacteriaceae, while it was seen at 11.1% and 23.5% in Pseudomonas and Acinetobacter strains, respectively. Conclusion: A shift was detected from gram-negative bacteria to gram-positive in the etiology over the years and central lines were the most common sources of BSIs.

Quality of life concerns and depression among hematopoietic stem cell transplant survivors.

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Mosher, Catherine E; DuHamel, Katherine N; Rini, Christine; Corner, Geoffrey; Lam, Joanne; Redd, William H

2011-09-01

This study examined quality of life, transplant-related concerns, and depressive symptoms and their demographic and medical correlates at 1 to 3 years following hematopoietic stem cell transplantation (HSCT). HSCT survivors (N=406) completed telephone-administered questionnaires that assessed demographic variables, functional status, quality of life, transplant-related concerns, and depressive symptoms. The most prevalent concerns among HSCT survivors included physical symptoms (e.g., fatigue and pain), maintaining current health status and employment, changes in appearance, and lack of sexual interest and satisfaction. In addition, almost one-third (32%) of survivors age 40 years and younger reported concern about their ability to have children. Unemployed survivors and those with lower incomes and worse functional status were more likely to experience poorer quality of life in multiple domains. Fifteen percent of the sample reported moderate to severe depressive symptoms, and these symptoms were higher among allogeneic transplant recipients and those with lower functional status. Results suggest that interventions are needed to address physical symptoms, coping with an uncertain future, infertility, and sexual issues during the early phase of HSCT survivorship.

Blood and Bone Marrow Transplant?

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... Topics / Blood and Bone Marrow Transplant Blood and Bone Marrow Transplant Also known as Hematopoietic Stem Cell Transplant , Hematopoietic ... person, called a donor, it is an allogeneic transplant. Blood or bone marrow transplants most commonly are used to treat ...

Oral Cryotherapy for Preventing Oral Mucositis in Patients Receiving Cancer Treatment.

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Riley, Philip; McCabe, Martin G; Glenny, Anne-Marie

2016-10-01

In patients receiving treatment for cancer, does oral cryotherapy prevent oral mucositis? Oral cryotherapy is effective for the prevention of oral mucositis in adults receiving fluorouracil-based chemotherapy for solid cancers, and for the prevention of severe oral mucositis in adults receiving high-dose melphalan-based chemotherapy before hematopoietic stem cell transplantation (HSCT).

A new method of prefabricated vascularized allogenic bone grafts for maxillo-mandibular reconstruction

International Nuclear Information System (INIS)

Pill-Hoon Choung

1999-01-01

Although there are various applications of allogenic bone grafts, a new technique of prevascularized lyophilized allogenic bone grafting for maxillo-mandibular reconstruction will be presented. Allogenic bone has been made by author's protocol for jaw defects as a powder, chip or block bone type. The author used lyophilized allogenic bone grafts for discontinuity defects as a block bone. In those cases, neovascularization and resorption of the allogenic bone were important factors for success of grafting. To overcome the problems, the author designed the technique of prefabricated vascularization of allogenic bone, which was lyophilized cranium, with an application of bovine BMP or not. Lyophilized cranial bone was designed for the defects and was put into the scalp. After confirming a hot spot via scintigram several months later, vascularized allogenic bone was harvested pedicled on the parietotemporal fascia based on the superficial temporal artery and vein. Vascularized allogenic cranial bone was rotated into the defect and fixed rigidly. Postoperatively, there was no severe resorption and functional disturbance of the mandible. In this technique, BMP seems to be an important role to help osteogenesis and neovascularization. Eight patients underwent prefabricated vascularization of allogenic bone grafts. Among them, four cases of reconstruction in mandibular discontinuity defects and one case of reconstruction in maxillectomy defect underwent this method, which will be presented with good results. This method may be an alternative technique of microvascular free bone graft

Systemic Administration of Allogeneic Mesenchymal Stem Cells Does Not Halt Osteoporotic Bone Loss in Ovariectomized Rats.

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Shuo Huang

Full Text Available Mesenchymal stem cells (MSCs have innate ability to self-renew and immunosuppressive functions, and differentiate into various cell types. They have become a promising cell source for treating many diseases, particular for bone regeneration. Osteoporosis is a common metabolic bone disorder with elevated systemic inflammation which in turn triggers enhanced bone loss. We hypothesize that systemic infusion of MSCs may suppress the elevated inflammation in the osteoporotic subjects and slow down bone loss. The current project was to address the following two questions: (1 Will a single dose systemic administration of allogenic MSCs have any effect on osteoporotic bone loss? (2 Will multiple administration of allogenic MSCs from single or multiple donors have similar effect on osteoporotic bone loss? 18 ovariectomized (OVX rats were assigned into 3 groups: the PBS control group, MSCs group 1 (receiving 2x106 GFP-MSCs at Day 10, 46, 91 from the same donor following OVX and MSCs group 2 (receiving 2x106 GFP-MSCs from three different donors at Day 10, 46, 91. Examinations included Micro-CT, serum analysis, mechanical testing, immunofluorescence staining and bone histomorphometry analysis. Results showed that BV/TV at Day 90, 135, BMD of TV and trabecular number at Day 135 in the PBS group were significantly higher than those in the MSCs group 2, whereas trabecular spacing at Day 90, 135 was significantly smaller than that in MSCs group 2. Mechanical testing data didn't show significant difference among the three groups. In addition, the ELISA assay showed that level of Rantes in serum in MSCs group 2 was significantly higher than that of the PBS group, whereas IL-6 and IL-10 were significantly lower than those of the PBS group. Bone histomorphometry analysis showed that Oc.S/BS and Oc.N/BS in the PBS group were significant lower than those in MSCs group 2; Ob.S/BS and Ob.N/BS did not show significant difference among the three groups. The current study

Peripheral Red Blood Cell Split Chimerism as a Consequence of Intramedullary Selective Apoptosis of Recipient Red Blood Cells in a Case of Sickle Cell Disease

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Marco Marziali

2014-08-01

Full Text Available Allogeneic cellular gene therapy through hematopoietic stem cell transplantation is the only radical cure for congenital hemoglobinopathies like thalassemia and sickle cell anemia. Persistent mixed hematopoietic chimerism (PMC has been described in thalassemia and sickle cell anemia. Here, we describe the clinical course of a 6-year-old girl who had received bone marrow transplant for sickle cell anemia. After the transplant, the patient showed 36% donor hematopoietic stem cells in the bone marrow, whereas in the peripheral blood there was evidence of 80%  circulating donor red blood cells (RBC. The analysis of apoptosis at the Bone Marrow  level suggests that Fas might contribute to the cell death of host erythroid precursors. The increase in NK cells and the regulatory T cell population observed in this patient suggests that these cells might contribute to the condition of mixed chimerism.

Patient-reported outcomes and socioeconomic status as predictors of clinical outcomes following hematopoietic stem cell transplantation: A study from the BMT CTN 0902 trial

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Knight, Jennifer M; Syrjala, Karen L; Majhail, Navneet S; Martens, Michael; Le-Rademacher, Jennifer; Logan, Brent R; Lee, Stephanie J; Jacobsen, Paul B; Wood, William A; Jim, Heather SL; Wingard, John R; Horowitz, Mary M; Abidi, Muneer H; Fei, Mingwei; Rawls, Laura; Rizzo, J Douglas

2016-01-01

This secondary analysis of a large, multi-center Blood and Marrow Transplant Clinical Trials Network (BMT CTN) randomized trial assessed whether patient-reported outcomes (PROs) and socioeconomic status (SES) before hematopoietic stem cell transplantation (HCT) are associated with each other and predictive of clinical outcomes including time to hematopoietic recovery, acute graft-versus-host disease, hospitalization days, and overall survival (OS) among 646 allogeneic and autologous HCT recipients. Pre-transplant Cancer and Treatment Distress (CTXD), Pittsburgh Sleep Quality Index (PSQI), and mental and physical component scores (MCS and PCS) of the SF-36 were correlated with each other and with SES variables. PROs and SES variables were further evaluated as predictors of clinical outcomes, with the PSQI and CTXD evaluated as OS predictors (pincome was related to worse physical functioning (p=.005) and increased distress (p=.008); lack of employment pre-transplant was associated with worse physical functioning (p<.01); unmarried status was associated with worse sleep (p=.003). In this large heterogeneous cohort of HCT recipients, while PROs and SES variables were correlated at baseline, they were not associated with any clinical outcomes. Future research should focus on HCT recipients at greater psychosocial disadvantage. PMID:27565521

Expression of antigens coded in murine leukemia viruses on thymocytes of allogeneic donor origin in AKR mice following syngeneic or allogeneic bone marrow transplantation

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Wustrow, T.P.; Good, R.A.

1985-01-01

Removal of T-lymphocytes from marrow inoculum with monoclonal antibody plus complement permitted establishment of long-lived allogeneic chimeras between C57BL/6 and AKR/J mice. Development of leukemia was prevented for 15 mo. Protection from leukemia occurred with both young (4 wk) and older (4 mo) recipients. AKR mice reconstituted with syngeneic marrow or control AKR mice all developed leukemia-lymphoma before 1 yr of age. During spontaneous lymphomagenesis in AKR mice, amplified expression of gag or env gene-coded virus antigens on the surface of thymocytes preceded leukemia development and evidence for amplification of other virus genes. These changes generally appeared before 6 mo. Similar viral gene expression and viral gene amplification occurred in the thymus and spleen cells of leukemia-resistant chimeric mice. Using monoclonal antibodies to Mr 70,000 glycoprotein epitopes characteristic of ecotropic, xenotropic, or dualtropic viruses, antigens marking each virus form were found on thymocytes of allogeneic 4-wk and 4-mo chimeras as well as on the cells of AKR mice and of AKR mice reconstituted with syngeneic marrow. Flow cytometric analysis showed amplification of the virus genes in mice protected from leukemia-lymphoma by allogeneic bone marrow transplantation from leukemia-resistant mice. Allogeneic chimeras and syngeneically transplanted mice both showed evidence of accelerated viremia and of recombinant virus formation. The findings suggest that an event essential to leukemogenesis which occurs within the AKR lymphoid cells or their environment is lacking in the allogeneic chimeras. The nature of this influence of a resistance gene or genes introduced into AKR mice by allogeneic bone marrow transplantation deserves further study

Late Mortality and Causes of Death among Long-Term Survivors after Allogeneic Stem Cell Transplantation.

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Atsuta, Yoshiko; Hirakawa, Akihiro; Nakasone, Hideki; Kurosawa, Saiko; Oshima, Kumi; Sakai, Rika; Ohashi, Kazuteru; Takahashi, Satoshi; Mori, Takehiko; Ozawa, Yukiyasu; Fukuda, Takahiro; Kanamori, Heiwa; Morishima, Yasuo; Kato, Koji; Yabe, Hiromasa; Sakamaki, Hisashi; Taniguchi, Shuichi; Yamashita, Takuya

2016-09-01

We sought to assess the late mortality risks and causes of death among long-term survivors of allogeneic hematopoietic stem cell transplantation (HCT). The cases of 11,047 relapse-free survivors of a first HCT at least 2 years after HCT were analyzed. Standardized mortality ratios (SMR) were calculated and specific causes of death were compared with those of the Japanese population. Among relapse-free survivors at 2 years, overall survival percentages at 10 and 15 years were 87% and 83%, respectively. The overall risk of mortality was significantly higher compared with that of the general population. The risk of mortality was significantly higher from infection (SMR = 57.0), new hematologic malignancies (SMR = 2.2), other new malignancies (SMR = 3.0), respiratory causes (SMR = 109.3), gastrointestinal causes (SMR = 3.8), liver dysfunction (SMR = 6.1), genitourinary dysfunction (SMR = 17.6), and external or accidental causes (SMR = 2.3). The overall annual mortality rate showed a steep decrease from 2 to 5 years after HCT; however, the decrease rate slowed after 10 years but was still higher than that of the general population at 20 years after HCT. SMRs in the earlier period of 2 to 4 years after HCT and 5 years or longer after HCT were 16.1 and 7.4, respectively. Long-term survivors after allogeneic HCT are at higher risk of mortality from various causes other than the underlying disease that led to HCT. Screening and preventive measures should be given a central role in reducing the morbidity and mortality of HCT recipients on long-term follow-up. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Hematopoietic stem cell transplantation for acquired aplastic anemia

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Georges, George E.; Storb, Rainer

2016-01-01

Purpose of review There has been steady improvement in outcomes with allogeneic bone marrow transplantation (BMT) for severe aplastic anemia (SAA), due to progress in optimization of the conditioning regimens, donor hematopoietic cell source and supportive care. Here we review recently published data that highlight the improvements and current issues in the treatment of SAA. Recent findings Approximately one-third of AA patients treated with immune suppression therapy (IST) have acquired mutations in myeloid cancer candidate genes. Because of the greater probability for eventual failure of IST, human leukocyte antigen (HLA)-matched sibling donor BMT is the first-line of treatment for SAA. HLA-matched unrelated donor (URD) BMT is generally recommended for patients who have failed IST. However, in younger patients for whom a 10/10-HLA-allele matched URD can be rapidly identified, there is a strong rationale to proceed with URD BMT as first-line therapy. HLA-haploidentical BMT using post-transplant cyclophosphamide (PT-CY) conditioning regimens, is now a reasonable second-line treatment for patients who failed IST. Summary Improved outcomes have led to an increased first-line role of BMT for treatment of SAA. The optimal cell source from an HLA-matched donor is bone marrow. Additional studies are needed to determine the optimal conditioning regimen for HLA-haploidentical donors. PMID:27607445

Hepatotoxicity induced by horse ATG and reversed by rabbit ATG: a case report

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Al-Anazi Khalid A

2007-06-01

Full Text Available Abstract Background The use of antilymphocyte agents has improved patient and graft survival in hematopoietic stem cell and solid organ transplantation but has been associated with the development of short-term toxicities as well as long-term complications. Case presentation We report a young female with Fanconi anemia who received antithymocyte globulin as part of the conditioning regimen prior to her planned allogeneic hematopoietic stem cell transplant at King Faisal Specialist Hospital and Research Centre in Riyadh. She developed sudden and severe hepatotoxicity after receiving the first dose of horse antithymocyte globulin, manifested by marked elevation of serum transaminases and mild elevation of serum bilirubin level. Immediately after withdrawal of the offending agent and shifting to the rabbit form of antithymocyte globulin, the gross liver dysfunction started to subside and the hepatic profile results returned to the pre-transplant levels few weeks later. The patient had her allogeneic hematopoietic stem cell transplant as planned without any further hepatic complications. After having a successful allograft, she was discharged from the stem cell transplant unit. During her follow up at the outpatient clinic, the patient remained very well and no major complication was encountered. Conclusion Hepatotoxicity related to the utilization of antithymocyte globulin varies considerably in severity and may be transient or long standing. There may be individual or population based susceptibilities to the development of side effects and these adverse reactions may also vary with the choice of the agent used. Encountering adverse effects with one type of antithymocyte agents should not discourage clinicians from shifting to another type in situations where continuation of the drug is vital.

Evolution, trends, outcomes, and economics of hematopoietic stem cell transplantation in severe autoimmune diseases.

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Snowden, John A; Badoglio, Manuela; Labopin, Myriam; Giebel, Sebastian; McGrath, Eoin; Marjanovic, Zora; Burman, Joachim; Moore, John; Rovira, Montserrat; Wulffraat, Nico M; Kazmi, Majid; Greco, Raffaella; Snarski, Emilian; Kozak, Tomas; Kirgizov, Kirill; Alexander, Tobias; Bader, Peter; Saccardi, Riccardo; Farge, Dominique

2017-12-26

Hematopoietic stem cell transplantation (HSCT) has evolved for >20 years as a specific treatment of patients with autoimmune disease (AD). Using European Society for Blood and Marrow Transplantation registry data, we summarized trends and identified factors influencing activity and outcomes in patients with AD undergoing first autologous HSCT (n = 1951; median age, 37 years [3-76]) and allogeneic HSCT (n = 105; median age, 12 years [<1-62]) in 247 centers in 40 countries from 1994 to 2015. Predominant countries of activity were Italy, Germany, Sweden, the United Kingdom, The Netherlands, Spain, France, and Australia. National activity correlated with the Human Development Index ( P = .006). For autologous HSCT, outcomes varied significantly between diseases. There was chronological improvement in progression-free survival (PFS, P < 10 -5 ), relapse/progression ( P < 10 -5 ), and nonrelapse mortality ( P = .01). Health care expenditure was associated with improved outcomes in systemic sclerosis and multiple sclerosis (MS). On multivariate analysis selecting adults for MS, systemic sclerosis, and Crohn disease, better PFS was associated with experience (≥23 transplants for AD, P = .001), learning (time from first HSCT for AD ≥6 years, P = .01), and Joint Accreditation Committee of the International Society for Cellular Therapy and European Society for Blood and Marrow Transplantation accreditation status ( P = .02). Despite improved survival over time ( P = .02), allogeneic HSCT use remained low and largely restricted to pediatric practice. Autologous HSCT has evolved into a treatment modality to be considered alongside other modern therapies in severe AD. Center experience, accreditation, interspecialty networking, and national socioeconomic factors are relevant for health service delivery of HSCT in AD.

Epstein-Barr virus (EBV) load in cerebrospinal fluid and peripheral blood of patients with EBV-associated central nervous system diseases after allogeneic hematopoietic stem cell transplantation.

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Liu, Q-F; Ling, Y-W; Fan, Z-P; Jiang, Q-L; Sun, J; Wu, X-L; Zhao, J; Wei, Q; Zhang, Y; Yu, G-P; Wu, M-Q; Feng, R

2013-08-01

To evaluate the diagnostic and prognostic utility of monitoring the Epstein-Barr virus (EBV) load in the cerebrospinal fluid (CSF) and peripheral blood for the patients with EBV-associated central nervous system (CNS) diseases after allogeneic hematopoietic stem cell transplantation (allo-HSCT), 172 patients undergoing allo-HSCT were enrolled in the study. The EBV DNA levels of blood were monitored regularly in recipients of transplants for 3 years post transplantation. The EBV DNA levels of CSF were monitored in patients with EBV-associated CNS diseases before the treatment and at different points following the treatment. Post-transplant EBV-associated diseases developed in 27 patients, including 12 patients with EBV-associated CNS diseases. The 3-year cumulative incidences of EBV-associated diseases and EBV-associated CNS diseases were 19.5 ± 3.5% and 8.6 ± 2.4%, respectively. Patients with EBV-associated diseases showed higher loads of EBV DNA in their blood compared with patients with EBV DNA-emia. No difference was seen between the EBV DNA levels of blood in patients with CNS involvement and patients without CNS involvement. The EBV DNA loads of blood increased 3-14 days before the clinical manifestations of EBV-associated diseases emerged. The EBV DNA loads of CSF were higher than that of blood in patients with EBV-associated CNS diseases. In 12 patients with EBV-associated CNS diseases, EBV DNA levels were declining in both blood and CSF with the control of diseases, and the EBV DNA loads of CSF decreased faster than that of blood in 5 patients who responded to treatment, and the EBV DNA levels of CSF increased in 5 patients who were unresponsive to treatment. On multivariate analysis, the use of anti-thymocyte globulin and intensified conditioning regimens were independent risk factors for EBV-associated diseases and EBV-associated CNS diseases. EBV-associated CNS diseases are not rare after allo-HSCT. The EBV DNA loads of CSF could act as an important

Second allogeneic hematopoietic SCT for relapsed ALL in children.

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Kato, M; Horikoshi, Y; Okamoto, Y; Takahashi, Y; Hasegawa, D; Koh, K; Takita, J; Inoue, M; Kigasawa, H; Ogawa, A; Sasahara, Y; Kawa, K; Yabe, H; Sakamaki, H; Suzuki, R; Kato, K

2012-10-01

A second SCT is generally accepted as the only potentially curative approach for ALL patients that relapse after SCT, but the role of second SCT for pediatric ALL is not fully understood. We performed a retrospective analysis of 171 pediatric patients who received a second allo-SCT for relapsed ALL after allo-SCT. OS at 2 years was 29.4 ± 3.7%, the cumulative incidence of relapse was 44.1 ± 4.0% and non-relapse mortality was 18.8 ± 3.5%. Relapse occurred faster after the second SCT than after the first SCT (117 days vs 164 days, P=0.04). Younger age (9 years or less), late relapse (180 days or more after first SCT), CR at the second SCT, and myeloablative conditioning were found to be related to longer survival. Neither acute GVHD nor the type of donor influenced the outcome of second SCT. Multivariate analysis showed that younger age and late relapse were associated with better outcomes. Our analysis suggests that second SCT for relapsed pediatric ALL is an appropriate treatment option for patients that have achieved CR, which is associated with late relapse after the first SCT.

Hematopoietic Stem Cell Transplantation Activity and Trends at a Pediatric Transplantation Center in Turkey During 1998-2008

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Volkan Hazar

2012-06-01

Full Text Available OBJECTIVE: The aim of this study was to document hematopoietic stem cell transplantation (HSCT activity and trends at our treatment center. METHODS: Data collected over a 10-year period were retrospectively analyzed, concentrating primarily on types of HSCT, transplant-related mortality (TRM, stem cell sources, indications for HSCT, and causes of death following HSCT. RESULTS: In total, 222 allogeneic (allo-HSCT (87.4% and 32 autologous (auto-HSCT (12.6% procedures were performed between 1998 and 2008. Stem cells obtained from unrelated donors were used in 22.6% (50/222 of the allo- HSCTs. Cord blood was the source of hematopoietic stem cells (HSC in 12.2% of all transplants. The most common indication for allo-HSCT was hemoglobinopathy (43.2%, versus neuroblastoma (53.1% for auto-HSCT. The TRM rate 1 year post transplantation was 18.3% ± 2.5% for all transplants, but differed according to transplantation type (23.5% ± 7.9% for auto-HSCT and 17.5% ± 2.6% for allo-HSCT. The most common cause of death 1 year post HSCT was infection (35.9%. CONCLUSION: The TRM rate in the patients that underwent allo-HSCT was similar to that which has been previously reported; however, the TRM rate in the patients that underwent auto-HSCT was higher than previously reported in developed countries. The selection of these patients to be transplanted must be made attentively.

T Cell-Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia.

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How, Joan; Slade, Michael; Vu, Khoan; DiPersio, John F; Westervelt, Peter; Uy, Geoffrey L; Abboud, Camille N; Vij, Ravi; Schroeder, Mark A; Fehniger, Todd A; Romee, Rizwan

2017-04-01

Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant.

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Rouce, Rayne H; Louis, Chrystal U; Heslop, Helen E

2014-11-01

Epstein-Barr virus (EBV) reactivation can cause significant morbidity and mortality after allogeneic hematopoietic stem cell transplant. Delays in reconstitution of EBV-specific T lymphocyte activity can lead to life-threatening EBV lymphoproliferative disease (EBV-PTLD). This review highlights recent advances in the understanding of pathophysiology, risk factors, diagnosis, and management of EBV viremia and PTLD. During the past decade, early detection strategies, such as serial measurement of EBV-DNA load, have helped identify high-risk patients and diagnose early lymphoproliferation. The most significant advances have come in the form of innovative treatment options, including manipulation of the balance between outgrowing EBV-infected B cells and the EBV cytotoxic T lymphocyte response, and targeting infected B cells with monoclonal antibodies, chemotherapy, unmanipulated donor lymphocytes, and donor or more recently third-party EBV cytotoxic T lymphocytes. Defining criteria for preemptive therapy remains a challenge. EBV reactivation is a significant complication after stem cell transplant. Continued improvements in risk stratification and treatment options are required to improve the morbidity and mortality caused by EBV-associated diseases. Current approaches use rituximab to deplete B cells or adoptive transfer of EBV cytotoxic T lymphocyte to reconstitute immunity. The availability of rapid EBV-specific T cell products offers the possibility of improved outcomes.

New insights into hematopoietic stem cell transplantation for chronic lymphocytic leukemia: a 2015 perspective.

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McClanahan, Fabienne; Gribben, John

2015-09-01

A considerable body of evidence demonstrates that allogeneic hematopoietic stem cell transplantation (HSCT) offers the only potentially curative treatment option for patients with chronic lymphocytic leukemia (CLL). However, this approach is suitable for only a minority of CLL patients, owing to its significant treatment-related mortality and morbidity. Until recently, internationally accepted guidelines suggested that HSCT should be considered in physically fit CLL patients who carry poor-risk features, such as TP53 abnormalities, or who had a short response to previous immunochemotherapy. However, several new agents and alternative treatment strategies are available that demonstrate impressive and durable responses, even in CLL patients who previously might have been candidates for transplant. The decision about which patients merit HSCT therefore remains important, and HSCT must now be considered in light of other less toxic therapies. Until data on the long-term efficacy of novel treatment approaches mature, the choice of HSCT vs alternative strategies must be assessed on a patient-by-patient basis, and treatment in the setting of randomized clinical trials should be pursued whenever possible.

Validation of a Pediatric Early Warning Score in Hospitalized Pediatric Oncology and Hematopoietic Stem Cell Transplant Patients.

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Agulnik, Asya; Forbes, Peter W; Stenquist, Nicole; Rodriguez-Galindo, Carlos; Kleinman, Monica

2016-04-01

To evaluate the correlation of a Pediatric Early Warning Score with unplanned transfer to the PICU in hospitalized oncology and hematopoietic stem cell transplant patients. We performed a retrospective matched case-control study, comparing the highest documented Pediatric Early Warning Score within 24 hours prior to unplanned PICU transfers in hospitalized pediatric oncology and hematopoietic stem cell transplant patients between September 2011 and December 2013. Controls were patients who remained on the inpatient unit and were matched 2:1 using age, condition (oncology vs hematopoietic stem cell transplant), and length of hospital stay. Pediatric Early Warning Scores were documented by nursing staff at least every 4 hours as part of routine care. Need for transfer was determined by a PICU physician called to evaluate the patient. A large tertiary/quaternary free-standing academic children's hospital. One hundred ten hospitalized pediatric oncology patients (42 oncology, 68 hematopoietic stem cell transplant) requiring unplanned PICU transfer and 220 matched controls. None. Using the highest score in the 24 hours prior to transfer for cases and a matched time period for controls, the Pediatric Early Warning Score was highly correlated with the need for PICU transfer overall (area under the receiver operating characteristic = 0.96), and in the oncology and hematopoietic stem cell transplant groups individually (area under the receiver operating characteristic = 0.95 and 0.96, respectively). The difference in Pediatric Early Warning Score results between the cases and controls was noted as early as 24 hours prior to PICU admission. Seventeen patients died (15.4%). Patients with higher Pediatric Early Warning Scores prior to transfer had increased PICU mortality (p = 0.028) and length of stay (p = 0.004). We demonstrate that our institution's Pediatric Early Warning Score is highly correlated with the need for unplanned PICU transfer in hospitalized oncology and

Private Cord Blood Banking: Experiences And Views Of Pediatric Hematopoietic Cell Transplantation Physicians

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Thornley, Ian; Eapen, Mary; Sung, Lillian; Lee, Stephanie J.; Davies, Stella M.; Joffe, Steven

2011-01-01

Objective Private cord blood banks are for-profit companies that facilitate storage of umbilical cord blood for personal or family use. Pediatric hematopoietic cell transplantation (HCT) physicians are currently best situated to use cord blood therapeutically. We sought to describe the experiences and views of these physicians regarding private cord blood banking. Participants and Methods Emailed cross-sectional survey of pediatric HCT physicians in the United States and Canada. 93/152 potentially eligible physicians (93/130 confirmed survey recipients) from 57 centers responded. Questions addressed the number of transplants performed using privately banked cord blood, willingness to use banked autologous cord blood in specific clinical settings, and recommendations to parents regarding private cord blood banking. Results Respondents reported having performed 9 autologous and 41 allogeneic transplants using privately banked cord blood. In 36/40 allogeneic cases for which data were available, the cord blood had been collected because of a known indication in the recipient. Few respondents would choose autologous cord blood over alternative stem cell sources for treatment of acute lymphoblastic leukemia in second remission. In contrast, 55% would choose autologous cord blood to treat high-risk neuroblastoma, or to treat severe aplastic anemia in the absence of an available sibling donor. No respondent would recommend private cord blood banking for a newborn with one healthy sibling when both parents were of Northern European descent; 11% would recommend banking when parents were of different minority ethnicities. Conclusions Few transplants have been performed using cord blood stored in the absence of a known indication in the recipient. Willingness to use banked autologous cord blood varies depending on disease and availability of alternative stem cell sources. Few pediatric HCT physicians endorse private cord blood banking in the absence of an identified recipient

The evolving role of chemotherapy and hematopoietic cell transplants in Ph-positive acute lymphoblastic leukemia in adults.

