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Sample records for reduced-intensity conditioning hematopoietic

  1. Reduced-intensity conditioning allogeneic hematopoietic-cell transplantation for older patients with acute myeloid leukemia.

    Science.gov (United States)

    Goyal, Gaurav; Gundabolu, Krishna; Vallabhajosyula, Saraschandra; Silberstein, Peter T; Bhatt, Vijaya Raj

    2016-06-01

    Elderly patients (>60 years) with acute myeloid leukemia have a poor prognosis with a chemotherapy-alone approach. Allogeneic hematopoietic-cell transplantation (HCT) can improve overall survival (OS). However, myeloablative regimens can have unacceptably high transplant-related mortality (TRM) in an unselected group of older patients. Reduced-intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning regimens preserve the graft-versus-leukemia effects but reduce TRM. NMA regimens result in minimal cytopenia and may not require stem cell support for restoring hematopoiesis. RIC regimens, intermediate in intensity between NMA and myeloablative regimens, can cause prolonged myelosuppresion and usually require stem cell support. A few retrospective and prospective studies suggest a possibility of lower risk of relapse with myeloablative HCT in fit older patients with lower HCT comorbidity index; however, RIC and NMA HCTs have an important role in less-fit patients and those with significant comorbidities because of lower TRM. Whether early tapering of immunosuppression, monitoring of minimal residual disease, and post-transplant maintenance therapy can improve the outcomes of RIC and NMA HCT in elderly patients will require prospective trials.

  2. Donor chimerism early after reduced-intensity conditioning hematopoietic stem cell transplantation predicts relapse and survival.

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    Koreth, John; Kim, Haesook T; Nikiforow, Sarah; Milford, Edgar L; Armand, Philippe; Cutler, Corey; Glotzbecker, Brett; Ho, Vincent T; Antin, Joseph H; Soiffer, Robert J; Ritz, Jerome; Alyea, Edwin P

    2014-10-01

    The impact of early donor cell chimerism on outcomes of T cell-replete reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is ill defined. We evaluated day 30 (D30) and 100 (D100) total donor cell chimerism after RIC HSCT undertaken between 2002 and 2010 at our institution, excluding patients who died or relapsed before D30. When available, donor T cell chimerism was also assessed. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), relapse, and nonrelapse mortality (NRM). We evaluated 688 patients with hematologic malignancies (48% myeloid and 52% lymphoid) and a median age of 57 years (range, 18 to 74) undergoing RIC HSCT with T cell-replete donor grafts (97% peripheral blood; 92% HLA-matched), with a median follow-up of 58.2 months (range, 12.6 to 120.7). In multivariable analysis, total donor cell and T cell chimerism at D30 and D100 each predicted RIC HSCT outcomes, with D100 total donor cell chimerism most predictive. D100 total donor cell chimerism D100 total donor cell chimerism or T cell chimerism. Low donor chimerism early after RIC HSCT is an independent risk factor for relapse and impaired survival. Donor chimerism assessment early after RIC HSCT can prognosticate for long-term outcomes and help identify high-risk patient cohorts who may benefit from additional therapeutic interventions. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  3. Reduced intensity conditioning is superior to nonmyeloablative conditioning for older chronic myelogenous leukemia patients undergoing hematopoietic cell transplant during the tyrosine kinase inhibitor era

    DEFF Research Database (Denmark)

    Warlick, Erica; Ahn, Kwang Woo; Pedersen, Tanya L;

    2012-01-01

    Tyrosine kinase inhibitors (TKIs) and reduced intensity conditioning (RIC)/nonmyeloablative (NMA) conditioning hematopoietic cell transplants (HCTs) have changed the therapeutic strategy for chronic myelogenous leukemia (CML) patients. We analyzed post-HCT outcomes of 306 CML patients reported to...

  4. Reduced-intensity conditioning for alternative donor hematopoietic stem cell transplantation in patients with dyskeratosis congenita.

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    Nishio, Nobuhiro; Takahashi, Yoshiyuki; Ohashi, Haruhiko; Doisaki, Sayoko; Muramatsu, Hideki; Hama, Asahito; Shimada, Akira; Yagasaki, Hiroshi; Kojima, Seiji

    2011-03-01

    DC is an inherited bone marrow failure syndrome mainly characterized by nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Bone marrow failure is the most common cause of death in patients with DC. Because previous results of HSCT with a myeloablative regimen were disappointing, we used a reduced-intensity conditioning regimen for two patients with classic DC, and one patient with cryptic DC who harbored the TERT mutation. Graft sources included two mismatched-related bone marrow (BM) donors and one unrelated BM donor. Successful engraftment was achieved with few regimen-related toxicities in all patients. They were alive 10, 66, and 72 months after transplantation, respectively. Long-term follow-up is crucial to determine the late effects of our conditioning regimen.

  5. Reduced intensity conditioning, combined transplantation of haploidentical hematopoietic stem cells and mesenchymal stem cells in patients with severe aplastic anemia.

    Directory of Open Access Journals (Sweden)

    Xiao-Hong Li

    Full Text Available We examined if transplantation of combined haploidentical hematopoietic stem cells (HSC and mesenchymal stem cells (MSC affected graft failure and graft-versus-host disease (GVHD in patients with severe aplastic anemia (SAA. Patients with SAA-I (N = 17 received haploidentical HSCT plus MSC infusion. Stem cell grafts used a combination of granulocyte colony-stimulating factor (G-CSF-primed bone marrow and G-CSF-mobilized peripheral blood stem cells of haploidentical donors and the culture-expanded third-party donor-derived umbilical cord MSCs (UC-MSCs, respectively. Reduced intensity conditioning consisted of fludarabine (30 mg/m2·d+cyclosphamide (500 mg/m2·d+anti-human thymocyte IgG. Transplant recipients also received cyclosporin A, mycophenolatemofetil, and CD25 monoclonal antibody. A total of 16 patients achieved hematopoietic reconstitution. The median mononuclear cell and CD34 count was 9.3×10(8/kg and 4.5×10(6/kg. Median time to ANC was >0.5×10(9/L and PLT count >20×10(9/L were 12 and 14 days, respectively. Grade III-IV acute GVHD was seen in 23.5% of the cases, while moderate and severe chronic GVHD were seen in 14.2% of the cases. The 3-month and 6-month survival rates for all patients were 88.2% and 76.5%, respectively; mean survival time was 56.5 months. Combined transplantation of haploidentical HSCs and MSCs on SAA without an HLA-identical sibling donor was safe, effectively reduced the incidence of severe GVHD, and improved patient survival.

  6. Health-Related Quality of Life in leukemia Survivors of Allogeneic Hematopoietic Stem Cell Transplantation Employing the Mexican Reduced-Intensity Conditioning.

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    González-Ramírez, Mónica P; Miravete-Lagunes, Karla; Gómez-de-León, Andrés; Ponce-de-León, Sergio; Tenorio-Rojo, Andrea P; Martagón-Herrera, Nora A; Hernández-Reyes, Jesús A; García-Villasenor, Arturo; Burguette, Esteban; Vallejo-Villalobos, María Fernanda; Ruiz-Delgado, Guillermo J; Gómez-Almaguer, David; Ruiz-Argüelles, Guillermo J

    2015-01-01

    Quality of life (QOL) is an important consideration in the counseling, implementation, and post-treatment management of arduous treatments for life-threatening conditions such as allogeneic hematopoietic cell transplantation (allo-HCT). To analyze the QOL of leukemia patients allografted with the Mexican reduced-intensity conditioning regimen in two Mexican academic medical centers. By means of the quality metric short form 36 version 2 to measure generic health concepts, relevant QOL was analyzed in leukemia patients who underwent allo-HCT using reduced-intensity conditioning on an outpatient basis at either the Centro de Hematología y Medicina Interna de Puebla of the Clínica Ruiz or the Hematology Service of the Internal Medicine Department of the Hospital "Dr. José Eleuterio González" of the Universidad Autónoma de Nuevo León, and who had survived more than 12 months after the allograft, who could be approached, who were in a continued complete remission (with or without graft-versus-host disease), and who were willing to respond to the questionnaire. Thirty-five patients fulfilling these requirements were included, and a sex- and age-matched group of 35 reference subjects was also studied. Allografted patients were found to have a slightly better mental component summary than the reference subjects (53.23 vs. 48.66 points; p = 0.01), whereas the physical component summary did not show a difference (54.53 vs. 52.05 points; p = 0.59). Most of the differences between allografted individuals and reference subject controls were not significant. Despite several sources of bias, these data suggest that allografted individuals employing the Mexican reduced-intensity conditioning regimen enjoy a health-related QOL life similar to that of reference subjects, adding another advantage of this method of conducting stem cell allografts. However, more work needs to be done to elucidate the impact of reduced-intensity conditioning on post allo-HCT QOL.

  7. An intermediate alemtuzumab schedule reduces the incidence of mixed chimerism following reduced-intensity conditioning hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis.

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    Marsh, Rebecca A; Kim, Mi-Ok; Liu, Chunyan; Bellman, Denise; Hart, Laura; Grimley, Michael; Kumar, Ashish; Jodele, Sonata; Myers, Kasiani C; Chandra, Sharat; Leemhuis, Tom; Mehta, Parinda A; Bleesing, Jack J; Davies, Stella M; Jordan, Michael B; Filipovich, Alexandra H

    2013-11-01

    Reduced-intensity conditioning (RIC) improves the outcomes of hematopoietic cell transplantation (HCT) in patients with hemophagocytic lymphohistiocytosis (HLH). Proximal (ie, close to graft infusion) dosing of alemtuzumab is associated with a high incidence of mixed chimerism, whereas distal (ie, distant from graft infusion) dosing is associated with less mixed chimerism but more acute graft-versus-host disease (GVHD). The alemtuzumab dose per kilogram of body weight also influences these outcomes. We hypothesized that an intermediate alemtuzumab dosing schedule would reduce mixed chimerism and maintain a low incidence of acute GVHD. In this study, 24 consecutive HCTs were performed in patients with HLH or a related disorder using a novel intermediate alemtuzumab schedule of 1 mg/kg starting on day -14. The cumulative incidences (CIs) of mixed chimerism, upfront acute GVHD grades II-IV, and receipt of additional hematopoietic cell products after HCT were compared in patients treated with a distal alemtuzumab schedule (n = 15) and those treated with a proximal alemtuzumab schedule (n = 33). All patients received fludarabine and melphalan. The CI of mixed chimerism was 31% in the intermediate group, 72% in the proximal group (P alemtuzumab (P = .03). The CI of acute GVHD grades II-IV before the development of mixed chimerism was 4% in the intermediate group, 0% in the proximal group, and 13% in the distal group (P = .04, proximal versus distal). The 1-year CI of administration of additional hematopoietic cell products for mixed chimerism (donor lymphocyte infusion ± hematopoietic stem cell boost ± repeat HCT) was 14% in the intermediate group, 53% in the proximal group (P = .01), and 38% in the distal ≥2 mg/kg alemtuzumab group (P = .02). Our findings indicate that intermediate RIC reduces the incidence of mixed chimerism, is associated with a low incidence of upfront acute GVHD, and decreases the need for additional hematopoietic cell

  8. Elderly patients (66-70 years) with acute leukemia or high-risk MDS who, underwent allogenic transplant of peripheral hematopoietic progenitors after reduced-intensity conditioning. | EU Clinical Trials Register [EU Clinical Trials Register

    Lifescience Database Archive (English)

    Full Text Available ad alte dosi nella profilassi della GVHD in pazienti anziani (66-70 anni), affetti da leucemia acuta o miel...matopoietic progenitors after reduced-intensity conditioning. Pazienti anziani (66-70 anni), affetti da leucemia...erwent allogenic transplant. Pazienti anziani (66-70 anni), affetti da leucemia acuta o mielodisplasia ad al... sfavorevole o intermedia – cariotipo normale con alterazioni molecolari sfavorevoli – fallimento del 1° ciclo d’induzione – leucemia

  9. Reduced-Intensity Conditioning Combined with (188)Rhenium Radioimmunotherapy before Allogeneic Hematopoietic Stem Cell Transplantation in Elderly Patients with Acute Myeloid Leukemia: The Role of In Vivo T Cell Depletion.

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    Schneider, Sebastian; Strumpf, Annette; Schetelig, Johannes; Wunderlich, Gerd; Ehninger, Gerhard; Kotzerke, Jörg; Bornhäuser, Martin

    2015-10-01

    The combination of reduced-intensity conditioning, (188)rhenium anti-CD66 radioimmunotherapy, and in vivo T cell depletion was successfully applied in elderly patients with acute myeloid leukemia or myelodysplastic syndrome. Within a prospective phase II protocol, we investigated whether a dose reduction of alemtuzumab (from 75 mg to 50 mg MabCampath) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients (median age, 67 years; range, 54 to 76) received radioimmunotherapy followed by fludarabine 150 mg/m(2) and busulfan 8 mg/kg combined with either 75 mg (n = 26) or 50 mg (n = 32) alemtuzumab. Although we observed a trend towards a shorter duration of neutropenia in the 50 mg group (median, 19 versus 21 days; P = .07), the time from transplantation to neutrophil and platelet engraftment as well as the overall incidence of engraftment did not differ. The incidence of severe acute graft-versus-host disease tended to be higher after the lower alemtuzumab dose (17% versus 4%; P = .15). No significant differences in the cumulative incidences of relapse (38% versus 35%; P = .81) or nonrelapse mortality (46% versus 27%; P = .31) were observed. Accordingly, disease-free and overall survival were not significantly different between groups. Although the feasibility of radioimmunotherapy plus reduced-intensity conditioning could be demonstrated in elderly patients, the dose reduction of alemtuzumab had no positive impact on overall outcome.

  10. Myeloablative Versus Reduced-Intensity Hematopoietic Cell Transplantation for Acute Myeloid Leukemia and Myelodysplastic Syndromes.

    Science.gov (United States)

    Scott, Bart L; Pasquini, Marcelo C; Logan, Brent R; Wu, Juan; Devine, Steven M; Porter, David L; Maziarz, Richard T; Warlick, Erica D; Fernandez, Hugo F; Alyea, Edwin P; Hamadani, Mehdi; Bashey, Asad; Giralt, Sergio; Geller, Nancy L; Leifer, Eric; Le-Rademacher, Jennifer; Mendizabal, Adam M; Horowitz, Mary M; Deeg, H Joachim; Horwitz, Mitchell E

    2017-04-10

    Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

  11. 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

    NARCIS (Netherlands)

    Giebel, S.; Labopin, M.; Mohty, M.; Mufti, G. J.; Niederwieser, D.; Cornelissen, J. J.; Janssen, J. J. W. M.; Milpied, N.; Vindelov, L.; Petersen, E.; Arnold, R.; Bacigalupo, A.; Blaise, D.; Craddock, C.; Nagler, A.; Frassoni, F.; Sadus-Wojciechowska, M.; Rocha, V.

    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 or

  12. 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

    DEFF Research Database (Denmark)

    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...

  13. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

    NARCIS (Netherlands)

    C. Schmid (Christoph); M. Labopin (Myriam); A. Nagler (Arnon); D. Niederwieser (Dietger); L. Castagna (Luca); R. Tabrizi (Reza); M. Stadler (Michael); J. Kuball (Jürgen); J.J. Cornelissen (Jan); J. Vorlicek (Jiri); G. Socié (Gerard); M. Falda (M.); L. Vindelov (Lars); P. Ljungman (Per); G. Jackson (Graham); N. Kröger; A. Rank (Andreas); E. Polge (Emmanuelle); V. Rocha (Vanderson); M. Mohty (Mohamad)

    2012-01-01

    textabstractBecause information on management and outcome of AML relapse after allogeneic hematopoietic stem cell transplantation (HSCT) with reduced intensity conditioning (RIC) is scarce, a retrospective registry study was performed by the Acute LeukemiaWorking Party of EBMT. Among 2815 RIC

  14. Treatment, risk factors, and outcome of adults with relapsed AML after reduced intensity conditioning for allogeneic stem cell transplantation

    DEFF Research Database (Denmark)

    Schmid, Christoph; Labopin, Myriam; Nagler, Arnon

    2012-01-01

    Since information on management and outcome of adults with AML relapsing after allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning (RIC HSCT) is scarce, a retrospective registry study was performed by the Acute Leukemia Working Party of EBMT. Among 2815 RIC tran...