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Litzow, M R; Fielding, A K; Luger, S M; Paietta, E; Ofran, Y; Rowe, J M; Goldstone, A H; Tallman, M S; Lazarus, H M

2017-12-01

The introduction of the tyrosine kinase inhibitors (TKI) into the treatment of patients with Ph or BCR-ABL1-positive acute lymphoblastic leukemia has revolutionized the treatment of this poor prognosis acute leukemia. The combination of TKI with chemotherapy has improved response rates and allowed more patients to proceed to allogeneic hematopoietic cell transplant (alloHCT). Older patients have excellent responses to TKI and corticosteroids or in combination with minimal chemotherapy. This raises the question as to whether patients require full-intensity chemotherapy with TKI to achieve molecular remissions. The pediatricians have proposed that cure is achievable without alloHCT in children. These results have suggested that many patients may not require traditional chemotherapy in addition to TKI to achieve remission, and that patients who achieve a negative minimal residual disease state may not require alloHCT. The data in support of these questions is presented here and a suggested future clinical trial design based on these data is proposed.

Potential contribution of a novel Tax epitope-specific CD4+ T cells to graft-versus-Tax effect in adult T cell leukemia patients after allogeneic hematopoietic stem cell transplantation.

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Tamai, Yotaro; Hasegawa, Atsuhiko; Takamori, Ayako; Sasada, Amane; Tanosaki, Ryuji; Choi, Ilseung; Utsunomiya, Atae; Maeda, Yasuhiro; Yamano, Yoshihisa; Eto, Tetsuya; Koh, Ki-Ryang; Nakamae, Hirohisa; Suehiro, Youko; Kato, Koji; Takemoto, Shigeki; Okamura, Jun; Uike, Naokuni; Kannagi, Mari

2013-04-15

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for adult T cell leukemia/lymphoma (ATL) caused by human T cell leukemia virus type 1 (HTLV-1). We previously reported that Tax-specific CD8(+) cytotoxic T lymphocyte (CTL) contributed to graft-versus-ATL effects in ATL patients after allo-HSCT. However, the role of HTLV-1-specific CD4(+) T cells in the effects remains unclear. In this study, we showed that Tax-specific CD4(+) as well as CD8(+) T cell responses were induced in some ATL patients following allo-HSCT. To further analyze HTLV-1-specific CD4(+) T cell responses, we identified a novel HLA-DRB1*0101-restricted epitope, Tax155-167, recognized by HTLV-1-specific CD4(+) Th1-like cells, a major population of HTLV-1-specific CD4(+) T cell line, which was established from an ATL patient at 180 d after allo-HSCT from an unrelated seronegative donor by in vitro stimulation with HTLV-1-infected cells from the same patient. Costimulation of PBMCs with both the identified epitope (Tax155-167) and known CTL epitope peptides markedly enhanced the expansion of Tax-specific CD8(+) T cells in PBMCs compared with stimulation with CTL epitope peptide alone in all three HLA-DRB1*0101(+) patients post-allo-HSCT tested. In addition, direct detection using newly generated HLA-DRB1*0101/Tax155-167 tetramers revealed that Tax155-167-specific CD4(+) T cells were present in all HTLV-1-infected individuals tested, regardless of HSCT. These results suggest that Tax155-167 may be the dominant epitope recognized by HTLV-1-specific CD4(+) T cells in HLA-DRB1*0101(+)-infected individuals and that Tax-specific CD4(+) T cells may augment the graft-versus-Tax effects via efficient induction of Tax-specific CD8(+) T cell responses.

HLA-Matched Sibling versus Unrelated versus Haploidentical Related Donor Allogeneic Hematopoietic Stem Cell Transplantation for Patients Aged Over 60 Years with Acute Myeloid Leukemia: A Single-Center Donor Comparison.

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Devillier, Raynier; Legrand, Faezeh; Rey, Jérôme; Castagna, Luca; Fürst, Sabine; Granata, Angela; Charbonnier, Aude; Harbi, Samia; d'Incan, Evelyne; Pagliardini, Thomas; Faucher, Catherine; Lemarie, Claude; Saillard, Colombe; Calmels, Boris; Mohty, Bilal; Maisano, Valerio; Weiller, Pierre-Jean; Chabannon, Christian; Vey, Norbert; Blaise, Didier

2018-02-12

Haploidentical related donor (HRD) allogeneic hematopoietic stem cell transplantation (allo-HSCT) was developed as a valid option for the treatment of acute myeloid leukemia (AML) in the absence of a matched donor. However, many investigators are reluctant to consider the use of this alternative in elderly patients, anticipating high morbidity. Here, we report a single-center comparison of HRD versus matched sibling donor (MSD) and unrelated donor (UD) allo-HSCT for patients with AML aged ≥60 years. Ninety-four patients (MSD: n = 31; UD: n = 30; HRD: n = 33) were analyzed. The median age was 65 (range, 60 to 73) years. We observed a higher cumulative incidence of grade 3 to 4 acute graft-versus-host disease (GVHD) after UD allo-HSCT (MSD versus UD versus HRD: 3% versus 33% versus 6%, respectively; P = .006). Two-year cumulative incidence of moderate or severe chronic GVHD was 17%, 27%, and 16% in the MSD, UD, and HRD groups, respectively (P = .487). No difference was observed in the 2-year cumulative incidence of relapse or nonrelapse mortality (NRM) (relapse: MSD versus UD versus HRD: 32% versus 25% versus 25%, respectively; P = .411; NRM: MSD versus UD versus HRD: 19% versus 27% versus 24%, respectively; P = .709). At 2 years, progression-free survival, overall survival, and GVHD- and relapse-free survival were 48%, 50%, and 39%, respectively, in the MSD group; 48%, 51%, and 23%, respectively, in the UD group; and 50%, 52%, and 32%, respectively, in the HRD group, without statistically significant differences between the groups. We conclude that HRD allo-HSCT is highly feasible and no less efficient than MSD or UD allo-HSCT in patients with AML aged ≥60 years. Thus, the absence of a HLA-identical donor should not limit the consideration of allo-HSCT for the treatment of AML. Copyright © 2018 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

High incidence of chronic graft-versus-host disease after myeloablative allogeneic stem cell transplantation for chronic lymphocytic leukemia in Sweden: graft-versus-leukemia effect protects against relapse.

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Machaczka, Maciej; Johansson, Jan-Erik; Remberger, Mats; Hallböök, Helene; Lazarevic, Vladimir Lj; Wahlin, Björn Engelbrekt; Omar, Hamdy; Wahlin, Anders; Juliusson, Gunnar; Kimby, Eva; Hägglund, Hans

2013-12-01

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a potentially curative treatment option for eligible patients with chronic lymphocytic leukemia (CLL). However, it is known that cure of CLL is only possible if a graft-versus-leukemia effect is present. Between 1994 and 2007, 48 adults underwent allo-SCT for poor-risk CLL in Sweden. Of these, ten (21%) patients aged 24-53 years (median: 46 years) received myeloablative conditioning (MAC), based on TBI and cyclophosphamide. All MAC patients had refractory, poorly controlled CLL before allo-SCT (partial remission in 9/10 patients and progressive disease in one). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II-IV was 30%. Nine patients developed chronic GVHD; extensive in four. Rates of nonrelapse mortality at 1, 3 and 10 years were 0, 10 and 20%, respectively. Two patients relapsed 36 and 53 months after transplantation. Six patients were still alive after a median follow-up time of 11.5 years (range 5.9-13.7). The probabilities of relapse-free and overall survival from 1, 3 and 5 years after transplantation were 100, 90 and 70%, and 100, 90 and 80%, respectively. Nevertheless, our analysis of long-term outcome after MAC allo-SCT for CLL suggests that younger patients with poorly controlled CLL may benefit from MAC allo-SCT.

Sclerodermatous GVHD after Allogeneic Bone Marrow Transplant: a Review

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Gagan Raju

2017-05-01

Full Text Available Chronic graft versus host disease (cGVHD is the leading cause of non-relapse mortality after allogeneic hematopoietic bone marrow transplantation (HCT for blood malignancy in patients who survive for more than two years. cGVHD can significantly affect quality of life and cause decreased mobility amongst other grave consequences such as end-organ damage, contributing to morbidity and mortality rates for recipients of HCT. Unlike acute GVHD (aGVHD, the chronic variant of graft versus host disease (GVHD has complex immunopathology involving both humoral and cell immunity. It typically affects the integumentary system, though is known to also affect myofascial, mucocutaneous tissues as well as cause end organ damage ultimately resulting in death. Sclerodermatous cGVHD is a type of cGVHD characterized by involvement of the skin, subcutaneous tissue and fascia without evidence of disease in the viscera. Manifestations of this disease are often evocative of autoimmune disease, which is a self-directed inflammatory reaction to the innate and adaptive immune system in various tissues or multiple organ systems. This inflammatory reaction gives rise to autoantibodies as well as B-cell and T-cell mediated direct toxicity which can cause chronic inflammatory changes of tissues ultimately resulting in tissue scarring and end organ dysfunction. We aim to review the literature on this grave disease and elucidate aspects of the immunopathology of chronic sclerodermatous GVHD in hopes that it may lead to revelations inspiring novel therapies after its diagnosis or preventative measures before stem cell transplantation for malignancy.

Ready-made allogeneic ABO-specific serum eye drops

DEFF Research Database (Denmark)

Harritshøj, Lene Holm; Nielsen, Connie; Ullum, Henrik

2014-01-01

serum treatment. CONCLUSION: Ready-made ABO-identical allogeneic serum eye drops were straightforwardly produced, quality-assured and registered as a safe standard blood product for the treatment of certain cases of severe dry eye disease. Therapeutic efficacy was comparable to previous reports......PURPOSE: To overcome problems and delays of the preparation of autologous serum eye drops, a production line of ABO-specific allogeneic serum eye drops from male blood donors was set up in a blood bank. Feasibility, clinical routine, safety and efficacy were evaluated in a cohort of patients...

Allogeneic tumor cell vaccines: the promise and limitations in clinical trials.

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Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N; Imasuen, Imade E; He, Sara; Daniels, Danielle; Selvaraj, Periasamy

2014-01-01

The high mortality rate associated with cancer and its resistance to conventional treatments such as radiation and chemotherapy has led to the investigation of a variety of anti-cancer immunotherapies. The development of novel immunotherapies has been bolstered by the discovery of tumor-associated antigens (TAAs), through gene sequencing and proteomics. One such immunotherapy employs established allogeneic human cancer cell lines to induce antitumor immunity in patients through TAA presentation. Allogeneic cancer immunotherapies are desirable in a clinical setting due to their ease of production and availability. This review aims to summarize clinical trials of allogeneic tumor immunotherapies in various cancer types. To date, clinical trials have shown limited success due potentially to extensive degrees of inter- and intra-tumoral heterogeneity found among cancer patients. However, these clinical results provide guidance for the rational design and creation of more effective allogeneic tumor immunotherapies for use as monotherapies or in combination with other therapies.

Umbilical Cord-Derived Mesenchymal Stem Cells for Hematopoietic Stem Cell Transplantation

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Yu-Hua Chao

2012-01-01

Full Text Available Hematopoietic stem cell transplantation (HSCT is becoming an effective therapeutic modality for a variety of diseases. Mesenchymal stem cells (MSCs can be used to enhance hematopoietic engraftment, accelerate lymphocyte recovery, reduce the risk of graft failure, prevent and treat graft-versus-host disease, and repair tissue damage in patients receiving HSCT. Till now, most MSCs for human clinical application have been derived from bone marrow. However, acquiring bone-marrow-derived MSCs involves an invasive procedure. Umbilical cord is rich with MSCs. Compared to bone-marrow-derived MSCs, umbilical cord-derived MSCs (UCMSCs are easier to obtain without harm to the donor and can proliferate faster. No severe adverse effects were noted in our previous clinical application of UCMSCs in HSCT. Accordingly, application of UCMSCs in humans appears to be feasible and safe. Further studies are warranted.

Exogenous endothelial cells as accelerators of hematopoietic reconstitution

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Mizer J

2012-11-01

Full Text Available Abstract Despite the successes of recombinant hematopoietic-stimulatory factors at accelerating bone marrow reconstitution and shortening the neutropenic period post-transplantation, significant challenges remain such as cost, inability to reconstitute thrombocytic lineages, and lack of efficacy in conditions such as aplastic anemia. A possible means of accelerating hematopoietic reconstitution would be administration of cells capable of secreting hematopoietic growth factors. Advantages of this approach would include: a ability to regulate secretion of cytokines based on biological need; b long term, localized production of growth factors, alleviating need for systemic administration of factors that possess unintended adverse effects; and c potential to actively repair the hematopoietic stem cell niche. Here we overview the field of hematopoietic growth factors, discuss previous experiences with mesenchymal stem cells (MSC in accelerating hematopoiesis, and conclude by putting forth the rationale of utilizing exogenous endothelial cells as a novel cellular therapy for acceleration of hematopoietic recovery.

[Alternatives to allogenous blood transfusion].

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Cernea, Daniela; Vlădoianu, Alice; Stoica, Maria; Novac, M; Berteanu, Cristina

2009-01-01

Blood transfusion is usually meant to lower morbidity and mortality rates. Allogenous blood transfusion implies certain risks that can be avoided by autologous blood transfusions techniques including: preoperatory autologous blood donation, acute normovolemic hemodilution, intraoperatory and postoperatory blood salvage. Preoperatory blood donation and acute normovolemic hemodilution are used for planned interventions with an estimated blood loss higher than 20% of blood volume. These methods imply Erythropoietin and iron treatment. Intraoperatory and postoperatory blood salvage is performed by personnel trained in blood donation, handling and storage. Autologous blood transfusions are used for certain surgical procedures that commonly require transfusions: orthopedic surgery, radical prostatectomy, cardiovascular surgery, organ transplantation. An alternative to allogenous blood transfusion is the use of artificial oxygen transporters: human or animal hemoglobin solutions or pefluorocarbonate solutions. These solutions do not require cross reactions, do not carry diseases and are generally well tolerated and easily stored in the operating room, ambulance and other transport means. They have however a slight degree of toxicity.

Clinical Benefit of Allogeneic Melanoma Cell Lysate-Pulsed Autologous Dendritic Cell Vaccine in MAGE-Positive Colorectal Cancer Patients

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Toh, Han Chong; Wang, Who-Whong; Chia, Whay Kuang

2009-01-01

PURPOSE: We evaluated the clinical benefit of an allogeneic melanoma cell lysate (MCL)-pulsed autologous dendritic cell (DC) vaccine in advanced colorectal cancer patients expressing at least one of six MAGE-A antigens overexpressed by the cell line source of the lysate. EXPERIMENTAL DESIGN: DCs...... were cultured from peripheral blood mononuclear cells (PBMC), pulsed with the allogeneic MCL, and matured using cytokines that achieved high CD83- and CCR7-expressing DCs. Each patient received up to 10 intradermal vaccinations (3-5 x 10(6) cells per dose) at biweekly intervals. RESULTS: Twenty......-free for >27 and >37 months, respectively. This result is particularly meaningful as all patients had progressive disease before treatment. Overall, DC vaccination was associated with a serial decline in regulatory T cells. Using an antibody array, we characterized plasma protein profiles in responding...

Outcome of allogeneic SCT in patients with chronic myeloid leukemia in the era of tyrosine kinase inhibitor therapy.

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Oyekunle, Anthony; Zander, Axel R; Binder, Mascha; Ayuk, Francis; Zabelina, Tatjana; Christopeit, Maximilian; Stübig, Thomas; Alchalby, Haefaa; Schafhausen, Philippe; Lellek, Heinrich; Wolschke, Christine; Müller, Ingo; Bacher, Ulrike; Kröger, Nicolaus

2013-04-01

The introduction of tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) led to a dramatic change in the role of allogeneic stem cell transplantation (SCT) with a rapid decline in the number of patients receiving SCT in first chronic phase (CP1). We evaluated 68 consecutive patients in all phases of CML (male/female = 39:29, 27 in CP1), who received SCT from related/unrelated donors (related/unrelated = 23:45) under myeloablative or reduced intensity conditioning (MAC/RIC = 45:23). Forty-eight patients (71 %) received TKIs pre-SCT, 20 patients post-SCT (29 %). Overall survival (OS) of CP1 patients achieved a plateau of 85 % at 10 months. Relapse-free survival (RFS) of CP1 patients was 85 % at 1 and 2 years, and 81 % at 5 years. Multivariate analysis showed adverse OS and RFS for patients transplanted >CP1 (hazard ratio (HR) = 6.61 and 4.62) and those who had grade III-IV aGvHD (HR = 2.45 and 1.82). Patients with advanced CML had estimated OS of 65 and 47 %; and RFS of 41 and 32 % at 1 and 2 years respectively. Therefore, for patients with advanced CML phases, allogeneic SCT provides an acceptable chance of cure. Transplant research should focus on improving conditioning regimens and post-SCT management for this subgroup of CML patients.

Experimental study on therapy of acute radiation sickness with transplantation of allogeneic peripheral blood hemopoietic stem cells

International Nuclear Information System (INIS)

Ma Enpu; Bi Jianjin; Zhan Aiqin

1995-01-01

In the study, 10 beagles were used. All the dogs were irradiated with 6.5 Gy of γ-rays from a 60 Co source (dose rate, 95.6-107.9 R/min) and divided into three groups. All the three dogs in the control group died, having survived 7.5 days on the average after irradiation. In the second group, four dogs were transplanted with allogeneic peripheral blood hemopoietic stem cells (PBHSC) without removing T lymphocytes. The results of sex chromosome tests after irradiation and transplantation showed that the cells were of donor type. All the four dogs died of severe graft versus-host disease (GVHD) and survived 41.6 days on the average after irradiation. In the third group, three dogs received transplantation of allogeneic PBHSC without T lymphocytes. Two of them died, and the third developed mild GVHD and survived over 4 years

[Information and consent forms for hematopoietic stem cell transplantation donors and recipients: Guidelines from the Franchophone society of bone marrow transplantation and cellular therapy (SFGM-TC)].

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Bruno, Bénédicte; Thibert, Jean-Baptiste; Bancillon, Nelly; Desbos, Anna; Fawaz, Abir; Fournier, Isabelle; Genty, Carole; Issarni, Dominique; Leveille, Sandrine; Premel, Christelle; Polomeni, Alice; Renault, Myriam; Tarillon, Sylvie; Wallart, Anne; Yakoub-Agha, Ibrahim; Bordessoule, Dominique

2016-11-01

Within the context of the SFGM-TC's 6th workshop series on the harmonization of clinical practices, our workshop proposes a standardization of the informed consent process for hematopoietic stem cell donors and recipients leading up to an autologous or allogenic transplantation. All informed consent was for bone marrow or peripheral stem cell donors, and mononuclear/lymphocyte donors according to usual procedures. The informed consent for autologous and allogenic related or unrelated adults and pediatric transplantation patients have been included. A first step has been conducted for collecting in advance the informed consent forms used routinely in all francophone transplantation centers. In a second step, a comprehensive version has been re-written by a multidisciplinary team. For the purposes of understanding the risks and advantages, language has been carefully considered and streamlined. In the third step, texts were sent to stem cell transplantation experts, experts at the French biomedical agency (agence de la biomédecine [ABM]), law specialists, members of the ethical committee of the French society of hematology and several transplant recipients to be edited and proofread. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Allogeneic Peripheral Blood Stem Cell Harvest

Indian Academy of Sciences (India)

First page Back Continue Last page Overview Graphics. Allogeneic Peripheral Blood Stem Cell Harvest. Mobilization protocol. G-CSF 10 mcg/Kg / day for 5 days. Pheresis. Cobe Spectra; Haemonetics mcs+. Enumeration. CD34 counts; Cfu-GM assays.

Comparison of outcomes in hematological malignancies treated with haploidentical or HLA-identical sibling hematopoietic stem cell transplantation following myeloablative conditioning: A meta-analysis

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Guo, Dan; Xu, Peipei; Chen, Bing

2018-01-01

Purpose Haploidentical and human leukocyte antigen (HLA)-identical sibling hematopoietic stem transplantation are two main ways used in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In recent years, remarkable progress has been made in haploidentical allo-HSCT (HID-SCT), and some institutions found HID-SCT had similar outcomes as HLA-identical sibling allo-HSCT (ISD-SCT). To clarify if HID-SCT has equal effects to ISD-SCT in hematologic malignancies, we performed this meta-analysis. Methods Relevant articles published prior to February 2017 were searched on PubMed. Two reviewers assessed the quality of the included studies and extracted data independently. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated for statistical analysis. Results Seven studies including 1919 patients were included. The rate of platelet engraftment is significantly lower after HID-SCT versus ISD-SCT while there is no difference in neutrophil engraftment (OR = 2.58, 95% CI = 1.70–3.93, P SCT versus ISD-SCT (OR = 1.88, 95% CI = 1.42–2.49, P SCT group (OR = 0.70, 95% CI = 0.55–0.90, P = 0.005). The incidence rates of overall survival (OS) and disease-free-survival/leukemia-free survival/relapse-free survival (DFS/LFS/RFS) after ISD-SCT are all significantly superior to HID-SCT (OR = 1.32, 95% CI = 1.08–1.62, P = 0.006; OR = 1.25, 95% CI = 1.03–1.52, P = 0.02). There is no significant difference in transplantation related mortality (TRM) rate after HID-SCT and ISD-SCT. Conclusion After myeloablative conditioning, patients receiving ISD-SCT have a faster engraftment, lower acute GVHD and longer life expectancy compared to HID-SCT with GVHD prophylaxis (cyclosporine A, methotrexate, mycophenolate mofetil and antithymoglobulin; CsA + MTX + MMF + ATG). Currently, HID-SCT with GVHD prophylaxis (CsA + MTX + MMF + ATG) may not replace ISD-SCT when HLA-identical sibling donor available. PMID:29381772

Peripheral blood CD34+ cell count as a predictor of adequacy of hematopoietic stem cell collection for autologous transplantation

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Combariza, Juan F.

2016-10-01

Full Text Available Introduction: In order to carry out an autologous transplantation, hematopoietic stem cells should be mobilized to peripheral blood and later collected by apheresis. The CD34+ cell count is a tool to establish the optimal time to begin the apheresis procedure. Objective: To evaluate the association between peripheral blood CD34+ cell count and the successful collection of hematopoietic stem cells. Materials and methods: A predictive test evaluation study was carried out to establish the usefulness of peripheral blood CD34+ cell count as a predictor of successful stem cell collection in patients that will receive an autologous transplantation. Results: 77 patients were included (median age: 49 years; range: 5-66. The predominant baseline diagnosis was lymphoma (53.2 %. The percentage of patients with successful harvest of hematopoietic stem cells was proportional to the number of CD34+cells in peripheral blood at the end of the mobilization procedure. We propose that more than 15 CD34+cells/μL must be present in order to achieve an adequate collection of hematopoietic stem cells. Conclusion: Peripheral blood CD34+ cell count is a useful tool to predict the successful collection of hematopoietic stem cells.

Clinical features and outcomes of patients with primary myelofibrosis in Japan: report of a 17-year nationwide survey by the Idiopathic Disorders of Hematopoietic Organs Research Committee of Japan.

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Takenaka, Katsuto; Shimoda, Kazuya; Uchida, Naoyuki; Shimomura, Taizo; Nagafuji, Koji; Kondo, Tadakazu; Shibayama, Hirohiko; Mori, Takehiko; Usuki, Kensuke; Azuma, Taichi; Tsutsumi, Yutaka; Tanaka, Junji; Dairaku, Hitomi; Matsuo, Keitaro; Ozawa, Keiya; Kurokawa, Mineo; Arai, Shunya; Akashi, Koichi

2017-01-01

We conducted a 17-year nationwide survey (1999-2015) to elucidate the clinical outcomes of patients with primary myelofibrosis (PMF) in Japan. Questionnaires were sent annually to approximately 500 hematology departments. Newly diagnosed patients with PMF were enrolled in this study, and were followed up annually to collect prognostic information. Approximately 50 patients were enrolled per year, yielding a total of 780 patients with PMF included in this study. The median age at diagnosis was 66 years. At the time of analysis, the median survival duration was 47 months, and the 3-year overall survival rate was 59 %. Infection and disease transformation into acute leukemia were the most frequent causes of death. Of the proposed prognostic models for predicting the outcomes of PMF patients in Japan, the Dynamic International Prognostic Scoring System of PMF plus model was the most feasible. Forty-three patients received allogeneic hematopoietic stem cell transplantation (alloSCT) at a median of 343 days after diagnosis. This treatment significantly prolonged the survival of PMF patients, and the 3-year overall survival rate after first alloSCT was 84 %. A long-term registration study is required for further evaluation of prognosis and the impact of treatments on survival.

Allogeneic stem cell transplantation for advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and French Study Group on Cutaneous Lymphomas

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de Masson, Adèle; Beylot-Barry, Marie; Bouaziz, Jean-David; de Latour, Régis Peffault; Aubin, François; Garciaz, Sylvain; d’Incan, Michel; Dereure, Olivier; Dalle, Stéphane; Dompmartin, Anne; Suarez, Felipe; Battistella, Maxime; Vignon-Pennamen, Marie-Dominique; Rivet, Jacqueline; Adamski, Henri; Brice, Pauline; François, Sylvie; Lissandre, Séverine; Turlure, Pascal; Wierzbicka-Hainaut, Ewa; Brissot, Eolia; Dulery, Rémy; Servais, Sophie; Ravinet, Aurélie; Tabrizi, Reza; Ingen-Housz-Oro, Saskia; Joly, Pascal; Socié, Gérard; Bagot, Martine

2014-01-01

The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38–0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41–0.77) and progression-free survival 31% (95%CI: 0.19–0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1–0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3–6.2; P=0.01) but also transplant-related mortality (HR=10−7, 95%CI: 4.10−8–2.10−7; P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides. PMID:24213148

Tetanus after allogeneic bone-marrow transplantation

International Nuclear Information System (INIS)

Kendra, J.R.; Halil, O.; Barrett, A.J.; Selwyn, S.

1982-01-01

A brief report is presented of a case of tetanus after allogeneic bone-marrow transplantation complicated by radiation-induced pneumonitis. A 30-year-old army sergeant received a bone-marrow transplant from his brother for the treatment of a granulocytic sarcoma after local radiotherapy to the tumour. Six years earlier he had sustained an open, compound fracture of the left tibia and fibula while on army exercise. At the time a pin and plate had been inserted and booster anti-tetanus administered. Bone-marrow transplantation was performed after total body irradiation. Cyclosporin A was given against graft-versus-host disease. Fifty four days after transplantation tetanus was diagnosed and death followed 14 days later. Necropsy disclosed radiation-induced pneumonitis, but no organisms were cultured from the lungs or the old fracture site. It is suggested that spores were incorporated into the wound site before surgery and that oxygenation around the plate became compromised after transplantation, permitting germination of dormant spores, immunosuppression allowing development of the disease. (U.K.)

Sequence typing of human adenoviruses isolated from Polish patients subjected to allogeneic hematopoietic stem cell transplantation - a single center experience.

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Przybylski, Maciej; Rynans, Sylwia; Waszczuk-Gajda, Anna; Bilinski, Jarosław; Basak, Grzegorz W; Jędrzejczak, Wiesław W; Wróblewska, Marta; Młynarczyk, Grażyna; Dzieciątkowski, Tomasz

2018-03-28

Human adenoviruses (HAdV) from species A, B and C are commonly recognized as pathogens causing severe morbidity and mortality in hematopoietic stem cell transplant (HSCT) recipients. The purpose of the present study was to determine HAdV types responsible for viremia in HSCT recipients at a large tertiary hospital in Poland. Analysis of partial nucleotide sequences of HAdV hexon gene was used to type 40 clinical isolates of HAdV obtained from 40 HSCT recipients. We identified six different HAdV serotypes belonging to species B, C and E. We demonstrated high variability in sequences of detected HAdV types, and patients infected with the same HAdV types were not hospitalized at the same time, which suggests the low possibility of cross-infection. In almost all patients, anti-HAdV antibodies in IgG class were detected, which indicates a history of HAdV infection in the past. Clinical symptoms accompanying HAdV viremia were in 89%, and in 61.5% of individuals, HAdV was a sole pathogen detected. There were no cases with high-level HAdV viremia and severe systemic or organ infections. Graft-versus-host disease (GvHD) was present in patients infected with species B and C, but grade II of GvHD was observed only in patients infected with HAdV-B. The predominance of HAdV-C and common presence of anti-HAdV antibodies in IgG class may strongly suggest that most infections in the present study were reactivations of HAdV persisting into the patient's mucosa-associated lymphoid tissues. Variability of HAdV sequences suggests that cross-infections between patients were very rare. GvHD: graft-versus-host disease; HAdV: human adenoviruses; HSCT: hematopoietic stem cell transplantation.