  15. Survival Advantage and Comparable Toxicity in Reduced-Toxicity Treosulfan-Based versus Reduced-Intensity Busulfan-Based Conditioning Regimen in Myelodysplastic Syndrome and Acute Myeloid Leukemia Patients after Allogeneic Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Sakellari, Ioanna; Mallouri, Despina; Gavriilaki, Eleni; Batsis, Ioannis; Kaliou, Maria; Constantinou, Varnavas; Papalexandri, Apostolia; Lalayanni, Chrysavgi; Vadikolia, Chrysanthi; Athanasiadou, Anastasia; Yannaki, Evangelia; Sotiropoulos, Damianos; Smias, Christos; Anagnostopoulos, Achilles

    2017-03-01

    Treosulfan has been incorporated in conditioning regimens for sustained remission without substantial toxicity and treatment-related mortality (TRM). We aimed to analyze the safety and efficacy of a fludarabine 150 mg/m(2) and treosulfan 42 g/m(2) (FluTreo) conditioning regimen in medically infirm patients. Outcomes were compared with those of a similar historical group treated with fludarabine 150 mg/m(2) to 180 mg/m(2), busulfan 6.4 mg/kg, and antithymocyte globulin (ATG) 5 mg/kg to 7.5 mg/kg (FluBuATG). Thirty-one consecutive patients with acute myeloid leukemia (AML; n = 21), myelodysplastic syndrome (MDS; n = 6), or treatment-related AML (n = 4) received FluTreo conditioning. The historical group consisted of 26 consecutive patients treated with FluBuATG. In the FluTreo group, engraftment was prompt in all patients and 74% achieved >99% donor chimerism by day +30. No grades III or IV organ toxicities were noted. One-year cumulative incidences (CI) of acute and chronic graft-versus-host disease (GVHD) were 19.4% and 58.4%. The groups were similar for age, disease risk, lines of treatment, hematopoietic cell transplantation-specific comorbidity index, and acute or chronic GVHD incidence, except that there were more matched unrelated donor recipients in the FluTreo group (P < .001). With 20 (range, 2 to 36) months follow-up for FluTreo and 14 (range, 2 to 136) for FluBuATG, the 1-year cumulative overall survival (OS) probability was 76% versus 57%, respectively (P = .026); 1-year disease-free survival (DFS) was 79% versus 38% (P < .001). In multivariate analysis, the only significantly favorable factor for OS and DFS was FluTreo (P = .010 and P = .012). The CI of relapse mortality was markedly decreased in FluTreo versus FluBuATG (7.4% versus 42.3%, P < .001). In conclusion, the treosulfan-based regimen resulted in favorable OS and DFS with acceptable toxicity and low relapse rates compared with busulfan-based conditioning.

  16. Reduced-intensity conditioning regimen in HLA-haploidentical hematopoietic stem cell transplantation%减低剂量预处理方案在亲缘HLA单倍体相合造血干细胞移植中的应用

    Institute of Scientific and Technical Information of China (English)

    杨廷; 江明

    2015-01-01

    BACKGROUND:Reduced-intensity conditioning alogeneic hematopoietic stem cel transplantation (RIC-alo-HSCT) is proved being one of the effective methods to cure hematologic malignancies recently, which has been used more and more in patients with matched sibling or matched unrelated donor year by year. It is more suitable for elderly patients or younger patients combined with any organ dysfunction or complications. However, matched sibling and matched unrelated donors are not easy to be obtained for RIC-alo-HSCT. While HLA-haploidentical donor can be quickly found in family members for the patients who need receiving RIC-alo-HSCT. Fewer papers for reduced-intensity conditioning haploidentical hematopoietic stem cel transplantation (RIC-haplo-HSCT) have been reported in the world, and none in China, so the review for RIC-haplo-HSCT is necessary. OBJECTIVE:To reveiw the application of RIC-haplo-HSCT and its prospect. METHODS:Using “nonmyeloablative conditioning, reduced intensity conditioning, HLA-haploidentical, hematopoietic stem cel transplantation” as key words, we retrieved Wanfang, CNKI and PubMed databases, and foreign language search platform (1997-2014) by computer for literatures about RIC-haplo-HSCT. According to the inclusion and exclusion criteria, 25 articles in English were selected for our review ultimately. RESULTS AND CONCLUSION: This review shows that RIC-alo-HSCT with matched sibling and matched unrelated donor is widely used and has a better result increasingly. RIC-haplo-HSCT is carried out relatively late and less, and its engraftment, infection, transplant-related mortality, graft-versus-host disease, long-term disease-free survival and overal survival in the early period is a bit weak, but overal the situation has been recently improved significantly. Currently RIC-haplo-HSCT is feasible, especialy for patients lack of matched sibling donor and matched unrelate donor, and HLA haploidentical donor becomes the most potential source of

  17. Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis.

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    Robin, Marie; Porcher, Raphael; Wolschke, Christine; Sicre de Fontbrune, Flore; Alchalby, Haefaa; Christopeit, Maximilian; Cassinat, Bruno; Zabelina, Tatjana; Peffault de Latour, Régis; Ayuk, Francis; Socié, Gérard; Kröger, Nicolaus

    2016-07-01

    Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced-intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens.

  18. Cytomegalovirus infections following umbilical cord blood transplantation using reduced intensity conditioning regimens for adult patients.

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    Matsumura, Tomoko; Narimatsu, Hiroto; Kami, Masahiro; Yuji, Koichiro; Kusumi, Eiji; Hori, Akiko; Murashige, Naoko; Tanaka, Yuji; Masuoka, Kazuhiro; Wake, Atsushi; Miyakoshi, Shigesaburo; Kanda, Yoshinobu; Taniguchi, Shuichi

    2007-05-01

    Cytomegalovirus (CMV) infection is a major complication after allogeneic hematopoietic stem cell transplantation (Allo-HSCT); however, we have little information on the clinical features of CMV reactivation after cord blood transplantation using reduced-intensity regimens (RI-CBT) for adults. We reviewed medical records of 140 patients who underwent RI-CBT at Toranomon Hospital between January 2002 and March 2005. All the patients were monitored for CMV-antigenemia weekly, and, if turned positive, received preemptive foscarnet or ganciclovir. Seventy-seven patients developed positive antigenemia at a median onset of day 35 (range, 4-92) after transplant. Median of the maximal number of CMV pp65-positive cells per 50,000 cells was 22 (range, 1-1806). CMV disease developed in 22 patients on a median of day 35 (range, 15-106); 21 had enterocolitis and 1 had adrenalitis. CMV antigenemia had not been detected in 2 patients, when CMV disease was diagnosed. CMV disease was successfully treated using ganciclovir or foscarnet in 14 patients. The other 8 patients died without improvement of CMV disease. In multivariate analysis, grade II-IV acute graft-versus-host disease was a risk factor of CMV disease (relative risk 3.48, 95% confidential interval 1.47-8.23). CMV reactivation and disease develop early after RI-CBT. CMV enterocolitis may be a common complication after RI-CBT.

  19. REDUCED INTENSITY HEMATOPOIETIC CELL TRANSPLANTATION FOR PATIENTS WITH PRIMARY MYELOFIBROSIS: A COHORT ANALYSIS FROM THE CENTER FOR INTERNATIONAL BLOOD AND MARROW TRANSPLANT RESEARCH

    Science.gov (United States)

    Gupta, Vikas; Malone, Adriana K.; Hari, Parameswaran N.; Ahn, Kwang Woo; Hu, Zhen-Huan; Gale, Robert Peter; Ballen, Karen K.; Hamadani, Mehdi; Olavarria, Eduardo; Gerds, Aaron T.; Waller, Edmund K.; Costa, Luciano J.; Antin, Joseph H.; Kamble, Rammurti T.; van Besien, Koen M.; Savani, Bipin N.; Schouten, Harry C.; Szer, Jeffrey; Cahn, Jean-Yves; de Lima, Marcos J.; Wirk, Baldeep; Aljurf, Mahmoud D.; Popat, Uday; Bejanyan, Nelli; Litzow, Mark R.; Norkin, Maxim; Lewis, Ian D.; Hale, Gregory A.; Woolfrey, Ann E.; Miller, Alan M.; Ustun, Celalettin; Jagasia, Madan H.; Lill, Michael; Maziarz, Richard T.; Cortes, Jorge; Kalaycio, Matt E.; Saber, Wael

    2014-01-01

    We evaluated the outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced intensity conditioning (RIC). Median age at HCT was 55 years. Donors were: matched sibling donor (MSD), 34%; HLA-well-matched unrelated donors (URD), 45%; and partially/mismatched URD, 21%. Risk stratification according to Dynamic International Prognostic Scoring System (DIPSS): low, 12%; intermediate-1, 49%; intermediate-2, 37%; and high, 1%. The probability of survival at 5-years was 47% (95% CI 40–53). In a multivariate analysis, donor type was the only independent factor associated with survival. Adjusted probabilities of survival at 5-years for MSD, well matched URD and partially matched/mismatched URD were 56% (95% CI 44–67), 48% (95% CI 37–58), and 34% (95% CI 21–47), respectively (p=0.002). Relative risks (RR) for NRM for well-matched URD and partially matched/mismatched URD were 3.92 (p=0.006) and 9.37 (p<0.0001), respectively. A trend towards increased NRM (RR 1.7, p=0.07) and inferior survival (RR 1.37, p=0.10) was observed in DIPSS-intermediate-2/high-risk patients compared to DIPSS-low/intermediate-1 risk patients. RIC HCT is a potentially curative option for patients with MF, and donor type is the most important factor influencing survival in these patients. PMID:24161923

  20. Frequency and Risk Factors Associated with Cord Graft Failure after Transplant with Single-Unit Umbilical Cord Cells Supplemented by Haploidentical Cells with Reduced-Intensity Conditioning.

    Science.gov (United States)

    Tsai, Stephanie B; Liu, Hongtao; Shore, Tsiporah; Fan, Yun; Bishop, Michael; Cushing, Melissa M; Gergis, Usama; Godley, Lucy; Kline, Justin; Larson, Richard A; Martinez, Guadalupe; Mayer, Sebastian; Odenike, Olatoyosi; Stock, Wendy; Wickrema, Amittha; van Besien, Koen; Artz, Andrew S

    2016-06-01

    Delayed engraftment and cord graft failure (CGF) are serious complications after unrelated cord blood (UCB) hematopoietic stem cell transplantation (HSCT), particularly when using low-cell-dose UCB units. The haplo-cord HSCT approach allows the use of a lower dose single UCB unit by co-infusion of a CD34(+) selected haploidentical graft, which provides early transient engraftment while awaiting durable UCB engraftment. We describe the frequency, complications, and risk factors of CGF after reduced-intensity conditioning haplo-cord HSCT. Among 107 patients who underwent haplo-cord HSCT, 94 were assessable for CGF, defined as risk of CGF. We conclude that assessing chimerism at day 30 may foretell impending CGF, and avoidance of high haploidentical cell doses may reduce risk of CGF after haplo-cord HSCT. However, long-term survival is possible after CGF because of predominant haploidentical or mixed chimerism and hematopoietic function.

  1. Reduced-intensity hematopoietic cell transplantation for patients with primary myelofibrosis: a cohort analysis from the center for international blood and marrow transplant research.

    Science.gov (United States)

    Gupta, Vikas; Malone, Adriana K; Hari, Parameswaran N; Ahn, Kwang Woo; Hu, Zhen-Huan; Gale, Robert Peter; Ballen, Karen K; Hamadani, Mehdi; Olavarria, Eduardo; Gerds, Aaron T; Waller, Edmund K; Costa, Luciano J; Antin, Joseph H; Kamble, Rammurti T; van Besien, Koen M; Savani, Bipin N; Schouten, Harry C; Szer, Jeffrey; Cahn, Jean-Yves; de Lima, Marcos J; Wirk, Baldeep; Aljurf, Mahmoud D; Popat, Uday; Bejanyan, Nelli; Litzow, Mark R; Norkin, Maxim; Lewis, Ian D; Hale, Gregory A; Woolfrey, Ann E; Miller, Alan M; Ustun, Celalettin; Jagasia, Madan H; Lill, Michael; Maziarz, Richard T; Cortes, Jorge; Kalaycio, Matt E; Saber, Wael

    2014-01-01

    We evaluated outcomes and associated prognostic factors in 233 patients undergoing allogeneic hematopoietic cell transplantation (HCT) for primary myelofibrosis (MF) using reduced-intensity conditioning (RIC). The median age at RIC HCT was 55 yr. Donors were a matched sibling donor (MSD) in 34% of RIC HCTs, an HLA well-matched unrelated donor (URD) in 45%, and a partially matched/mismatched URD in 21%. Risk stratification according to the Dynamic International Prognostic Scoring System (DIPSS) was 12% low, 49% intermediate-1, 37% intermediate-2, and 1% high. The probability of survival at 5 yr was 47% (95% confidence interval [CI], 40% to 53%). In a multivariate analysis, donor type was the sole independent factor associated with survival. Adjusted probabilities of survival at 5-yr were 56% (95% CI, 44% to 67%) for MSD, 48% (95% CI, 37% to 58%) for well-matched URD, and 34% (95% CI, 21% to 47%) for partially matched/mismatched URD (P = .002). The relative risk (RR) for NRM was 3.92 (P = .006) for well-matched URD and 9.37 (P < .0001) for partially matched/mismatched URD. Trends toward increased NRM (RR, 1.7; P = .07) and inferior survival (RR, 1.37; P = .10) were observed in DIPSS intermediate-2/high-risk patients compared with DIPSS low/intermediate-1 risk patients. Our data indicate that RIC HCT is a potentially curative option for patients with MF, and that donor type is the most important factor influencing survival in these patients. Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  2. Double umbilical cord blood transplantation with reduced intensity conditioning and sirolimus-based GVHD prophylaxis.

    Science.gov (United States)

    Cutler, C; Stevenson, K; Kim, H T; Brown, J; McDonough, S; Herrera, M; Reynolds, C; Liney, D; Kao, G; Ho, V; Armand, P; Koreth, J; Alyea, E; Dey, B R; Attar, E; Spitzer, T; Boussiotis, V A; Ritz, J; Soiffer, R; Antin, J H; Ballen, K

    2011-05-01

    The main limitations to umbilical cord blood (UCB) transplantation (UCBT) in adults are delayed engraftment, poor immunological reconstitution and high rates of non-relapse mortality (NRM). Double UCBT (DUCBT) has been used to circumvent the issue of low cell dose, but acute GVHD remains a significant problem. We describe our experience in 32 subjects, who underwent DUCBT after reduced-intensity conditioning with fludarabine/melphalan/antithymocyte globulin and who received sirolimus and tacrolimus to prevent acute GVHD. Engraftment of neutrophils occurred in all patients at a median of 21 days, and platelet engraftment occurred at a median of 42 days. Three subjects had grade II-IV acute GVHD (9.4%) and chronic GVHD occurred in four subjects (cumulative incidence 12.5%). No deaths were caused by GVHD and NRM at 100 days was 12.5%. At 2 years, NRM, PFS and OS were 34.4, 31.2 and 53.1%, respectively. As expected, immunologic reconstitution was slow, but PFS and OS were associated with reconstitution of CD4(+) and CD8(+) lymphocyte subsets, suggesting that recovery of adaptive immunity is required for the prevention of infection and relapse after transplantation. In summary, sirolimus and tacrolimus provide excellent GVHD prophylaxis in DUCBT, and this regimen is associated with low NRM after DUCBT.

  3. Fatal deep vein thrombosis after allogeneic reduced intensity hematopoietic stem cell transplantation for the treatment of metastatic gastric cancer.

    Science.gov (United States)

    Kamitsuji, Yuri; Mori, Shin-Ichiro; Kami, Masahiro; Yamada, Hirofumi; Shirakawa, Kazuo; Kishi, Yukiko; Murashige, Naoko; Kim, Sung-Won; Heike, Yuji; Takaue, Yoichi

    2004-08-01

    A 61-year-old man received reduced intensity stem cell transplantation (RIST) for the treatment of metastatic gastric cancer. The cytoreductive course of RIST was uneventful until day 0, when fever suddenly developed and his performance status deteriorated. Edema developed in the bilateral lower extremities by day 7, which was diagnosed by Doppler ultrasonography as deep vein thrombosis (DVT) involving the femoral veins to the inferior vena cava. While the edema improved with anticoagulation treatment, gastrointestinal graft-versus-host disease (GVHD) followed on day 13. Diarrhea subsided spontaneously, but hypoalbuminemia persisted, with the subsequent development of oliguria and jaundice on day 18. He died of sepsis on day 30, without any evidence of cancer progression. This case demonstrates that DVT is a potentially significant problem following RIST for solid tumors.

  4. Reduced-intensity hematopoietic stem-cell transplantation for malignant lymphoma: a retrospective survey of 112 adult patients in Japan.

    Science.gov (United States)

    Kusumi, E; Kami, M; Kanda, Y; Murashige, N; Kishi, Y; Suzuki, R; Takeuchi, K; Tanimoto, T E; Mori, T; Muta, K; Tamaki, T; Tanaka, Y; Ogawa, H; Yamane, T; Taniguchi, S; Takaue, Y

    2005-08-01

    We conducted a nation-wide survey of 112 adult Japanese patients who underwent reduced-intensity stem cell transplantation (RIST) from 1999 to 2002. Underlying diseases included indolent (n=45), aggressive (n=58) and highly aggressive lymphomas (n=9). Median age of the patients was 49 years. A total of 40 patients (36%) had relapsed diseases after autologous stem cell transplantation and 36 patients (32%) had received radiotherapy. RIST regimens were fludarabine-based (n=95), low-dose total body irradiation-based (n=6) and others (n=11). Cumulative incidences of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were, respectively, 49 and 59%. Cumulative incidences of progression and progression-free mortality were 18 and 25%, respectively. With a median follow-up of 23.9 months, 3-year overall survival rates were 59%. A multivariate analysis identified three significant factors for progression, which are history of radiation (relative risk (RR) 3.45, confidential interval (CI) 1.12-10.0, P=0.03), central nervous system involvement (RR 6.25, CI 2.08-20.0, P=0.001) and development of GVHD (RR 0.28, CI 0.090-0.86, P=0.026). RIST may have decreased the rate of transplant-related mortality, and GVHD may have induced a graft-versus-lymphoma effect. However, whether or not these potential benefits can be directly translated into improved patient survival should be evaluated in further studies.