Development of PET Imaging to Visualize Activated Macrophages Accumulated in the Transplanted iPSc-Derived Cardiac Myocytes of Allogeneic Origin for Detecting the Immune Rejection of Allogeneic Cell Transplants in Mice.

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Noriyuki Kashiyama

Full Text Available Allogeneic transplantation (Tx of induced pluripotent stem cells (iPSCs is a promising tissue regeneration therapy. However, this inevitably induces macrophage-mediated immune response against the graft, limiting its therapeutic efficacy. Monitoring the magnitude of the immune response using imaging tools would be useful for prolonging graft survival and increasing the therapy longevity. Minimally invasive quantitative detection of activated macrophages by medical imaging technologies such as positron emission tomography (PET imaging targets translocator protein (TSPO, which is highly expressed on mitochondrial membrane, especially in activated macrophage. N,N-diethyl-2-[4-(2-fluoroethoxy phenyl]-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-acetamide (DPA-714 is known as a TSPO ligand used in clinical settings. We herein hypothesized that immune rejection of the transplanted iPSC-derived cardiomyocytes (iPSC-CMs of allogeneic origin may be quantitated using 18F-DPA-714-PET imaging study. iPSC-CM cell-sheets of C57BL/6 mice origin were transplanted on the surface of the left ventricle (LV of C57BL/6 mice as a syngeneic cell-transplant model (syngeneic Tx group, or Balb/c mice as an allogeneic model (allogeneic Tx group. 18F-DPA-714-PET was used to determine the uptake ratio, calculated as the maximum standardized uptake value in the anterior and septal wall of the LV. The uptake ratio was significantly higher in the allogeneic Tx group than in the syngeneic group or the sham group at days 7 and day 10 after the cell transplantation. In addition, the immunochemistry showed significant presence of CD68 and CD3-positive cells at day 7 and 10 in the transplanted graft of the allogeneic Tx group. The expression of TSPO, CD68, IL-1 beta, and MCP-1 was significantly higher in the allogeneic Tx group than in the syngeneic Tx and the sham groups at day 7. The 18F-DPA-714-PET imaging study enabled quantitative visualization of the macrophages-mediated immune

Bendamustine added to allogeneic conditioning improves long-term outcomes in patients with CLL.

Science.gov (United States)

Khouri, I F; Sui, D; Jabbour, E J; Samuels, B I; Turturro, F; Alatrash, G; Anderlini, P; Ahmed, S; Oran, B; Ciurea, S O; Marin, D; Olson, A; Patel, K K; Popat, U R; Ledesma, C; Kadia, T M; Ferrajoli, A; Burger, J A; Jorgensen, J L; Medeiros, L J; Bassett, R L; Gulbis, A M

2017-01-01

Bendamustine has shown a favorable safety profile when included in chemotherapy regimens for several types of lymphoma, including CLL. This study investigated the long-term effect of adding bendamustine to a conditioning regimen on survival, rate of engraftment, immune recovery and GvHD after allogeneic stem cell transplantation (alloSCT) in CLL patients. These outcomes were compared with the fludarabine, cyclophosphamide and rituximab (FCR) conditioning regimen. We reviewed the data for 89 CLL patients treated on three trials at our institution. Twenty-six (29%) patients received bendamustine, fludarabine and rituximab (BFR) and 63 (71%) received FCR. Patient characteristics were similar in both groups. Ten (38%) BFR-treated patients vs only two (3%) FCR-treated patients did not experience severe neutropenia (P=CLL patients is associated with improved survival and lower mortality, myelosuppression, and GvHD.

Parvovirus B19 in the Context of Hematopoietic Stem Cell Transplantation: Evaluating Cell Donors and Recipients

Science.gov (United States)

Gama, Bianca E.; Emmel, Vanessa E.; Oliveira-Silva, Michelle; Gutiyama, Luciana M.; Arcuri, Leonardo; Colares, Marta; de Cássia Tavares, Rita; Bouzas, Luis F.; Abdelhay, Eliana; Hassan, Rocio

2017-01-01

Background Parvovirus B19 (B19V) is a common human pathogen, member of the family Parvoviridae. Typically, B19V has been found to infect erythroid progenitors and cause hematological disorders, such as anemia and aplastic crisis. However, the persistence of genomic deoxyribonucleic acid (DNA) has been demonstrated in tonsils, liver, skin, brain, synovial, and testicular tissues as well as bone marrow, for both symptomatic and asymptomatic subjects. Although the molecular and cellular mechanisms of persistence remain undefined, it raises questions about potential virus transmissibility and its effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Methods With this aim, we retrospectively screened allogeneic stem cell donors from 173 patients admitted for allo-HSCT from January 2008 to May 2013 using a seminested polymerase chain reaction approach. Results We found 8 positive donor samples, yielding a 4.6% of parvovirus prevalence (95% confidence interval, 2.36-8.85). Pre- and post-HSCT samples (n = 51) from the 8 recipients of the positive donors were also investigated, and 1 case exhibited B19V DNA in the post-HSCT follow-up (D + 60). Direct DNA sequencing was performed to determine the genotype of isolates and classification, performed by phylogenetic reconstruction, showed a predominance of genotype 1a, whereas the rare genotype 3b was detected in 2 additional patients. By molecular cloning, different B19V 1a substrains polymorphisms were evidenced in the single case in which donor and its recipient were B19V+. Conclusions Our results suggest that HSCT allografts are not a main source for B19V transmission, pointing to potential events of reinfection or endogenous viral reactivation. PMID:29184906

Parvovirus B19 in the Context of Hematopoietic Stem Cell Transplantation: Evaluating Cell Donors and Recipients.

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Gama, Bianca E; Emmel, Vanessa E; Oliveira-Silva, Michelle; Gutiyama, Luciana M; Arcuri, Leonardo; Colares, Marta; de Cássia Tavares, Rita; Bouzas, Luis F; Abdelhay, Eliana; Hassan, Rocio

2017-11-01

Parvovirus B19 (B19V) is a common human pathogen, member of the family Parvoviridae. Typically, B19V has been found to infect erythroid progenitors and cause hematological disorders, such as anemia and aplastic crisis. However, the persistence of genomic deoxyribonucleic acid (DNA) has been demonstrated in tonsils, liver, skin, brain, synovial, and testicular tissues as well as bone marrow, for both symptomatic and asymptomatic subjects. Although the molecular and cellular mechanisms of persistence remain undefined, it raises questions about potential virus transmissibility and its effects in the context of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. With this aim, we retrospectively screened allogeneic stem cell donors from 173 patients admitted for allo-HSCT from January 2008 to May 2013 using a seminested polymerase chain reaction approach. We found 8 positive donor samples, yielding a 4.6% of parvovirus prevalence (95% confidence interval, 2.36-8.85). Pre- and post-HSCT samples (n = 51) from the 8 recipients of the positive donors were also investigated, and 1 case exhibited B19V DNA in the post-HSCT follow-up (D + 60). Direct DNA sequencing was performed to determine the genotype of isolates and classification, performed by phylogenetic reconstruction, showed a predominance of genotype 1a, whereas the rare genotype 3b was detected in 2 additional patients. By molecular cloning, different B19V 1a substrains polymorphisms were evidenced in the single case in which donor and its recipient were B19V+. Our results suggest that HSCT allografts are not a main source for B19V transmission, pointing to potential events of reinfection or endogenous viral reactivation.

Alternative procedures for reducing allogeneic blood transfusion in elective orthopedic surgery.

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Kleinert, Kathrin; Theusinger, Oliver M; Nuernberg, Johannes; Werner, Clément M L

2010-09-01

Perioperative blood loss is a major problem in elective orthopedic surgery. Allogeneic transfusion is the standard treatment for perioperative blood loss resulting in low postoperative hemoglobin, but it has a number of well-recognized risks, complications, and costs. Alternatives to allogeneic blood transfusion include preoperative autologous donation and intraoperative salvage with postoperative autotransfusion. Orthopedic surgeons are often unaware of the different pre- and intraoperative possibilities of reducing blood loss and leave the management of coagulation and use of blood products completely to the anesthesiologists. The goal of this review is to compare alternatives to allogeneic blood transfusion from an orthopedic and anesthesia point of view focusing on estimated costs and acceptance by both parties.

Impact of Allogeneic Stem Cell Transplantation in First Complete Remission in Acute Myeloid Leukemia

DEFF Research Database (Denmark)

Østgård, Lene Sofie Granfeldt; Lund, Jennifer L; Nørgaard, Jan Maxwell

2018-01-01

To examine the outcome of allogeneic stem cell transplantation (HSCT) in first complete remission (CR1) compared to chemotherapy alone in a population-based setting, we identified a cohort of acute myeloid leukemia (AML) patients aged 15-70 years diagnosed between 2000-2014 in Denmark. Using...... the Danish National Acute Leukemia Registry, we compared relapse risk, relapse-free survival (RFS), and overall survival between patients with non-favorable cytogenetic features receiving post-remission therapy with conventional chemotherapy-only versus those undergoing HSCT in CR1. To minimize immortal time...

Regulatory Immunotherapy in Bone Marrow Transplantation

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Vanessa Morales-Tirado

2011-01-01

Full Text Available Every year individuals receive hematopoietic stem cell transplantation (HSCT to eradicate malignant and nonmalignant disease. The immunobiology of allotransplantation is an area of ongoing discovery, from the recipient's conditioning treatment prior to the transplant to the donor cell populations responsible for engraftment, graft-versus-host disease, and graft-versus-tumor effect. In this review, we focus on donor-type immunoregulatory T cells, namely, natural killer T cells (NKT and regulatory T cells (Treg, and their current and potential roles in tolerance induction after allogeneic HSCT.

Transplantation Tolerance through Hematopoietic Chimerism: Progress and Challenges for Clinical Translation

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Benedikt Mahr

2017-12-01

Full Text Available The perception that transplantation of hematopoietic stem cells can confer tolerance to any tissue or organ from the same donor is widely accepted but it has not yet become a treatment option in clinical routine. The reasons for this are multifaceted but can generally be classified into safety and efficacy concerns that also became evident from the results of the first clinical pilot trials. In comparison to standard immunosuppressive therapies, the infection risk associated with the cytotoxic pre-conditioning necessary to allow allogeneic bone marrow engraftment and the risk of developing graft-vs.-host disease (GVHD constitute the most prohibitive hurdles. However, several approaches have recently been developed at the experimental level to reduce or even overcome the necessity for cytoreductive conditioning, such as costimulation blockade, pro-apoptotic drugs, or Treg therapy. But even in the absence of any hazardous pretreatment, the recipients are exposed to the risk of developing GVHD as long as non-tolerant donor T cells are present. Total lymphoid irradiation and enriching the stem cell graft with facilitating cells emerged as potential strategies to reduce this peril. On the other hand, the long-lasting survival of kidney allografts, seen with transient chimerism in some clinical series, questions the need for durable chimerism for robust tolerance. From a safety point of view, loss of chimerism would indeed be favorable as it eliminates the risk of GVHD, but also complicates the assessment of tolerance. Therefore, other biomarkers are warranted to monitor tolerance and to identify those patients who can safely be weaned off immunosuppression. In addition to these safety concerns, the limited efficacy of the current pilot trials with approximately 40–60% patients becoming tolerant remains an important issue that needs to be resolved. Overall, the road ahead to clinical routine may still be rocky but the first successful long

Hematopoietic Cell Transplantation for Systemic Mature T-Cell Non-Hodgkin Lymphoma

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Smith, Sonali M.; Burns, Linda J.; van Besien, Koen; LeRademacher, Jennifer; He, Wensheng; Fenske, Timothy S.; Suzuki, Ritsuro; Hsu, Jack W.; Schouten, Harry C.; Hale, Gregory A.; Holmberg, Leona A.; Sureda, Anna; Freytes, Cesar O.; Maziarz, Richard Thomas; Inwards, David J.; Gale, Robert Peter; Gross, Thomas G.; Cairo, Mitchell S.; Costa, Luciano J.; Lazarus, Hillard M.; Wiernik, Peter H.; Maharaj, Dipnarine; Laport, Ginna G.; Montoto, Silvia; Hari, Parameswaran N.

2013-01-01

Purpose To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma. Patients and Methods Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes. Results AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival. Conclusion These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology. PMID:23897963

Induction of transplantation tolerance by combining non-myeloablative conditioning with delivery of alloantigen by T cells

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Tian, Chaorui; Yuan, Xueli; Bagley, Jessamyn; Blazar, Bruce R.; Sayegh, Mohamed H.; Iacomini, John

2008-01-01

The observation that bone marrow derived hematopoietic cells are potent inducers of tolerance has generated interest in trying to establish transplantation tolerance by inducing a state of hematopoietic chimerism through allogeneic bone marrow transplantation. However, this approach is associated with serious complications that limit its utility for tolerance induction. Here we describe the development of a novel approach that allows for tolerance induction without the need for an allogeneic bone marrow transplant by combining non-myeloablative host conditioning with delivery of donor alloantigen by adoptively transferred T cells. CBA/Ca mice were administered 2.5Gy whole body irradiation (WBI). The following day the mice received Kb disparate T cells from MHC class I transgenic CBK donor mice, as well as rapamycin on days 0–13 and anti-CD40L monoclonal antibody on days 0–5, 8,11 and 14 relative to T cell transfer. Mice treated using this approach were rendered specifically tolerant to CBK skin allografts through a mechanism involving central and peripheral deletion of alloreactive T cells. These data suggest robust tolerance can be established without the need for bone marrow transplantation using clinically relevant non-myeloablative conditioning combined with antigen delivery by T cells. PMID:18280792

Validation of the EBMT risk score in chronic myeloid leukemia in Brazil and allogeneic transplant outcome.

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De Souza, Carmino Antonio; Vigorito, Afonso Celso; Ruiz, Milton Artur; Nucci, Márcio; Dulley, Frederico Luiz; Funcke, Vaneusa; Tabak, Daniel; Azevedo, Alexandre Mello; Byington, Rita; Macedo, Maria Cristina; Saboya, Rosaura; Penteado Aranha, Francisco José; Oliveira, Gislaine Barbosa; Zulli, Roberto; Martins Miranda, Eliana Cristina; Azevedo, Wellington Moraes; Lodi, Fernanda Maria; Voltarelli, Júlio Cesar; Simões, Belinda Pinto; Colturato, Vergílio; De Souza, Mair Pedro; Silla, Lúcia; Bittencourt, Henrique; Piron-Ruiz, Lilian; Maiolino, Angelo; Gratwohl, Alois; Pasquini, Ricardo

2005-02-01

The management of chronic myeloid leukemia (CML) has changed radically since the introduction of imatinib therapy. The decision of whether to offer a patient a hematopoietic stem cell transplant (HSCT) must be based on the probability of success of the procedure. The aim of this retrospective analysis of 1,084 CML patients who received an allogeneic HSCT in 10 Brazilian Centers between February 1983 and March 2003 was to validate the EBMT risk score. The study population comprised 647 (60%) males and 437 (40%) females, with a median age of 32 years old (range 1 - 59); 898 (83%) were in chronic phase, 146 (13%) were in accelerated phase and 40 (4%) were in blast crisis; 151 (14%) were younger than 20 years old, 620 (57%) were between 20 and 40 and 313 (29%) were older than 40; 1,025 (94%) received an HLA fully matched sibling transplant and only 59 (6%) received an unrelated transplant. In 283 cases (26%) a male recipient received a graft from a female donor. The interval from diagnosis to transplantation was less than 12 months in 223 (21%) cases and greater in 861 (79%). The overall survival, disease-free survival, transplant-related mortality and relapse incidence were 49%, 50%, 45% and 25%, respectively. Of the 1084 patients, 179 (17%) had a risk score of 0 or 1, 397 (37%) had a score of 2, 345 (32%) had a score of 3, 135 (12%) had a score of 4 and 28 (2%) a score of 5 or 6. The overall survival (OS) rate in patients with risk scores 0-1 and 2 was similar (58% and 55%, respectively) but significantly better than that in patients with scores 3 or more (score 3 - 44%, 4 - 36 % and 5-6 - 27%, respectively) pp<0.001). Disease-free survival (DFS) and transplant related mortality (TRM) in a patients with a score of 3 or more were 46% and 49%, respectively and the relapse rate beyond score 5-6 was 77%. Disease status had a negative impact on all outcomes (OS, DFS, TRM, and relapse). The OS rate for male recipients of a graft from a female donor was 40% compared to 52

Allogeneic human dermal fibroblasts are viable in peripheral blood mononuclear co-culture

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Restu Syamsul Hadi

2014-08-01

Full Text Available Background Transplanted allogeneic dermal fibroblasts retain stem cell subpopulations, and are easily isolated, expanded and stored using standard techniques. Their potential for regenerative therapy of chronic wounds should be evaluated. The aim of this study was to determine allogeneic fibroblast viability in the presence of peripheral blood mononuclear cells (PBMC. Methods In this experimental study, fibroblasts were isolated from foreskin explants, expanded in the presence of serum, and stored using slow-freezing. We used one intervention group of allogeneic fibroblasts co-cultured with PBMC and 2 control groups of separate fibroblast and PBMC cultures.Fibroblasts were characterized by their collagen secretion and octamer-binding transcription factor 4 (OCT4 expression. Viability was evaluated using water soluble tetrazolium-1 (WST-1 proliferation assay. Absorbances were measured at 450 nm. Data analysis was performed by student’s paired t-test. Results Dermal fibroblasts were shown to secrete collagen, express OCT4, be recoverable after cryopreservation, and become attached to the culture dish in a co-culture with PBMC. Co-cultured and control fibroblasts had no significantly different cell viabilities (p>0.05. Calculated viable cell numbers increased 1.8 and 5.1-fold, respectively, at days 2 and 4 in vitro. Both groups showed comparable doubling times at days 2 and 4 in vitro. PBMC did not interfere with allogeneic fibroblast viability and proliferative capacity Conclusions Allogeneic fibroblasts remain viable and proliferate in the presence of host PBMC. Future research should evaluate allogeneic human dermal fibroblast competency in clinical settings. Dermal fibroblasts are a potential source for cell therapy in chronic wound management.

Chimeric autologous/allogeneic constructs for skin regeneration.

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Rasmussen, Cathy Ann; Tam, Joshua; Steiglitz, Barry M; Bauer, Rebecca L; Peters, Noel R; Wang, Ying; Anderson, R Rox; Allen-Hoffmann, B Lynn

2014-08-01

The ideal treatment for severe cutaneous injuries would eliminate the need for autografts and promote fully functional, aesthetically pleasing autologous skin regeneration. NIKS progenitor cell-based skin tissues have been developed to promote healing by providing barrier function and delivering wound healing factors. Independently, a device has recently been created to "copy" skin by harvesting full-thickness microscopic tissue columns (MTCs) in lieu of autografts traditionally harvested as sheets. We evaluated the feasibility of combining these two technologies by embedding MTCs in NIKS-based skin tissues to generate chimeric autologous/allogeneic constructs. Chimeric constructs have the potential to provide immediate wound coverage, eliminate painful donor site wounds, and promote restoration of a pigmented skin tissue possessing hair follicles, sweat glands, and sebaceous glands. After MTC insertion, chimeric constructs and controls were reintroduced into air-interface culture and maintained in vitro for several weeks. Tissue viability, proliferative capacity, and morphology were evaluated after long-term culture. Our results confirmed successful MTC insertion and integration, and demonstrated the feasibility of generating chimeric autologous/allogeneic constructs that preserved the viability, proliferative capacity, and structure of autologous pigmented skin. These feasibility studies established the proof-of-principle necessary to further develop chimeric autologous/allogeneic constructs for the treatment of complex skin defects. Reprint & Copyright © 2014 Association of Military Surgeons of the U.S.

'Mini' total body irradiation and allogeneic bone marrow transplantation

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Gocheva, L.; Sergieva, K.; Koleva, I.; Avramova, V.; Vassileva, V.; Georgieva, S.; Sultanov, B.

2006-01-01

Full text: The total body irradiation (TBI) combined with intensive chemotherapy plays an important role in the preparation of patients for bone marrow transplantation (BMT). The first autologous BMT in Bulgaria was performed in 1997 in the Specialized Pediatric Hospital for Active Treatment (SPHAT) of oncohematological diseases. The first TBI, followed by allogeneic BMT, was carried out in 2002 in the 'Queen Giovanna' University Hospital, after which its routine application as a basic form of large field radiotherapy and a main stage of the conditioning regimen for BMT was started. Fourteen allogeneic BMTs including TBI as a basic conditioning regimen have been performed till May 2006. The objective of the present report is to present the first clinical observations in the Bulgarian oncological practice on 'mini' TBI followed by allogeneic blood stem cell transplantation. During the period October 2005 - May 2006, 'mini' TBI followed by allogeneic BMT was carried out for two patients of the age 43 and 50 years. The diagnosis of both patients was acute non-lymphoblastic leukemia, in the remission stage, after one relapse, respectively. Intensive preceding chemotherapy was applied for both patients. A conditioning regimen was applied including the fludarabine purine analogue (3 x 30 mg/m 2 ) and 200 cGy TBI. It was followed by transplantation of allogeneic cell concentrate containing 2.5 x10 6 /kg CD34+ and 4.0 x10 6 /kg CD34+ blood stem cells of partially compatible family donors (a sister and a son), which were tolerable for the patients without complications. Cyclosporine and mycophelonate mofetile were applied as post-transplantation treatment. Active antibiotic, antiviral, symptomatic and substituting therapy, as well as GvHD prophylaxis was applied for both patients. Good clinical tolerance was recorded for the applied low dose conditioning regimen. The patients were discharged within 30 days in good general condition and stable draft action, with

Granulocyte-colony stimulating factor for hematopoietic stem cell donation from healthy female donors during pregnancy and lactation: what do we know?

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Pessach, Ilias; Shimoni, Avichai; Nagler, Arnon

2013-01-01

BACKGROUND Hematopoietic growth factors (HGFs) are mostly used as supportive measures to reduce infectious complications associated with neutropenia. Over the past decade, the use of HGFs became a common method for mobilizing human CD34+ stem cells, either for autologous or allogeneic transplantation. However, since their introduction the long-term safety of the procedure has become a major focus of discussion and research. Most information refers to healthy normal donors and data concerning pregnant and lactating women are scarce. The clinical question, which is the core of this review, is whether stem cell donation, preceded by administration of granulocyte-colony stimulating factor (G-CSF) for mobilization, is a safe procedure for pregnant donors. METHODS Literature searches were performed in Pubmed for English language articles published before the end of May 2012, focusing on G-CSF administration during pregnancy, lactation and hematopoietic stem cell donation. Searches included animal and human studies. RESULTS Data from animals (n = 15 studies) and women (n = 46 studies) indicate that G-CSF crosses the placenta, stimulates fetal granulopoiesis, improves neonatal survival mostly for very immature infants, promotes trophoblast growth and placental metabolism and has an anti-abortive role. Granulocyte macrophage-CSF is a key cytokine in the maternal immune tolerance towards the implanted embryo and exerts protective long-term programming effects to preimplantation embryos. The available data suggest that probably CSFs should not be administered during the time of most active organogenesis (first trimester), except perhaps for the first week during which implantation takes place. Provided CSF is administered during the second and third trimesters, it appears to be safe, and pregnant women receiving the CSF treatment can become hematopoietic stem cell donors. There are also risks related to the anesthesia, which is required for the bone marrow aspiration. During

Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia

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Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T.; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R.; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D.; Lutz, Christoph

2017-01-01

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. PMID:28550184

Reduced hematopoietic stem cell frequency predicts outcome in acute myeloid leukemia.

Science.gov (United States)

Wang, Wenwen; Stiehl, Thomas; Raffel, Simon; Hoang, Van T; Hoffmann, Isabel; Poisa-Beiro, Laura; Saeed, Borhan R; Blume, Rachel; Manta, Linda; Eckstein, Volker; Bochtler, Tilmann; Wuchter, Patrick; Essers, Marieke; Jauch, Anna; Trumpp, Andreas; Marciniak-Czochra, Anna; Ho, Anthony D; Lutz, Christoph

2017-09-01

In patients with acute myeloid leukemia and low percentages of aldehyde-dehydrogenase-positive cells, non-leukemic hematopoietic stem cells can be separated from leukemic cells. By relating hematopoietic stem cell frequencies to outcome we detected poor overall- and disease-free survival of patients with low hematopoietic stem cell frequencies. Serial analysis of matched diagnostic and follow-up samples further demonstrated that hematopoietic stem cells increased after chemotherapy in patients who achieved durable remissions. However, in patients who eventually relapsed, hematopoietic stem cell numbers decreased dramatically at the time of molecular relapse demonstrating that hematopoietic stem cell levels represent an indirect marker of minimal residual disease, which heralds leukemic relapse. Upon transplantation in immune-deficient mice cases with low percentages of hematopoietic stem cells of our cohort gave rise to leukemic or no engraftment, whereas cases with normal hematopoietic stem cell levels mostly resulted in multi-lineage engraftment. Based on our experimental data, we propose that leukemic stem cells have increased niche affinity in cases with low percentages of hematopoietic stem cells. To validate this hypothesis, we developed new mathematical models describing the dynamics of healthy and leukemic cells under different regulatory scenarios. These models suggest that the mechanism leading to decreases in hematopoietic stem cell frequencies before leukemic relapse must be based on expansion of leukemic stem cells with high niche affinity and the ability to dislodge hematopoietic stem cells. Thus, our data suggest that decreasing numbers of hematopoietic stem cells indicate leukemic stem cell persistence and the emergence of leukemic relapse. Copyright© 2017 Ferrata Storti Foundation.

Enhancement of committed hematopoietic stem cell colony formation by nandrolone decanoate after sublethal whole body irradiation

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Gallicchio, V.S.; Chen, M.G.; Watts, T.D.

1984-11-01

The ability of an anabolic steroid, nandrolone decanoate, to increase committed topoietic stem cell (CFU-gm, CFU-e, and BFU-e) colony formation after sublethal irradiation was evaluated. Immediately after receiving whole body irradiation and on the next two days, each mouse was injected intraperitoneally with nandrolone decanoate (1.25 mg) in propylene glycol. Irradiated control mice received only propylene glycol. Compared to controls, drug-treated mice showed marked peripheral blood leukocytosis and more stable packed red cell volume. Drug-treated mice also demonstrated increased erythropoiesis, as CFU-e/BFU-e concentrations from both marrow (9% to 581%) and spleen (15% to 797%) were elevated. Granulopoiesis was increased similarly, as CFU-gm concentrations from marrow (38% to 685%) and spleen (9% to 373%) were elevated. These results demonstrate that nandrolone decanoate enhances hematopoietic stem cell recovery after sublethal whole body irradiation. This suggests that following hematopoietic suppression, nandrolone decanoate may stimulate the recovery of hematopoiesis at the stem cell level and in peripheral blood.

Enhancement of committed hematopoietic stem cell colony formation by nandrolone decanoate after sublethal whole body irradiation

International Nuclear Information System (INIS)

Gallicchio, V.S.; Chen, M.G.; Watts, T.D.

1984-01-01

The ability of an anabolic steroid, nandrolone decanoate, to increase committed topoietic stem cell (CFU-gm, CFU-e, and BFU-e) colony formation after sublethal irradiation was evaluated. Immediately after receiving whole body irradiation and on the next two days, each mouse was injected intraperitoneally with nandrolone decanoate (1.25 mg) in propylene glycol. Irradiated control mice received only propylene glycol. Compared to controls, drug-treated mice showed marked peripheral blood leukocytosis and more stable packed red cell volume. Drug-treated mice also demonstrated increased erythropoiesis, as CFU-e/BFU-e concentrations from both marrow (9% to 581%) and spleen (15% to 797%) were elevated. Granulopoiesis was increased similarly, as CFU-gm concentrations from marrow (38% to 685%) and spleen (9% to 373%) were elevated. These results demonstrate that nandrolone decanoate enhances hematopoietic stem cell recovery after sublethal whole body irradiation. This suggests that following hematopoietic suppression, nandrolone decanoate may stimulate the recovery of hematopoiesis at the stem cell level and in peripheral blood

Angiopoietin-like protein 3 promotes preservation of stemness during ex vivo expansion of murine hematopoietic stem cells.

Science.gov (United States)

Farahbakhshian, Elnaz; Verstegen, Monique M; Visser, Trudi P; Kheradmandkia, Sima; Geerts, Dirk; Arshad, Shazia; Riaz, Noveen; Grosveld, Frank; van Til, Niek P; Meijerink, Jules P P

2014-01-01

Allogeneic hematopoietic stem cell (HSC) transplantations from umbilical cord blood or autologous HSCs for gene therapy purposes are hampered by limited number of stem cells. To test the ability to expand HSCs in vitro prior to transplantation, two growth factor cocktails containing stem cell factor, thrombopoietin, fms-related tyrosine kinase-3 ligand (STF) or stem cell factor, thrombopoietin, insulin-like growth factor-2, fibroblast growth factor-1 (STIF) either with or without the addition of angiopoietin-like protein-3 (Angptl3) were used. Culturing HSCs in STF and STIF media for 7 days expanded long-term repopulating stem cells content in vivo by ∼6-fold and ∼10-fold compared to freshly isolated stem cells. Addition of Angptl3 resulted in increased expansion of these populations by ∼17-fold and ∼32-fold, respectively, and was further supported by enforced expression of Angptl3 in HSCs through lentiviral transduction that also promoted HSC expansion. As expansion of highly purified lineage-negative, Sca-1+, c-Kit+ HSCs was less efficient than less pure lineage-negative HSCs, Angptl3 may have a direct effect on HCS but also an indirect effect on accessory cells that support HSC expansion. No evidence for leukemia or toxicity was found during long-term follow up of mice transplanted with ex vivo expanded HSCs or manipulated HSC populations that expressed Angptl3. We conclude that the cytokine combinations used in this study to expand HSCs ex vivo enhances the engraftment in vivo. This has important implications for allogeneic umbilical cord-blood derived HSC transplantations and autologous HSC applications including gene therapy.

Monitoring of a new approach of immunotherapy with allogenic 111In-labelled NK cells in patients with renal cell carcinoma

International Nuclear Information System (INIS)

Meller, Birgit; Lauer, Isabel; Schelper, Lutz F.; Hof, Katharina von; Richter, Eckart; Baehre, Manfred; Frohn, Christoph; Brand, Joerg-Matthias; Kirchner, Holger

2004-01-01

The transfusion of allogenic, in vitro expanded natural killer cells (NKC) is a novel therapy option in oncology. To date, however, the biodistribution and kinetics of allogenic NKC have not been investigated. Therefore, in this study three patients with renal cell carcinoma received 3-7 x 10 8 NKC labelled with indium-111 oxine with a tenfold excess of unlabelled cells during NKC therapy. Whole-body scintigrams were obtained (0.5-144 h) in the anterior and posterior views. Scintigrams were analysed using a region of interest technique, and single-photon emission tomography (SPET) studies of the abdomen were performed. Results were compared to those obtained with polymerase chain reaction (PCR) of the peripheral blood (determination of foreign DNA, nested PCR, limit of detection 0.01%). Shortly after transfusion of NKC, more than 50% of the activity was accumulated in the lungs. We observed redistribution effects from lungs to liver, spleen and bone marrow. No significant loss of activity could be detected. In two of four large metastases, tracer accumulation could be proven by SPET. As confirmed by scintigrams and PCR, the fraction of circulating transfused cells was low at all times. Long-term activity retention might be caused either by survival of the allogenic cells, as confirmed by PCR (up to 3 days p.i.), or by phagocytosis of labelled cellular fragments. However, PCR data and uptake in metastases indicated long survival of a portion of allogenic NKC. Such long survival and low retention of the cells in the lung are requirements for an effective immunotherapeutic approach. (orig.)

Hematopoietic stem cell expansion : challenges and opportunities

NARCIS (Netherlands)

Walasek, Marta A.; van Os, Ronald; de Haan, Gerald; Kanz, L; Fibbe, WE; Lengerke, C; Dick, JE

2012-01-01

Attempts to improve hematopoietic reconstitution and engraftment potential of ex vivo-expanded hematopoietic stem and progenitor cells (HSPCs) have been largely unsuccessful due to the inability to generate sufficient stem cell numbers and to excessive differentiation of the starting cell

Tolerance, immunocompetence, and secondary disease in fully allogeneic radiation chimeras

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Rayfield, L.S.; Brent, L.

1983-01-01

The aim of this study was to ascertain the extent to which secondary disease and mortality in fully allogeneic chimeras (C57BL leads to CBA) is caused (if at all) by a delayed graft-versus-host reaction. Adult CBA males were thymectomized, irradiated, and reconstituted with T-lymphocyte-depleted C57BL or CBA bone marrow cells (BMC), followed three weeks after irradiation by implantation under the kidney capsule of thymic lobes from C57BL or CBA fetal or adult donors. These mice were observed for the development of secondary disease for periods in excess of 250 days, and they were examined at 5 weeks or 4 months for T lymphocyte reactivity and tolerance to alloantigens, using the cell-mediated lympholysis assay (CML). The following results were obtained. First, removal of T lymphocytes with anti-Thy 1 antibody and complement from allogeneic bone marrow did not prevent wasting and eventual death, although it prolonged the lifespan of mice substantially. Second, T lymphocytes generated from bone marrow-derived precursor cells became tolerant of the histocompatibility antigens of the thymus donor strain but remained normally reactive to third-party antigens. Third, allogeneic radiation chimeras did not survive as well as animals reconstituted with syngeneic cells, even when they were demonstrably tolerant in CML. Fourth, C57BL BMC maturing in a CBA host equipped with a C57BL thymus graft did not become tolerant of host antigens, indicating that extra-thymic tolerance does not occur in fully allogeneic--as opposed to semiallogeneic--chimeras. It is argued that the function of B lymphocytes and/or accessory cells is impaired in fully allogeneic radiation chimeras, and that the mortality observed was directly related to the resulting immunodeficiency. The relevance of the results described in this paper to clinical bone marrow transplantation is discussed

Lethal graft-versus-host disease: modification with allogeneic cultured donor cells

International Nuclear Information System (INIS)

Mauch, P.; Lipton, J.M.; Hamilton, B.; Obbagy, J.; Kudisch, M.; Nathan, D.; Hellman, S.

1984-01-01

The use of the bone marrow culture technique was studied as a means to prepare donor marrow for bone marrow transplantation to avoid lethal graft-versus-host disease (GVHD). Preliminary experiments demonstrated the rapid loss of theta-positive cells in such cultures, so that theta-positive cells were not detected after 6 days. Initial experiments in C3H/HeJ (H-2k, Hbbd) recipients prepared with 900 rad demonstrated improved survival when 3-day cultured C57BL/6 (H-2b, Hbbs) donor cells were used in place of hind limb marrow for transplantation. However, hemoglobin typing of recipient animals revealed only short-term donor engraftment, with competitive repopulation of recipient marrow occurring. Subsequent experiments were done in 1,200-rad prepared recipients, with long-term donor engraftment demonstrated. The majority of 1,200-rad prepared animals receiving cultured allogeneic cells died of GVHD, but animals receiving 28-day cultured cells had an improved 90-day survival and a delay in GVHD development over animals receiving hind limb marrow or marrow from shorter times in culture. In addition, animals receiving anti-theta-treated, 3-day nonadherent cells had an improved survival (44%) over animals receiving anti-theta-treated hind limb marrow (20%). These experiments demonstrate modest benefit for the use of cultured cells in bone marrow transplantation across major H-2 histocompatibility complex differences

Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant.

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Chen, Joey; Seabrook, Jamie; Fulford, Adrienne; Rajakumar, Irina

2017-03-01

Background Up to 70% of patients receiving hematopoietic stem cell transplant develop oral mucositis as a side effect of high-dose melphalan conditioning chemotherapy. Oral cryotherapy has been documented to be potentially effective in reducing oral mucositis. The aim of this study was to examine the effectiveness of the cryotherapy protocol implemented within the hematopoietic stem cell transplant program. Methods A retrospective chart review was conducted of adult multiple myeloma patients who received high-dose melphalan conditioning therapy for autologous hematopoietic stem cell transplant. Primary endpoints were incidence and severity of oral mucositis. Secondary endpoints included duration of oral mucositis, duration of hospital stay, parenteral narcotics use and total parenteral nutrition use. Results One hundred and forty patients were included in the study, 70 patients in both no cryotherapy and cryotherapy groups. Both oral mucositis incidence and severity were found to be significantly lower in the cryotherapy group. Fifty (71.4%) experienced mucositis post cryotherapy compared to 67 (95.7%) in the no cryotherapy group (p cryotherapy group (p = 0.03). Oral mucositis duration and use of parenteral narcotics were also significantly reduced. Duration of hospital stay and use of parenteral nutrition were similar between the two groups. Conclusion The cryotherapy protocol resulted in a significantly lower incidence and severity of oral mucositis. These results provide evidence for the continued use of oral cryotherapy, an inexpensive and generally well-tolerated practice.

Reduction in requirements for allogeneic blood products: nonpharmacologic methods.

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Hardy, J F; Bélisle, S; Janvier, G; Samama, M

1996-12-01

Various strategies have been proposed to decrease bleeding and allogeneic transfusion requirements during and after cardiac operations. This article attempts to document the usefulness, or lack thereof, of the nonpharmacologic methods available in clinical practice. Blood conservation methods were reviewed in chronologic order, as they become available to patients during the perisurgical period. The literature in support of or against each strategy was reexamined critically. Avoidance of preoperative anemia and adherence to published guidelines for the practice of transfusion are of paramount importance. Intraoperatively, tolerance of low hemoglobin concentrations and use of autologous blood (predonated or harvested before bypass) will reduce allogeneic transfusions. The usefulness of plateletpheresis and retransfusion of shed mediastinal fluid remains controversial. Intraoperatively and postoperatively, maintenance of normothermia contributes to improved hemostasis. Several approaches have been shown to be effective. An efficient combination of methods can reduce, and sometimes abolish, the need for allogeneic blood products after cardiac operations, inasmuch as all those involved in the care of cardiac surgical patients adhere thoughtfully to existing transfusion guidelines.

Effects of combined radiation-burn injury on survival rate of allogeneic skin grafts and immune reaction in rats

International Nuclear Information System (INIS)

Ran Xinze; Yan Yongtang; Cheng Tianmin; Li Yuan; Wei Shuqing

1996-01-01

The effects of combined radiation-burn injury on survival rate of allogeneic skin grafts and immune reaction were studied in rats with combined injury of 3-8 Gy 60 Co γ-ray irradiation plus 15% total body surface area full thickness burn induced by exposure to a 5 kw bromotungsten lamp. The allogeneic skin was transplanted 24 hours after injury. It was found that all the skin grafts failed to survive in 10 days and the immune reaction significantly increased in the early stage of burn injury. But the immune reaction was obviously suppressed by the combined radiation-burn injury. The survival rates of skin grafts were 20% and 30% in the combined injury of burn plus 3 and 4 Gy irradiation respectively. When the radiation doses increased to 5,6 and 8 Gy, the survival rates elevated to 69%, 88% and 100% respectively (in the group of 8 Gy, bone marrow transplantation was conducted before receiving skin graft). At day 30 post-transplantation the survival rates were still 36%, 42% and 100% respectively. Compared with burn group, there was a significant difference in survival rate when the radiation doses were higher than 5 Gy. These results indicate that the survival rate of the allogeneic skin graft increases concurrently with the increase in radiation dose and decreases with the elapse of the post-transplantation time

Biology and flow cytometry of proangiogenic hematopoietic progenitors cells.

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Rose, Jonathan A; Erzurum, Serpil; Asosingh, Kewal

2015-01-01

During development, hematopoiesis and neovascularization are closely linked to each other via a common bipotent stem cell called the hemangioblast that gives rise to both hematopoietic cells and endothelial cells. In postnatal life, this functional connection between the vasculature and hematopoiesis is maintained by a subset of hematopoietic progenitor cells endowed with the capacity to differentiate into potent proangiogenic cells. These proangiogenic hematopoietic progenitors comprise a specific subset of bone marrow (BM)-derived cells that homes to sites of neovascularization and possess potent paracrine angiogenic activity. There is emerging evidence that this subpopulation of hematopoietic progenitors plays a critical role in vascular health and disease. Their angiogenic activity is distinct from putative "endothelial progenitor cells" that become structural cells of the endothelium by differentiation into endothelial cells. Proangiogenic hematopoietic progenitor cell research requires multidisciplinary expertise in flow cytometry, hematology, and vascular biology. This review provides a comprehensive overview of proangiogenic hematopoietic progenitor cell biology and flow cytometric methods to detect these cells in the peripheral blood circulation and BM. © 2014 International Society for Advancement of Cytometry.

BACTERIAL INFECTIONS IN HEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENTS

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Elisa Balletto

2015-07-01

Full Text Available Bacterial infections are major complications after Hematopoietic Stem Cell Transplant (HSCT. They consist mainly of bloodstream infections (BSI, followed by pneumonia and gastrointestinal infections, including typhlitis and Clostridium difficile infection. Microbiological data come mostly from BSI. Coagulase negative staphylococci and Enterobacteriaceae are the most frequent pathogens causing approximately 25% of BSI each, followed by enterococci, P. aeruginosa and viridans streptococci. Bacterial pneumonia is frequent after HSCT, and Gram-negatives are predominant. Clostridium difficile infection affects approximately 15% of HSCT recipients, being more frequent in case of allogeneic than autologous HSCT. The epidemiology and the prevalence of resistant strains vary significantly between transplant centres. In some regions, multi-drug resistant Gram-negative rods are increasingly frequent. In others, vancomycin-resistant enterococci are predominant. In the era of an increasing resistance to antibiotics, the efficacy of fluoroquinolone prophylaxis and standard treatment of febrile neutropenia have been questioned. Therefore, thorough evaluation of local epidemiology is mandatory in order to decide the need for prophylaxis and the choice of the best regimen for empirical treatment of febrile neutropenia. For the latter, individualised approach has been proposed, consisting of either escalation or de-escalation strategy. De-escalation strategy is recommended is resistant bacteria should be covered upfront, mainly in patients with severe clinical presentation and previous infection or colonisation with a resistant pathogens. Non-pharmacological interventions, such as screening for resistant bacteria, applying isolation and contact precautions should be put in place in order to limit the spread of MDR bacteria. Antimicrobial stewardship program should be implemented in transplant centres.

Unrelated hematopoietic stem cell transplantation in the pediatric population: single institution experience

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Daniela Hespanha Marinho

2015-08-01

Full Text Available OBJECTIVE: Hematopoietic stem cell transplantation has been successfully used to treat the pediatric population with malignant and non-malignant hematological diseases. This paper reports the results up to 180 days after the procedure of all unrelated hematopoietic stem cell transplantations in pediatric patients that were performed in one institution.METHODS: A retrospective review was performed of all under 18-year-old patients who received unrelated transplantations between 1995 and 2009. Data were analyzed using the log-rank test, Cox stepwise model, Kaplan-Meier method, Fine and Gray model and Fisher's exact test.RESULTS: This study included 118 patients (46.8% who received bone marrow and 134 (53.2% who received umbilical cord blood transplants. Engraftment occurred in 89.47% of the patients that received bone marrow and 65.83% of those that received umbilical cord blood (p-value < 0.001. Both neutrophil and platelet engraftments were faster in the bone marrow group. Acute graft-versus-host disease occurred in 48.6% of the patients without statistically significant differences between the two groups (p-value = 0.653. Chronic graft-versus-host disease occurred in 9.2% of the patients with a higher incidence in the bone marrow group (p-value = 0.007. Relapse occurred in 24% of the 96 patients with malignant disease with 2-year cumulative incidences of 45% in the bone marrow group and 25% in the umbilical cord blood group (p-value = 0.117. Five-year overall survival was 47%, with an average survival time of 1207 days, and no significant differences between the groups (p-value = 0.4666.CONCLUSION: Despite delayed engraftment in the umbilical cord blood group, graft-versus-host disease, relapse and survival were similar in both groups.

The biochemistry of hematopoietic stem cell development

NARCIS (Netherlands)

P. Kaimakis (Polynikis); M. Crisan (Mihaela); E.A. Dzierzak (Elaine)

2013-01-01

textabstractBackground: The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short

Allogeneic peripheral blood stem cell transplantation in patients with haematological malignancies

International Nuclear Information System (INIS)

Shamsi, T.S.; Irfan, M.; Ansari, S.H.; Farzana, T.; Kahlid, M.Z.; Panwani, V.K.; Baig, M.I.; Shakoor, N.

2004-01-01

Objective: To report the initial data on allogeneic peripheral blood stem cell transplantation for haematogical malignancies in Pakistan. Patients and Methods: Patients with haematological malignancies were included who had received allogeneic PBSC transplantation of Filgrastim (rhG-CSF) mobilized peripheral blood stem cells from HLA-identical siblings (except one 5/6 antigen sibling) with Busulphan and Cyclophosphamide standard conditioning therapy in all patients. No patient received antibiotics for gut decontamination. Empirical antibiotics included Ceftriaxone and Amikacin for febrile neutropenia, oral Itraconazole for antifungal prophylaxis while oral acyclovir was used for antiviral prophylaxis. All donors and recipients were CMV IgG positive Cyclosporin A / Methotrexate were given for graft versus host disease (GvHD) prophylaxis. Stem cells were harvested using Haemonetics MCS+ cell separator. All patients received G-CSF starting from day +4 until their neutrophil count rose to normal. Results: There were 21 patients with age range of 8-38 years and male to female ratio of 2:1. Engraftment was achieved in all patients; median time to absolute neutrophil count of > 0.5 x 10/sup 9/I was 10 days (range 8 -12 days) and platelet count of > 20 x 10/sup 9/1 was 14 days (12-17 days). Acute graft versus host disease (aGvHD) was seen in 7 patients; one patient had grade IV skin and hepatic GvHD; another patient had grade III gut GvHD, grade II GvHD was seen in 3 patients while grade I skin aGvHD was seen in 2 patients. Median hospital stay was 34 days. Treatment related mortality was seen in 3 patients (18%). Chronic GvHD was seen in 5 patients. Four more patients died during the follow-up period. Malaria was seen in 2 while tuberculosis developed in one case. Relapse was seen in 2 patients. The estimated probability of survival at one hundred day, at one year and five years was 82, 47 and 40 percent respectively. Conclusion: Haematopoietic stem cell transplant

Clinical Allogeneic and Autologous Islet Cell Transplantation: Update

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Shinichi Matsumoto

2011-06-01

Full Text Available Islet cell transplantation is categorized as a β-cell replacement therapy for diabetic patients who lack the ability to secrete insulin. Allogeneic islet cell transplantation is for the treatment of type 1 diabetes, and autologous islet cell transplantation is for the prevention of surgical diabetes after a total pancreatectomy. The issues of allogeneic islet cell transplantation include poor efficacy of islet isolation, the need for multiple donor pancreata, difficulty maintaining insulin independence and undesirable side effects of immunosuppressive drugs. Those issues have been solved step by step and allogeneic islet cell transplantation is almost ready to be the standard therapy. The donor shortage will be the next issue and marginal and/or living donor islet cell transplantation might alleviate the issue. Xeno-islet cell transplantation, β-cell regeneration from human stem cells and gene induction of the naïve pancreas represent the next generation of β-cell replacement therapy. Autologous islet cell transplantation after total pancreatectomy for the treatment of chronic pancreatitis with severe abdominal pain is the standard therapy, even though only limited centers are able to perform this treatment. Remote center autologous islet cell transplantation is an attractive option for hospitals performing total pancreatectomies without the proper islet isolation facilities.

Tritium contamination of hematopoietic stem cells alters long-term hematopoietic reconstitution

International Nuclear Information System (INIS)

Di Giacomo, F.; Barroca, V.; Laurent, D.; Lewandowski, D.; Saintigny, Y.; Romeo, P.H.; Granotier, Ch.; Boussin, F.D.

2011-01-01

Purpose: In vivo effects of tritium contamination are poorly documented. Here, we study the effects of tritiated Thymidine ([ 3 H] Thymidine) or tritiated water (HTO) contamination on the biological properties of hematopoietic stem cells (HSC). Materials and methods: Mouse HSC were contaminated with concentrations of [ 3 H] Thymidine ranging from 0.37-37.03 kBq/ml or of HTO ranging from 5-50 kBq/ml. The biological properties of contaminated HSC were studied in vitro after HTO contamination and in vitro and in vivo after [ 3 H] Thymidine contamination. Results: Proliferation, viability and double-strand breaks were dependent on [ 3 H] Thymidine or HTO concentrations used for contamination but in vitro myeloid differentiation of HSC was not affected by [ 3 H] Thymidine contamination. [ 3 H] Thymidine contaminated HSC showed a compromised long-term capacity of hematopoietic reconstitution and competition experiments showed an up to two-fold decreased capacity of contaminated HSC to reconstitute hematopoiesis. These defects were not due to impaired homing in bone marrow but to an initial decreased proliferation rate of HSC. Conclusion: These results indicate that contaminations of HSC with doses of tritium that do not result in cell death, induce short-term effects on proliferation and cell cycle and long-term effects on hematopoietic reconstitution capacity of contaminated HSC. (authors)

Nicaraven attenuates radiation-induced injury in hematopoietic stem/progenitor cells in mice.

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Miho Kawakatsu

Full Text Available Nicaraven, a chemically synthesized hydroxyl radical-specific scavenger, has been demonstrated to protect against ischemia-reperfusion injury in various organs. We investigated whether nicaraven can attenuate radiation-induced injury in hematopoietic stem/progenitor cells, which is the conmen complication of radiotherapy and one of the major causes of death in sub-acute phase after accidental exposure to high dose radiation. C57BL/6 mice were exposed to 1 Gy γ-ray radiation daily for 5 days in succession (a total of 5 Gy, and given nicaraven or a placebo after each exposure. The mice were sacrificed 2 days after the last radiation treatment, and the protective effects and relevant mechanisms of nicaraven in hematopoietic stem/progenitor cells with radiation-induced damage were investigated by ex vivo examination. We found that post-radiation administration of nicaraven significantly increased the number, improved the colony-forming capacity, and decreased the DNA damage of hematopoietic stem/progenitor cells. The urinary levels of 8-oxo-2'-deoxyguanosine, a marker of DNA oxidation, were significantly lower in mice that were given nicaraven compared with those that received a placebo treatment, although the levels of intracellular and mitochondrial reactive oxygen species in the bone marrow cells did not differ significantly between the two groups. Interestingly, compared with the placebo treatment, the administration of nicaraven significantly decreased the levels of the inflammatory cytokines IL-6 and TNF-α in the plasma of mice. Our data suggest that nicaraven effectively diminished the effects of radiation-induced injury in hematopoietic stem/progenitor cells, which is likely associated with the anti-oxidative and anti-inflammatory properties of this compound.

Allogeneic epidermal substitutes in the treatment of chronic diabetic leg and foot ulcers

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Andrea Marchesi

2014-09-01

Full Text Available Aim: Diabetic foot ulcers are the most common cause of nontraumatic lower extremity amputations in the industrialized world. Tissue-engineering products offer a lower extremity salvage strategy when healing does not proceed according to the standard of care. New allogeneic sheets are available for the management of diabetic leg and foot ulcers. Methods: The endpoints of this case series study regard preliminary outcomes of the application of allogeneic keratinocytes composed of benzyl ester of hyaluronic acid to 16 diabetic foot and leg ulcers in 11 patients with type 2 diabetes mellitus. Results: Between 21 and 70 days after cellular therapy, 6 out of 16 lesions were completely healed, reducing the wound dimension by 70% and improving the wound bed score by 52%. Conclusion: The clinical results of the new allogeneic sheets indicate that allogeneic keratinocytes may represent an effective and safe therapy for diabetic foot and leg ulcers in the multidisciplinary approach to this diabetes-related complication.

Monitoring of a new approach of immunotherapy with allogenic {sup 111}In-labelled NK cells in patients with renal cell carcinoma

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Meller, Birgit; Lauer, Isabel; Schelper, Lutz F.; Hof, Katharina von; Richter, Eckart; Baehre, Manfred [Clinic of Radiotherapy and Nuclear Medicine, University of Luebeck, Ratzeburger Allee 160, 23538, Luebeck (Germany); Frohn, Christoph; Brand, Joerg-Matthias; Kirchner, Holger [Institute of Immunology and Transfusion Medicine, University of Luebeck, Ratzeburger Allee 160, 23538, Luebeck (Germany)

2004-03-01

The transfusion of allogenic, in vitro expanded natural killer cells (NKC) is a novel therapy option in oncology. To date, however, the biodistribution and kinetics of allogenic NKC have not been investigated. Therefore, in this study three patients with renal cell carcinoma received 3-7 x 10{sup 8} NKC labelled with indium-111 oxine with a tenfold excess of unlabelled cells during NKC therapy. Whole-body scintigrams were obtained (0.5-144 h) in the anterior and posterior views. Scintigrams were analysed using a region of interest technique, and single-photon emission tomography (SPET) studies of the abdomen were performed. Results were compared to those obtained with polymerase chain reaction (PCR) of the peripheral blood (determination of foreign DNA, nested PCR, limit of detection 0.01%). Shortly after transfusion of NKC, more than 50% of the activity was accumulated in the lungs. We observed redistribution effects from lungs to liver, spleen and bone marrow. No significant loss of activity could be detected. In two of four large metastases, tracer accumulation could be proven by SPET. As confirmed by scintigrams and PCR, the fraction of circulating transfused cells was low at all times. Long-term activity retention might be caused either by survival of the allogenic cells, as confirmed by PCR (up to 3 days p.i.), or by phagocytosis of labelled cellular fragments. However, PCR data and uptake in metastases indicated long survival of a portion of allogenic NKC. Such long survival and low retention of the cells in the lung are requirements for an effective immunotherapeutic approach. (orig.)

The Role of Allogeneic Transplantation in the Treatment of Multiple Myeloma.

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Majolino, I

1998-01-01

In multiple myeloma (MM) attempts to improve upon the results of standard melphalanpredisone with other conventional dose drug combinations, have generally been unsuccessful, producing only minor improvements in response rate, with little effect on survival. The only treatment capable of producing a dramatic change in response and life expectancy is high-dose chemo-radiotherapy followed by stem cell transplantation. However, after autologous transplant relapse will almost inevitably occur, and freedom from recurrence curves show no plateau in most studies. Besides the resistance of the disease to chemotherapy, another possible explanation is tumor contamination of the graft. This is one major advantage of allogeneic transplantation over autologous, the other being an immune mediated mechanism of tumor suppression in part related to GVHD. Application of allogeneic transplantation to MM has met a number of obstacles, but is now entering a phase of reappraisal, due in part to a tendency to earlier transplantation, in part to the use of novel technologies such as allogeneic peripheral blood stem cells instead of marrow. The goal should be the reduction of transplant related deaths, to better exploit the higher eradication potential of allogeneic cell therapies. The most intriguing perspectives are those related to immune manipulation of recipient and/or donor.

Barriers to Mental Health Service Use among Hematopoietic Stem Cell Transplant Survivors

OpenAIRE

Mosher, Catherine E.; DuHamel, Katherine N.; Rini, Christine M.; Li, Yuelin; Isola, Luis; Labay, Larissa; Rowley, Scott; Papadopoulos, Esperanza; Moskowitz, Craig; Scigliano, Eileen; Grosskreutz, Celia; Redd, William H.

2009-01-01

Summary This study examined barriers to mental health service use and their demographic, medical, and psychosocial correlates among hematopoietic stem cell transplant (HSCT) survivors. A sample of 253 HSCT survivors who were 1- to 3-years post-transplant completed measures of demographic, physical, psychological, and social characteristics as well as a newly modified measure of barriers to mental health service use. Only 50% of distressed HSCT survivors had received mental health services. An...