  5. Low CD34 dose is associated with poor survival after reduced-intensity conditioning allogeneic transplantation for acute myeloid leukemia and myelodysplastic syndrome.

    Science.gov (United States)

    Törlén, Johan; Ringdén, Olle; Le Rademacher, Jennifer; Batiwalla, Minoo; Chen, Junfang; Erkers, Tom; Ho, Vincent; Kebriaei, Partow; Keever-Taylor, Carolyn; Kindwall-Keller, Tamila; Lazarus, Hillard M; Laughlin, Mary J; Lill, Michael; O'Brien, Tracey; Perales, Miguel-Angel; Rocha, Vanderson; Savani, Bipin N; Szwajcer, David; Valcarcel, David; Eapen, Mary

    2014-09-01

    Reduced-intensity conditioning/nonmyeloablative conditioning regimens are increasingly used in allogeneic hematopoietic cell transplantation (HCT). Reports have shown CD34(+) dose to be important for transplantation outcome using myeloablative conditioning. The role of CD34(+) dose of peripheral blood progenitor cells (PBPC) has not been previously analyzed in a large population undergoing reduced-intensity conditioning/nonmyeloablative HCT. We studied 1054 patients, ages 45 to 75 years, with acute myeloid leukemia or myelodysplastic syndrome who underwent transplantation between 2002 and 2011. Results of multivariate analysis showed that PBPC from HLA-matched siblings containing after myeloablative HCT, CD34(+) dose did not affect relapse or graft-versus-host disease with either donor type. An upper cell dose limit was not associated with adverse outcomes. These data suggest that PBPC CD34(+) doses >4 × 10(6) CD34(+)/kg and >6 × 10(6) CD34(+)/kg are optimal for HLA-matched sibling and unrelated donor HCT, respectively.

  6. Cost utility analysis of reduced intensity hematopoietic stem cell transplantation in adolescence and young adult with severe thalassemia compared to hypertransfusion and iron chelation program

    Science.gov (United States)

    2013-01-01

    Background Hematopoieticic stem cell transplantation is the only therapeutic option that can cure thalassemia disease. Reduced intensity hematopoietic stem cell transplantation (RI-HSCT) has demonstrated a high cure rate with minimal complications compared to other options. Because RI-HSCT is very costly, economic justification for its value is needed. This study aimed to estimate the cost-utility of RI-HSCT compared with blood transfusions combined with iron chelating therapy (BT-ICT) for adolescent and young adult with severe thalassemia in Thailand. Methods A Markov model was used to estimate the relevant costs and health outcomes over the patients’ lifetimes using a societal perspective. All future costs and outcomes were discounted at a rate of 3% per annum. The efficacy of RI-HSCT was based a clinical trial including a total of 18 thalassemia patients. Utility values were derived directly from all patients using EQ-5D and SF-6D. Primary outcomes of interest were lifetime costs, quality adjusted life-years (QALYs) gained, and the incremental cost-effectiveness ratio (ICER) in US ($) per QALY gained. One-way and probabilistic sensitivity analyses (PSA) were conducted to investigate the effect of parameter uncertainty. Results In base case analysis, the RI-HSCT group had a better clinical outcomes and higher lifetime costs. The incremental cost per QALY gained was US $ 3,236 per QALY. The acceptability curve showed that the probability of RI-HSCT being cost-effective was 71% at the willingness to pay of 1 time of Thai Gross domestic product per capita (GDP per capita), approximately US $ 4,210 per QALY gained. The most sensitive parameter was utility of severe thalassemia patients without cardiac complication patients. Conclusion At a societal willingness to pay of 1 GDP per capita, RI-HSCT was a cost-effective treatment for adolescent and young adult with severe thalassemia in Thailand compared to BT-ICT. PMID:23379888

  7. Alternative donor hematopoietic stem cell transplantation for mature lymphoid malignancies after reduced-intensity conditioning regimen

    DEFF Research Database (Denmark)

    Rodrigues, Celso Arrais; Rocha, Vanderson; Dreger, Peter;

    2014-01-01

    We have reported encouraging results of unrelated cord blood transplantation for patients with lymphoid malignancies. Whether those outcomes are comparable to matched unrelated donor transplants remains to be defined. We studied 645 adult patients with mature lymphoid malignancies who received an...

  8. Impact of graft-versus-host disease after reduced-intensity conditioning allogeneic stem cell transplantation for acute myeloid leukemia

    DEFF Research Database (Denmark)

    Baron, F; Labopin, M; Niederwieser, D;

    2012-01-01

    This report investigated the impact of graft-versus-host disease (GVHD) on transplantation outcomes in 1859 acute myeloid leukemia patients given allogeneic peripheral blood stem cells after reduced-intensity conditioning (RIC allo-SCT). Grade I acute GVHD was associated with a lower risk of rela...... of relapse (hazards ratio (HR)=0.7, P=0.02) translating into a trend for better overall survival (OS; HR=1.3; P=0.07). Grade II acute GVHD had no net impact on OS, while grade III-IV acute GVHD was associated with a worse OS (HR=0.4, P...

  9. Sequential regimen of clofarabine, cytosine arabinoside and reduced-intensity conditioned transplantation for primary refractory acute myeloid leukemia

    Science.gov (United States)

    Mohty, Mohamad; Malard, Florent; Blaise, Didier; Milpied, Noel; Socié, Gérard; Huynh, Anne; Reman, Oumédaly; Yakoub-Agha, Ibrahim; Furst, Sabine; Guillaume, Thierry; Tabrizi, Resa; Vigouroux, Stéphane; Peterlin, Pierre; El-Cheikh, Jean; Moreau, Philippe; Labopin, Myriam; Chevallier, Patrice

    2017-01-01

    The prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients’ outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33–71) at 1 year and 38% (95% CI: 18–46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26–64) at 1 year and 29% (95% CI: 13–48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1–24) at 1 year and 12% (95% CI: 3–19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174. PMID:27561720

  10. Impact of postremission consolidation chemotherapy on outcome after reduced-intensity conditioning allogeneic stem cell transplantation for patients with acute myeloid leukemia in first complete remission

    DEFF Research Database (Denmark)

    Yeshurun, Moshe; Labopin, Myriam; Blaise, Didier;

    2014-01-01

    The objective of the current study was to investigate the role of postremission consolidation chemotherapy before reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (alloSCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1).......The objective of the current study was to investigate the role of postremission consolidation chemotherapy before reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (alloSCT) for patients with acute myeloid leukemia (AML) in first complete remission (CR1)....

  11. Fludarabine-based reduced intensity conditioning transplants have a higher incidence of cytomegalovirus reactivation compared with myeloablative transplants.

    Science.gov (United States)

    George, B; Kerridge, I; Gilroy, N; Huang, G; Hertzberg, M; Gottlieb, D; Bradstock, K

    2010-05-01

    Two hundred and ten adult CMV seropositive patients undergoing myeloablative conditioning (MAC) [n=127] or reduced intensity conditioning (RIC) [n=83] transplants (HCT) were serially monitored for CMV reactivation and disease, using a qualitative polymerase chain reaction (PCR) followed by quantitation with pp65 antigen or quantitative PCR. CMV reactivation occurred in 53 RIC (63.9%) and 61 MAC (48%; P=0.03) transplants at a median of 47 days (range: 24-1977). Risk factors identified included acute GVHD (P=0.001), RIC regimen (P=0.03), unrelated donor (P=0.02), use of anti-thymocyte globulin/alemtuzumb (P=0.02) and use of bone marrow in MAC transplants (P=0.011). On multivariate analysis, RIC transplants and acute GVHD remained independent predictors. Treatment with antiviral drugs resulted in CMV negativity rates of 86.8% in MAC and 88.6% in RIC transplants. CMV disease occurred in 10.8% of RIC and 4.7% of MAC transplants (P=0.15). At a median follow-up of 26 months (range: 3-88), 48.1% of RIC and 50.3% of MAC transplants are alive. The higher incidence of CMV reactivation among RIC transplants suggests the need for novel prophylactic or pre-emptive strategies in this high-risk group of patients.

  12. Mycophenolate mofetil and cyclosporine for graft-versus-host disease prophylaxis following reduced intensity conditioning allogeneic stem cell transplantation.

    Science.gov (United States)

    Mohty, M; de Lavallade, H; Faucher, C; Bilger, K; Vey, N; Stoppa, A-M; Gravis, G; Coso, D; Viens, P; Gastaut, J-A; Blaise, D

    2004-09-01

    The use of reduced intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT) can result in a significant decrease in early procedure-related toxicity in patients not eligible for standard myeloablative regimens. However, acute graft-versus-host disease (aGVHD) remains a matter of concern after RIC allo-SCT, and its incidence might be expected to be higher in elderly and high-risk patients. This report investigated mycophenolate mofetil (MMF) and cyclosporin A (CsA) combination (n=14) in comparison to CsA alone (n=20) for GVHD prophylaxis in cancer patients aged over 50 years (27 haematological malignancies and seven solid tumours) receiving an HLA-identical sibling antithymocyte-globulin (ATG)-based RIC allo-SCT. Baseline demographic characteristics and risk factors for aGVHD were comparable between both groups. Although MMF administration was not associated with any significant toxicity, the cumulative incidence of any form of GVHD was comparable between both groups (cumulative incidence of grade II-IV aGVHD, 50% (95% CI, 28-72%) for CsA alone, as compared to 64% (95% CI, 39-89%) to CsA and MMF, P=NS), suggesting that adjunction of MMF to CsA is feasible, but does not translate towards a significant reduction of aGVHD, at least in the context ATG-based RIC allo-SCT.

  13. Impact of Cyclosporine Levels on the Development of Acute Graft versus Host Disease after Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Irene García Cadenas

    2014-01-01

    Full Text Available We analyze the impact of cyclosporine (CsA levels in the development of acute graft-versus-host disease (aGVHD after reduced intensity conditioning allogeneic hematopoietic transplantation (allo-RIC. We retrospectively evaluated 156 consecutive patients who underwent HLA-identical sibling allo-RIC at our institution. CsA median blood levels in the 1st, 2nd, 3rd and 4th weeks after allo-RIC were 134 (range: 10–444, 219 (54–656, 253 (53–910 and 224 (30–699 ng/mL; 60%, 16%, 11% and 17% of the patients had median CsA blood levels below 150 ng/mL during these weeks. 53 patients developed grade 2–4 aGVHD for a cumulative incidence of 45% (95% CI 34–50% at a median of 42 days. Low CsA levels on the 3rd week and sex-mismatch were associated with the development of GVHD. Risk factors for 1-year NRM and OS were advanced disease status (HR: 2.2, P=0.02 and development of grade 2–4 aGVHD (HR: 2.5, P<0.01, while there was a trend for higher NRM in patients with a low median CsA concentration on the 3rd week (P=0.06. These results emphasize the relevance of sustaining adequate levels of blood CsA by close monitoring and dose adjustments, particularly when engraftment becomes evident. CsA adequate management will impact on long-term outcomes in the allo-RIC setting.

  14. The impact of histopathologic examination of graft-versus-host disease in the era of reduced-intensity conditioning regimen: a study from the Gruppo Italiano Trapianto di Midollo Osseo.

    Science.gov (United States)

    Massi, Daniela; Fondi, Cristina; Nozzoli, Chiara; Benemei, Silvia; Lapi, Francesco; Albarello, Luca; Avellini, Claudio; Bonoldi, Emanuela; Casini, Marco; Cesinaro, Anna Maria; Ciceri, Fabio; Colombetti, Vito; Comin, Camilla Eva; Donelli, Amedea; Fortunato, Mirella; Fratoni, Stefano; Guidi, Stefano; Messerini, Luca; Milone, Giuseppe; Rapezzi, Davide; Negri, Giovanni; Patriarca, Francesca; Peccatori, Fedro Alessandro; Ponzoni, Maurilio; Rafaniello, Paola; Raimondi, Roberto; Salomone, Edvige; Tendas, Andrea; Villari, Loredana; Santucci, Marco; Bosi, Alberto

    2011-02-01

    Reduced-intensity conditioning regimens have reshaped the clinical presentation of graft-versus-host disease after hematopoietic stem cell transplants. However, histopathologic features of graft-versus-host disease following reduced-intensity conditioning regimens have not been fully characterized. In a series of 112 biopsies (skin, n = 60; gastrointestinal [GI] tract, n = 44; liver, n = 8), we described the morphologic profile of graft-versus-host disease following reduced-intensity conditioning and investigated whether histopathologic changes of graft-versus-host disease following reduced-intensity conditioning have a diagnostic and/or prognostic value. Forty-four patients (49.5%) experienced acute graft-versus-host disease, 2 (2.2%) late-onset acute graft-versus-host disease (grade I, n = 13; grade II-IV, n = 33), 24 (27.0%) chronic graft-versus-host disease (de novo n = 12, progressive n = 12) and 19 (21.3%) overlap syndrome. In the skin, we observed: (i) phase-nonspecific changes, such as acute graft-versus-host disease features in chronic graft-versus-host disease patients (n = 4/24; 16.6%), (ii) subtle alterations such as superficial fibrosis in widened dermal papillae (n = 8), in acute graft-versus-host disease/late-onset graft-versus-host disease (n = 6/46; 13.0%) or chronic graft-versus-host disease (n = 2/24, 8.3%) patients, and (iii) features of chronic and acute graft-versus-host disease coexisting in the same specimen in overlap syndrome (n = 3/19; 15.7%). In the GI tract, we did not demonstrate peculiar features differing from those commonly observed in the myeloablative setting. By univariate analysis, a reduced overall survival was associated with graft-versus-host disease type (chronic graft-versus-host disease P = .006, acute graft-versus-host disease P = .03), older age (P = .04), and histopathologic diagnosis of "consistent with" + definite graft-versus-host disease (P = .02). Histopathologic diagnosis retained an independent prognostic value

  15. Similar Survival for Patients Undergoing Reduced-Intensity Total Body Irradiation (TBI) Versus Myeloablative TBI as Conditioning for Allogeneic Transplant in Acute Leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Mikell, John L., E-mail: jmikell@emory.edu [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Waller, Edmund K. [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Switchenko, Jeffrey M. [Department of Biostatistics and Bioinformatics, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Rangaraju, Sravanti; Ali, Zahir; Graiser, Michael [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Hall, William A. [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Langston, Amelia A. [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Esiashvili, Natia [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Khoury, H. Jean [Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States); Khan, Mohammad K. [Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia (United States)

    2014-06-01

    Purpose: Hematopoietic stem cell transplantation (HSCT) is the mainstay of treatment for adults with acute leukemia. Total body irradiation (TBI) remains an important part of the conditioning regimen for HCST. For those patients unable to tolerate myeloablative TBI (mTBI), reduced intensity TBI (riTBI) is commonly used. In this study we compared outcomes of patients undergoing mTBI with those of patients undergoing riTBI in our institution. Methods and Materials: We performed a retrospective review of all patients with acute leukemia who underwent TBI-based conditioning, using a prospectively acquired database of HSCT patients treated at our institution. Patient data including details of the transplantation procedure, disease status, Karnofsky performance status (KPS), response rates, toxicity, survival time, and time to progression were extracted. Patient outcomes for various radiation therapy regimens were examined. Descriptive statistical analysis was performed. Results: Between June 1985 and July 2012, 226 patients with acute leukemia underwent TBI as conditioning for HSCT. Of those patients, 180 had full radiation therapy data available; 83 had acute lymphoblastic leukemia and 94 had acute myelogenous leukemia; 45 patients received riTBI, and 135 received mTBI. Median overall survival (OS) was 13.7 months. Median relapse-free survival (RFS) for all patients was 10.2 months. Controlling for age, sex, KPS, disease status, and diagnosis, there were no significant differences in OS or RFS between patients who underwent riTBI and those who underwent mTBI (P=.402, P=.499, respectively). Median length of hospital stay was shorter for patients who received riTBI than for those who received mTBI (16 days vs 23 days, respectively; P<.001), and intensive care unit admissions were less frequent following riTBI than mTBI (2.22% vs 12.69%, respectively, P=.043). Nonrelapse survival rates were also similar (P=.186). Conclusions: No differences in OS or RFS were seen between

  16. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia : a population-matched analysis

    NARCIS (Netherlands)

    Dreger, P; Brand, R; Milligan, D; Corradini, P; Finke, J; Deliliers, GL; Martino, R; Russell, N; van Biezen, A; Michallet, M; Niederwieser, D

    2005-01-01

    To elucidate whether reduced-intensity conditioning (RIC) decreases treatment-related mortality (TRM) after allogeneic stem cell transplantation (allo-SCT) for chronic lymphocytic leukemia (CLL), we retrospectively compared 73 RIC cases from a recent EBMT survey with 82 patients from the EBMT databa

  17. Tandem autologous/reduced-intensity conditioning allogeneic stem-cell transplantation versus autologous transplantation in myeloma: long-term follow-up

    NARCIS (Netherlands)

    Bjorkstrand, B.; Iacobelli, S.; Hegenbart, U.; Gruber, A.; Greinix, H.; Volin, L.; Narni, F.; Musto, P.; Beksac, M.; Bosi, A.; Milone, G.; Corradini, P.; Goldschmidt, H.; Witte, T.J.M. de; Morris, C.; Niederwieser, D.; Gahrton, G.