Quantitative assessment of hematopoietic chimerism by quantitative real-time polymerase chain reaction of sequence polymorphism systems after hematopoietic stem cell transplantation.

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Qin, Xiao-ying; Li, Guo-xuan; Qin, Ya-zhen; Wang, Yu; Wang, Feng-rong; Liu, Dai-hong; Xu, Lan-ping; Chen, Huan; Han, Wei; Wang, Jing-zhi; Zhang, Xiao-hui; Li, Jin-lan; Li, Ling-di; Liu, Kai-yan; Huang, Xiao-jun

2011-08-01

Analysis of changes in recipient and donor hematopoietic cell origin is extremely useful to monitor the effect of hematopoietic stem cell transplantation (HSCT) and sequential adoptive immunotherapy by donor lymphocyte infusions. We developed a sensitive, reliable and rapid real-time PCR method based on sequence polymorphism systems to quantitatively assess the hematopoietic chimerism after HSCT. A panel of 29 selected sequence polymorphism (SP) markers was screened by real-time PCR in 101 HSCT patients with leukemia and other hematological diseases. The chimerism kinetics of bone marrow samples of 8 HSCT patients in remission and relapse situations were followed longitudinally. Recipient genotype discrimination was possible in 97.0% (98 of 101) with a mean number of 2.5 (1-7) informative markers per recipient/donor pair. Using serial dilutions of plasmids containing specific SP markers, the linear correlation (r) of 0.99, the slope between -3.2 and -3.7 and the sensitivity of 0.1% were proved reproducible. By this method, it was possible to very accurately detect autologous signals in the range from 0.1% to 30%. The accuracy of the method in the very important range of autologous signals below 5% was extraordinarily high (standard deviation real-time PCR method over short tandem repeat PCR chimerism assays is the absence of PCR competition and plateau biases, with demonstrated greater sensitivity and linearity. Finally, we prospectively analyzed bone marrow samples of 8 patients who received allografts and presented the chimerism kinetics of remission and relapse situations that illustrated the sensitivity level and the promising clinical application of this method. This SP-based real-time PCR assay provides a rapid, sensitive, and accurate quantitative assessment of mixed chimerism that can be useful in predicting graft rejection and early relapse.

Successful Large-volume Leukapheresis for Hematopoietic Stem Cell Collection in a Very-low-weight Brain Tumor Infant with Coagulopathy

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Yu-Mei Liao

2013-06-01

Full Text Available Peripheral apheresis has become a safe procedure to collect hematopoietic stem cells, even in pediatric patients and donors. However, the apheresis procedure for small and sick children is more complicated due to difficult venous access, relatively large extracorporeal volume, toxicity of citrate, and unstable hemostasis. We report a small and sick child with refractory medulloblastoma, impaired liver function, and coagulopathy after several major cycles of cisplatin-based chemotherapy. She successfully received large-volume leukapheresis for hematopoietic stem cell collection, although the patient experienced severe coagulopathy during the procedures. Health care providers should be alert to this potential risk.

Granulocyte Colony-stimulating Factor-primed Bone Marrow: An Excellent Stem-cell Source for Transplantation in Acute Myelocytic Leukemia and Chronic Myelocytic Leukemia

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Yuhang Li

2015-01-01

Full Text Available Background: Steady-state bone marrow (SS-BM and granulocyte colony-stimulating growth factor-primed BM/peripheral blood stem-cell (G-BM/G-PBSC are the main stem-cell sources used in allogeneic hematopoietic stem-cell transplantation. Here, we evaluated the treatment effects of SS-BM and G-BM/G-PBSC in human leucocyte antigen (HLA-identical sibling transplantation. Methods: A total of 226 patients (acute myelogenous leukemia-complete remission 1, chronic myelogenous leukemia-chronic phase 1 received SS-BM, G-BM, or G-PBSC from an HLA-identical sibling. Clinical outcomes (graft-versus-host disease [GVHD], overall survival, transplant-related mortality [TRM], and leukemia-free survival [LFS] were analyzed. Results: When compared to SS-BM, G-BM gave faster recovery time to neutrophil or platelet (P 0.05. Conclusions: G-CSF-primed bone marrow shared the advantages of G-PBSC and SS-BM. We conclude that G-BM is an excellent stem-cell source that may be preferable to G-PBSC or SS-BM in patients receiving HLA-identical sibling hematopoietic stem-cell transplantation.

IMMUNE STATE IN PATIENTS WITH HEMATOLOGICAL MALIGNANCIES AT LATE TERMS AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION

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N. V. Minaeva

2012-01-01

Full Text Available Abstract. Autologous hematopoietic stem cell transplantation (auto-HSCT is one of the most effective methods for treatment of patients with various forms of hemoblastoses, both in adults and children. However, high-dose chemotherapy protocols used in this procedure are characterized by pronounced myeloand immunotoxicity. Appropriate data concerning immune state at long terms after high-dose chemotherapy and auto-HSCT are sparse and controversial, and there is no consensus on time dynamics of immune system reconstitution. The aim of this study was a comprehensive evaluation of immunity in recipients of auto-HSCT at longer terms. Clinical and immunological testing was performed in ninety-eight patients with hematological malignancies before starting a high-dose chemotherapy, and at late post-transplant period. The state of cellular immunity was assessed as expression of surface CD3+, CD4+, CD8+, CD16+, CD19+ lymphocyte antigens. Humoral immunity was evaluated by serum IgG, IgA, and IgM levels. The studies have revealed disorders of cellular and humoral immunity, as well as nonspecific immune resistance factors in recipients of autologous hematopoietic stem cells at late terms post-transplant. Immune reconstitution in patients receiving highdose consolidation treatment followed by auto-HSCT takes longer time than in patients who did not receive autologous hematopoietic stem cells. Severity of these disturbances and immune reconstitution rates depend on the type of conditioning regimen, and the source of haematopoietic stem cells used for transplantation.

Comprehensive evaluation of nutritional status before and after hematopoietic stem cell transplantation in 170 patients with hematological diseases.

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Liu, Peng; Wang, Boshi; Yan, Xia; Cai, Jingjing; Wang, Yu

2016-12-01

To investigate the nutritional status of patients before and after hematopoietic stem cell transplantation (HSCT), and explore optimal methods for assessing nutritional status in patients with hematological diseases. This cohort study enrolled 170 patients who were diagnosed with hematological diseases and underwent allogeneic HSCT in the Department of Hematology, Peking University People's Hospital between May 2011 and April 2013. We used fixed-point continuous sampling and four nutritional screening tools, Nutritional Risk Screening 2002 (NRS-2002), Mini Nutritional Assessment (MNA), Subjective Global Assessment (SGA) and Malnutrition Universal Screening Tools (MUST), in combination with body measurements, to extensively screen and evaluate nutritional risks and status in patients receiving HSCT before entering and after leaving laminar air flow rooms. After HSCT, patients had significant reduction in weight, hip circumference, waist-hip ratio, calf circumference, mid-upper arm circumference, and suprailiac skinfold thickness compared with pre-HSCT measurements. Before HSCT, NRS-2002 identified that 21.2% of patients were at nutritional risks, compared with 100% after HSCT. MUST indicated that before HSCT, 11.77% of patients were at high nutritional risk, compared with 59.63% after HSCT. MNA assessed that 0.06% of patients were malnourished before HSCT, compared with 19.27% after HSCT. SGA identified that before HSCT, 1.76% of patients had mild to severe malnutrition, which increased to 83.3% after HSCT. There is a significant increase in the nutritional risk and malnutrition in patients who received HSCT. Before HSCT, some patients already had nutritional risk or nutritional deficiencies, and prompt and close nutritional screening or assessment should be performed. The nutritional status of patients after HSCT was generally deteriorated compared with that before transplantation. Body measurements should be taken more frequently during the subsequent treatment

Two Hemocyte Lineages Exist in Silkworm Larval Hematopoietic Organ

OpenAIRE

Nakahara, Yuichi; Kanamori, Yasushi; Kiuchi, Makoto; Kamimura, Manabu

2010-01-01

BACKGROUND: Insects have multiple hemocyte morphotypes with different functions as do vertebrates, however, their hematopoietic lineages are largely unexplored with the exception of Drosophila melanogaster. METHODOLOGY/PRINCIPAL FINDINGS: To study the hematopoietic lineage of the silkworm, Bombyx mori, we investigated in vivo and in vitro differentiation of hemocyte precursors in the hematopoietic organ (HPO) into the four mature hemocyte subsets, namely, plasmatocytes, granulocytes, oenocyto...

Semi-allogeneic dendritic cells can induce antigen-specific T-cell activation, which is not enhanced by concurrent alloreactivity.

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Wells, James W; Cowled, Chris J; Darling, David; Guinn, Barbara-Ann; Farzaneh, Farzin; Noble, Alistair; Galea-Lauri, Joanna

2007-12-01

Alloreactive T-cell responses are known to result in the production of large amounts of proinflammatory cytokines capable of activating and maturing dendritic cells (DC). However, it is unclear whether these allogeneic responses could also act as an adjuvant for concurrent antigen-specific responses. To examine effects of simultaneous alloreactive and antigen-specific T-cell responses induced by semi-allogeneic DC. Semi-allogeneic DC were generated from the F(1) progeny of inbred strains of mice (C57BL/6 and C3H, or C57BL/6 and DBA). We directly primed antigen-specific CD8(+) and CD4(+) T-cells from OT-I and OT-II mice, respectively, in the absence of allogeneic responses, in vitro, and in the presence or absence of alloreactivity in vivo. In vitro, semi-allogeneic DC cross-presented ovalbumin (OVA) to naïve CD8(+) OT-I transgenic T-cells, primed naïve CD4(+) OT-II transgenic T-cells and could stimulate strong alloreactive T-cell proliferation in a primary mixed lymphocyte reaction (MLR). In vivo, semi-allogeneic DC migrated efficiently to regional lymph nodes but did not survive there as long as autologous DC. In addition, they were not able to induce cytotoxic T-lymphocyte (CTL) activity to a target peptide, and only weakly stimulated adoptively transferred OT-II cells. The CD4(+) response was unchanged in allo-tolerized mice, indicating that alloreactive T-cell responses could not provide help for concurrently activated antigen-specific responses. In an EL4 tumour-treatment model, vaccination with semi-allogeneic DC/EL4 fusion hybrids, but not allogeneic DC/EL4 hybrids, significantly increased mouse survival. Expression of self-Major histocompatibility complex (MHC) by semi-allogeneic DC can cause the induction of antigen-specific immunity, however, concurrently activated allogeneic bystander responses do not provide helper or adjuvant effects.

Differentiation of embryonic stem cells towards hematopoietic cells: progress and pitfalls.

Science.gov (United States)

Tian, Xinghui; Kaufman, Dan S

2008-07-01

Hematopoietic development from embryonic stem cells has been one of the most productive areas of stem cell biology. Recent studies have progressed from work with mouse to human embryonic stem cells. Strategies to produce defined blood cell populations can be used to better understand normal and abnormal hematopoiesis, as well as potentially improve the generation of hematopoietic cells with therapeutic potential. Molecular profiling, phenotypic and functional analyses have all been utilized to demonstrate that hematopoietic cells derived from embryonic stem cells most closely represent a stage of hematopoiesis that occurs at embryonic/fetal developmental stages. Generation of hematopoietic stem/progenitor cells comparable to hematopoietic stem cells found in the adult sources, such as bone marrow and cord blood, still remains challenging. However, genetic manipulation of intrinsic factors during hematopoietic differentiation has proven a suitable approach to induce adult definitive hematopoiesis from embryonic stem cells. Concrete evidence has shown that embryonic stem cells provide a powerful approach to study the early stage of hematopoiesis. Multiple hematopoietic lineages can be generated from embryonic stem cells, although most of the evidence suggests that hematopoietic development from embryonic stem cells mimics an embryonic/fetal stage of hematopoiesis.

Remission induction using alemtuzumab can permit chemotherapy-refractory chronic lymphocytic leukemia (CLL) patients to undergo allogeneic stem cell transplantation.

Science.gov (United States)

Knauf, Wolfgang; Rieger, Kathrin; Blau, Wolfgang; Hegenbart, Ute; Von Gruenhagen, Ulrich; Niederwieser, Dietger; Thiel, Eckhard

2004-12-01

The outcome of allogeneic stem cell transplantation depends upon the disease status before transplantation. Patients with refractory disease are at high risk for relapse. To improve the curative potential of the transplant procedure, we treated 3 chemotherapy-refractory CLL patients with alemtuzumab before allogeneic stem cell transplantation. Prior to therapy, all patients suffered from B-symptoms, and had massive adenopathy, splenomegaly, thrombocytopenia, and anemia; two patients had hepatomegaly. Alemtuzumab greatly reduced tumor mass in blood and bone marrow, B-symptoms resolved, and organomegaly improved. Two patients became blood product independent. All patients proceeded to transplantation after conditioning with TBI 2 Gy (n=1) or Treosulfan (n=2) in combination with Fludarabine either from an HLA-matched sibling (n=2) or from an HLA-matched unrelated donor (n=1). All patients engrafted, and are alive and well. Two patients reached complete remission (CR); one patient attained stable partial remission (PR). These heavily pre-treated refractory patients gained substantial clinical benefit from alemtuzumab, and received successful allografts.

Prophylactic defibrotide in allogeneic stem cell transplantation: minimal morbidity and zero mortality from veno-occlusive disease.

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Dignan, F; Gujral, D; Ethell, M; Evans, S; Treleaven, J; Morgan, G; Potter, M

2007-07-01

Veno-occlusive disease (VOD) is a common and high-risk complication of allogeneic stem cell transplantation (SCT). Defibrotide has recently been used successfully to treat the disorder. We report on 58 patients who received defibrotide prophylaxis without concurrent heparin. No patients fulfilled the Baltimore criteria for VOD or died of the condition within 100 days of SCT. None of this group developed haemorrhagic complications secondary to defibrotide. These observations suggest that prophylaxis with defibrotide alone may reduce the incidence of VOD post-SCT although a randomised controlled trial is warranted to further evaluate its role.

Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model

OpenAIRE

Saso, Srdjan; Petts, Gemma; David, Anna L.; Thum, Meen-Yau; Chatterjee, Jayanta; Vicente Antón, José Salvador; Marco Jiménez, Francisco; Corless, David; Boyd, Michael; Noakes, David; Lindsay, Iain; Del Priorei, Giuseppe; Ghaem-Maghami, Sadaf; Smith, J. Richard

2015-01-01

[EN] Objective: Uterine transplantation (UTx) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI). The goal of UTx remains achieving pregnancy and live birth of a healthy neonate following allogeneic UTx. Our aim was to assess whether fertility was possible following allogeneic uterine transplantation (UTx), when the recipient had demonstrated long-term survival and had been administered immunosuppression. Study desig...

Response to intravenous allogeneic equine cord-blood-derived mesenchymal stromal cells administered from chilled or frozen state in serum and protein free media

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Lynn Brandon Williams

2016-07-01

Full Text Available Equine Mesenchymal stromal cells (MSC are commonly transported, chilled or frozen, to veterinary clinics. These MSC must remain viable and minimally affected by culture, transport, or injection processes. The safety of two carrier solutions developed for optimal viability and excipient use were evaluated in ponies, with and without allogeneic cord blood-derived (CB MSC. We hypothesized that neither the carrier solutions nor CB-MSC would elicit measurable changes in clinical, hematological, or biochemical parameters. In 9 ponies (study 1 a bolus of HypoThermosol® FRS (HTS-FRS, CryoStor® CS10 (CS10 or saline was injected IV (n=3/treatment. Study 2, following a one week washout period 5x107 pooled allogeneic CB-MSC were administered IV in HTS-FRS following 24h simulated chilled transport. Study 3, following another one week washout period 5x107 pooled allogeneic CB-MSC were administered IV in CS10 immediately after thawing. Nine ponies received CB-MSCs in study 2 and 3 and three ponies received the cell carrier media without cells. CB-MSCs were pooled in equal numbers from five unrelated donors. In all studies ponies were monitored with physical examination, and blood collection for 7 days following injection. CD4 and CD8 lymphocyte populations were also evaluated in each blood sample.In all three studies, physical exam, complete blood cell count, serum biochemistry, and coagulation panel did not deviate from established normal ranges. Proportions of CD4+ and CD8+ lymphocytes increased at 168h post injection in CB-MSC treatment groups regardless of the carrier solution. Decreases in CD4+/CD8+ double positive populations were observed at 24 h and 72 h in CB-MSC treated animals. There was no difference in viability between CB-MSC suspended in HTS-FRS or CS10.HTS-FRS and CS10 used for low volume excipient injection of MSC suspensions was not associated with short-term adverse reactions. HTS-FRS and CS10 both adequately maintain CB-MSC viability

Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials

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Kharfan-Dabaja Mohamed A

2013-01-01

Full Text Available Abstract Background Despite advances in understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM and availability of more effective therapies, MM remains incurable. The autologous-allogeneic (auto-allo hematopoietic cell transplantation (HCT strategy is based on combining cytoreduction from high-dose (chemo- or chemoradio-therapy with adoptive immunotherapy. However, conflicting results have been reported when an auto-allo HCT approach is compared to tandem autologous (auto-auto HCT. A previously published meta-analysis has been reported; however, it suffers from serious methodological flaws. Methods A systematic search identified 152 publications, of which five studies (enrolling 1538 patients met inclusion criteria. All studies eligible for inclusion utilized biologic randomization. Results Assessing response rates by achievement of at least a very good partial response did not differ among the treatment arms [risk ratio (RR (95% CI = 0.97 (0.87-1.09, p = 0.66]; but complete remission was higher in the auto-allo HCT arm [RR = 1.65 (1.25-2.19, p = 0.0005]. Event-free survival did not differ between auto-allo HCT group versus auto-auto HCT group using per-protocol analysis [hazard ratio (HR = 0.78 (0.58-1.05, p = 0.11] or using intention-to-treat analysis [HR = 0.83 (0.60-1.15, p = 0.26]. Overall survival (OS did not differ among these treatment arms whether analyzed on per-protocol [HR = 0.88 (0.33-2.35, p = 0.79], or by intention-to-treat [HR = 0.80 (0.48-1.32, p = 0.39] analysis. Non-relapse mortality (NRM was significantly worse with auto-allo HCT [RR (95%CI = 3.55 (2.17-5.80, p  Conclusion Despite higher complete remission rates, there is no improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. At present, totality of evidence suggests that an auto-allo HCT approach for patients with newly diagnosed

Effects of X-rays and γ-rays on reconstitution of hematopoiesis and immunity after allogeneic bone marrow transplantation

International Nuclear Information System (INIS)

Pan Bin; Zeng Lingyu; Cheng Hai; Song Guoliang; Jia Lu; Yan Zhiling; Chen Chong; Xu Kailin

2011-01-01

Objective: To determine the conditioning regimen suitable for mice allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Twelve BALB/c mice were randomly divided into 2 equal groups to undergo X-ray irradiation by linear accelerator at the dose of 7.0 Gy (pure X-ray group) or 60 Co source irradiation at the dose of 7.0 Gy (pure γ-ray group). Thirty mice were randomly divided into 2 equal groups to undergo X-ray irradiation and then infusion of bone marrow from donor mice via caudal vein (X-ray + transplantation group) or γ-ray and then infusion of bone marrow via caudal vein (γ-ray + transplantation group). 3, 5, 7, 10, 15, 20, and 30 d later peripheral blood samples were collected to calculate the number of white blood cells (WBCs) and detect the chimeric rates of lymphocytes by flow cytometry. 5, 10, and 20 d after irradiation 15 mice were killed with their lung, liver, small intestine, spleen, and femurs taken out to undergo pathological examination. Results: The survival rates during the period 5-15 days of the γ-ray + transplantation group were all significantly higher than those of the X-ray + transplantation group. The pathological changes of organs of the X-ray + transplantation group were all more severe than those of the γ-ray + transplantation group. Since the fifth day after transplantation cells originating from the donor began to appear in the peripheral blood. The chimeric rate of the γ-ray + transplantation group 10 days after transplantation was (95.53± 2.57) %. The chimeric rates 5, 10, and 20 days after transplantation of the γ-ray + transplantation group were all significantly higher than those of the X-ray + transplantation group (t=15.263, 3.256, P<0.05). The WBC count of both irradiation groups decreased to the lowest level 5 d later and began to increase 10 days after transplantation and the WBC counts of the γ-ray + transplantation group 10 and 20 days after transplantation were both significantly higher than

Gene transfer to pre-hematopoietic and committed hematopoietic precursors in the early mouse Yolk Sac: a comparative study between in situ electroporation and retroviral transduction

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Lécluse Yann

2007-07-01

Full Text Available Abstract Background Hematopoietic development in vertebrate embryos results from the sequential contribution of two pools of precursors independently generated. While intra-embryonic precursors harbour the features of hematopoietic stem cells (HSC, precursors formed earlier in the yolk sac (YS display limited differentiation and self-renewal potentials. The mechanisms leading to the generation of the precursors in both sites are still largely unknown, as are the molecular basis underlying their different potential. A possible approach to assess the role of candidate genes is to transfer or modulate their expression/activity in both sites. We thus designed and compared transduction protocols to target either native extra-embryonic precursors, or hematopoietic precursors. Results One transduction protocol involves transient modification of gene expression through in situ electroporation of the prospective blood islands, which allows the evolution of transfected mesodermal cells in their "normal" environment, upon organ culture. Following in situ electroporation of a GFP reporter construct into the YS cavity of embryos at post-streak (mesodermal/pre-hematopoietic precursors or early somite (hematopoietic precursors stages, high GFP expression levels as well as a good preservation of cell viability is observed in YS explants. Moreover, the erythro-myeloid progeny typical of the YS arises from GFP+ mesodermal cells or hematopoietic precursors, even if the number of targeted precursors is low. The second approach, based on retroviral transduction allows a very efficient transduction of large precursor numbers, but may only be used to target 8 dpc YS hematopoietic precursors. Again, transduced cells generate a progeny quantitatively and qualitatively similar to that of control YS. Conclusion We thus provide two protocols whose combination may allow a thorough study of both early and late events of hematopoietic development in the murine YS. In situ

Effect of selective T cell depletion of host and/or donor bone marrow on lymphopoietic repopulation, tolerance, and graft-vs-host disease in mixed allogeneic chimeras (B10 + B10.D2----B10)

International Nuclear Information System (INIS)

Ildstad, S.T.; Wren, S.M.; Bluestone, J.A.; Barbieri, S.A.; Stephany, D.; Sachs, D.H.

1986-01-01

Reconstitution of lethally irradiated mice with a mixture of T cell-depleted syngeneic plus T cell-depleted allogeneic bone marrow (B10 + B10.D2----B10) leads to the induction of mixed lymphopoietic chimerism, excellent survivals, specific in vivo transplantation tolerance to subsequent donor strain skin grafts, and specific in vitro unresponsiveness to allogeneic donor lymphoid elements as assessed by mixed lymphocyte reaction (MLR) proliferative and cell-mediated lympholysis (CML) cytotoxicity assays. When B10 recipient mice received mixed marrow inocula in which the syngeneic component had not been T cell depleted, whether or not the allogeneic donor marrow was treated, they repopulated exclusively with host-type cells, promptly rejected donor-type skin allografts, and were reactive in vitro to the allogeneic donor by CML and MLR assays. In contrast, T cell depletion of the syngeneic component of the mixed marrow inocula resulted in specific acceptance of allogeneic donor strain skin grafts. Such animals were specifically unreactive to allogeneic donor lymphoid elements in vitro by CML and MLR, but were reactive to third party. When both the syngeneic and allogeneic marrow were T cell depleted, variable percentages of host- and donor-type lymphoid elements were detected in the mixed reconstituted host. When only the syngeneic bone marrow was T cell depleted, animals repopulated exclusively with donor-type cells. Although these animals had detectable in vitro anti-host (B10) reactivity by CML and MLR and reconstituted as fully allogeneic chimeras, they exhibited excellent survival and had no in vivo evidence for graft-vs-host disease. Experiments in which untreated donor spleen cells were added to the inocula in this last group suggest that the presence of T cell-depleted syngeneic bone marrow cells diminishes graft-vs-host disease and the mortality from it

Allogenic bone grafts used at Central Hospital during June 1995 to July 1998

International Nuclear Information System (INIS)

Yolchai Jongjirasiri; Yongyudh Vajaradul

1999-01-01

Producing and using allogenic bone graft in Thailand began ten years ago. There are approximately 1,000 cases a year on orthopaedic surgery at Central Hospital. For using allogenic bone graft from the Bangkok Biomaterial Center, 66 cases were operated since June 1995. This was generated by 30 in males, 36 in females and by ages between 12-81 years old. After the operation, 43 cases had bone gap from injuries and 19 cases, fusion of spondylolisthesis and scoliosis were done. Four cases had tumor surgery, and 59 out of 66 cases had good bone union that is 89%. Delayed union happened in 6 cases only. Immune response to allogenic bone graft has not been found yet

Differential Requirements for c-Myc in Chronic Hematopoietic Hyperplasia and Acute Hematopoietic Malignancies in Pten-null Mice

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Zhang, Jun; Xiao, Yechen; Guo, Yinshi; Breslin, Peter; Zhang, Shubin; Wei, Wei; Zhang, Zhou; Zhang, Jiwang

2011-01-01

Myeloproliferative disorders (MPDs), lymphoproliferative disorders (LPDs), acute T-lymphocytic or myeloid leukemia and T-lymphocytic lymphoma were developed in inducible Pten-knockout (Pten−/−) mice. The appearance of these multiple diseases in one animal model provides an opportunity to study the pathogenesis of multiple diseases simultaneously. To study whether Myc function is required for the development of these hematopoietic disorders in Pten−/− mice, we generated inducible Pten/Myc double-knockout mice (Pten−/−/Myc−/−). By comparing the hematopoietic phenotypes of these double-knockout mice with those of Pten−/− mice, we found that both sets of animals developed MPDs and LPDs. However, none of the compound-mutant mice developed acute leukemia or lymphoma. Interestingly, in contrast to the MPDs which developed in Pten−/− mice which are dominated by granulocytes, megakaryocytes predominate in the MPDs of Pten−/−/Myc−/− mice. Our study suggests that the deregulation of PI3K/Akt signaling in Pten−/− hematopoietic cells protects these cells from apoptotic cell death, resulting in chronic proliferative disorders. But due to the differential requirement for Myc in granulocyte as compared to megakaryocyte proliferation, Myc deletion converts Pten−/− MPDs from granulocyte-dominated to megakaryocyte-dominated conditions. Myc is absolutely required for the development of acute hematopoietic malignancies. PMID:21926961

Hematopoietic tissue repair under chronic low daily dose irradiation

International Nuclear Information System (INIS)

Seed, T.M.

1994-01-01

The capacity of the hematopoietic system to repair constantly accruing cellular damage under chronic, low daily dose gamma irradiation is essential for the maintenance of a functional hematopoietic system, and, in turn, long term survival. In certain individuals, however, such continuous cycles of damage and repair provide an essential inductive environment for selected types of hematopathologies, e.g., myeloid leukemia (ML). We have been studying temporal and causal relationships between hematopoietic capacity, associated repair functions, and propensities for hematologic disease in canines under variable levels of chronic radiation stress (0.3-26.3 cGy d -1 ). Results indicate that the maximum exposure rate tolerated by the hematopoietic system is highly individual-specific and is based largely on the degree to which repair capacity, and, in turn, hematopoietic restoration, is augmented under chronic exposure. In low-tolerance individuals (prone to aplastic anemia, subgroup (1), the failure to augment basic m-pair functions seemingly results in a progressive accumulation of genetic and cellular damage within vital progenitorial marrow compartments particularly marked within erythroid compartments. that results in loss of reproductive capacity and ultimately in collapse of the hematopoietic system. The high-tolerance individuals (radioaccomodated and either prone- or not prone to ML, subgroup 2 ampersand 3 appear to minimize the accumulating damage effect of daily exposures by extending repair functions, which preserves reproductive integrity and fosters regenerative hematopoietic responses. As the strength of the regenerative response manifests the extent of repair augmentation, the relatively strong response of high- tolerance individuals progressing to patent ML suggests an insufficiency of repair quality rather than repair quantity

Hematopoietic (stem) cell development — how divergent are the roads taken?

NARCIS (Netherlands)

M.-L. Kauts (Mari-Liis); C.S. Vink (Chris); E.A. Dzierzak (Elaine)

2016-01-01

textabstractThe development of the hematopoietic system during early embryonic stages occurs in spatially and temporally distinct waves. Hematopoietic stem cells (HSC), the most potent and self-renewing cells of this system, are produced in the final ‘definitive’ wave of hematopoietic cell

Hematopoietic stem cells transplant in patients with common variable immunodeficiency. Is a therapeutic option?

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Julio César Cambray-Gutiérrez

2017-02-01

Full Text Available Background: Patients with common variable immunodeficiency show higher incidence of sinopulmonary and gastrointestinal infections, as well as lymphoproliferative and autoimmune diseases. The treatment of choice is replacement therapy with human gamma-globulin. Hematopoietic stem cell transplantation is a non-conventional therapeutic modality. Clinical case: Twenty-six-year old woman with no family or hereditary history of primary immune deficiencies or consanguinity, with repeated episodes of otitis, sinusitis, gastroenteritis and bronchitis since childhood. At adolescence, she was diagnosed with common variable immunodeficiency; she was prescribed intravenous gamma-globulin, broad-spectrum antimicrobials and macrolides. At 22 years of age, she underwent hematopoietic stem cell transplantation owing to continued severe infections. At 4 months, post-transplantation she was diagnosed with hypothyroidism and ovarian insufficiency. During the following 3 years, she had no infections, but at 25 years of age she had immune thrombocytopenic purpura diagnosed, which persists together with Raynaud’s disease and upper respiratory tract persistent infections. At the moment of this report she is being treated with intravenous gamma-globulin and receiving prophylaxis with clarithromycin, without steroids or danazol. Conclusions: Given the high rate of morbidity and mortality associated and immune reconstitution failure, hematopoietic stem cell transplantation should be carefully evaluated in patients with treatment-unresponsive infections or lymphoproliferative disorders.

Achieving an early pregnancy following allogeneic uterine transplantation in a rabbit model.

Science.gov (United States)

Saso, Srdjan; Petts, Gemma; David, Anna L; Thum, Meen-Yau; Chatterjee, Jayanta; Vicente, Jose S; Marco-Jimenez, Francisco; Corless, David; Boyd, Michael; Noakes, David; Lindsay, Iain; Del Priore, Giuseppe; Ghaem-Maghami, Sadaf; Smith, J Richard

2015-02-01

Uterine transplantation (UTx) has been proposed as a treatment option for women diagnosed with absolute uterine factor infertility (AUFI). The goal of UTx remains achieving pregnancy and live birth of a healthy neonate following allogeneic UTx. Our aim was to assess whether fertility was possible following allogeneic uterine transplantation (UTx), when the recipient had demonstrated long-term survival and had been administered immunosuppression. Nine allogeneic UTx in New Zealand White rabbits were performed using a pre-determined protocol. Tacrolimus was the immunosuppressant selected. Embryos were transferred into both cornua of the sole living recipient via a mini-midline laparotomy. The pregnancy was monitored with regular reproductive profiles and serial trans-abdominal ultrasound to measure conceptus growth (gestation sac and crown rump length (CRL)). In the sole surviving doe a gestation sac was visualised on ultrasound from Day 9 (D9) after embryo transfer. Gestation sac diameter and CRL increased from D9 to D16 but by D18 the gestation sac had reduced in size. The fetus was no longer visible, suggesting fetal resorption had occurred. Subsequent scans on D22 and D25 did not demonstrate a gestation sac. Scheduled necropsy on D27 and histopathology confirmed evidence of a gravid uterus and presence of a gestational sac. A single episode of acute rejection occurred on D13. Pregnancy was achieved after rabbit allogeneic UTx but serial ultrasound suggested that fetal demise occurred prior to scheduled necropsy. The study represents only the third example of conception and pregnancy following an animal allogeneic UTx. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Allogeneic radiation chimeras induced in SPF mice

International Nuclear Information System (INIS)

Sado, Toshihiko; Kamisaku, Hitoko

1977-01-01

During the past two decades much has been learned concerning the immunobiology of bone marrow chimeras induced in experimental animals as well as in man. However, from the basic as well as clinical points of view, there still remain many unsolved questions yet to be resolved. In this presentation, we discussed some of our recent results on the immunobiology of radiation chimeras induced in specific-pathogen-free (SPF) mice. These included the following: (a) contribution of graft versus host reaction (GVHR) as well non- GVHR mediated immunologic mechanism(s) to the expression of immunologic dysfunctions observed in allogeneic and certain semiallogeneic chimeras, (b) existence of immunoregulatory mechanism as a basis for the apparent lack of immunologic reactivity (tolerance) to the host- as well as to the donor-type alloantigens in situ in successful allogeneic bone marrow chimeras, and (c) the effect of microflora of the environment on the stability of such immunoregulatory mechanisms and its possible mechanism of action. (auth.)

Hematopoietic defects in response to reduced Arhgap21

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Juliana Xavier-Ferrucio

2018-01-01

Full Text Available Arhgap21 is a member of the Rho GTPase activating protein (RhoGAP family, which function as negative regulators of Rho GTPases. Arhgap21 has been implicated in adhesion and migration of cancer cells. However, the role of Arhgap21 has never been investigated in hematopoietic cells. Herein, we evaluated functional aspects of hematopoietic stem and progenitor cells (HSPC using a haploinsufficient (Arhgap21+/− mouse. Our results show that Arhgap21+/− mice have an increased frequency of phenotypic HSC, impaired ability to form progenitor colonies in vitro and decreased hematopoietic engraftment in vivo, along with a decrease in LSK cell frequency during serial bone marrow transplantation. Arhgap21+/− hematopoietic progenitor cells have impaired adhesion and enhanced mobilization of immature LSK and myeloid progenitors. Arhgap21+/− mice also exhibit reduced erythroid commitment and differentiation, which was recapitulated in human primary cells, in which knockdown of ARHGAP21 in CMP and MEP resulted in decreased erythroid commitment. Finally, we observed enhanced RhoC activity in the bone marrow cells of Arhgap21+/− mice, indicating that Arhgap21 functions in hematopoiesis may be at least partially mediated by RhoC inactivation. Keywords: Arhgap21, Hematopoiesis, Erythroid cells, Hematopoietic stem and progenitor cells, Fate decision

Induction of tolerance and prolongation of islet allograft survival by syngeneic hematopoietic stem cell transplantation in mice.

Science.gov (United States)

Yang, Shi-feng; Xue, Wu-jun; Lu, Wan-hong; Xie, Li-yi; Yin, Ai-ping; Zheng, Jin; Sun, Ji-ping; Li, Yang

2015-10-01

Syngeneic or autologous hematopoietic stem cells transplantation (HSCT) has been proposed to treat autoimmune diseases because of its immunosuppressive and immunomodulatory effects, which can also contribute to posttransplant antirejection therapy. In this study, we explored the tolerogenic effect of syngeneic HSCT on prolonging islet allograft survival. C57BL/6 mice received syngeneic HSCT plus preconditioning with sublethal irradiation. Then islets of BALB/c mice were transplanted into the renal subcapsular of C57BL/6 mice after chemically induced into diabetes. HSCT mice exhibited improved islet allograft survival and increased serum insulin compared to control mice. Islet allografts of HSCT mice displayed lower level lymphocyte infiltration and stronger insulin staining than control mice. T cells of HSCT mice proliferated poorly in response to allogeneic splenocytes compared to control mice. Mice appeared reversed interferon-γ (IFN-γ)/interleukin-4 (IL-4) ratio to a Th2 immune deviation after syngeneic HSCT. The percentage of CD8(+) T cells was lower, while percentage of CD4(+)CD25(+)Foxp3(+) T regulatory cells (Tregs) was higher in HSCT mice than control mice. HSCT mice showed higher percentage of CTLA-4(+) T cells and expression of CTLA-4 mRNA than control mice. Targeting of CTLA-4 by intraperitoneal injection of anti-CTLA-4 mAb abrogated the effect of syngeneic HSCT on prolonging islet allograft survival, inhibiting activity of T cells in response to alloantigen, promoting Th1 to Th2 immune deviation and up regulating CD4(+)CD25(+)Foxp3(+) Tregs. Syngeneic HSCT plus preconditioning of sublethal irradiation induces tolerance and improves islet allograft survival in fully mismatched mice model. Th1 to Th2 immune deviation, increased CD4(+)CD25(+)Foxp3(+) Tregs and up-regulation of CTLA-4 maybe contribute to the tolerogenic effect induced by syngeneic HSCT. Copyright © 2015 Elsevier B.V. All rights reserved.

Preoperative Acute Normovolemic Hemodilution for Minimizing Allogeneic Blood Transfusion: A Meta-Analysis.

Science.gov (United States)

Zhou, Xuelong; Zhang, Chenjing; Wang, Yin; Yu, Lina; Yan, Min

2015-12-01

Previous studies have evaluated the efficacy of preoperative acute normovolemic hemodilution (PANH) in reducing the need for allogeneic blood transfusion. However, the results to date have been controversial. In this study, we sought to reassess the efficacy and safety of PANH based on newly emerging evidence. Medline, EMBASE, ISI Web of Knowledge, and Cochrane Central Register of Controlled Trials databases were searched using the key words "hemodilution," "autotransfusion," or "hemorrhage" to retrieve all randomized controlled trials examining the benefits of PANH compared with control patients not undergoing PANH in any type of surgery. Sixty-three studies involving 3819 patients were identified. The risk of requiring an allogeneic blood transfusion and the overall volume of allogeneic red blood cell transfused during the perioperative period were reduced in the PANH group compared with the control group (relative risk, 0.74; 95% confidence interval, 0.63 to 0.88; P = 0.0006; weighted mean difference, -0.94 units; 95% confidence interval, -1.27 to -0.61 units; P transfusion. Perioperative blood loss, adverse events, and the length of hospitalization were comparable between these groups. Although these results suggest that PANH is effective in reducing allogeneic blood transfusion, we identified significant heterogeneity and publication bias, which raises concerns about the true efficacy of PANH.

Complications of hematopoietic stem transplantation: Fungal infections.

Science.gov (United States)

Omrani, Ali S; Almaghrabi, Reem S

2017-12-01

Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of invasive fungal infections, especially during the early neutropenic phase and severe graft-versus-host disease. Mold-active prophylaxis should be limited to the highest risk groups. Empiric antifungal therapy for HSCT with persistent febrile neutropenia is associated with unacceptable response rates, unnecessary antifungal therapy, increased risk of toxicity, and inflated costs. Empiric therapy should not be a substitute for detailed work up to identify the cause of fever in such patients. The improved diagnostic performance of serum biomarkers such as galactomannan and β-D-glucan, as well as polymerase chain reaction assays has allowed the development of diagnostic-driven antifungal therapy strategies for high risk patients. Diagnostic-driven approaches have resulted in reduced unnecessary antifungal exposure, improved diagnosis of invasive fungal disease, and reduced costs without increased risk of mortality. The appropriateness of diagnostic-driven antifungal strategy for individual HSCT centers depends on the availability and turnaround times for diagnostics, multidisciplinary expertise, and the local epidemiology of invasive fungal infections. Echinocandins are the treatment of choice for invasive candidiasis in most HSCT recipients. Fluconazole may be used for the treatment of invasive candidiasis in hemodynamically stable patients with no prior azole exposure. The primary treatment of choice for invasive aspergillosis is voriconazole. Alternatives include isavuconazole and lipid formulations of amphotericin. Currently available evidence does not support routine primary combination antifungal therapy for invasive aspergillosis. However, combination salvage antifungal therapy may be considered in selected patients. Therapeutic drug monitoring is recommended for the majority of HSCT recipients on itraconazole, posaconazole, or voriconazole. Copyright © 2017

Growth and development after hematopoietic cell transplant in children.

Science.gov (United States)

Sanders, J E

2008-01-01

Hematopoietic cell transplantation (HCT) following high-dose chemotherapy or chemoradiotherapy for children with malignant or nonmalignant hematologic disorders has resulted in an increasing number of long-term disease-free survivors. The preparative regimens include high doses of alkylating agents, such as CY with or without BU, and may include TBI. These agents impact the neuroendocrine system in growing children and their subsequent growth and development. Children receiving high-dose CY or BUCY have normal thyroid function, but those who receive TBI-containing regimens may develop thyroid function abnormalities. Growth is not impacted by chemotherapy-only preparative regimens, but TBI is likely to result in growth hormone deficiency and decreased growth rates that need to be treated with synthetic growth hormone therapy. Children who receive high-dose CY-only have normal development through puberty, whereas those who receive BUCY have a high incidence of delayed pubertal development. Following fractionated TBI preparative regimens, approximately half of the patients have normal pubertal development. These data demonstrate that the growth and development problems after HCT are dependent upon the preparative regimen received. All children should be followed for years after HCT for detection of growth and development abnormalities that are treatable with appropriate hormone therapy.

Allogeneic cellular immunotherapy for chronic B-cell leukemia

NARCIS (Netherlands)

Hoogendoorn, Mels

2007-01-01

Allogeneic stem cell transplantation (SCT) following reduced-intensity conditioning (RIC) as treatment modality has curative potential in patients suffering from chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL), illustrating susceptibility of these leukemic cells for the

Fetal liver stromal cells promote hematopoietic cell expansion

International Nuclear Information System (INIS)

Zhou, Kun; Hu, Caihong; Zhou, Zhigang; Huang, Lifang; Liu, Wenli; Sun, Hanying

2009-01-01

Future application of hematopoietic stem and progenitor cells (HSPCs) in clinical therapies largely depends on their successful expansion in vitro. Fetal liver (FL) is a unique hematopoietic organ in which hematopoietic cells markedly expand in number, but the mechanisms involved remain unclear. Stromal cells (StroCs) have been suggested to provide a suitable cellular environment for in vitro expansion of HSPCs. In this study, murine StroCs derived from FL at E14.5, with a high level of Sonic hedgehog (Shh) and Wnt expression, were found to have an increased ability to support the proliferation of HSPCs. This effect was inhibited by blocking Shh signaling. Supplementation with soluble Shh-N promoted the proliferation of hematopoietic cells by activating Wnt signaling. Our findings suggest that FL-derived StroCs support proliferation of HSPCs via Shh inducing an autocrine Wnt signaling loop. The use of FL-derived StroCs and regulation of the Shh pathway might further enhance HPSC expansion.

Utilization of Collaborative Practice Agreements between Physicians and Pharmacists as a Mechanism to Increase Capacity to Care for Hematopoietic Stem Cell Transplant Recipients

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Merten, Julianna A.; Shapiro, Jamie F.; Gulbis, Alison M.; Rao, Kamakshi V.; Bubalo, Joseph; Lanum, Scott; Engemann, Ashley Morris; Shayani, Sepideh; Williams, Casey; Leather, Helen; Walsh-Chocolaad, Tracey

2013-01-01

Survival following hematopoietic stem cell transplantation (HSCT) has improved and the number of allogeneic HSCTs performed annually in the United States is expected to reach 10,000 by 2015. The National Marrow Donor Program created the System Capacity Initiative to formulate mechanisms to care for the growing number of HSCT recipients. One proposed method to increase capacity is utilization of pharmacists to manage drug therapy via collaborative practice agreements (CPAs). Pharmacists have managed drug therapy in oncology patients with CPAs for decades; however, there are limited HSCT centers that employ this practice. Engaging in collaborative practice and billing agreements with credentialed pharmacists to manage therapeutic drug monitoring, chronic medical conditions and supportive care in HSCT recipients may be cost-effective and enable physicians to spend more time on new or more complex patients. The goal of this paper is to provide a framework for implementation of a CPA and address how it may improve HSCT program capacity. PMID:23419976

Allogeneic mesenchymal precursor cells (MPCs): an innovative approach to treating advanced heart failure.

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Westerdahl, Daniel E; Chang, David H; Hamilton, Michele A; Nakamura, Mamoo; Henry, Timothy D

2016-09-01

Over 37 million people worldwide are living with Heart Failure (HF). Advancements in medical therapy have improved mortality primarily by slowing the progression of left ventricular dysfunction and debilitating symptoms. Ultimately, heart transplantation, durable mechanical circulatory support (MCS), or palliative care are the only options for patients with end-stage HF. Regenerative therapies offer an innovative approach, focused on reversing myocardial dysfunction and restoring healthy myocardial tissue. Initial clinical trials using autologous (self-donated) bone marrow mononuclear cells (BMMCs) demonstrated excellent safety, but only modest efficacy. Challenges with autologous stem cells include reduced quality and efficacy with increased patient age. The use of allogeneic mesenchymal precursor cells (MPCs) offers an "off the shelf" therapy, with consistent potency and less variability than autologous cells. Preclinical and initial clinical trials with allogeneic MPCs have been encouraging, providing the support for a large ongoing Phase III trial-DREAM-HF. We provide a comprehensive review of preclinical and clinical data supporting MPCs as a therapeutic option for HF patients. The current data suggest allogeneic MPCs are a promising therapy for HF patients. The results of DREAM-HF will determine whether allogeneic MPCs can decrease major adverse clinical events (MACE) in advanced HF patients.

Outcomes of haploidentical stem cell transplantation for chronic lymphocytic leukemia: a retrospective study on behalf of the chronic malignancies working party of the EBMT.

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van Gorkom, Gwendolyn; van Gelder, Michel; Eikema, Dirk-Jan; Blok, Henric-Jan; van Lint, M T; Koc, Yener; Ciceri, Fabio; Beelen, Dietrich; Chevallier, Patrice; Selleslag, Dominik; Blaise, Didier; Foá, Roberto; Corradini, Paolo; Castagna, Luca; Moreno, Carol; Solano, Carlos; Müller, Lutz Peter; Tischer, Johanna; Hilgendorf, Inken; Hallek, Michael; Bittenbring, Jörg; Theobald, Matthias; Schetelig, Johannes; Kröger, Nicolaus

2018-03-01

Allogeneic hematopoietic stem cell transplantation (HCT) may result in long-term disease control in high-risk chronic lymphocytic leukemia (CLL). Recently, haploidentical HCT is gaining interest because of better outcomes with post-transplantation cyclophosphamide (PTCY). We analyzed patients with CLL who received an allogeneic HCT with a haploidentical donor and whose data were available in the EBMT registry. In total 117 patients (74% males) were included; 38% received PTCY as GVHD prophylaxis. For the whole study cohort OS at 2 and 5 yrs was 48 and 38%, respectively. PFS at 2 and 5 yrs was 38 and 31%, respectively. Cumulative incidence (CI) of NRM in the whole group at 2 and 5 years were 40 and 44%, respectively. CI of relapse at 2 and 5 yrs were 22 and 26%, respectively. All outcomes were not statistically different in patients who received PTCY compared to other types of GVHD prophylaxis. In conclusion, results of haploidentical HCT in CLL seem almost identical to those with HLA-matched donors. Thereby, haploidentical HCT is an appropriate alternative in high risk CLL patients with a transplant indication but no available HLA-matched donor. Despite the use of PTCY, the CI of relapse seems not higher than observed after HLA-matched HCT.

Baseline Characteristics Predicting Very Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Patients With High Cytogenetic Risk Chronic Lymphocytic Leukemia - A Retrospective Analysis From the Chronic Malignancies Working Party of the EBMT.

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van Gelder, Michel; Ziagkos, Dimitris; de Wreede, Liesbeth; van Biezen, Anja; Dreger, Peter; Gramatzki, Martin; Stelljes, Matthias; Andersen, Niels Smedegaard; Schaap, Nicolaas; Vitek, Antonin; Beelen, Dietrich; Lindström, Vesa; Finke, Jürgen; Passweg, Jacob; Eder, Matthias; Machaczka, Maciej; Delgado, Julio; Krüger, William; Raida, Luděk; Socié, Gerard; Jindra, Pavel; Afanasyev, Boris; Wagner, Eva; Chalandon, Yves; Henseler, Anja; Schoenland, Stefan; Kröger, Nicolaus; Schetelig, Johannes

2017-10-01

Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase- and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population. Risk factors for 2-year NRM and 8-year PFS were identified in patients < 50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90.4 months) by Cox regression modeling, and predicted probabilities of NRM and PFS of 2 reference patients with favorable or unfavorable characteristics were plotted. Predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.1-2.5) and partially human leukocyte antigen (HLA)-mismatched unrelated donor (HR, 2.8; 95% CI, 1.5-5.2). The latter variable also predicted a higher risk of 2-year NRM (HR, 4.0; 95% CI, 1.4-11.6) compared with HLA-matched sibling donors. Predicted 2-year NRM and 8-year PFS of a high cytogenetic risk (del(17p) and/or del(11q)) patient in remission with a matched related donor were 12% (95% CI, 3%-22%) and 54% (95% CI, 38%-69%), and for an unresponsive patient with a female partially HLA-matched unrelated donor 37% (95% CI, 12%-62%) and 38% (95% CI, 13%-63%). Low predicted NRM and high 8-year PFS in favorable transplant high cytogenetic risk patients compares favorably with outcomes with KI or BCL2i. Taking into account the amount of uncertainty for predicting survival after alloHCT and after sequential administration of KI and BCL2i, alloHCT remains a valid option for younger patients with high cytogenetic risk chronic lymphocytic leukemia with a well-HLA-matched donor. Copyright © 2017 Elsevier Inc. All rights reserved.

Decreased mental health care utilization following a psychosocial intervention in caregivers of hematopoietic stem cell transplant patients

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Rita Ouseph

2014-03-01

Full Text Available Caregivers are known to experience increased morbidity when compared to non-caregivers. Does an intervention targeting caregiver distress affect their health care utilization? One hundred forty-eight caregivers of allogeneic hematopoietic stem cell transplant patients were randomized to treatment as usual (TAU or a psychoeducation, paced respiration, and relaxation (PEPRR intervention. Assessments of caregivers’ service utilization were collected at baseline and 1, 3, and 6 months post-transplant. During the first 30 days after patient transplant, caregiver medical and mental health professional service use decreased while support group attendance peaked. Mixed model regressions showed a significant decrease in mental health service use by the PEPRR group (P=0.001. At six months caregivers in TAU had predicted marginal probabilities of mental health services utilization over 10 times as high as caregivers in PEPRR (18.1% vs 1.5%. Groups failed to differ in medical service (P=0.861 or support group (P=0.067 use. We can conclude that participation in PEPRR compared to TAU was associated with reduced mental health service utilization. Caregiver psychosocial support services are critical to improve caregiver outcomes.

A standardized multidisciplinary approach reduces the use of allogeneic blood products in patients undergoing cardiac surgery

NARCIS (Netherlands)

van der Linden, P.; de Hert, S.; Daper, A.; Trenchant, A.; Jacobs, D.; de Boelpaepe, C.; Kimbimbi, P.; Defrance, P.; Simoens, G.

2001-01-01

PURPOSE: Individual and institutional practices remain an independent predictor factor for allogeneic blood transfusion. Application of a standardized multidisciplinary transfusion strategy should reduce the use of allogeneic blood transfusion in major surgical patients. METHODS: This prospective

Challenges around Access to and Cost of Life-Saving Medications after Allogeneic Hematopoietic Cell Transplantation for Medicare Patients.

Science.gov (United States)

Farnia, Stephanie; Ganetsky, Alex; Silver, Alicia; Hwee, Theresa; Preussler, Jaime; Griffin, Joan; Khera, Nandita

2017-08-01

Hematopoietic cell transplantation (HCT) is an expensive, medically complicated, and potentially life-threatening therapy for multiple hematologic and nonhematologic disorders with a prolonged trajectory of recovery. Similar to financial issues in other cancer treatments, adverse financial consequences of HCT are emerging as an important issue and may be associated with poor quality of life and increased distress in HCT survivors. Prescription medicine coverage for HCT for Medicare and some Medicaid beneficiaries, especially in the long-term, remains suboptimal because of inadequate payer formularies or prohibitive copays. With an increasing number of older patients undergoing HCT and improvement in the overall survival after HCT, the problem of financial burden faced by Medicare beneficiaries with fixed incomes is going to worsen. In this article, we describe the typical financial burden borne by HCT recipients based on estimated copayment amounts attached to the categories of key medications as elucidated through 2 case studies. We also suggest some possible solutions for consideration to help these patients and families get through the HCT by minimizing the financial burden from essential medications needed during the post-HCT period. Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

The Role of Toll Like Receptors in Hematopoietic Malignancies

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Darlene Monlish

2016-09-01

Full Text Available Toll-like receptors (TLRs are a family of pattern recognition receptors (PRRs that shape the innate immune system by identifying pathogen-associated molecular patterns (PAMPS and host-derived damage associated molecular patterns (DAMPS. TLRs are widely expressed on both immune cells and non-immune cells, including hematopoietic stem and progenitor cells, effector immune cell populations, and endothelial cells. In addition to their well-known role in the innate immune response to acute infection or injury, accumulating evidence supports a role for TLRs in the development of hematopoietic and other malignancies. Several hematopoietic disorders, including lymphoproliferative disorders and myelodysplastic syndromes, which possess a high risk of transformation to leukemia, have been linked to aberrant TLR signaling. Furthermore, activation of TLRs leads to the induction of a number of pro-inflammatory cytokines and chemokines, which can promote tumorigenesis by driving cell proliferation and migration and providing a favorable microenvironment for tumor cells. Beyond hematopoietic malignancies, the upregulation of a number of TLRs has been linked to promoting tumor cell survival, proliferation, and metastasis in a variety of cancers, including those of the colon, breast, and lung. This review focuses on the contribution of TLRs to hematopoietic malignancies, highlighting the known direct and indirect effects of TLR signaling on tumor cells and their microenvironment. In addition, the utility of TLR agonists and antagonists as potential therapeutics in the treatment of hematopoietic malignancies is discussed.

Development of hematopoietic stem and progenitor cells from human pluripotent stem cells.

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Chen, Tong; Wang, Fen; Wu, Mengyao; Wang, Zack Z

2015-07-01

Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), provide a new cell source for regenerative medicine, disease modeling, drug discovery, and preclinical toxicity screening. Understanding of the onset and the sequential process of hematopoietic cells from differentiated hPSCs will enable the achievement of personalized medicine and provide an in vitro platform for studying of human hematopoietic development and disease. During embryogenesis, hemogenic endothelial cells, a specified subset of endothelial cells in embryonic endothelium, are the primary source of multipotent hematopoietic stem cells. In this review, we discuss current status in the generation of multipotent hematopoietic stem and progenitor cells from hPSCs via hemogenic endothelial cells. We also review the achievements in direct reprogramming from non-hematopoietic cells to hematopoietic stem and progenitor cells. Further characterization of hematopoietic differentiation in hPSCs will improve our understanding of blood development and expedite the development of hPSC-derived blood products for therapeutic purpose. © 2015 Wiley Periodicals, Inc.

Current status of grafts and implants in rhinoplasty: Part II. Homologous grafts and allogenic implants.

Science.gov (United States)

Sajjadian, Ali; Naghshineh, Nima; Rubinstein, Roee

2010-03-01

After reading this article, the participant should be able to: 1. Understand the challenges in restoring volume and structural integrity in rhinoplasty. 2. Identify the appropriate uses of various homologous grafts and allogenic implants in reconstruction, including: (a) freeze-dried acellular allogenic cadaveric dermis grafts, (b) irradiated cartilage grafts, (c) hydroxyapatite mineral matrix, (d) silicone implants, (e) high-density polyethylene implants, (f) polytetrafluoroethylene implants, and (g) injectable filler materials. 3. Identify the advantages and disadvantages of each of these biomaterials. 4. Understand the specific techniques that may aid in the use these grafts or implants. This review specifically addresses the use of homologous grafts and allogenic implants in rhinoplasty. It is important to stress that autologous materials remain the preferred graft material for use in rhinoplasty, owing to their high biocompatibility and low risk of infection and extrusion. However, concerns of donor-site morbidity, graft availability, and graft resorption have motivated the development and use of homologous and allogenic implants.

Hematopoiesis and hematopoietic organs in arthropods.