    2011-01-01

    PURPOSE: Results of allogeneic stem-cell transplantation (allo) in myeloma are controversial. In this trial autologous stem-cell transplantation (auto) followed by reduced-intensity conditioning matched sibling donor allo (auto-allo) was compared with auto only in previously untreated multiple myelo

  18. Radiolabeled anti-CD45 antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome.

    Science.gov (United States)

    Mawad, Raya; Gooley, Ted A; Rajendran, Joseph G; Fisher, Darrell R; Gopal, Ajay K; Shields, Andrew T; Sandmaier, Brenda M; Sorror, Mohamed L; Deeg, Hans Joachim; Storb, Rainer; Green, Damian J; Maloney, David G; Appelbaum, Frederick R; Press, Oliver W; Pagel, John M

    2014-09-01

    We treated patients under age 50 years with iodine-131 ((131)I)-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332 to 1561 mCi of (131)I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however, no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed grade II graft-versus-host disease (GVHD), 1 patient developed grade III GVHD, and no patients developed grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of nonrelapse mortality were observed in the first year after transplantation. However, 2 patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplantation, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using (131)I-anti-CD45 antibody in addition to standard reduced-intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse.

  19. IMPACT OF PRETRANSPLANT DONOR AND RECIPIENT CYTOMEGALOVIRUS SEROSTATUS ON OUTCOME FOR MULTIPLE MYELOMA PATIENTS UNDERGOING REDUCED INTENSITY CONDITIONING ALLOGENEIC STEM CELL TRANSPLANTATION.

    Directory of Open Access Journals (Sweden)

    Jean Elcheikh

    2013-04-01

    Full Text Available To investigate the impact of pre-transplant CMV serostatus of donor or recipient on outcome of patients undergoing allogeneic hematopoietic stem cell transplantation (Allo-SCT for Multiple Myeloma (MM. To our knowledge no data are available in the literature about this issue. We retrospectively followed 99 consecutive patients who underwent reduced-intensity conditioning (RIC Allo-SCT for MM in our cancer centre at Marseille between January 2000 and January 2012. Based upon CMV serostatus, patients were classified as low risk (donor [D]-/recipient [R]- 17 patients (17.1%, intermediate risk (D+/R 14 patients (14.1%, or high risk – either (D-/R+ 31 patients (31.3% or (D+/R+, 37 patients (37.3%. Cumulative incidence of CMV reactivation was 39% with a median time of 61 days (26–318. Three patients (3% developed CMV disease. Two factors were associated with CMV reactivation: CMV serostatus group (low: 0% vs intermediate: 29% vs high: 50%; p=0.001 and the presence of grade II–IV acute GvHD (Hazard Ratio: HR=2.1 [1.1–3.9]. Thirty-six of the 39 patients (92% with CMV reactivation did not present positive detection of CMV after a 21-day median duration preemptive treatment with ganciclovir. Cumulative incidence of day 100 grade II–IV acute GvHD, 1-year chronic GvHD and day 100 transplantation related mortality (TRM were 37%, 36% and 9%, respectively. CMV reactivation and serostatus were not associated with increased GvHD and TRM or short survival. Only the presence of acute GvHD as a time dependent variable was significantly associated with increased TRM (p=0.005. Two-year overall and progression free survival were 56% and 34%, respectively. Donor and recipient CMV serostatus and acute GvHD are independent factors for increased CMV reactivation in high-risk MM patients undergoing RIC Allo-SCT. However, we did not find any influence of CMV reactivation on post transplantation outcome. CMV monitoring and pre-emptive treatment strategy could in

  20. Hematopoietic stem cell transplantation conditioning with use of rituximab in EBV related lymphoproliferative disorders.

    Science.gov (United States)

    Shamriz, Oded; Vilk, Shoshana Revel; Wolf, Dana G; Ta-Shma, Asaf; Averbuch, Diana; Weintraub, Michael; Stepensky, Polina

    2014-04-01

    X-linked lymphoproliferative disease (XLP) and IL-2-inducible T cell kinase (ITK) deficiency are rare immunodeficiencies with a spectrum of clinical manifestations. Although there are no official guidelines for allogeneic hematopoietic stem cell transplantation (HSCT) in these patients, previous reports have shown that reduced intensity conditioning regimens provide successful engraftment with limited toxicity. Here, we report on three children with XLP and one with ITK deficiency, who underwent successful HSCT using a rituximab containing conditioning regimen, and review the current literature. Copyright © 2014 Elsevier Inc. All rights reserved.

  1. Allogeneic stem cell transplantation for X-linked agammaglobulinemia using reduced intensity conditioning as a model of the reconstitution of humoral immunity

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    Kazuhiro Ikegame

    2016-02-01

    Full Text Available Abstract Background We herein report the first case of X-linked agammaglobulinemia (XLA that underwent allogeneic stem cell transplantation using reduced intensity conditioning (RIC. We chronologically observed the reconstitution of humoral immunity in this case. Case presentation The patient was a 28-year-old Japanese male with XLA who previously had life-threatening infectious episodes and was referred for the possible indication of allogeneic stem cell transplantation. After a thorough discussion within specialists from different backgrounds, we decided to perform allogeneic peripheral stem cell transplantation from his HLA-identical elder brother. Due to the non-malignant nature of XLA, we selected RIC consisting of fludarabine, cyclophosphamide, anti-thymocyte globulin, and 3 Gy of total body irradiation. Neutrophil engraftment was achieved on day 11 with complete donor chimerism. No major complications, except for stage 1 skin graft-versus-host disease, were observed. The patient was discharged on day 75 and has been followed as an outpatient without any infectious episodes for more than 500 days. Conclusions Regarding immune reconstitution, CD19+ cells, IgA, and IgM, which were undetectable before allogeneic stem cell transplantation (allo-SCT, started to increase in number 10 days after allo-SCT and continued to increase for more than 1 year. Anti-B antibodies appeared as early as day 10. Total IgG levels decreased after the discontinuation of IgG replacement and spontaneously recovered after day 350. However, most anti-viral IgG titers, except EB virus-virus capsid antigen IgG, disappeared after the discontinuation of IgG replacement. A seasonal vaccination to influenza was performed on day 148, with neither anti-influenza type A nor type B being positive after the vaccination. The transient transfer of allergic immunity to orchard grass was observed. Similar Bruton’s tyrosine kinase (BTK expression levels in monocytes and B

  2. Thrombotic microangiopathy after allogeneic stem cell transplantation in the era of reduced-intensity conditioning: The incidence is not reduced.

    Science.gov (United States)

    Shimoni, Avichai; Yeshurun, Moshe; Hardan, Izhar; Avigdor, Abraham; Ben-Bassat, Isaac; Nagler, Arnon

    2004-07-01

    Thrombotic microangiopathy (TMA) is one of the most severe complications of stem cell transplantation (SCT). Endothelial cell injury caused by the toxic effects of high-dose chemoradiotherapy is likely the primary event in pathogenesis. The incidence, clinical settings, and risk factors for TMA in the era of nonmyeloablative conditioning have not been well defined. The data on 147 consecutive SCTs in a single center were collected, and patients with TMA were identified. Patient characteristics, response to therapy, and outcome were recorded, and risk factors were determined. TMA occurred in 22 of 147 transplantations, with a projected incidence of 20% +/- 4%. TMA occurred in 3 clinical settings: classic multifactorial TMA, TMA associated with severe hepatic graft-versus-host disease (GVHD), and TMA associated with second SCT, with a projected incidence of 8% +/- 3%, 73% +/- 14%, and 70% +/- 16% of patients at risk, respectively. TMA occurred after 23% +/- 6% of nonmyeloablative and 16% +/- 5% of myeloablative conditioning regimens (not significant). Univariate analysis determined SCT from unrelated donors, SCT during advanced or active disease, second SCT within 6 months of a prior SCT, and acute GVHD as risk factors for TMA. The last 2 factors remained significant in a multivariate model. Thirty-two percent of patients responded to therapy. The peri-TMA mortality rate was 68% +/- 10%. Six patients had diffuse alveolar hemorrhage complicating TMA. SCT-associated TMA is a relatively common complication with unsatisfactory therapy and grim prognosis. Fludarabine-based nonmyeloablative conditioning does not confer a lesser risk for TMA. This observation may relate to the selective use of these regimens in elderly and heavily pretreated patients or to the lack of reduction of GVHD with these regimens, and fludarabine itself may be involved in causing endothelial damage. Further exploration of novel preventive and therapeutic measurements is required in high

  3. The impact of HLA-matching on reduced intensity conditioning regimen unrelated donor allogeneic stem cell transplantation for acute myeloid leukemia in patients above 50 years—a report from the EBMT acute leukemia working party

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    Marie T. Rubio

    2016-08-01

    Full Text Available Abstract Background Data comparing fully matched and mismatched-unrelated-donor (M- and mM-URD allogeneic hematopoietic stem cell transplant (allo-SCT following reduced intensity conditioning regimens for acute myeloid leukemia are limited. Methods We retrospectively compared the outcome of 3398 patients above the age of 50 years who underwent 10/10 M-URD (n = 2567, 9/10 (n = 723, or 8/10 (n = 108 mM-URD allo-SCT for acute myeloid leukemia after reduced intensity conditioning regimen between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate. Results HLA matching had no impact on engraftment (p = 0.31. In univariate analysis, in comparison to 10/10 M-URD, mM-URD was associated with higher incidence of grade II–IV acute graft-versus-host disease (GVHD (p = 0.0002, similar rates of chronic GVHD (p = 0.138 but increased incidence of its extensive form (p = 0.047. Compared to 10/10 M-URD, patients transplanted in the first complete remission (CR1 with a 9 or an 8/10 mM-URD had decreased 2-year leukemia free (LFS (p = 0.005 and overall survivals (OS (56.7, 46.1, and 50.2 %, respectively, p = 0.005, while outcomes were comparable between all groups for patients transplanted beyond CR1. In multivariate analysis, 9/10 versus 10/10 URD was associated with higher non-relapse mortality (HR 1.34, p = 0.001, similar risk of relapse and chronic GVHD and inferior LFS (HR 1.25, p = 0.0001, and OS (HR 1.27, p = 0.0001. There was no difference in adjusted transplant outcomes between 9/10 and 8/10 mM-URD. Conclusions Reduced intensity conditioned allo-SCT with a 10/10 M-URD remains the preferable option for AML patients above the age of 50 years. The use of a 9/10 or an 8/10 mM-URD in patients not having a fully matched donor represents an alternative therapeutic option that should be compared to other

  4. Gemcitabine, Fludarabine, and Melphalan for Reduced-Intensity Conditioning and Allogeneic Stem Cell Transplantation for Relapsed and Refractory Hodgkin Lymphoma.

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    Anderlini, Paolo; Saliba, Rima M; Ledesma, Celina; Plair, Tamera; Alousi, Amin M; Hosing, Chitra M; Khouri, Issa F; Nieto, Yago; Popat, Uday R; Shpall, Elizabeth J; Fanale, Michelle A; Hagemeister, Frederick B; Oki, Yasuhiro; Neelapu, Saatva; Romaguera, Jorge E; Younes, Anas; Champlin, Richard E

    2016-07-01

    Forty patients (median age, 31 years; range, 20 to 63) with Hodgkin lymphoma underwent an allogeneic stem cell transplant with the gemcitabine-fludarabine-melphalan reduced-intensity conditioning regimen. Thirty-one patients (77%) had undergone a prior autologous stem cell transplant, with a median time to progression after transplant of 6 months (range, 1 to 68). Disease status at transplant was complete remission/complete remission, undetermined (n = 23; 57%), partial remission (n = 14; 35%), and other (n = 3; 8%). Twenty-six patients (65%) received brentuximab vedotin before allotransplant. The overall complete response rate before allotransplant was 65% in brentuximab-treated patients versus 42% in brentuximab-naive patients (P = .15). At the latest follow-up (October 2015) 31 patients were alive. The median follow-up was 41 months (range, 5 to 87). Transplant-related mortality rate at 3 years was 17%. Pulmonary, skin toxicities, and nausea were seen in 13 (33%), 11 (28%), and 37 (93%) patients, respectively. At 3 years, estimates for overall and progression-free survival were 75% (95% CI, 57% to 86%) and 54% (95% CI, 36% to 70%). Overall incidence for disease progression was 28% (95% CI, 16% to 50%). We believe the gemcitabine-fludarabine-melphalan regimen allows moderate dose intensification with acceptable morbidity and mortality. The inclusion of gemcitabine affected nausea, pulmonary, and likely skin toxicity. Exposure to brentuximab vedotin allowed more patients to reach allogeneic stem cell transplantation in complete remission. With over 50% of patients progression-free at 3 years, allogeneic stem cell transplantation with reduced-intensity conditioning remains an effective and relevant treatment option for Hodgkin lymphoma in the brentuximab vedotin era.

  5. Reduced-intensity conditioning and HLA-matched haemopoietic stem-cell transplantation in patients with chronic granulomatous disease: a prospective multicentre study.

    Science.gov (United States)

    Güngör, Tayfun; Teira, Pierre; Slatter, Mary; Stussi, Georg; Stepensky, Polina; Moshous, Despina; Vermont, Clementien; Ahmad, Imran; Shaw, Peter J; Telles da Cunha, José Marcos; Schlegel, Paul G; Hough, Rachel; Fasth, Anders; Kentouche, Karim; Gruhn, Bernd; Fernandes, Juliana F; Lachance, Silvy; Bredius, Robbert; Resnick, Igor B; Belohradsky, Bernd H; Gennery, Andrew; Fischer, Alain; Gaspar, H Bobby; Schanz, Urs; Seger, Reinhard; Rentsch, Katharina; Veys, Paul; Haddad, Elie; Albert, Michael H; Hassan, Moustapha

    2014-02-01

    In chronic granulomatous disease allogeneic haemopoietic stem-cell transplantation (HSCT) in adolescents and young adults and patients with high-risk disease is complicated by graft-failure, graft-versus-host disease (GVHD), and transplant-related mortality. We examined the effect of a reduced-intensity conditioning regimen designed to enhance myeloid engraftment and reduce organ toxicity in these patients. This prospective study was done at 16 centres in ten countries worldwide. Patients aged 0-40 years with chronic granulomatous disease were assessed and enrolled at the discretion of individual centres. Reduced-intensity conditioning consisted of high-dose fludarabine (30 mg/m(2) [infants <9 kg 1·2 mg/kg]; one dose per day on days -8 to -3), serotherapy (anti-thymocyte globulin [10 mg/kg, one dose per day on days -4 to -1; or thymoglobuline 2·5 mg/kg, one dose per day on days -5 to -3]; or low-dose alemtuzumab [<1 mg/kg on days -8 to -6]), and low-dose (50-72% of myeloablative dose) or targeted busulfan administration (recommended cumulative area under the curve: 45-65 mg/L × h). Busulfan was administered mainly intravenously and exceptionally orally from days -5 to -3. Intravenous busulfan was dosed according to weight-based recommendations and was administered in most centres (ten) twice daily over 4 h. Unmanipulated bone marrow or peripheral blood stem cells from HLA-matched related-donors or HLA-9/10 or HLA-10/10 matched unrelated-donors were infused. The primary endpoints were overall survival and event-free survival (EFS), probabilities of overall survival and EFS at 2 years, incidence of acute and chronic GVHD, achievement of at least 90% myeloid donor chimerism, and incidence of graft failure after at least 6 months of follow-up. 56 patients (median age 12·7 years; IQR 6·8-17·3) with chronic granulomatous disease were enrolled from June 15, 2003, to Dec 15, 2012. 42 patients (75%) had high-risk features (ie, intractable infections and

  6. Effect of acute and chronic graft-versus-host disease on relapse and survival after reduced-intensity conditioning allogeneic transplantation for myeloma

    Science.gov (United States)

    Ringdén, Olle; Shrestha, Smriti; da Silva, Gisela Tunes; Zhang, Mei-Jie; Dispenzieri, Angela; Remberger, Mats; Kamble, Rammurti; Freytes, Cesar O.; Gale, Robert Peter; Gibson, John; Gupta, Vikas; Holmberg, Leona; Lazarus, Hillard; McCarthy, Philip; Meehan, Kenneth; Schouten, Harry; Milone, Gustavo A.; Lonial, Sagar; Hari, Parameswaran N

    2011-01-01

    We evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on relapse and survival after allogeneic haematopoietic stem cell transplantation (HSCT) for multiple myeloma (MM) using non-myeloablative conditioning (NMA) and reduced-intensity conditioning (RIC). The outcomes of 177 HLA-identical sibling HSCT recipients between 1997 and 2005 following NMA (n=98) or RIC (n=79) were analyzed. In 105 patients, autografting was followed by planned NMA/RIC allogeneic transplantation. The impact of GVHD was assessed as a time-dependent covariate using Cox models. The incidence of acute GVHD (grades I–IV) was 42% (95% confidence interval (CI) 35 – 49%) and of chronic GVHD at five years was 59% (95% CI 49 – 69%), with 70% developing extensive chronic GVHD. In multivariate analysis, acute GVHD (≥ grade I) was associated with an increased risk of TRM (relative risk (RR)=2.42; p=0.016), whereas limited chronic GVHD significantly decreased the risk of myeloma relapse (RR=0.35, p=0.035) and was associated with superior event-free survival (RR=0.40, p=0.027). Acute GVHD had a detrimental effect on survival, especially in those receiving autologous followed by allogeneic HSCT (RR=3.52; p=0.001). The reduction in relapse risk associated with chronic GVHD is consistent with a beneficial graft-versus-myeloma effect, but this did not translate into a survival advantage. PMID:21946381

  7. Initial fluconazole prophylaxis may not be required in adults with acute leukemia or myelodysplastic/myeloproliferative disorders after reduced intensity conditioning peripheral blood stem cell allogeneic transplantation.