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Grigorian, Melina; Hartenstein, Volker

2013-03-01

Hemocytes (blood cells) are motile cells that move throughout the extracellular space and that exist in all clades of the animal kingdom. Hemocytes play an important role in shaping the extracellular environment and in the immune response. Developmentally, hemocytes are closely related to the epithelial cells lining the vascular system (endothelia) and the body cavity (mesothelia). In vertebrates and insects, common progenitors, called hemangioblasts, give rise to the endothelia and blood cells. In the adult animal, many differentiated hemocytes seem to retain the ability to proliferate; however, in most cases investigated closely, the bulk of hemocyte proliferation takes place in specialized hematopoietic organs. Hematopoietic organs provide an environment where undifferentiated blood stem cells are able to self-renew, and at the same time generate offspring that differentiate into different blood cell types. Hematopoiesis in vertebrates, taking place in the bone marrow, has been subject to intensive research by immunologists and stem cell biologists. Much less is known about blood cell formation in invertebrate animals. In this review, we will survey structural and functional properties of invertebrate hematopoietic organs, with a main focus on insects and other arthropod taxa. We will then discuss similarities, at the molecular and structural level, that are apparent when comparing the development of blood cells in hematopoietic organs of vertebrates and arthropods. Our comparative review is intended to elucidate aspects of the biology of blood stem cells that are more easily missed when focusing on one or a few model species.

Allogeneic radiation chimeras respond to TNP-modified donor and host targets

International Nuclear Information System (INIS)

Lattime, E.C.; Gershon, H.E.; Stutman, O.

1980-01-01

Tolerance to major histocompatibility antigens as well as the ability to mount a cytotoxic response to hapten-modified cells of bone marrow donor and host origin was studied in allogeneic radiation chimeras. Lethally irradiated (C57BL/6 x DBA/2)F1 hosts reconstituted with anti-Thy 1.2 + C-treated bone marrow from (C57BL/6 x CBA)F1 mice showed tolerance to the MHC antigens of the three parental strains as measured by MLC and CML assay. The chimeras responded normally to unrelated allogeneic cells. Chimeric animals generated a cytotoxic response to hapten-modified cells of both donor (CBA) and host (DBA/2) haplotypes, as well as to C57BL/6, demonstrating that tolerance to the hapten-presenting host haplotype is sufficient to allow a cytotoxic antihapten response, and that processing through a semiallogeneic host environment does not affect the ability to generate a response to hapten in conjunction with self-determinants. Chimeras failed to mount a cytotoxic response to hapten presented on nontolerated allogeneic spleen cells

Effect of donor STAT4 polymorphism rs7574865 on clinical outcomes of pediatric acute leukemia patients after hematopoietic stem cell transplant.

Science.gov (United States)

Wun, Cheng Mun; Piao, Zhe; Hong, Kyung Taek; Choi, Jung Yoon; Hong, Che Ry; Park, June Dong; Park, Kyung Duk; Shin, Hee Young; Kang, Hyoung Jin

2017-02-01

STAT4 polymorphism, rs7574865 is linked to various autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Its T minor allele is associated with higher STAT4 mRNA and protein expression, indicating a stronger skewed immune response than the norm. Although widely studied in autoimmune disease patients and the general population, its effect on immunocompromised subjects is still unknown. Especially in situations, i.e. post-hematopoietic stem cell transplantation (post-HSCT), where control of the immune response is crucial. Hence, this study investigates if the presence of the T minor allele in donors would affect immunological response and clinical outcomes post-HSCT. Samples from 161 pediatric patients who underwent allogeneic HSCT for acute leukemia and showed complete chimerism by donor cells were obtained. Six clinical outcomes were investigated; hepatic veno-occlusive disease, acute graft-vs-host disease, chronic graft-vs-host disease, cytomegalovirus (CMV) infection, relapse and overall survival. The TT genotype was found to be significant in the occurrence of CMV infection (P=0.049), showing higher incidence of CMV infection compared to the others. Multivariate analysis confirmed that association of the TT genotype is independent from other variables in CMV infection occurrence (P=0.010). This is the first study on STAT4 polymorphism rs7574865 in allogeneic HSCT as well as immunocompromised patients. As the TT genotype is associated with autoimmune diseases, our results seem at a paradox with current evidence hinting at a different role of STAT4 in normal circumstances versus immunocompromised patients. Further investigation is needed to elicit the reason behind this and discover novel applications for better post-transplant outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

[Role of stem cell transplantation in treatment of primary cutaneous T‑cell lymphoma].

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Stranzenbach, R; Theurich, S; Schlaak, M

2017-09-01

Within the heterogeneous group of cutaneous T‑cell lymphomas (CTCL) the therapeutic options for advanced and progressive forms are particularly limited. The therapeutic value of hematopoietic stem cell transplantation in CTCL was analyzed. A literature search using the keywords "hematopoietic stem cell transplantation" and "cutaneous T‑cell lymphoma" was performed in PubMed. Studies between 1990 and 2017 were taken into account. The studies identified were analyzed for relevance and being up to date. After reviewing the currently available literature no prospective randomized studies were found. Wu et al. showed a superiority of allogeneic transplantation in a comparison of autologous and allogeneic stem cell transplantation for cutaneous lymphoma. The graft-versus-lymphoma effect plays a significant role in a prolonged progression-free survival after allogeneic transplantation. By using a non-myeloablative conditioning regimen, stem cell transplantation can also be an option for elderly patients. The most extensive long-term data after allogeneic stem cell transplantation were reported by Duarte et al. in 2014. Autologous stem cell transplantation does not currently represent a therapeutic option, whereas allogeneic stem cell transplantation for advanced cutaneous T‑cell lymphoma, using a non-myeloablative conditioning scheme, does represent a therapeutic option. However, there is no consensus on the appropriate patients and the right timing. Morbidity and mortality of complications should be taken into account. Thus, this procedure is currently subject to an individual case decision.

Mobilization of hematopoietic stem and progenitor cells in mice

NARCIS (Netherlands)

Robinson, Simon N; van Os, Ronald P; Bunting, Kevin

2008-01-01

Animal models have added significantly to our understanding of the mechanism(s) of hematopoietic stem and progenitor cell (HSPC) mobilization. Such models suggest that changes in the interaction between the HSPC and the hematopoietic microenvironmental 'niche' (cellular and extracellular components)

Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion

Science.gov (United States)

2017-09-01

AWARD NUMBER: W81XWH-15-1-0234 TITLE: Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion PRINCIPAL...14/2017 4. TITLE AND SUBTITLE Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion 5a. CONTRACT NUMBER 5b. GRANT...tolerance induction of all types of allografts. In this study, we investigate whether co-infusion of amnion- derived multipotent progenitor (AMP) cells

Clinical and immunologic outcome of patients with cartilage hair hypoplasia after hematopoietic stem cell transplantation.

Science.gov (United States)

Bordon, Victoria; Gennery, Andrew R; Slatter, Mary A; Vandecruys, Els; Laureys, Genevieve; Veys, Paul; Qasim, Waseem; Waseem, Qasim; Friedrich, Wilhelm; Wulfraat, Nico M; Scherer, Franziska; Cant, Andrew J; Fischer, Alain; Cavazzana-Calvo, Marina; Cavazanna-Calvo, Marina; Bredius, Robbert G M; Notarangelo, Luigi D; Mazzolari, Evelina; Neven, Benedicte; Güngör, Tayfun; Tayfun, Güngör

2010-07-08

Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disease caused by mutations in the RMRP gene. Beside dwarfism, CHH has a wide spectrum of clinical manifestations including variable grades of combined immunodeficiency, autoimmune complications, and malignancies. Previous reports in single CHH patients with significant immunodeficiencies have demonstrated that allogeneic hematopoietic stem cell transplantation (HSCT) is an effective treatment for the severe immunodeficiency, while growth failure remains unaffected. Because long-term experience in larger cohorts of CHH patients after HSCT is currently unreported, we performed a European collaborative survey reporting on 16 patients with CHH and immunodeficiency who underwent HSCT. Immune dysregulation, lymphoid malignancy, and autoimmunity were important features in this cohort. Thirteen patients were transplanted in early childhood ( approximately 2.5 years). The other 3 patients were transplanted at adolescent age. Of 16 patients, 10 (62.5%) were long-term survivors, with a median follow-up of 7 years. T-lymphocyte numbers and function have normalized, and autoimmunity has resolved in all survivors. HSCT should be considered in CHH patients with severe immunodeficiency/autoimmunity, before the development of severe infections, major organ damage, or malignancy might jeopardize the outcome of HSCT and the quality of life in these patients.

Total Body Irradiation for Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia

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Chung, Su Mi; Choi, Ihl Bohng; Kang, Ki Mun; Kim, In Ah; Shinn, Kyung Sub; Kim, Choon Choo; Kim, Dong Jip [Catholic University College of Medicine, Seoul (Korea, Republic of)

1994-06-15

Between July 1987 and December 1992, we treated 22 patients with chromic myelogenous leukemia; 14 in the chronic phase and 8 with more advanced disease. All were received with allogeneic bone marrow transplantation from HLA-identical sibling donors after a total body irradiation (TBI) cyclophosphamide conditioning regimen. Patients were non-randomly assigned to either 1200 cGy/6 fractions/3 days (6 patients) or 1320 cGy/8 fractions/4 days (16 patients) by dose of TBI. Of the 22 patients, 8 were prepared with cyclophosphamide alone, 14 were conditioned with additional adriamycin or daunorubicin. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with methotrexate. The actuarial survival and leukemic-free survival at four years were 58.5% and 41.2%, respectively, and the relapse rate was 36% among 22 patients. There was a statistically significant difference in survival between the patients in chronic phase and more advanced phase (76% vs 33%, p=0.05). The relapse rate of patients receiving splenectomy was higher than that of patients receiving splenic irradiation (50% vs 0%, p=0.04). We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase.

Total Body Irradiation for Allogeneic Bone Marrow Transplantation in Chronic Myelogenous Leukemia

International Nuclear Information System (INIS)

Chung, Su Mi; Choi, Ihl Bohng; Kang, Ki Mun; Kim, In Ah; Shinn, Kyung Sub; Kim, Choon Choo; Kim, Dong Jip

1994-01-01

Between July 1987 and December 1992, we treated 22 patients with chromic myelogenous leukemia; 14 in the chronic phase and 8 with more advanced disease. All were received with allogeneic bone marrow transplantation from HLA-identical sibling donors after a total body irradiation (TBI) cyclophosphamide conditioning regimen. Patients were non-randomly assigned to either 1200 cGy/6 fractions/3 days (6 patients) or 1320 cGy/8 fractions/4 days (16 patients) by dose of TBI. Of the 22 patients, 8 were prepared with cyclophosphamide alone, 14 were conditioned with additional adriamycin or daunorubicin. To prevent graft versus host disease, cyclosporine was given either alone or in conjunction with methotrexate. The actuarial survival and leukemic-free survival at four years were 58.5% and 41.2%, respectively, and the relapse rate was 36% among 22 patients. There was a statistically significant difference in survival between the patients in chronic phase and more advanced phase (76% vs 33%, p=0.05). The relapse rate of patients receiving splenectomy was higher than that of patients receiving splenic irradiation (50% vs 0%, p=0.04). We conclude that the probability of cure is highest if transplantation is performed while the patient remains in the chronic phase

Donor characteristics and hematopoietic stem cell transplantation outcome: experience of a single center in Southern Brazil

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Alessandra Paz

2018-04-01

Full Text Available Background: Hematopoietic stem cell transplantation is a curative treatment for many patients with hematological disorders. Donor–recipient genetic disparity, especially involving the human leukocyte antigen system is a critical factor for transplant outcome. Objective: To evaluate retrospectively donor characteristics and correlations with the occurrence of acute and chronic graft-versus-host disease, disease-free survival and overall survival in a Brazilian population submitted to allogeneic hematopoietic stem cell transplantation between 1994 and 2012 in a single center. Results: Three hundred and forty-seven consecutive transplantations were included. Related transplants (81.2% were significantly more common than unrelated transplants (18.7%; donor and recipient median ages were 34 (range: 1–61 and 33 (range: 3–65 years respectively with donor HLAs being matched for 333 (95.9% patients. Donor gender, cytomegalovirus status and ABO incompatibility did not influence the five-year overall survival. In univariate analyses, overall survival was negatively influenced by the presence of acute graft-versus-host disease (33% vs. 47%, respectively; p-value = 0.04, unrelated transplant (41.5% vs. 50.9%, respectively; p-value = 0.045 and donors aged over 40 years (41% vs. 52%, respectively; p-value = 0.03. Older donors were associated with a higher rate of acute (52% vs. 65.8%; p-value = 0.03 and chronic graft-versus-host disease (60% vs. 43%, respectively; p-value = 0.015. In multivariate analyses, acute graft-versus-host disease [relative risk (RR: 1.8; 95% confidence interval (CI: 1.1–29; p-value = 0.008] and older donors (RR: 1.6; 95% CI 1.11–2.24; p-value = 0.013 were associated with higher transplant-related mortality. Conclusions: In transplant patients, to have a donor older than 40 years of age seems to significantly increase the incidence of acute and chronic graft-versus-host disease and transplant-related mortality

Comparison of autogeneic and allogeneic natural killer cells immunotherapy on the clinical outcome of recurrent breast cancer

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Liang S

2017-08-01

Full Text Available Shuzhen Liang,1,2 Kecheng Xu,1,2 Lizhi Niu,1,2 Xiaohua Wang,1 Yingqing Liang,1 Mingjie Zhang,3 Jibing Chen,1,2 Mao Lin1,2 1Department of Central Laboratory, Fuda Cancer Hospital, Jinan University School of Medicine, Guangzhou, Guangdong, China; 2Fuda Cancer Institute, Guangzhou, Guangdong, China; 3Hank Bioengineering Co., Ltd, Shenzhen, China Abstract: In the present study, we aimed to compare the clinical outcome of autogeneic and allogeneic natural killer (NK cells immunotherapy for the treatment of recurrent breast cancer. Between July 2016 and February 2017, 36 patients who met the enrollment criteria were randomly assigned to two groups: autogeneic NK cells immunotherapy group (group I, n=18 and allogeneic NK cells immunotherapy group (group II, n=18. The clinical efficacy, quality of life, immune function, circulating tumor cell (CTC level, and other related indicators were evaluated. We found that allogeneic NK cells immunotherapy has better clinical efficacy than autogeneic therapy. Moreover, allogeneic NK cells therapy improves the quality of life, reduces the number of CTCs, reduces carcinoembryonic antigen and cancer antigen 15-3 (CA15-3 expression, and significantly enhances immune function. To our knowledge, this is the first clinical trial to compare the clinical outcome of autogeneic and allogeneic NK cells immunotherapy for recurrent breast cancer. Keywords: clinical outcome, autogeneic, allogeneic, natural killer cells, recurrent breast cancer

Delayed allogeneic skin graft rejection in CD26-deficient mice.

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Zhao, Xiangli; Zhang, Kai; Daniel, Peter; Wisbrun, Natali; Fuchs, Hendrik; Fan, Hua

2018-03-23

Organ transplantation is an effective therapeutic tool for treating many terminal diseases. However, one of the biggest challenges of transplantation is determining how to achieve the long-term survival of the allogeneic or xenogeneic transplant by, for example, preventing transplant rejection. In the current study, CD26 gene-knockout mice were used to investigate the potential role of CD26/dipeptidyl peptidase-4 (DPPIV) in allogeneic skin graft rejection by tail-skin transplantation. Compared with wild-type (CD26 +/+ ) counterparts, CD26 -/- mice showed reduced necrosis of grafts and delayed graft rejection after skin transplantation. Concentrations of serum IgG, including its subclasses IgG1 and IgG2a, were significantly reduced in CD26 -/- mice during graft rejection. Moreover, after allogeneic skin transplantation, the secretion levels of the cytokines IFN-γ, IL-2, IL-6, IL-4, and IL-13 were significantly reduced, whereas the level of the cytokine IL-10 was increased in the serum of CD26 -/- mice compared with that in the serum of CD26 +/+ mice. Additionally, the concentration of IL-17 in serum and the percentage of cells secreting IL-17 in mouse peripheral blood lymphocytes (MPBLs) were both significantly lower, while the percentage of regulatory T cells (Tregs) was significantly higher in MPBLs of CD26 -/- mice than in those of CD26 +/+ mice. Furthermore, a lower percentage of CD8 + T cells in MPBLs and fewer infiltrated macrophages and T cells in graft tissues of CD26 -/- mice were detected during graft rejection. These results indicate that CD26 is involved in allogeneic skin graft rejection and provides another hint that CD26 deficiency leads to less rejection due to lower activation and proliferation of host immune cells.

Direct observation of hematopoietic progenitor chimerism in fetal freemartin cattle

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Taponen Juhani

2007-11-01

Full Text Available Abstract Background Cattle twins are well known as blood chimeras. However, chimerism in the actual hematopoietic progenitor compartment has not been directly investigated. Here, we analyzed fetal liver of chimeric freemartin cattle by combining a new anti-bovine CD34 antibody and Y-chromosome specific in situ hybridization. Results Bull-derived CD34+ cells were detected in the liver of the female sibling (freemartin at 60 days gestation. The level of bull-derived CD34+ cells was lower in the freemartin than in its male siblings. Bull (Y+ and cow hematopoietic cells often occurred in separate clusters. Around clusters of Y+CD34+ cells, Y+CD34- cells were typically observed. The thymi were also strongly chimeric at 60 days of gestation. Conclusion The fetal freemartin liver contains clusters of bull-derived hematopoietic progenitors, suggesting clonal expansion and differentiation. Even the roots of the hematopoietic system in cattle twins are thus strongly chimeric from the early stages of fetal development. However, the hematopoietic seeding of fetal liver apparently started already before the onset of functional vascular anastomosis.

In patients older than 55 years with AML in first CR, should we search for a matched unrelated donor when an old sibling donor is available?

DEFF Research Database (Denmark)

Peffault de Latour, R; Labopin, M; Cornelissen, J

2015-01-01

Allogeneic hematopoietic transplantation is increasingly used in patients aged 55 years or more with AML. The question of whether outcomes can be improved with an allele-level 8/8 HLA-matched unrelated donor (MUD) rather than an older HLA-matched sibling (MSD, more than 55 years) is still...... unanswered. We thus analyzed outcomes in 714 patients aged 55 years and older with AML in first CR (CR1) who received PBSCs after a reduced-intensity conditioning hematopoietic cell transplant from a MUD (n=310) or a MSD (n=404) in a recent period (2005-2010). The 3-year cumulative incidences (CIs) of non......-relapse mortality were 17% and 23% with MSD and MUD, respectively (P=0.17). The 3-year CIs of relapse were 37% and 30%, respectively (P=0.12), resulting in a 3-year CI of leukemia-free survival of 46% and 47%, respectively (P=0.51). The 3-year overall survival was 49% with both MSD and MUD. In conclusion, HLA...

The biochemistry of hematopoietic stem cell development.

Science.gov (United States)

Kaimakis, P; Crisan, M; Dzierzak, E

2013-02-01

The cornerstone of the adult hematopoietic system and clinical treatments for blood-related disease is the cohort of hematopoietic stem cells (HSC) that is harbored in the adult bone marrow microenvironment. Interestingly, this cohort of HSCs is generated only during a short window of developmental time. In mammalian embryos, hematopoietic progenitor and HSC generation occurs within several extra- and intraembryonic microenvironments, most notably from 'hemogenic' endothelial cells lining the major vasculature. HSCs are made through a remarkable transdifferentiation of endothelial cells to a hematopoietic fate that is long-lived and self-renewable. Recent studies are beginning to provide an understanding of the biochemical signaling pathways and transcription factors/complexes that promote their generation. The focus of this review is on the biochemistry behind the generation of these potent long-lived self-renewing stem cells of the blood system. Both the intrinsic (master transcription factors) and extrinsic regulators (morphogens and growth factors) that affect the generation, maintenance and expansion of HSCs in the embryo will be discussed. The generation of HSCs is a stepwise process involving many developmental signaling pathways, morphogens and cytokines. Pivotal hematopoietic transcription factors are required for their generation. Interestingly, whereas these factors are necessary for HSC generation, their expression in adult bone marrow HSCs is oftentimes not required. Thus, the biochemistry and molecular regulation of HSC development in the embryo are overlapping, but differ significantly from the regulation of HSCs in the adult. HSC numbers for clinical use are limiting, and despite much research into the molecular basis of HSC regulation in the adult bone marrow, no panel of growth factors, interleukins and/or morphogens has been found to sufficiently increase the number of these important stem cells. An understanding of the biochemistry of HSC

Novel therapies and their integration into allogeneic stem cell transplant for chronic lymphocytic leukemia.

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Jaglowski, Samantha M; Byrd, John C

2012-01-01

Over the past decade, numerous advances have been made in elucidating the biology of and improving treatment for chronic lymphocytic leukemia (CLL). These studies have led to identification of select CLL patient groups that generally have short survival dating from time of treatment or initial disease relapse who benefit from more aggressive therapeutic interventions. Allogeneic transplantation represents the only potentially curative option for CLL, but fully ablative regimens applied in the past have been associated with significant morbidity and mortality. Reduced-intensity preparative regimens has made application of allogeneic transplant to CLL patients much more feasible and increased the number of patients proceeding to this modality. Arising from this has been establishment of guidelines where allogeneic stem cell transplantation should be considered in CLL. Introduction of new targeted therapies with less morbidity, which can produce durable remissions has the potential to redefine where transplantation is initiated in CLL. This review briefly summarizes the field of allogeneic stem cell transplant in CLL and the interface of new therapeutics with this modality. Copyright © 2012 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

Intestinal Microbiota and Relapse After Hematopoietic-Cell Transplantation.

Science.gov (United States)

Peled, Jonathan U; Devlin, Sean M; Staffas, Anna; Lumish, Melissa; Khanin, Raya; Littmann, Eric R; Ling, Lilan; Kosuri, Satyajit; Maloy, Molly; Slingerland, John B; Ahr, Katya F; Porosnicu Rodriguez, Kori A; Shono, Yusuke; Slingerland, Ann E; Docampo, Melissa D; Sung, Anthony D; Weber, Daniela; Alousi, Amin M; Gyurkocza, Boglarka; Ponce, Doris M; Barker, Juliet N; Perales, Miguel-Angel; Giralt, Sergio A; Taur, Ying; Pamer, Eric G; Jenq, Robert R; van den Brink, Marcel R M

2017-05-20

Purpose The major causes of mortality after allogeneic hematopoietic-cell transplantation (allo-HCT) are relapse, graft-versus-host disease (GVHD), and infection. We have reported previously that alterations in the intestinal flora are associated with GVHD, bacteremia, and reduced overall survival after allo-HCT. Because intestinal bacteria are potent modulators of systemic immune responses, including antitumor effects, we hypothesized that components of the intestinal flora could be associated with relapse after allo-HCT. Methods The intestinal microbiota of 541 patients admitted for allo-HCT was profiled by means of 16S ribosomal sequencing of prospectively collected stool samples. We examined the relationship between abundance of microbiota species or groups of related species and relapse/progression of disease during 2 years of follow-up time after allo-HCT by using cause-specific proportional hazards in a retrospective discovery-validation cohort study. Results Higher abundance of a bacterial group composed mostly of Eubacterium limosum in the validation set was associated with a decreased risk of relapse/progression of disease (hazard ratio [HR], 0.82 per 10-fold increase in abundance; 95% CI, 0.71 to 0.95; P = .009). When the patients were categorized according to presence or absence of this bacterial group, presence also was associated with less relapse/progression of disease (HR, 0.52; 95% CI, 0.31 to 0.87; P = .01). The 2-year cumulative incidences of relapse/progression among patients with and without this group of bacteria were 19.8% and 33.8%, respectively. These associations remained significant in multivariable models and were strongest among recipients of T-cell-replete allografts. Conclusion We found associations between the abundance of a group of bacteria in the intestinal flora and relapse/progression of disease after allo-HCT. These might serve as potential biomarkers or therapeutic targets to prevent relapse and improve survival after allo-HCT.

Microarray Gene Expression Analysis to Evaluate Cell Type Specific Expression of Targets Relevant for Immunotherapy of Hematological Malignancies.

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M J Pont

Full Text Available Cellular immunotherapy has proven to be effective in the treatment of hematological cancers by donor lymphocyte infusion after allogeneic hematopoietic stem cell transplantation and more recently by targeted therapy with chimeric antigen or T-cell receptor-engineered T cells. However, dependent on the tissue distribution of the antigens that are targeted, anti-tumor responses can be accompanied by undesired side effects. Therefore, detailed tissue distribution analysis is essential to estimate potential efficacy and toxicity of candidate targets for immunotherapy of hematological malignancies. We performed microarray gene expression analysis of hematological malignancies of different origins, healthy hematopoietic cells and various non-hematopoietic cell types from organs that are often targeted in detrimental immune responses after allogeneic stem cell transplantation leading to graft-versus-host disease. Non-hematopoietic cells were also cultured in the presence of IFN-γ to analyze gene expression under inflammatory circumstances. Gene expression was investigated by Illumina HT12.0 microarrays and quality control analysis was performed to confirm the cell-type origin and exclude contamination of non-hematopoietic cell samples with peripheral blood cells. Microarray data were validated by quantitative RT-PCR showing strong correlations between both platforms. Detailed gene expression profiles were generated for various minor histocompatibility antigens and B-cell surface antigens to illustrate the value of the microarray dataset to estimate efficacy and toxicity of candidate targets for immunotherapy. In conclusion, our microarray database provides a relevant platform to analyze and select candidate antigens with hematopoietic (lineage-restricted expression as potential targets for immunotherapy of hematological cancers.

Single-centre experience of allogeneic haemopoietic stem cell ...

African Journals Online (AJOL)

Allogeneic haemopoietic stem cell transplant (Allo-HSCT) is used to treat a broad but well-defined range of paediatric conditions, most frequently in paediatric oncology for treatment intensification or salvage therapy for acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL). Allo-HSCT is also indicated in.

Neural Crossroads in the Hematopoietic Stem Cell Niche.

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Agarwala, Sobhika; Tamplin, Owen J

2018-05-29

The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

On the Feasibility of Utilizing Allogeneic Bone Blocks for Atrophic Maxillary Augmentation

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Alberto Monje

2014-01-01

Full Text Available Purpose. This systematic review was aimed at assessing the feasibility by means of survival rate, histologic analysis, and causes of failure of allogeneic block grafts for augmenting the atrophic maxilla. Material and Methods. A literature search was conducted by one reviewer in several databases. Articles were included in this systematic review if they were human clinical trials in which outcomes of allogeneic bone block grafts were studied by means of survival rate. In addition other factors were extracted in order to assess their influence upon graft failure. Results. Fifteen articles fulfilled the inclusion criteria and subsequently were analyzed in this systematic review. A total of 361 block grafts could be followed 4 to 9 months after the surgery, of which 9 (2.4% failed within 1 month to 2 months after the surgery. Additionally, a weighed mean 4.79 mm (95% CI: 4.51–5.08 horizontal bone gain was computed from 119 grafted sites in 5 studies. Regarding implant cumulative survival rate, the weighed mean was 96.9% (95% CI: 92.8–98.7%, computed from 228 implants over a mean follow-up period of 23.9 months. Histologic analysis showed that allogeneic block grafts behave differently in the early stages of healing when compared to autogenous block grafts. Conclusion. Atrophied maxillary reconstruction with allogeneic bone block grafts represents a reliable option as shown by low block graft failure rate, minimal resorption, and high implant survival rate.

Antibody responses in allogeneic radiation chimeras

International Nuclear Information System (INIS)

Coico, R.F.

1982-01-01

The construction of long-lived allogeneic radiation chimeras, free of graft-versus-host disease, has been achieved using serologic elimination of Thy 1 + cells from donor bone marrow. Humoral immune function was not restored in these animals as evidenced by lack of primary antibody responses to a T cell-dependent antigen, namely, sheep erythrocytes (SRBC) both in vivo and in vitro. No evidence for a suppressor cell-mediated mechanism was found. Using separated chimera spleen cell populations and specific helper cell soluble mediators, the functional capabilities of chimera B cells, T cells, and macrophages were assessed. These findings suggested that the failure of chimeras to produce antibody is not the result of impaired B cell, T cell, or macrophage function, but rather, that it is due to ineffective cellular interactions. Physiologic cellular interactions depend upon the sharing of major histocompatibility complex (MHC) determinants between interacting cells. However, the self-recognition repertoire of developing T cells may be influenced by the environment which these cells differentiate such that they learn to recognize host MHC determinants as self. These findings support the interpretation that the immunologic hyporeactivity of allogeneic bone marrow chimeras reflects the role of the host environment in restricting the interactive capabilities of donor-derived cells

Will Post-Transplantation Cell Therapies for Pediatric Patients Become Standard of Care?

NARCIS (Netherlands)

Lankester, Arjan C.; Locatelli, Franco; Bader, Peter; Rettinger, Eva; Egeler, Maarten; Katewa, Satyendra; Pulsipher, Michael A.; Nierkens, Stefan; Schultz, Kirk; Handgretinger, Rupert; Grupp, Stephan A.; Boelens, Jaap Jan; Bollard, Catherine M.

Although allogeneic hematopoietic stem cell transplantation (HSCT) is a curative approach for many pediatric patients with hematologic malignancies and some nonmalignant disorders, some critical obstacles remain to be overcome, including relapse, engraftment failure, graft-versus-host disease

Effects of nonpharmacological interventions on reducing fatigue after hematopoietic stem cell transplantation

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Hedayat Jafari

2017-01-01

Full Text Available Fatigue is one of the main complaints of patients undergoing allogeneic and autologous hematopoietic stem cell transplantation (HSCT. Since nonpharmacological interventions are cost-effective and causes fewer complications, this study aimed to review the studies performed on the effects of nonpharmacological interventions on fatigue in patients undergoing HSCT during September 2016. MEDLINE, CINAHL, Scientific Information Database, IranMedex, PubMed, ScienceDirect, Scopus, Magiran, and IRANDOC databases were searched using Persian and English keywords. A total of 1217 articles were retrieved, 21 of which were used in this study. Exercise is known as an effective intervention in alleviating physical and mental problems of patients undergoing stem cell transplant. This review-based study showed that nonpharmacological methods such as exercise might be effective in decreasing fatigue in patients undergoing stem cell transplant. There is a multitude of studies on some of the complementary and alternative therapy methods, such as music therapy, yoga, relaxation, and therapeutic massage. These studies demonstrated the positive effects of the aforementioned therapies on reduction of fatigue in patients undergoing stem cell transplantation. All the investigated methods in this study were nonaggressive, safe, and cost-effective and could be used along with common treatments or even as an alternative for pharmacological treatments for the reduction, or elimination of fatigue in patients undergoing stem cell transplantation. Given the advantages of complementary and alternative medicine, conducting further studies on this issue is recommended to reduce fatigue in patients after stem cell transplantation.

Instruction of hematopoietic lineage choice by cytokine signaling

Energy Technology Data Exchange (ETDEWEB)

Endele, Max; Etzrodt, Martin; Schroeder, Timm, E-mail: timm.schroeder@bsse.ethz.ch

2014-12-10

Hematopoiesis is the cumulative consequence of finely tuned signaling pathways activated through extrinsic factors, such as local niche signals and systemic hematopoietic cytokines. Whether extrinsic factors actively instruct the lineage choice of hematopoietic stem and progenitor cells or are only selectively allowing survival and proliferation of already intrinsically lineage-committed cells has been debated over decades. Recent results demonstrated that cytokines can instruct lineage choice. However, the precise function of individual cytokine-triggered signaling molecules in inducing cellular events like proliferation, lineage choice, and differentiation remains largely elusive. Signal transduction pathways activated by different cytokine receptors are highly overlapping, but support the production of distinct hematopoietic lineages. Cellular context, signaling dynamics, and the crosstalk of different signaling pathways determine the cellular response of a given extrinsic signal. New tools to manipulate and continuously quantify signaling events at the single cell level are therefore required to thoroughly interrogate how dynamic signaling networks yield a specific cellular response. - Highlights: • Recent studies provided definite proof for lineage-instructive action of cytokines. • Signaling pathways involved in hematopoietic lineage instruction remain elusive. • New tools are emerging to quantitatively study dynamic signaling networks over time.

Image-guided total-marrow irradiation using helical tomotherapy in patients with multiple myeloma and acute leukemia undergoing hematopoietic cell transplantation.

Science.gov (United States)

Wong, Jeffrey Y C; Rosenthal, Joseph; Liu, An; Schultheiss, Timothy; Forman, Stephen; Somlo, George

2009-01-01

Total-body irradiation (TBI) has an important role in patients undergoing hematopoietic cell transplantation (HCT), but is associated with significant toxicities. Targeted TBI using helical tomotherapy results in reduced doses to normal organs, which predicts for reduced toxicities compared with standard TBI. Thirteen patients with multiple myeloma were treated in an autologous tandem transplantation Phase I trial with high-dose melphalan, followed 6 weeks later by total-marrow irradiation (TMI) to skeletal bone. Dose levels were 10, 12, 14, and 16 Gy at 2 Gy daily/twice daily. In a separate allogeneic HCT trial, 8 patients (5 with acute myelogenous leukemia, 1 with acute lymphoblastic leukemia, 1 with non-Hodgkin's lymphoma, and 1 with multiple myeloma) were treated with TMI plus total lymphoid irradiation plus splenic radiotherapy to 12 Gy (1.5 Gy twice daily) combined with fludarabine/melphalan. For the 13 patients in the tandem autologous HCT trial, median age was 54 years (range, 42-66 years). Median organ doses were 15-65% that of the gross target volume dose. Primarily Grades 1-2 acute toxicities were observed. Six patients reported no vomiting; 9 patients, no mucositis; 6 patients, no fatigue; and 8 patients, no diarrhea. For the 8 patients in the allogeneic HCT trial, median age was 52 years (range, 24-61 years). Grades 2-3 nausea, vomiting, mucositis, and diarrhea were observed. In both trials, no Grade 4 nonhematologic toxicity was observed, and all patients underwent successful engraftment. This study shows that TMI using helical tomotherapy is clinically feasible. The reduced acute toxicities observed compare favorably with those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI-containing regimens to patients unable to tolerate standard approaches.

Image-Guided Total-Marrow Irradiation Using Helical Tomotherapy in Patients With Multiple Myeloma and Acute Leukemia Undergoing Hematopoietic Cell Transplantation

International Nuclear Information System (INIS)

Wong, Jeffrey Y.C.; Rosenthal, Joseph; Liu An; Schultheiss, Timothy; Forman, Stephen; Somlo, George

2009-01-01

Purpose: Total-body irradiation (TBI) has an important role in patients undergoing hematopoietic cell transplantation (HCT), but is associated with significant toxicities. Targeted TBI using helical tomotherapy results in reduced doses to normal organs, which predicts for reduced toxicities compared with standard TBI. Methods and Materials: Thirteen patients with multiple myeloma were treated in an autologous tandem transplantation Phase I trial with high-dose melphalan, followed 6 weeks later by total-marrow irradiation (TMI) to skeletal bone. Dose levels were 10, 12, 14, and 16 Gy at 2 Gy daily/twice daily. In a separate allogeneic HCT trial, 8 patients (5 with acute myelogenous leukemia, 1 with acute lymphoblastic leukemia, 1 with non-Hodgkin's lymphoma, and 1 with multiple myeloma) were treated with TMI plus total lymphoid irradiation plus splenic radiotherapy to 12 Gy (1.5 Gy twice daily) combined with fludarabine/melphalan. Results: For the 13 patients in the tandem autologous HCT trial, median age was 54 years (range, 42-66 years). Median organ doses were 15-65% that of the gross target volume dose. Primarily Grades 1-2 acute toxicities were observed. Six patients reported no vomiting; 9 patients, no mucositis; 6 patients, no fatigue; and 8 patients, no diarrhea. For the 8 patients in the allogeneic HCT trial, median age was 52 years (range, 24-61 years). Grades 2-3 nausea, vomiting, mucositis, and diarrhea were observed. In both trials, no Grade 4 nonhematologic toxicity was observed, and all patients underwent successful engraftment. Conclusions: This study shows that TMI using helical tomotherapy is clinically feasible. The reduced acute toxicities observed compare favorably with those seen with standard TBI. Initial results are encouraging and warrant further evaluation as a method to dose escalate with acceptable toxicity or to offer TBI-containing regimens to patients unable to tolerate standard approaches

Alternative allogeneic donor sources for transplantation for childhood diseases: unrelated cord blood and haploidentical family donors.

Science.gov (United States)

Cairo, Mitchell S; Rocha, Vanderson; Gluckman, Eliane; Hale, Gregory; Wagner, John

2008-01-01

Allogeneic stem cell transplantation has been demonstrated to be curative in a wide variety of pediatric malignant and nonmalignant diseases, and can be traced back over 50 years ago to the original report of Thomas et al. HLA matched sibling donors have been the gold standard for pediatric recipients requiring allogeneic donors for both nonmalignant and malignant conditions. However, only 25% of potential pediatric recipients possesses an HLA-matched sibling donor, and the frequency is even less in those with genetic nonmalignant conditions because of genetically affected other siblings within the family. Therefore, 75% to 90% of potential pediatric recipients require alternative allogeneic donor cells for treatment of their underlying conditions. Potential alternative allogeneic donor sources include unrelated cord blood donors, unrelated adult donors, and haploidentical family donors. In this article we review the experience of both unrelated cord blood donor and haploidentical family donor transplants in selected pediatric malignant and nonmalignant conditions.

Effect of allogenic thymic cells on radioleukaemogenesis in AKR-T1ALD mice

International Nuclear Information System (INIS)

Legrand, E.; Sankar-Mistry, P.; Kressmann, M.C.

1975-01-01

When AKR mice are irradiated with a sub-lethal dose (4 times 175 R), thymic lymphosarcomas (L.S.) occur earlier than in controls. This accelerated leukaemogenesis is not inhibited by syngenic restoration with bone marrows cells (BM). Using the AKR/T1ALD substrain which bears 38 chromosomes with 1 metacentric markers, it has been shown that AKR radio-chimaeras restored by T1ALD BM developed two kinds of L.S.: early (radiation-induced) L.S. originating mainly from host cells surviving irradiation and late L.S. from donor cells. The experiments were to investigate the potential influence of normal allogenic thymic cells, with or without syngenic B.M., on the incidence, latency and origin of LS appearing in irradiated AKR recipients. Adding C3H allogenic thymic cells to syngenic B.M. increases the percentage of early L.S. whose latencies are unchanged. Besides, when C3H thymic cells are injected to irradiated controls without syngenic B.M. cells, L.S. are seen to occur significantly earlier than in just the irradiated animals alone. In radio-chimaeras restored by allogenic thymic cells and syngenic B.M., except in one case, all the L.S. were seen to originate from B.M. cells. The interpretation of these results depends on the possible role of allogenic thymic cells on host cells surviving the irradiation, or the exogeneous B.M. In the first case, allogenic thymocytes could induce a graft versus host reaction increasing the post-irradiation depletion of lymphoid system and hastening thymic endoregeneration which is supposed to be the first step towards leukaemogenesis. The second hypothesis, which seems the most likely, would be that C1H thymic cells could selectively act on host cells surviving irradiation and enhance the differenciation of haemopoietic precursors at the expense of the lymphoid cells [fr

Antibiotic prophylaxis in hematopoietic stem cell transplantation. A meta-analysis of randomized controlled trials.

Science.gov (United States)

Kimura, Shun-ichi; Akahoshi, Yu; Nakano, Hirofumi; Ugai, Tomotaka; Wada, Hidenori; Yamasaki, Ryoko; Ishihara, Yuko; Kawamura, Koji; Sakamoto, Kana; Ashizawa, Masahiro; Sato, Miki; Terasako-Saito, Kiriko; Nakasone, Hideki; Kikuchi, Misato; Yamazaki, Rie; Kako, Shinichi; Kanda, Junya; Tanihara, Aki; Nishida, Junji; Kanda, Yoshinobu

2014-07-01

We performed a meta-analysis to evaluate the impact of systemic antibiotic prophylaxis in hematopoietic stem cell transplantation (HSCT) recipients. We collected reports from PubMed, the Cochrane Library, EMBASE, CINAHL, and Web of Science, along with references cited therein. We included prospective, randomized studies on systemic antibiotic prophylaxis in HSCT recipients. Seventeen trials with 1453 autologous and allogeneic HSCT recipients were included. Systemic antibiotic prophylaxis was compared with placebo or no prophylaxis in 10 trials and with non-absorbable antibiotics in two trials. Systemic antibiotics other than fluoroquinolones were evaluated in five of these 12 trials. Four trials evaluated the effect of the addition of antibiotics for gram-positive bacteria to fluoroquinolones. One trial compared two different systemic antibiotic regimens: fluoroquinolones versus trimethoprim-sulfamethoxazole. As a result, systemic antibiotic prophylaxis reduced the incidence of febrile episodes (OR 0.16; 95%CI 0.09-0.30), clinically or microbiologically documented infection (OR 0.38; 95%CI 0.22-0.63) and bacteremia (OR 0.31; 95%CI 0.16-0.59) without significantly affecting all-cause mortality or infection-related mortality. Systemic antibiotic prophylaxis successfully reduced the incidence of infection. However, there was no significant impact on mortality. The clinical benefits of prophylaxis with fluoroquinolones were inconclusive because of the small number of clinical trials evaluated. Copyright © 2014 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Prolonged Survival of Subcutaneous Allogeneic Islet Graft by Donor Chimerism without Immunosuppressive Treatment

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Brend Ray-Sea Hsu

2017-01-01

Full Text Available The aim of this study was to investigate whether tolerance-induced protection of islets in the renal subcapsular space can also prevent subcutaneous allogeneic islets from being rejected. We used bone marrow stem cells from C57BL/6 (H2b mice to construct donor chimerism in conditioned diabetic BALB/c (H2d mice and investigated the effect of donor chimerism on engraftment and survival of subcutaneously transplanted allogeneic islets in streptozotocin-induced diabetic mice. We also studied the anti-inflammatory effect of mesenchymal stem cell on islet engraftment. Full but not low-grade or no donor chimerism was associated with successful engraftment of allogeneic islets and restoration of normoglycemia in the treated diabetic mice. The temporary hyperglycemia was 11 ± 1 versus 19 ± 5 days (p<0.05 for the mice with full donor chimerism with transplanted islets in the renal subcapsular space versus the subcutaneous space, respectively. Cotransplantation of mesenchymal stem cell did not enhance alloislet engraftment. Full multilineage donor chimerism was associated with a higher transient expansion of CD11b+ and Gr-1+ myeloid progenitor cells and effector memory CD4 and CD8 T cells. In conclusion, full donor chimerism protected both renal subcapsular and subcutaneous allogeneic islets in this rodent transplantation model.

Prostaglandin E2 regulates hematopoietic stem cell

International Nuclear Information System (INIS)

Wang Yingying; Zhou Daohong; Meng Aimin

2013-01-01

Prostaglandin E2 (PGE2) is a bioactive lipid molecule produced by cyclooxygenase (COX), which plays an important role on hematopoiesis. While it can block differentiation of myeloid progenitors but enhance proliferation of erythroid progenitors. Recent research found that PGE2 have the effects on hematopoietic stem cell (HSC) function and these effects were independent from effects on progenitor cells. Exposure of HSC cells to PGE2 in vitro can increase homing efficiency of HSC to the murine bone marrow compartment and decrease HSC apoptosis, meanwhile increase long-term stem cell engraftment. In-vivo treatment with PGE2 expands short-term HSC and engraftment in murine bone marrow but not long-term HSC.In addition, PGE2 increases HSC survival after radiation injury and enhance hematopoietic recovery, resulting maintains hematopoietic homeostasis. PGE2 regulates HSC homeostasis by reactive oxygen species and Wnt pathway. Clinical beneficial of 16, 16-dimethyl-prostaglandin E2 treatment to enhance engraftment of umbilical cord blood suggest important improvements to therapeutic strategies. (authors)

The impact of allogenic blood transfusion on the outcomes of total pancreatectomy with islet autotransplantation.

Science.gov (United States)

Yoshimatsu, Gumpei; Shahbazov, Rauf; Saracino, Giovanna; Lawrence, Michael C; Kim, Peter T; Onaca, Nicholas; Beecherl, Ernest E; Naziruddin, Bashoo; Levy, Marlon F

2017-11-01

Allogenic blood transfusion (ABT) may be needed for severe bleeding during total pancreatectomy with autotransplantation (TPIAT), but may induce inflammation. This study investigated the impact of ABT. With a population of 83 patients who underwent TPIAT from 2006 to 2014, this study compared cytokine levels, patient characteristics, islet characteristics, metabolic outcomes, insulin requirements, and hemoglobin A1c for those who received a blood transfusion (BT) versus no blood transfusion (NBT). Initially, proinflammatory cytokines were moderately higher in the BT group than the NBT group. Despite longer procedures and more severe bleeding, the BT group had similar values to the NBT group for insulin requirements, serum C-peptide, hemoglobin A1c, and insulin independence rate. The probability of insulin independence was slightly higher in patients receiving ≥3 units of blood. ABT induced elevation of proinflammatory cytokines during the perioperative period in TPIAT, but these changes did not significantly change posttransplant islet function. Copyright © 2017 Elsevier Inc. All rights reserved.

Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia

International Nuclear Information System (INIS)

McGlave, P.B.; Miller, W.J.; Hurd, D.D.; Arthur, D.C.; Kim, T.

1981-01-01

We performed a pilot study to test the effectiveness of allogeneic bone marrow transplantation in the treatment of chronic myelogenous leukemia. Five patients in the advanced stages of chronic myelogenous leukemia (four in blast crisis, one in accelerated phase) with abnormal chromosomes underwent matched-sibling allogeneic bone marrow transplantation after preparation with busulfan, vincristine, cyclophosphamide, and fractionated total body irradiation. Engraftment and conversion to normal chromosome patterns after transplantation occurred in all five patients. None of the patients reverted to an abnormal chromosome pattern or demonstrated clinical or hematologic evidence of recurrent disease during the course of this study; however, longest survival from transplant was 248 days. Allogeneic bone marrow transplantation can eradicate the abnormal clone even in far advanced chronic myelogenous leukemia and can provide normal hematopoiesis. We suggest that clinical complications of chemotherapeutic toxicity and infection were responsible for the short survival in this group of patients, and that these complications could be decreased by performing transplantation in the chronic phase or early accelerated phase of the disease

Rituximab-containing reduced-intensity conditioning improves progression-free survival following allogeneic transplantation in B cell non-Hodgkin lymphoma

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Narendranath Epperla

2017-06-01

Full Text Available Abstract Background In B cell non-Hodgkin lymphoma (B-NHL, rituximab-containing reduced-intensity conditioning regimens (R-RIC have been shown to provide favorable outcomes in single-arm studies; however, large multicenter studies comparing R-RIC and non-rituximab-containing reduced-intensity conditioning regimens (nonR-RIC have not been performed. Using the CIBMTR database, we report the outcomes of R-RIC versus nonR-RIC regimens in B-NHL. Methods We evaluated 1401 adult B-NHL patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT who received nonR-RIC (n = 1022 or R-RIC (n = 379 regimens. Graft-versus-host disease (GVHD prophylaxis was limited to calcineurin inhibitor-based approaches. Results Median follow-up of survivors in the R-RIC and nonR-RIC groups was 47 and 37 months, respectively. On multivariate analysis, no difference was seen between the R-RIC and nonR-RIC cohorts in terms of acute GVHD grade II–IV (RR = 1.14, 95%CI = 0.83–1.56, p = 0.43 or grade III–IV (RR = 1.16, 95%CI = 0.72–1.89, p = 0.54, chronic GVHD (RR = 1.15, 95%CI = 0.92–1.46, p = 0.22, non-relapse mortality (RR = 0.90; 95%CI = 0.67–1.22; p = 0.51, relapse/progression (RR = 0.79; 95%CI = 0.63–1.01; p = 0.055, and mortality (RR = 0.84, 95%CI = 0.69–1.02, p = 0.08 risk. However, R-RIC was associated with a significantly improved progression-free survival (RR = 0.76; 95%CI 0.62–0.92; p = 0.006. On subgroup analysis, mortality benefit was noted in the R-RIC group patients not receiving busulfan-based RIC (RR = 0.76; 95%CI = 0.60–0.96; p = 0.02 and with the use of a higher cumulative rituximab dose (RR = 0.43; 95%CI = 0.21–0.90; p = 0.02. Conclusion Our analysis shows that inclusion of rituximab in RIC regimens improves progression-free survival in patients with B cell NHL. These data supports the use of R-RIC in B

COMPARISON OF THREE DISTINCT PROPHYLACTIC AGENTS AGAINST INVASIVE FUNGAL INFECTIONS IN PATIENTS UNDERGOING HAPLO-IDENTICAL HEMATOPOIETIC STEM CELL TRANSPLANTATION AND POST-TRANSPLANT CYCLOPHOSPHAMIDE

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Jean Elcheikh

2015-08-01

Full Text Available Over the past decade, invasive fungal infections (IFI have remained an important problem in patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-HSCT. The optimal approach for prophylactic antifungal therapy has yet to be determined. We conducted a retrospective, bi-institutional comparative clinical study, and compared the efficacy and safety of micafungin 50mg/day (iv with those of fluconazole (400mg/day or itraconazole 200mg/day (iv as prophylaxis for adult patients with various haematological diseases receiving haplo-identical allogeneic stem cell transplantation (haplo. Overall, 99 patients were identified; 30 patients received micafungin, and 69 patients received fluconazole or itraconazole. After a median follow-up of 13 months (range: 5-23, Proven or probable IFIs were reported in 3 patients (10% in the micafungin group and 8 patients (12% in the fluconazole or itraconazole group. Fewer patients in the micafungin group had invasive aspergillosis (1 [3%] vs. 5 [7%], P=0.6. A total of 4 (13% patients in the micafungin group and 23 (33% patients in the fluconazole or itraconazole group received empirical antifungal therapy (P = 0.14. No serious adverse events related to treatment were reported by patients and there was no treatment discontinuation because of drug-related adverse events in both groups. Despite the retrospective design of the study and limited sample, it contributes reassuring data to confirm results from randomised clinical trials, and to define a place for micafungin in prophylaxis after haplo.

Biodistribution and Immunogenicity of Allogeneic Mesenchymal Stem Cells in a Rat Model of Intraarticular Chondrocyte Xenotransplantation

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Maribel Marquina

2017-11-01

response. IL-2 measurements in cocultures of rat peripheral blood lymphocytes with PAC indicated that PAC injection induced some T-cell hyporesponsiveness that was not enhanced in the cohorts additionally receiving MSC. Thus, PAC injected intraarticularly in Lewis rats induced a cellular and humoral immune response that was not counteracted by the systemic administration of allogeneic MSC under the described conditions.

Allogeneic Transplantation In Chronic Myeloid Leukemia And The Effect Of Tyrosine Kinase Inhibitors On Survival, A Quasi-Experimental Study

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Mehmet Özen

2017-03-01

Full Text Available Objective: Tyrosine kinase inhibitors (TKIs have changed the indications for allogeneic hematopoietic stem cell transplantation (allo-HSCT in chronic myeloid leukemia (CML. Therefore, we aimed to evaluate the effect of TKIs on allo-HSCT in CML. Materials and Methods: In this quasi-experimental study, we compared patient, disease, and transplantation characteristics as well as allo-HSCT outcomes between the pre-TKI era (before 2002 and the post-TKI era (2002 and later in patients with CML. A total of 193 allo- HSCTs were performed between 1989 and 2012. Results: Patients in the post-TKI era had more advanced disease (>chronic phase 1 at the time of transplant and more frequently received reduced-intensity conditioning compared to patients in the pre-TKI era. Relapse/progression occurred more frequently in the year ≥2002 group than in the year <2002 group (48% vs. 32% at 5 years, p=0.01; however, overall survival (OS was similar in these two groups (5-year survival was 50.8% vs. 59.5%, respectively; p=0.3. TKIs (with donor lymphocyte infusions or alone for treatment of relapse after allo-HSCT were available in the post-TKI era and were associated with improved OS. While the rates of hematologic remission at 3 months after allo-HSCT were similar between TKI eras, patients having remission had better disease-free survival (DFS [relative risk (RR: 0.15, confidence interval (CI 95%: 0.09-0.24, p<0.001] and OS (RR: 0.14, CI 95%: 0.09-0.23, p<0.001. Male allo-HSCT recipients had worse DFS (RR: 1.7, CI 95%: 1.2-2.5, p=0.007 and OS (RR: 1.7, CI 95%: 1.1-2.6, p=0.02 than females. Conclusion: TKIs are an effective option for the treatment of relapse after allo-HSCT in CML. Hematologic remission after allo-HSCT is also an important factor for survival in CML patients.

Total-body irradiation - role and indications. Results from the German Registry for Stem Cell Transplantation (DRST)

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Heinzelmann, F.; Bamberg, M.; Belka, C.; Ottinger, H.; Mueller, C.H.; Allgaier, S.; Faul, C.

2006-01-01

Background and purpose: total-body irradiation (TBI) is a key part of the conditioning regimen before hematopoietic stem cell transplantation (HSCT). The exact role of TBI as part of the conditioning regimen is largely unclear. In order to determine the relevance of TBI, the status of TBI utilization was analyzed on the basis of a nationwide registry. Material and methods: 14,371 patients (1998-2002) documented in the German Stem Cell Transplantation Registry (DRST) were analyzed regarding TBI utilization prior to autologous or allogeneic transplantation, underlying disorder, type of donor, stem cell source, and size of the treatment center. Results: for autologous HSCT ∝10% of the patients (873/8,167) received TBI, with chronic lymphocytic leukemia (CLL, ∝80%, 171/214) and low-grade non-Hodgkin's lymphoma (l-NHL, ∝35%, 330/929) being the most important disorders. In the allogeneic setting 50% of the patients (2,399/4,904) received TBI, with acute lymphocytic leukemia (ALL, 85%, 794/930), acute myeloid leukemia (AML, 45%, 662/1,487) and chronic myeloid leukemia (CML, 49%, 561/1,156) being the key indications. The type of donor, stem cell source and center size did not strongly influence the use of TBI. Conclusion: TBI has only a limited role for the conditioning prior to autologous HCST. For allogeneic HSCT TBI is widely accepted with no major changes over the observation time. The use of TBI is generally accepted for ALL, whereas approximately half of the patients with CML or AML received TBI. Although a considerably large database was analyzed, no clear determinants for the use of TBI could be distinguished. (orig.)

Total-body irradiation - role and indications. Results from the German Registry for Stem Cell Transplantation (DRST)

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Heinzelmann, F.; Bamberg, M.; Belka, C. [Dept. of Radiation Oncology, Univ. of Tuebingen (Germany); Ottinger, H. [German Registry for Stem Cell Transplantation (DRST) Secretary, Univ. of Essen (Germany); Mueller, C.H.; Allgaier, S. [DRST Datacenter, DRK Bloodbank Center Ulm (Germany); Faul, C. [Dept. of Internal Medicine II, Univ. of Tuebingen (Germany)

2006-04-15

Background and purpose: total-body irradiation (TBI) is a key part of the conditioning regimen before hematopoietic stem cell transplantation (HSCT). The exact role of TBI as part of the conditioning regimen is largely unclear. In order to determine the relevance of TBI, the status of TBI utilization was analyzed on the basis of a nationwide registry. Material and methods: 14,371 patients (1998-2002) documented in the German Stem Cell Transplantation Registry (DRST) were analyzed regarding TBI utilization prior to autologous or allogeneic transplantation, underlying disorder, type of donor, stem cell source, and size of the treatment center. Results: for autologous HSCT {proportional_to}10% of the patients (873/8,167) received TBI, with chronic lymphocytic leukemia (CLL, {proportional_to}80%, 171/214) and low-grade non-Hodgkin's lymphoma (l-NHL, {proportional_to}35%, 330/929) being the most important disorders. In the allogeneic setting 50% of the patients (2,399/4,904) received TBI, with acute lymphocytic leukemia (ALL, 85%, 794/930), acute myeloid leukemia (AML, 45%, 662/1,487) and chronic myeloid leukemia (CML, 49%, 561/1,156) being the key indications. The type of donor, stem cell source and center size did not strongly influence the use of TBI. Conclusion: TBI has only a limited role for the conditioning prior to autologous HCST. For allogeneic HSCT TBI is widely accepted with no major changes over the observation time. The use of TBI is generally accepted for ALL, whereas approximately half of the patients with CML or AML received TBI. Although a considerably large database was analyzed, no clear determinants for the use of TBI could be distinguished. (orig.)