    Science.gov (United States)

    Brissot, Eolia; Cahu, Xavier; Guillaume, Thierry; Delaunay, Jacques; Ayari, Sameh; Peterlin, Pierre; Le Bourgeois, Amandine; Harousseau, Jean-Luc; Milpied, Noel; Bene, Marie-Christine; Moreau, Philippe; Mohty, Mohamad; Chevallier, Patrice

    2015-04-01

    In the myeloablative transplant setting, the early use of fluconazole prophylaxis provides a benefit in overall survival. Recent changes in transplantation practices, including the use of peripheral blood stem cells (PBSC) and/or reduced intensity conditioning (RIC) regimen may have favorably impacted the epidemiology of invasive fungal infections (IFI) after allogeneic stem cell transplantation (allo-SCT). Yet, the impact of removing fluconazole prophylaxis after RIC PBSC allotransplant is ill known. Here, a retrospective analysis was performed comparing patients who received fluconazole as antifungal prophylaxis (n = 53) or not (n = 56) after allo-SCT for acute leukemia or myelodysplastic/myeloproliferative syndrome. Sixteen IFI were documented (14 %) at a median time of 103 days after transplantation, including eight before day +100, at a similar rate, whether the patients received fluconazole prophylaxis (13 %) or not (16 %). IFI were due mainly to Aspergillus species (87 %), and only two Candida-related IFI (13 %) were documented in the non-fluconazole group before day +100. The incidences of IFI (overall, before or after day +100) as well as 3-year overall and disease-free survival, non-relapse mortality, or acute and chronic graft-versus-host disease (GVHD) were similar between both groups. In conclusion, this study suggests that fluconazole may not be required at the initial phase of RIC allo-SCT using PBSC. This result has to be confirmed prospectively while Aspergillus prophylaxis should be discussed in this particular setting.

  8. Fludarabine-Busulfan Reduced-Intensity Conditioning in Comparison with Fludarabine-Melphalan Is Associated with Increased Relapse Risk In Spite of Pharmacokinetic Dosing.

    Science.gov (United States)

    Damlaj, Moussab; Alkhateeb, Hassan B; Hefazi, Mehrdad; Partain, Daniel K; Hashmi, Shahrukh; Gastineau, Dennis A; Al-Kali, Aref; Wolf, Robert C; Gangat, Naseema; Litzow, Mark R; Hogan, William J; Patnaik, Mrinal M

    2016-08-01

    Fludarabine with busulfan (FB) and fludarabine with melphalan (FM) are commonly used reduced-intensity conditioning (RIC) regimens. Pharmacokinetic dosing of busulfan (Bu) is frequently done for myeloablative conditioning, but evidence for its use is limited in RIC transplants. We compared transplant outcomes of FB versus FM using i.v. Bu targeted to the area under the curve (AUC). A total of 134 RIC transplants (47 FB and 87 FM) for acute myelogenous leukemia and myelodysplastic syndrome were identified, and median follow-up of the cohort was 40 months (range, 0 to 63.3). A significantly higher 2-year cumulative incidence of relapse (CIR) was associated with FB versus FM at 35.6% versus 17.3%, respectively (P = .0058). Furthermore, 2-year progression-free survival rates were higher for FM versus FB at 60.5% versus 48.7%, respectively (P = .04). However, 2-year rates of nonrelapse mortality (NRM) and overall survival (OS) were similar. The need for dose adjustment based on AUC did not alter relapse risk or NRM. Patients with Karnofsky performance status ≥ 90 who received FM had a 2-year OS rate of 74.8% versus 48.3% for FB (P = .03). FB use remained prognostic for relapse in multivariable analysis (hazard ratio, 2.75; 95% confidence interval, 1.28 to 5.89; P = .0097). In summary, in spite of AUC-directed dosing, FB compared with FM was associated with a significantly higher CIR.

  9. Influence of Stem Cell Source on Outcomes of Allogeneic Reduced-Intensity Conditioning Therapy Transplants Using Haploidentical Related Donors.

    Science.gov (United States)

    Bradstock, Kenneth; Bilmon, Ian; Kwan, John; Blyth, Emily; Micklethwaite, Kenneth; Huang, Gillian; Deren, Stephanie; Byth, Karen; Gottlieb, David

    2015-09-01

    We compared outcomes for 2 retrospective cohorts of patients undergoing reduced-intensity conditioning (RIC) therapy transplants using haploidentical related donors and post-transplant prophylaxis against graft-versus-host disease (GVHD) with high-dose cyclophosphamide, tacrolimus, and mycophenolate. The first cohort of 13 was transplanted with bone marrow (BM) as the stem cell source, whereas the second cohort of 23 used peripheral blood stem cells (PBSCs) mobilized with granulocyte colony-stimulating factor. The BM cohort received a single 60-mg/kg dose of cyclophosphamide on day +3, whereas the PBSC cohort received 2 doses on days +3 and +4. Patients in the first cohort were slightly older and had a higher proportion of acute myeloid leukemia, but there were no differences in the distribution of Disease Risk Index scores between the 2 groups. Patients in the PBSC group received double the number of CD34(+) cells in the stem cell graft. Times to neutrophil and platelet recovery were not different between the 2 groups. Three patients, all in the PBSC group, failed to engraft but recovered with autologous hemopoiesis and survived. The 6-month cumulative incidences of acute GVHD were 55.1% for BM and 48.5% for PBSCs (P = .651), whereas 24-month cumulative rates for chronic GHVD were 28.6% for BM and 32.3% for PBSCs (P = .685). Only 2 patients, both in the BM group, died of nonrelapse causes, both of second cancers. The 2-year cumulative incidences of relapse were 43.9% for BM and 23.5% for PBSCs (P = .286). Overall survival at 2 years was significantly better for PBSC patients (P = .028), at 83.4% versus 52.7% for BM. Relapse-free and event-free survival did not differ significantly between BM and PBSC groups. In this retrospective analysis, we conclude that the use of PBSCs for haploidentical RIC transplants is a feasible strategy, with equivalent rates of acute and chronic GVHD and risk of relapse and low nonrelapse mortality compared with BM.

  10. FHL2 regulates hematopoietic stem cell functions under stress conditions

    Science.gov (United States)

    Hou, Yu; Wang, Xiaoqin; Li, LiPing; Fan, Rong; Chen, Ju; Zhu, Tongyu; Li, Wen; Jiang, Yanwen; Mittal, Nupur; Wu, Wenshu; Peace, David; Qian, Zhijian

    2014-01-01

    FHL2, a member of the four and one half LIM domain protein family, is a critical transcriptional modulator. Here, we identify FHL2 as a critical regulator of hematopoietic stem cells (HSCs) that is essential for maintaining HSC self-renewal under regenerative stress. We find that Fhl2 loss has limited effects on hematopoiesis under homeostatic conditions. In contrast, Fhl2-null chimeric mice reconstituted with Fhl2-null bone marrow cells developed abnormal hematopoiesis with significantly reduced numbers of HSCs, hematopoietic progenitor cells (HPCs), red blood cells and platelets as well as hemoglobin levels. In addition, HSCs displayed a significantly reduced self-renewal capacity and were skewed toward myeloid lineage differentiation. We find that Fhl2 loss reduces both HSC quiescence and survival in response to regenerative stress, probably as a consequence of Fhl2-loss-mediated down-regulation of cyclin dependent kinase (CDK)-inhibitors, including p21(Cip) and p27(Kip1). Interestingly, FHL2 is regulated under control of a tissue specific promoter in hematopoietic cells and it is down-regulated by DNA hypermethylation in the leukemia cell line and primary leukemia cells. Furthermore, we find that down-regulation of FHL2 frequently occurs in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients, raising a possibility that FHL2 down-regulation plays a role in the pathogenesis of myeloid malignancies. PMID:25179730

  11. Impact of conditioning intensity and TBI on acute GVHD after hematopoietic cell transplantation.

    Science.gov (United States)

    Nakasone, H; Fukuda, T; Kanda, J; Mori, T; Yano, S; Kobayashi, T; Miyamura, K; Eto, T; Kanamori, H; Iwato, K; Uchida, N; Mori, S; Nagamura-Inoue, T; Ichinohe, T; Atsuta, Y; Teshima, T; Murata, M

    2015-04-01

    The impact of the conditioning intensity and TBI on acute GVHD (aGVHD) is still a matter of debate. We analyzed 6848 adult recipients who received allogeneic hematopoietic cell transplants (HCT) between 2006 and 2011 in Japan. The subjects were divided into groups who had received myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), either with or without TBI. There was a significant difference in the incidence of aGVHD 2-4 among the different conditioning types: 39% in TBI-MAC, 35% in TBI-RIC and 32% in both no-TBI MAC and no-TBI-RIC (PTBI-MAC, but not no-TBI MAC, was significantly associated with an increased risk of aGVHD 2-4 (hazard ratio (HR) 1.33, PTBI-RIC was associated with an increased risk of GVHD 3-4 (HR 1.36, P=0.048). TBI-MAC and TBI-RIC were significantly associated with skin and gastrointestinal aGVHD. Subgroup analyses demonstrated that not only TBI-MAC, but also TBI-RIC, was significantly associated with aGVHD 2-4 in older patients. Furthermore, high-dose TBI only had an adverse impact on aGVHD 2-4 in HLA-matched HCT. Impacts of intensity and TBI on aGVHD differ by patient backgrounds, and this difference should be considered to establish a risk-adapted strategy for the prevention of aGVHD.

  12. Incidence and risk factors for moderate-to-severe veno-occlusive disease of the liver after allogeneic stem cell transplantation using a reduced intensity conditioning regimen.

    Science.gov (United States)

    Tsirigotis, P D; Resnick, I B; Avni, B; Grisariu, S; Stepensky, P; Or, R; Shapira, M Y

    2014-11-01

    The incidence and outcome of moderate-to-severe veno-occlusive (VOD) disease was analyzed in 271 consecutive patients with hematological malignancies who underwent allogeneic SCT (allo-SCT) using the same reduced intensity regimen (RIC). RIC consisted of fludarabine, BU and antithymocyte globulin (ATG). Twenty-four out of 271 patients (8.8%) developed VOD, which was severe in only 4 (1.4%) out of 24 cases. All four patients with severe VOD finally succumbed to their disease. In multivariate analysis, i.v. administration of BU was associated with significant reduced incidence of VOD as compared with per os administration. In conclusion, VOD remains a serious complication of allo-SCT using RIC regimens containing BU. Although the incidence of severe VOD is very low, the overall mortality rate in the group of patients with severe VOD remains extremely high and therefore novel treatment approaches are needed.

  13. Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission

    DEFF Research Database (Denmark)

    Nagler, Arnon; Labopin, Myriam; Shimoni, Avichai;

    2012-01-01

    to compare the outcome of mobilized peripheral blood stem cells (PBSC) (n = 1430) vs. bone marrow (BM) (n = 107) for acute myelogenous leukemia (AML) patients with complete remission that underwent RIC-alloSCT from compatible sibling donors. The leukemia features, the disease status, and the time from......, relapse, and NRM when comparing PBSC to BM grafts from sibling donors following RIC conditioning. This is the first study comparing PBSC to BM grafts in the RIC setting, analyzing a homogeneous population of patients with AML in remission. Whether PBSC should be preferred for advanced phases...

  14. Long-term outcomes among older patients following nonmyeloablative conditioning and allogeneic hematopoietic cell transplantation for advanced hematologic malignancies

    DEFF Research Database (Denmark)

    Sorror, Mohamed L; Sandmaier, Brenda M; Storer, Barry E

    2011-01-01

    A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions....

  15. Cytoreductive treatment with clofarabine/ara-C combined with reduced-intensity conditioning and allogeneic stem cell transplantation in patients with high-risk, relapsed, or refractory acute myeloid leukemia and advanced myelodysplastic syndrome.

    Science.gov (United States)

    Buchholz, Stefanie; Dammann, Elke; Stadler, Michael; Krauter, Juergen; Beutel, Gernot; Trummer, Arne; Eder, Matthias; Ganser, Arnold

    2012-01-01

    The combination of cytoreductive chemotherapy with reduced-intensity conditioning (RIC) is a highly effective antileukemic therapy. Purpose of this retrospective analysis was to evaluate the antileukemic efficacy and toxicity of clofarabine-based chemotherapy followed by RIC and allogeneic stem cell transplantation (SCT) for high-risk, relapsed, or refractory acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). From May 2007 until October 2009, a total of 27 patients underwent allogeneic SCT after treatment with clofarabine and ara-C for 5d and RIC (4Gy TBI/cyclophosphamide/ATG). Prophylaxis of graft-versus-host disease (GvHD) consisted of cyclosporine and mycophenolate mofetil. Unmanipulated G-CSF mobilized PBSC (n=26) or bone marrow cells (n=1) were transplanted from unrelated (n=21) or matched related (n=6) donors. Non-hematological toxicities of this regimen mainly affected liver and skin and were all reversible. Seven patients relapsed within a median time of 5.7 months. The overall survival (OS) and relapse-free survival rates were 56% and 52% at 2 yr, respectively. In this cohort of patients, cytoreduction with clofarabine/ara-C (ClAraC) followed by RIC allogeneic SCT was well tolerated and showed good antileukemic efficacy even in patients with high-risk AML or MDS, with engraftment and GvHD-incidence comparable to other RIC regimens.

  16. Impact of cytogenetics risk on outcome after reduced intensity conditioning allo-SCT from an HLA-identical sibling for patients with AML in first CR: a report from the acute leukemia working party of EBMT.

    Science.gov (United States)

    Chevallier, P; Labopin, M; Milpied, N; Cornelissen, J J; Blaise, D; Petersen, E; Sandstedt, A; Goker, H; Socie, G; Rocha, V; Mohty, M

    2012-11-01

    So far the impact of cytogenetics risk on outcome in the context of reduced intensity conditioning (RIC) allo-SCT has been poorly studied. We have identified 378 AML patients in first CR who underwent RIC allo-SCT from an HLA-matched sibling donor between 2000 and 2007 reported to the European Group for Bone and Marrow Transplantation and for whom detailed cytogenetics data were available (good risk: n=21; intermediate risk: n=304; and poor risk: n=53). With a median follow-up of 24 months (range: 1-93), 2-year non-relapse mortality, relapse rate (RR), leukemia-free survival (LFS) and OS were 14%, 31%, 55% and 61%, respectively. Cytogenetics was significantly associated with RR (good risk: 10%; intermediate risk: 28%; and poor risk: 55% at 2 years, Pcytogenetics group (P=0.001, P=0.004) and in patients with a higher WBC at diagnosis (>10 × 10(9)/L) (Pcytogenetics had increased RR and decreased LFS after RIC allo-SCT, requiring new prospective strategies to improve results in this subgroup.

  17. The prognostic value of YKL-40 concentrations in nonmyeloablative conditioning allogeneic hematopoietic cell transplantation

    DEFF Research Database (Denmark)

    Mørup, Anne Mette; Kornblit, Brian; Johansen, Julia S;

    2011-01-01

    and plasma YKL-40 concentrations as prognostic biomarkers in a cohort of 149 patients treated with hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies. Recipients with pretransplant YKL-40 concentrations above the age-adjusted 95th percentile (high) had...

  18. Radiation-sensitive severe combined immunodeficiency: The arguments for and against conditioning before hematopoietic cell transplantation--what to do?

    Science.gov (United States)

    Cowan, Morton J; Gennery, Andrew R

    2015-11-01

    Defects in DNA cross-link repair 1C (DCLRE1C), protein kinase DNA activated catalytic polypeptide (PRKDC), ligase 4 (LIG4), NHEJ1, and NBS1 involving the nonhomologous end-joining (NHEJ) DNA repair pathway result in radiation-sensitive severe combined immunodeficiency (SCID). Results of hematopoietic cell transplantation for radiation-sensitive SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of preconditioning with alkylating agents is associated with a greater likelihood of full T- and B-cell reconstitution compared with no conditioning or immunosuppression alone. A reduced-intensity regimen using fludarabine and low-dose cyclophosphamide might be effective for patients with LIG4, NHEJ1, and NBS1 defects, although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose-alkylating agents without significant late effects. Until nonchemotherapy agents, such as anti-CD45 or anti-CD117, become available, options include minimizing exposure to alkylators, such as single-agent low-dose targeted busulfan, or achieving T-cell reconstitution, followed several years later with a conditioning regimen to restore B-cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and graft-versus-host disease. Prospective multicenter studies are needed to evaluate these approaches in this rare but highly vulnerable patient population.

  19. Infections after allogeneic hematopoietic stem cell transplantation with a nonmyeloablative conditioning regimen.

    OpenAIRE

    Frere, Pascale; Baron, Frédéric; Bonnet, Christophe; HAFRAOUI, Kaoutar; Pereira-Martins, Maguy; Willems, Evelyne; Fillet, Georges; Beguin, Yves

    2006-01-01

    Hematopoietic cell transplantation (HCT) following nonmyeloablative conditioning (NMSCT) may be associated with a reduced risk of infection compared to standard allogeneic HCT. We retrospectively analyzed incidence and risk factors of infection in 62 patients undergoing NMSCT with low-dose TBI +/- fludarabine and postgrafting CsA and MMF. The proportion of patients with any infection was 77%, but the majority of infectious events occurred beyond day 30. Donor other than sibling, older age, ea...

  20. Graft rejection after hematopoietic cell transplantation with nonmyeloablative conditioning

    DEFF Research Database (Denmark)

    Masmas, T.N.; Petersen, S.L.; Madsen, H.O.;

    2008-01-01

    -dose fludarabine and total body irradiation (TBI). The association of pretransplantation risk factors with rejection and the effect of chimerism and graft-versus-host disease on rejection were analyzed. Overall survival (OS) and progression free survival (PFS) were compared between patients with and without...... rejection. Retransplantation was performed with increased TBI conditioning for all patients, and with increased mycophenolate mofetil doses for recipients with HLA-identical sibling donors. No known pretransplantation risk factors were confirmed in this study. Rejection episodes were unevenly distributed...

  1. Radiation-Sensitive Severe Combined Immunodeficiency: The arguments for and against conditioning prior to hematopoietic cell transplantation – What to do?

    Science.gov (United States)

    Cowan, MJ; Gennery, AR

    2015-01-01

    Defects in DCLRE1C, PRKDC, LIG4, NHEJ1, and NBS1, involving the non-homologous end joining (NHEJ) DNA repair pathway, result in radiation-sensitive severe combined immunodeficiency (RS-SCID). Results of hematopoietic cell transplantation for RS-SCID suggest that minimizing exposure to alkylating agents and ionizing radiation is important for optimizing survival and minimizing late effects. However, use of pre-conditioning with alkylating agents is associated with a greater likelihood of full T and B cell reconstitution compared to no conditioning or immunosuppression alone. A reduced intensity regimen using fludarabine and low dose cyclophosphamide may be effective for patients with LIG4, NHEJ1 and NBS1 defects although more data are needed to confirm these findings and characterize late effects. For patients with mutations in DCLRE1C (Artemis-deficient SCID), there is no optimal approach that uses standard dose alkylating agents without significant late effects. Until non-chemotherapy agents, e.g., anti-CD45 or anti-CD117 become available, options include minimizing exposure to alkylators, e.g., single agent low dose targeted Busulfan or achieving T cell reconstitution followed several years later with a conditioning regimen to restore B cell immunity. Gene therapy for these disorders will eventually remove the issues of rejection and GvHD. Prospective multi- center studies are needed to evaluate these approaches in this rare but highly vulnerable patient population. PMID:26055221

  2. Reduced intensity transplantation for primary immunodeficiency disorders

    Directory of Open Access Journals (Sweden)

    Paul Veys

    2011-06-01

    Full Text Available Studies so far indicate that reduced intensity transplantation (RIT may have an important role in treating patients with primary immunodeficiency disease (PID. Unlike more standard approaches, such regimens can be used without severe toxicity in patients with severe pulmonary or hepatic disease. RIT also offers the advantage that long-term sequelae such as infertility or growth retardation may be avoided or reduced. RIT appears to be most appropriate for those patients with significant co-morbidities (eg T cell deficiencies and those undergoing unrelated donor haematopoietic cell transplantation. More studies are required using pharmacokinetic monitoring (eg busulphan, treosulfan and alemtuzumab and varying stem cell sources to optimise graft vs marrow reactions and minimise graft vs host disease. In certain PID patients RIT will be the “first step” towards establishing donor cell engraftment; second infusions of donor stem cells, donor lymphocyte infusions, or a second myeloablative HCT, which appears to be well tolerated, may be required in some patients with low level donor chimerism or graft rejection.

  3. Successful clinical treatment and functional immunological normalization of human MALT1 deficiency following hematopoietic stem cell transplantation.

    Science.gov (United States)

    Rozmus, Jacob; McDonald, Rachel; Fung, Shan-Yu; Del Bel, Kate L; Roden, Juliana; Senger, Christof; Schultz, Kirk R; McKinnon, Margaret L; Davis, Jeffrey; Turvey, Stuart E

    2016-07-01

    MALT1 mutations impair normal NF-κB activation and paracaspase activity to cause a novel combined immunodeficiency. The clinical and immunological phenotype of MALT1 deficiency can be successfully treated with hematopoietic stem cell transplantation following reduced intensity conditioning.

  4. Impact of conditioning on outcome of hematopoietic stem cell transplantation for wiskott-Aldrich syndrome.

    Science.gov (United States)

    Stepensky, Polina; Krauss, Aviva; Goldstein, Gal; Zaidman, Irena; Elhasid, Ronit; Bielorai, Bela; Somech, Raz; Or, Reuven; Stein, Jerry; Revel-Vilk, Shoshana; Weintraub, Michael

    2013-08-01

    Hematopoietic stem cell transplantation (HSCT) is the treatment of choice for Wiskott-Aldrich syndrome (WAS). The aim of this retrospective study is to report the effect of the conditioning regimen and donor source on disease-free survival (DFS) in children undergoing HSCT for WAS. Fourteen children who underwent HSCT at 4 Israeli centers from 1996 to 2011 were included in this study. Five children were transplanted from matched related donors (4/5 siblings, 1/5 fully matched uncle) and other donors were used in 9 children. Six patients were conditioned with full dose busulfan/cyclophosphamide (Bu/Cy) whereas 8 patients were conditioned with other regimens. Thirteen of 14 patients (92.8%) are alive with a median follow-up of 3.4 years (range, 5 mo to 12.5 y). Nine patients (64.3%) survive with complete clinical, immunologic, and hematologic recovery. Children conditioned with full dose Bu/Cy had a 100% DFS, compared with children conditioned with other regimens, 25%±19% (P=0.022). Donor source was not associated with DFS. Graft failure was related to the use of conditioning regimens other than full dose Bu/Cy and not to the donor source. Further studies are required to determine the best conditioning regimen and optimal donor source for children with WAS.

  5. Allogeneic hematopoietic cell transplantation after conditioning with I-131-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

    Energy Technology Data Exchange (ETDEWEB)

    Pagel, John M.; Gooley, T. A.; Rajendran, Joseph G.; Fisher, Darrell R.; Wilson, Wendy A.; Sandmaier, B. M.; Matthews, D. C.; Deeg, H. Joachim; Gopal, Ajay K.; Martin, P. J.; Storb, R.; Press, Oliver W.; Appelbaum, Frederick R.

    2009-12-24

    We conducted a study to estimate the maximum tolerated dose (MTD) of I-131-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of I-131-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

  6. Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

    Science.gov (United States)

    Pagel, John M; Gooley, Theodore A; Rajendran, Joseph; Fisher, Darrell R; Wilson, Wendy A; Sandmaier, Brenda M; Matthews, Dana C; Deeg, H Joachim; Gopal, Ajay K; Martin, Paul J; Storb, Rainer F; Press, Oliver W; Appelbaum, Frederick R

    2009-12-24

    We conducted a study to estimate the maximum tolerated dose (MTD) of (131)I-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of (131)I-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  8. Rituximab, fludarabine, and total body irradiation as conditioning regimen before allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukemia: long-term prospective multicenter study.

    Science.gov (United States)

    Michallet, Mauricette; Socié, Gerard; Mohty, Mohamad; Sobh, Mohamad; Bay, Jacques-O; Morisset, Stéphane; Labussière-Wallet, Hélène; Tabrizi, Reza; Milpied, Noel; Bordigoni, Pierre; El-Cheikh, Jean; Blaise, Didier

    2013-02-01

    To evaluate the efficacy and toxicity of reduced-intensity conditioning (RIC) combining fludarabine, low-dose total body irradiation (TBI) and rituximab before allogeneic hematopoietic stem cell transplantation (allo-HSCT) from human leucocyte antigen (HLA) identical siblings, we conducted a prospective study in patients ≤65 years old with advanced chronic lymphocytic leukemia (CLL) stage B or C in response after a salvage treatment. Conditioning included rituximab (375 mg/m² on day 5), fludarabine (30 mg/m² from day 4 to day 2), TBI (2 Gy on day 0), and rituximab (500 mg/m² on days 1 and 8). Forty patients were included, 34 (85%) were male with a median age of 54 years (range, 35-65 years), 38 (95%) were in B stage, and 2 were in stage C; only 7 patients (17%) were in complete response. Seven (17%) patients did not receive rituximab. Thirty-nine (98%) patients engrafted, 17 patients developed acute graft-versus-host disease (GVHD) grade ≥II with a cumulative incidence at 3 months of 44% (36-52) with a significant protective effect of rituximab (p = 0.02). The cumulative incidence of chronic GVHD was 29% (21-36) at 12 months for both limited and extensive forms. The median overall survival was not reached with 5-years probability of 55% (41-74). The multivariate analysis showed a positive effect of rituximab on overall survival and event-free survival (hazard ratio [HR] = 0.1 [0-0.6], p = 0.02; and HR = 0.1 [0-0.4], p = 0.035, respectively). The association of fludarabine, TBI, and rituximab is feasible, well tolerated, and allows better outcomes in advanced CLL.

  9. Kinetics of engraftment in patients with hematologic malignancies given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

    Science.gov (United States)

    Baron, Frédéric; Baker, Jennifer E; Storb, Rainer; Gooley, Theodore A; Sandmaier, Brenda M; Maris, Michael B; Maloney, David G; Heimfeld, Shelly; Oparin, Dmitrij; Zellmer, Eustacia; Radich, Jerald P; Grumet, F Carl; Blume, Karl G; Chauncey, Thomas R; Little, Marie-Térèse

    2004-10-15

    We analyzed the kinetics of donor engraftment among various peripheral blood cell subpopulations and their relationship to outcomes among 120 patients with hematologic malignancies given hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning consisting of 2 Gy total body irradiation (TBI) with or without added fludarabine. While patients rapidly developed high degrees of donor engraftment, most remained mixed donor/host chimeras for up to 180 days after HCT. Patients given preceding chemotherapies and those given granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell (G-PBMC) grafts had the highest degrees of donor chimerism. Low donor T-cell (P = .003) and natural killer (NK) cell (P = .004) chimerism levels on day 14 were associated with increased probabilities of graft rejection. High T-cell chimerism on day 28 was associated with an increased probability of acute graft-versus-host disease (GVHD) (P = .02). Of 93 patients with measurable malignant disease at transplantation, 41 achieved complete remissions a median of 199 days after HCT; 19 of the 41 were mixed T-cell chimeras when complete remissions were achieved. Earlier establishment of donor NK-cell chimerism was associated with improved progression-free survival (P = .02). Measuring the levels of peripheral blood cell subset donor chimerisms provided useful information on HCT outcomes and might allow early therapeutic interventions to prevent graft rejection or disease progression.

  10. Relapse risk in patients with malignant diseases given allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.

    Science.gov (United States)

    Kahl, Christoph; Storer, Barry E; Sandmaier, Brenda M; Mielcarek, Marco; Maris, Michael B; Blume, Karl G; Niederwieser, Dietger; Chauncey, Thomas R; Forman, Stephen J; Agura, Edward; Leis, Jose F; Bruno, Benedetto; Langston, Amelia; Pulsipher, Michael A; McSweeney, Peter A; Wade, James C; Epner, Elliot; Bo Petersen, Finn; Bethge, Wolfgang A; Maloney, David G; Storb, Rainer

    2007-10-01

    Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m(2); n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.

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

    Energy Technology Data Exchange (ETDEWEB)

    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)

  12. Pharmacokinetic targeting of intravenous busulfan reduces conditioning regimen related toxicity following allogeneic hematopoietic cell transplantation for acute myelogenous leukemia

    Directory of Open Access Journals (Sweden)

    Nishihori Taiga

    2010-10-01

    Full Text Available Abstract Optimal conditioning therapy for hematopoietic cell transplantation (HCT in acute myelogenous leukemia (AML remains undefined. We retrospectively compared outcomes of a consecutive series of 51 AML patients treated with oral busulfan (1 mg/kg every 6 hours for 4 days and cyclophosphamide (60 mg/kg IV × 2 days - (Bu/Cy with 100 consecutive AML patients treated with pharmacokinetic targeted IV busulfan (AUC

  13. Oral cyclosporine A treatment is feasible after myeloablative conditioning in allogeneic hematopoietic stem cell transplantation

    DEFF Research Database (Denmark)

    Nygaard, M; Hovgaard, D; Schjødt, I M;

    2015-01-01

    underwent myeloablative hematopoietic stem cell transplantation. Twenty-one patients (44%) tolerated CsA orally throughout the transplantation period without increased incidence of acute graft versus host disease(aGVHD). Low concentration of CsA in week 2 was associated with increased incidence of a...

  14. Stroma-conditioned media improve expansion of human primitive hematopoietic stem cells and progenitor cells.

    Science.gov (United States)

    Breems, D A; Blokland, E A; Ploemacher, R E

    1997-01-01

    It has been reported that stroma-dependent cultures support proliferation of hematopoietic stem cells (HSC). In order to investigate the effect of soluble stromal factors, we developed short-term serum-low liquid cultures in which the effect of stroma-conditioned media (SCM) from the murine FBMD-1, and human L87/4 and L88/5 cell lines was studied on the maintenance and expansion of various human HSC subsets in CD34-positive selected mobilized peripheral blood stem cells (PBSC) from autologous transplants of lymphoma and multiple myeloma patients. The human cobblestone area forming cell (CAFC) assay was employed to determine the frequencies of both the CAFC weeks 2 to 4 as tentative indicators of progenitor and transiently repopulating HSC, and the more primitive CAFC weeks 6 to 8 as indicators of long-term repopulating HSC. In 7-day liquid cultures containing interleukin-3 (IL-3), stem cell factor (SCF) and IL-6, we recovered 3.0-fold more colony-forming cells (CFC) and 1.7- to 1.9-fold more CAFC weeks 2 and 4. The absolute number of primitive CAFC weeks 6 and 8 were only maintained (1.1- to 1.4-fold) in these liquid cultures. This modest expansion was significantly improved by the addition of SCM from the FBMD-1, L87/4 or L88/5 cell lines. Output CFC numbers were 6.8-, 5.8- and 9.9-fold higher, respectively, than the input values, while absolute CAFC week 2 to 4 numbers were 4.5-, 10.2- and 10.2-fold expanded, respectively. The addition of SCM also improved expansion of the more primitive CAFC week 6 to 8 stem cell subsets by 2.2-, 4.5- and 4.9-fold, respectively. The addition of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage-CSF (GM-CSF), IL-1beta, IL-11 or macrophage inflammatory protein-1alpha to cultures containing IL-3, SCF and IL-6 could not explain the SCM effect and in all these combinations SCM addition further increased the recovery of HSC subsets. Similarly, addition of anti-cytokine antibodies (ie alpha-G-CSF, alpha-GM-CSF, alpha

  15. High-dose total body irradiation and myeloablative conditioning before allogeneic hematopoietic cell transplantation: time to rethink?

    Science.gov (United States)

    Mohty, Mohamad; Malard, Florent; Savani, Bipin N

    2015-04-01

    Over the last decade, the care of patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) has significantly improved, leading to a decrease in deaths related to allo-HCT as well as improved long-term survival. However, for many patients, long-term survivorship is associated with a substantial burden of chronic morbidities. Indeed, malignant and nonmalignant late complications after allo-HCT are numerous and usually multifactorial, with all organs and tissues a potential target. In many cases, these long-term side effects are associated with the use of high-dose total body irradiation, myeloablative conditioning regimens, and the onset of chronic graft-versus-host disease. It appears to be essential to change the natural history of these late effects. This requires the introduction of improved conditioning regimens and the development of lifelong monitoring controls, patient counseling, and preventative treatment measures. This approach will allow us to pursue our efforts to improve patient outcome.

  16. A Trial of Alemtuzumab Adjunctive Therapy in Allogeneic Hematopoietic Cell Transplantation with Minimal Conditioning for Severe Combined Immunodeficiency

    Science.gov (United States)

    Dvorak, Christopher C.; Horn, Biljana N.; Puck, Jennifer M.; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J.

    2014-01-01

    For infants with severe combined immunodeficiency (SCID) the ideal conditioning regimen before allogeneic hematopoietic cell transplantation (HCT) would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled 4 patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The 2 patients who engrafted had delayed T cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T cell development in patients with SCID in the setting of a T-cell depleted graft. PMID:24977928

  17. Improved Outcomes of Hematopoietic Stem Cell Transplantation in Patients With Infantile Malignant Osteopetrosis Using Fludarabine-Based Conditioning.

    Science.gov (United States)

    Natsheh, Juma; Drozdinsky, Genady; Simanovsky, Natalia; Lamdan, Ron; Erlich, Odeya; Gorelik, Natan; Or, Reuven; Weintraub, Michael; Stepensky, Polina

    2016-03-01

    Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for infantile malignant osteopetrosis (IMO), but is associated with a high incidence of adverse outcomes. In this study, we present our experience with HSCT for IMO patients comparing different types of conditioning regimens. Thirty-eight patients with IMO (aged from 1 month to 6 years, median 0.66 years) who underwent allogeneic HSCT from 1983 in our hospital were included in this retrospective study. Fludarabine-based conditioning regimens were used in 26 patients and 12 patients were transplanted using other conditioning regimens. The overall survival after conditioning with fludarabine was 96% (25/26) versus 58% (7/12) for the alternative regimens (P = 0.004), with significantly fewer adverse effects including hypercalcemia and veno-occlusive disease of liver. All patients who survive are clinically well. We conclude that fludarabine-based conditioning regimens are safe and effective in patients with IMO, improving morbidity and mortality related to HSCT. © 2015 Wiley Periodicals, Inc.

  18. Unresolved issues in hematopoietic stem cell transplantation for severe combined immunodeficiency: need for safer conditioning and reduced late effects.

    Science.gov (United States)

    Horn, Biljana; Cowan, Morton J

    2013-05-01

    In this review we discuss recent outcomes of hematopoietic cell transplantation (HCT) for patients with severe combined immunodeficiency (SCID), including survival, T- and B-cell reconstitution, and late effects, particularly those related to genotype, use of conditioning regimen, and use of alternative donors. We identify the following issues that require additional data, which can be obtained through cooperative studies: outcomes of patients with SCID who did not receive conditioning before alternative donor HCT; outcomes of patients with SCID who did not receive graft-versus-host disease prophylaxis after T cell-replete HCT; late effects of HCT for patients with SCID, including neurocognitive outcomes, growth, and development; and their relationship to genotype and use of alkylating agents for conditioning. Careful follow-up of outcomes of all newborns receiving diagnoses based on newborn screening programs for SCID is essential because data are scarce on the effects of conditioning regimens in very young patients. A consensus on the definition of T- and B-cell recovery, criteria for additional "boosts," pharmacokinetic data of chemotherapy agents used in young children, and uniformity of the use of various chemotherapy agents are needed to compare results among institutions. Finally, development of new nontoxic conditioning regimens for HCT that can be safely used in very young children is required.

  19. Long-term survival and late events after allogeneic stem cell transplantation from HLA-matched siblings for acute myeloid leukemia with myeloablative compared to reduced-intensity conditioning: a report on behalf of the acute leukemia working party of European group for blood and marrow transplantation

    Directory of Open Access Journals (Sweden)

    Avichai Shimoni

    2016-11-01

    Full Text Available Abstract Background Myeloablative (MAC and reduced-intensity conditioning (RIC are established approaches for allogeneic stem cell transplantation (SCT in acute myeloid leukemia (AML. Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods We analyzed long-term outcomes in a cohort of 1423 AML patients, age ≥50 years, after SCT from HLA-matched siblings, during the years 1997–2005, median follow-up 8.3 years (0.1–17. Results The 10-year leukemia-free survival (LFS was 31 % (95CI, 27–35 and 32 % (28–35 after MAC and RIC, respectively (P = 0.57. The 10-year GVHD/ relapse-free survival (GRFS, a surrogate for quality of life was 22 % (18–25 and 21 % (18–24, respectively (P = 0.79. The 10-year non-relapse mortality (NRM was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65–76 and 73 % (67–78 after MAC and RIC, respectively (P = 0.76. Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches.

  20. Outcomes of Severe Combined Immunodeficiency Patients Treated with Hematopoietic Stem Cell Transplantation with and without Pre-conditioning

    Science.gov (United States)

    Patel, Niraj C.; Chinen, Javier; Rosenblatt, Howard M.; Hanson, I. Celine; Krance, Robert A.; Paul, Mary E.; Abramson, Stuart L.; Noroski, Lenora M.; Davis, Carla M.; Seeborg, Filiz O.; Foster, Samuel B.; Leung, Kathryn S.; Brown, Betty S.; Ritz, Jerome; Shearer, William T.

    2011-01-01

    Background The effect of pre-transplant conditioning upon the long-term outcomes of patients receiving hematopoietic stem cell transplantation (HSCT) for severe combined immunodeficiency (SCID) has not been completely determined. Objective To assess the outcomes of 23 mostly conditioned SCID patients and compare their outcomes to 25 nonconditioned SCID transplanted patients previously reported. Methods In the present study, we reviewed the medical records of these 23 consecutive mostly conditioned SCID patients transplanted between 1998 and 2007. Results Eighteen patients (median age at transplant 10 [range 0.8–108] mo) received haploidentical mismatched related donor, matched unrelated donor, or mismatched unrelated donor transplants, 17 of whom received pretransplant conditioning and one was not conditioned, 13 (72%) engrafted and survive a median of 3.8 [1.8–9.8] yr, 5 of 13 (38%) require IVIG, and 6 of 6 age-eligible children attend school. Of five recipients (median age at transplant 7 [range 2–23] mo) of matched related donor transplants, all 5 engrafted and survive a median of 7.5 [range 1.5–9.5] yr, 1 requires IVIG, and 3 of 3 age-eligible children attend school. Gene mutations were known in 16 cases: IL2γR in 7 patients, IL7αR in 4 patients, RAG1 in 2 patients, ADA in 2 patients, and AK2 in 1 patient. Early outcomes and quality of life of the previous non-conditioned vs. the present conditioned cohorts were not statistically different but longer-term follow-up is necessary for confirmation. Conclusions HSCT in SCID patients results in engraftment, long-term survival, and a good quality of life for the majority of patients with or without pre-transplant conditioning. PMID:19895994

  1. Antifungal prophylaxis following reduced-intensity stem cell transplantation.

    Science.gov (United States)

    Kami, M; Murashige, N; Tanaka, Y; Narimatsu, H

    2006-12-01

    Reduced-intensity stem cell transplantation (RIST) has been developed to be a novel curative option for advanced hematologic diseases. Its minimal toxicity allows for transplantation in patients with advanced age or with organ dysfunction. Young patients without comorbidity can undergo RIST as outpatients. However, fungal infection remains an important complication in RIST. Given the poor prognosis of fungal infection, prophylaxis is critical in its management. The prophylactic strategy is recently changing with the development of RIST. Hospital equipment is important for fungal prophylaxis; however, the median day for the development of fungal infection is day 100, when most RIST patients are followed as outpatients. The focus of fungal management after RIST needs to shift from in-hospital equipment to oral antifungals. Various antifungals have recently been developed and introduced for clinical use. A major change in antifungal management will probably occur within several years.

  2. Treosulfan-Based Conditioning and Hematopoietic Cell Transplantation for Nonmalignant Diseases: A Prospective Multi-Center Trial

    Science.gov (United States)

    Burroughs, Lauri M.; Nemecek, Eneida R.; Torgerson, Troy R.; Storer, Barry E.; Talano, Julie-An; Domm, Jennifer; Giller, Roger H.; Shimamura, Akiko; Delaney, Colleen; Skoda-Smith, Suzanne; Thakar, Monica S.; Baker, K. Scott; Rawlings, David J.; Englund, Janet A.; Flowers, Mary E. D.; Deeg, H. Joachim; Storb, Rainer; Woolfrey, Ann E.

    2015-01-01

    Hematopoietic cell transplantation (HCT) is effective in the treatment of patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM) particularly in patients with co-morbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n=4) or unrelated (n=27) grafts following conditioning with treosulfan (total dose: 42 g/m2), fludarabine (total dose: 150 mg/m2), ± thymoglobulin (6 mg/kg; n=22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II–IV and III–IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10% and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grade III-IV acute GVHD (0% versus 33%; P = 0.005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases, and support the need for future disease-specific clinical trials. PMID:25196857

  3. Invasive fungal infection following reduced-intensity cord blood transplantation for adult patients with hematologic diseases.

    Science.gov (United States)

    Miyakoshi, Shigesaburo; Kusumi, Eiji; Matsumura, Tomoko; Hori, Akiko; Murashige, Naoko; Hamaki, Tamae; Yuji, Koichiro; Uchida, Naoyuki; Masuoka, Kazuhiro; Wake, Atsushi; Kanda, Yoshinobu; Kami, Masahiro; Tanaka, Yuji; Taniguchi, Shuichi

    2007-07-01

    Invasive fungal infection (IFI) is a significant complication after allogeneic hematopoietic stem cell transplantation (HSCT); however, we have little information on its clinical features after reduced intensity cord blood transplantation (RICBT) for adults. We reviewed medical records of 128 patients who underwent RICBT at Toranomon Hospital between March 2002 and November 2005. Most of the patients received purine-analogbased preparative regimens. Graft-versus-host disease (GVHD) prophylaxis was a continuous infusion of either tacrolimus 0.03 mg/kg or cyclosporine 3 mg/kg. IFI was diagnosed according to the established EORTC/NIH-MSG criteria. IFI was diagnosed in 14 patients. Thirteen of the 14 had probable invasive pulmonary aspergillosis and the other had fungemia resulting from Trichosporon spp. Median onset of IFI was day 20 (range: 1-82), and no patients developed IFI after day 100. Three-year cumulative incidence of IA was 10.2%. Four of the 13 patients with invasive aspergillosis (IA) developed grade II-IV acute GVHD, and their IA was diagnosed before the onset of acute GVHD. The mortality rate of IFI was 86%. Multivariate analysis revealed that the use of prednisolone >0.2 mg/kg (relative risk 7.97, 95% confidence interval 2.24-28.4, P = .0014) was a significant risk factor for IA. This study suggests that IFI is an important cause of deaths after RICBT, and effective strategies are warranted to prevent IFI.

  4. Intestinal thrombotic microangiopathy following reduced-intensity umbilical cord blood transplantation.

    Science.gov (United States)

    Narimatsu, H; Kami, M; Hara, S; Matsumura, T; Miyakoshi, S; Kusumi, E; Kakugawa, Y; Kishi, Y; Murashige, N; Yuji, K; Masuoka, K; Yoneyama, A; Wake, A; Morinaga, S; Kanda, Y; Taniguchi, S

    2005-09-01

    Thrombotic microangiopathy (TMA) is a significant complication after hematopoietic stem-cell transplantation (HSCT); however, there is little information on it following reduced-intensity cord blood transplantation (RI-CBT). We reviewed the medical records of 123 adult patients who received RI-CBT at Toranomon Hospital between January 2002 and August 2004. TMA was diagnosed in seven patients based on intestinal biopsy (n = 6) or autopsy results (n = 1). While these patients showed some clinical symptoms such as diarrhea and/or abdominal pain, mental status alterations or neurological disorders were not observed in any of them. Laboratory results were mostly normal at the onset of TMA; >2% fragmented erythrocytes (n = 1), 200 IU/dl lactic dehydrogenase (LD) (n = 4). On endoscopic examination, TMA lesions, consisting of ulcers, erosions, and diffuse exfoliation, were distributed spottily from terminal ileum to rectum. Intestinal graft-versus-host disease (GVHD) and cytomegalovirus (CMV) colitis were confirmed in five and four patients, respectively. With therapeutic measures including supportive care (n = 4), fresh frozen plasma (n = 1), and a reduction of immunosuppressive agents (n = 1), TMA improved in four patients. The present study demonstrates that intestinal TMA is a significant complication after RI-CBT. Since conventional diagnostic criteria can overlook TMA, its diagnosis requires careful examination of the gastrointestinal tract using endoscopy with biopsy.

  5. Disseminated tuberculosis following reduced-intensity cord blood transplantation for adult patients with hematological diseases.

    Science.gov (United States)

    Maeda, T; Kusumi, E; Kami, M; Kawabata, M; Le Pavoux, A; Hara, S; Chizuka, A; Murashige, N; Tanimoto, T E; Matsumura, T; Yuji, K; Yuji, Ko; Wake, A; Miyakoshi, S; Morinaga, S; Taniguchi, S

    2005-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-SCT) recipients are prone to infections. The incidences of mycobacterial infections after allo-SCT in several case series vary from less than 0.1-5.5%. However, no study has been published on tuberculosis following unrelated cord blood transplantation (UCBT). We retrospectively reviewed medical records of 113 adult patients with a median age of 54 years who underwent reduced-intensity UCBT (RI-UCBT) at Toranomon Hospital from March 2002 to May 2004. Mycobacterium tuberculosis infections were diagnosed in three patients (2.7%), of these two patients developed primary infection and one patient developed reactivation of latent tuberculosis. The interval between RI-UCBT and the diagnosis of tuberculosis was 34, 41 and 61 days. All the patients had disseminated disease at diagnosis. Histological examination showed the lack of granuloma in caseous necrosis. Combination antituberculous treatments showed limited efficacy, and two patients died immediately after diagnosis. M. tuberculosis caused life-threatening illness, rapidly progressing in RI-UCBT recipients. The lack of granuloma in caseous necrosis suggests the impaired T-cell function in early post transplant phase of RI-UCBT. We should consider M. tuberculosis in the differential diagnoses of fever of unknown source after RI-UCBT.

  6. Successful treatment of acute myelogenous leukemia with favorable cytogenetics by reduced-intensity stem cell transplantation.

    Science.gov (United States)

    Kondo, Takeshi; Yasumoto, Atsushi; Arita, Kotaro; Sugita, Jun-Ichi; Shigematsu, Akio; Okada, Kohei; Takahata, Mutsumi; Onozawa, Masahiro; Kahata, Kaoru; Takeda, Yukari; Obara, Masato; Yamamoto, Satoshi; Endo, Tomoyuki; Nishio, Mitsufumi; Sato, Norihiro; Tanaka, Junji; Hashino, Satoshi; Koike, Takao; Asaka, Masahiro; Imamura, Masahiro

    2010-03-01

    Acute myelogenous leukemia (AML) with favorable cytogenetics responds well to chemotherapy. If the leukemia relapses, allogenic hematopoietic stem transplantation (allo-HSCT) is considered as a treatment option. Since the efficacy of reduced-intensity stem cell transplantation (RIST) for AML with favorable cytogenetics has not been established, we retrospectively analyzed the outcomes of allo-HSCT in AML patients according to cytogenetic risks. The outcome of allo-HSCT for AML patients with favorable cytogenetics seemed to be superior to that for AML patients with intermediate cytogenetics. In AML patients with favorable cytogenetics, the 3-year overall survival (OS) and relapse-free survival (RFS) rates were 88 and 76%, respectively, in the RIST group. Both the 3-year OS and RFS rates were 81% in the conventional stem cell transplantation (CST) group. The outcome of RIST for AML patients with favorable cytogenetics was comparable to that for patients who received CST despite the more advanced age and greater organ dysfunction in RIST group than in CST group. None of the patients died within 90 days after RIST. Moreover, there was no relapse in patients with favorable cytogenetics who were in hematological remission prior to RIST. Thus, RIST for AML patients with favorable cytogenetics in remission is safe and effective.

  7. Clinical and immunological correction of DOCK8 deficiency by allogeneic hematopoietic stem cell transplantation following a reduced toxicity conditioning regimen.

    Science.gov (United States)

    Boztug, Heidrun; Karitnig-Weiß, Cäcilia; Ausserer, Bernd; Renner, Ellen D; Albert, Michael H; Sawalle-Belohradsky, Julie; Belohradsky, Bernd H; Mann, Georg; Horcher, Ernst; Rümmele-Waibel, Alexandra; Geyeregger, Rene; Lakatos, Karoly; Peters, Christina; Lawitschka, Anita; Matthes-Martin, Susanne

    2012-10-01

    Dedicator of cytokinesis 8 protein (DOCK8) deficiency is a combined immunodeficiency disorder characterized by an expanding clinical picture with typical features of recurrent respiratory or gastrointestinal tract infections, atopic eczema, food allergies, chronic viral infections of the skin, and blood eosinophilia often accompanied by elevated serum IgE levels. The only definitive treatment option is allogeneic hematopoietic stem cell transplantation (HSCT). We report a patient with early severe manifestation of DOCK8 deficiency, who underwent unrelated allogeneic HSCT at the age of 3 years following a reduced toxicity conditioning regimen. The transplant course was complicated by pulmonary aspergilloma pretransplantation, adenovirus (ADV) reactivation, and cytomegalovirus (CMV) pneumonitis 4 weeks after transplantation. With antifungal and antiviral treatment the patient recovered. Seven months after transplantation the patient is in excellent clinical condition. Eczematous rash, chronic viral skin infections, and food allergies have subsided, associated with normalization of IgE levels and absolute numbers of eosinophils. Chimerism analysis shows stable full donor chimerism. DOCK8 deficiency can be successfully cured by allogeneic HSCT. This treatment option should be considered early after diagnosis, as opportunistic infections and malignancies that occur more frequently during the natural course of the disease are associated with higher morbidity and mortality.

  8. Practical Aspects of Allogeneic Hematopoietic Cell Transplantation for Patients with Poor-Risk Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Julio Delgado

    2011-01-01

    Full Text Available Allogeneic hematopoietic cell transplantation has become a viable option for younger patients with poor-risk chronic lymphocytic leukemia. The results obtained with either conventional or reduced-intensity conditioning regimens have been recently evaluated and compared with alternative nontransplant strategies. This manuscript deals with practical aspects of the procedure, including patient and donor selection, conditioning regimen, GVHD prophylaxis, disease monitoring, infectious and noninfectious complications, and timing of the procedure. Finally, we speculate on how we could improve the results obtained with the procedure and new advances currently in clinical trials.

  9. Busulfan and melphalan as conditioning regimen for allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission

    Directory of Open Access Journals (Sweden)

    Nadjanara Dorna Bueno

    2011-06-01

    Full Text Available BACKGROUND: Allogeneic hematopoietic stem cell transplantation with HLA-identical donors has been established for the treatment of acute myeloid leukemia patients for over 30 years with a cure rate of 50% to 60%. OBJECTIVES: To analyze the overall survival of patients and identify factors that influence the outcomes of this type of transplant in patients in 1st complete remission who received a busulfan and melphalan combination as conditioning regimen. METHODS: Twenty-five consecutive patients with acute myeloid leukemia were enrolled between 2003 and 2008. The median age was 34 years old (Range: 16 - 57 years. All patients received cyclosporine and methotrexate for prophylaxis against graft-versus-host disease. Median neutrophil engraftment time was 16 days (Range: 7 - 22 days and 17 days (Range: 7 - 46 days for platelets. Sinusoidal obstructive syndrome was observed in three patients, seven had grade II acute graft-versus-host disease and one extensive chronic graft-versus-host disease. RESULTS: The overall survival by the Kaplan-Meier method was 48% after 36 months with a plateau at 36 months after transplantation. Intensive consolidation with high-dose arabinoside resulted in an improved survival (p-value = 0.0001, as did grade II acute graft-versus-host disease (p-value = 0.0377 and mild chronic graft-versus-host disease (p-value < 0.0001. Thirteen patients died, five due to infection within 100 days of transplant, two due to hemorrhages, one to infection and graftversus-host disease and three relapses followed by renal failure (one and infection (two. The cause of death could not be determined for two patients. CONCLUSION: The busulfan and melphalan conditioning regimen is as good as other conditioning regimens providing an excellent survival rate.

  10. [Stability of high-dose etoposide dilutions for use in hematopoietic stem cell transplantation conditioning regimens].

    Science.gov (United States)

    Bauters, T; Vandenbroucke, J; Commeyne, S

    2015-12-01

    High-dose etoposide is used in conditioning regimens for allogeneic stem cell transplantation. The limited stability of the drug induces barriers for its use for pharmacists, nurses and patients. When using a concentration of 10 mg/mL etoposide in physiologic saline, limitations can be overcome. This study provides stability data for etoposide in a high concentration that can be used in conditioning regimens. The solution was stable for 48h at 5°C, for 48h at 5°C followed by 8h at 25°C and for 24 h at 25°C.

  11. Hematopoietic System

    Institute of Scientific and Technical Information of China (English)

    2011-01-01

    2011370 The efficacy and safety of second allogeneic hematopoietic stem cell transplantation for post-transplant hematologic malignancies relapse. CHEN Yuhong(陳育紅),et al.Instit Hematol,People’s Hosp,Peking Univ,Beijing 100044. Abstract:Objective To investigate the safety and efficacy of second allogeneic hematopoietic stem cell transplantation for the relapsed hematologic malignancies.Methods The data of 25 relapsed patients received the second allogeneic transplantation as a salvage therapy

  12. Hepatic injury following reduced intensity unrelated cord blood transplantation for adult patients with hematological diseases.

    Science.gov (United States)

    Kusumi, Eiji; Kami, Masahiro; Kanda, Yoshinobu; Murashige, Naoko; Seki, Kunihiko; Fujiwara, Masayo; Koyama, Rikako; Komatsu, Tsunehiko; Hori, Akiko; Tanaka, Yuji; Yuji, Koichiro; Matsumura, Tomoko; Masuoka, Kazuhiro; Wake, Atsushi; Miyakoshi, Shigesaburo; Taniguchi, Shuichi

    2006-12-01

    Liver injury is a common complication in allogeneic hematopoietic stem cell transplantation. Its major causes comprise graft-versus-host disease (GVHD), infection, and toxicities of preparative regimens and immunosuppressants; however, we have little information on liver injuries after reduced intensity cord blood transplantation (RICBT). We reviewed medical records of 104 recipients who underwent RICBT between March 2002 and May 2004 at Toranomon Hospital. Preparative regimen and GVHD prophylaxis comprised fludarabine/melphalan/total body irradiation and cyclosporine or tacrolimus. We assessed the etiology of liver injuries based on the clinical presentation, laboratory results, comorbid events, and imaging studies in 85 patients who achieved primary engraftment. The severity of liver dysfunction was assessed according to the National Cancer Institute Common Toxicity Criteria version 2.0. Hyperbilirubinemia was graded according to a report by Hogan et al (Blood. 2004;103:78-84). Moderate to very severe liver injuries were observed in 36 patients. Their causes included cholestatic liver disease (CLD) related to GVHD or sepsis (n = 15), GVHD (n = 7), cholangitis lenta (n = 5), and others (n = 9). Median onsets of CLD, GVHD, and cholangitis lenta were days 37, 40, and 22, respectively. Frequencies of grade 3-4 alanine aminotransferase elevation were comparable across the 3 types of hepatic injuries. Serum gamma-glutamil transpeptidase was not elevated in any patients with cholangitis lenta, whereas 27% and 40% of patients with CLD and GVHD, respectively, developed grade 3-4 gamma-glutamil transpeptidase elevation. Multivariate analysis identified 2 risk factors for hyperbilirubinemia; grade II-IV acute GVHD (relative risk, 2.23; 95% confidential interval, 1.11-4.47; P = .024) and blood stream infection (relative risk, 3.77; 95% confidential interval, 1.91-7.44; P = .00013). In conclusion, the present study has demonstrated that the hepatic injuries are significant

  13. Stem cells and the aging hematopoietic system.

    Science.gov (United States)

    Beerman, Isabel; Maloney, William J; Weissmann, Irving L; Rossi, Derrick J

    2010-08-01

    Advancing age is accompanied by a number of clinically significant conditions arising in the hematopoietic system that include: diminution and decreased competence of the adaptive immune system, elevated incidence of certain autoimmune diseases, increased hematological malignancies, and elevated incidence of age-associated anemia. As with most tissues, the aged hematopoietic system also exhibits a reduced capacity to regenerate and return to normal homeostasis after injury or stress. Evidence suggests age-dependent functional alterations within the hematopoietic stem cell compartment significantly contribute to many of these pathophysiologies. Recent developments have shed light on how aging of the hematopoietic stem cell compartment contributes to hematopoietic decline through diverse mechanisms.

  14. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: impact of tyrosine kinase inhibitor and minimal residual disease.

    Science.gov (United States)

    Bachanova, V; Marks, D I; Zhang, M-J; Wang, H; de Lima, M; Aljurf, M D; Arellano, M; Artz, A S; Bacher, U; Cahn, J-Y; Chen, Y-B; Copelan, E A; Drobyski, W R; Gale, R P; Greer, J P; Gupta, V; Hale, G A; Kebriaei, P; Lazarus, H M; Lewis, I D; Lewis, V A; Liesveld, J L; Litzow, M R; Loren, A W; Miller, A M; Norkin, M; Oran, B; Pidala, J; Rowe, J M; Savani, B N; Saber, W; Vij, R; Waller, E K; Wiernik, P H; Weisdorf, D J

    2014-03-01

    The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKIs), mostly imatinib; 39% (RIC) and 49% (MAC) were minimal residual disease (MRD)(neg) pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%; P=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (P=0.058). Overall survival (OS) was similar (RIC 39% (95% confidence interval (CI) 27-52) vs 35% (95% CI 27-44); P=0.62). Patients MRD(pos) pre-HCT had higher risk of relapse with RIC vs MAC (hazard ratio (HR) 1.97; P=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared with a similar MRD population after MAC (33%; P=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; P=0.057), but absence of pre-HCT TKI (HR 1.88; P=0.018), RIC (HR 1.891; P=0.054) and pre-HCT MRD(pos) (HR 1.6; P=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRD(neg) status is preferred pre-HCT.

  15. Ph+ ALL patients in first complete remission have similar survival after reduced intensity and myeloablative allogeneic transplantation: Impact of tyrosine kinase inhibitor and minimal residual disease

    Science.gov (United States)

    Bachanova, Veronika; Marks, David I.; Zhang, Mei-Jie; Wang, Hailin; de Lima, Marcos; Aljurf, Mahmoud D.; Arellano, Martha; Artz, Andrew S.; Bacher, Ulrike; Cahn, Jean-Yves; Chen, Yi-Bin; Copelan, Edward A.; Drobyski, William R.; Gale, Robert Peter; Greer, John P; Gupta, Vikas; Hale, Gregory A.; Kebriaei, Partow; Lazarus, Hillard M.; Lewis, Ian D.; Lewis, Victor A.; Liesveld, Jane L.; Litzow, Mark R.; Loren, Alison W.; Miller, Alan M.; Norkin, Maxim; Oran, Betul; Pidala, Joseph; Rowe, Jacob M.; Savani, Bipin N.; Saber, Wael; Vij, Ravi; Waller, Edmund K.; Wiernik, Peter H.; Weisdorf, Daniel J.

    2014-01-01

    The efficacy of reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) for Ph+ acute lymphoblastic leukemia (ALL) is uncertain. We analyzed 197 adults with Ph+ ALL in first complete remission; 67 patients receiving RIC were matched with 130 receiving myeloablative conditioning (MAC) for age, donor type, and HCT year. Over 75% received pre-HCT tyrosine kinase inhibitors (TKI), mostly imatinib; 39% (RIC) and 49% (MAC) were MRDneg pre-HCT. At a median 4.5 years follow-up, 1-year transplant-related mortality (TRM) was lower in RIC (13%) than MAC (36%;p=0.001) while the 3-year relapse rate was 49% in RIC and 28% in MAC (p=0.058). Overall survival was similar (RIC 39% [95% CI:27–52] vs. 35% [95% CI:270–44];p=0.62). Patients MRDpos pre-HCT had higher risk of relapse with RIC versus MAC (HR 1.97;p=0.026). However, patients receiving pre-HCT TKI in combination with MRD negativity pre-RIC HCT had superior OS (55%) compared to a similar MRDneg population after MAC (33%; p=0.0042). In multivariate analysis, RIC lowered TRM (HR 0.6; p=0.057), but absence of pre-HCT TKI (HR 1.88;p=0.018), RIC (HR 1.891;p=0.054) and pre-HCT MRDpos (HR 1.6; p=0.070) increased relapse risk. RIC is a valid alternative strategy for Ph+ ALL patients ineligible for MAC and MRDneg status is preferred pre-HCT. PMID:23989431

  16. Retrospective Study of Incidence and Prognostic Significance of Eosinophilia after Allogeneic Hematopoietic Stem Cell Transplantation: Influence of Corticosteroid Therapy

    Directory of Open Access Journals (Sweden)

    Wataru Yamamoto

    2016-08-01

    Full Text Available Objective: The clinical significance of eosinophilia after allogeneic hematopoietic stem cell transplantation is controversial. This study aimed to retrospectively study the impact of eosinophilia on the outcome of allogeneic hematopoietic stem cell transplantation by taking into account the influence of corticosteroid therapy. Materials and Methods: We retrospectively studied 204 patients with acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplantation from January 2001 to December 2010. Results: The median age was 43 years (minimum-maximum: 17- 65 years. Myeloablative conditioning was used in 153 patients and reduced intensity conditioning was employed in 51 patients. Donor cells were from bone marrow in 132 patients, peripheral blood in 34, and cord blood in 38. Eosinophilia was detected in 71 patients and there was no significant predictor of eosinophilia by multivariate analysis. There was no relationship between occurrence of eosinophilia and the incidence or grade of acute graft-versus-host disease when the patients were stratified according to corticosteroid treatment. Although eosinophilia was a prognostic factor for 5-year overall survival by univariate analysis, it was not a significant indicator by multivariate analysis. Conclusion: These results suggest that the clinical significance of eosinophilia in patients receiving allogeneic hematopoietic stem cell transplantation should be assessed with consideration of systemic corticosteroid administration.

  17. Retrospective Study of Incidence and Prognostic Significance of Eosinophilia after Allogeneic Hematopoietic Stem Cell Transplantation: Influence of Corticosteroid Therapy.

    Science.gov (United States)

    Yamamoto, Wataru; Ogusa, Eriko; Matsumoto, Kenji; Maruta, Atsuo; Ishigatsubo, Yoshiaki; Kanamori, Heiwa

    2016-09-05

    The clinical significance of eosinophilia after allogeneic hematopoietic stem cell transplantation is controversial. This study aimed to retrospectively study the impact of eosinophilia on the outcome of allogeneic hematopoietic stem cell transplantation by taking into account the influence of corticosteroid therapy. We retrospectively studied 204 patients with acute myeloid leukemia, acute lymphoblastic leukemia, and myelodysplastic syndrome who underwent allogeneic hematopoietic stem cell transplantation from January 2001 to December 2010. The median age was 43 years (minimum-maximum: 17-65 years). Myeloablative conditioning was used in 153 patients and reduced intensity conditioning was employed in 51 patients. Donor cells were from bone marrow in 132 patients, peripheral blood in 34, and cord blood in 38. Eosinophilia was detected in 71 patients and there was no significant predictor of eosinophilia by multivariate analysis. There was no relationship between occurrence of eosinophilia and the incidence or grade of acute graft-versus-host disease when the patients were stratified according to corticosteroid treatment. Although eosinophilia was a prognostic factor for 5-year overall survival by univariate analysis, it was not a significant indicator by multivariate analysis. These results suggest that the clinical significance of eosinophilia in patients receiving allogeneic hematopoietic stem cell transplantation should be assessed with consideration of systemic corticosteroid administration.

  18. Reduced-intensity bone marrow transplantation from an alternative unrelated donor for myelodysplastic syndrome of first-donor origin.

    Science.gov (United States)

    Komeno, Yukiko; Kanda, Yoshinobu; Kandabashi, Koji; Kawazu, Masahito; Goyama, Susumu; Takeshita, Masataka; Nannya, Yasuhito; Niino, Miyuki; Nakamoto, Tetsuya; Kurokawa, Mineo; Tsujino, Shiho; Ogawa, Seishi; Aoki, Katsunori; Chiba, Shigeru; Motokura, Toru; Hirai, Hisamaru

    2003-03-01

    A male patient had a relapse of myelodysplastic syndrome (MDS) 2 years after BMT from a female matched unrelated donor. Conventional cytogenetics, FISH, and short-tandem repeat chimerism analysis proved a relapse of donor origin. He underwent reduced-intensity BMT after a conditioning with fludarabine and busulfan, since he had impaired renal, liver, and pulmonary functions. Chimerism analysis on day 28 after the second BMT showed mixed chimerism of the first and the second donors, which later turned to full second-donor chimerism on day 60. He developed grade II acute GVHD of the skin and cytomegalovirus reactivation, but both were improved with methylprednisolone and ganciclovir, respectively. He remains in complete remission 6 months after the second BMT. Reduced-intensity second BMT from an alternative donor appeared to be a tolerable treatment option for donor-derived leukemia/MDS after the first conventional transplantation.

  19. Emerging drugs for prevention of graft failure after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Servais, Sophie; Beguin, Yves; Baron, Frédéric

    2013-06-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for many patients suffering from hematological malignancies, severe hemoglobinopathies, bone marrow failures or severe primary immunodeficiencies. Graft rejection/failure (GF) is a life-threatening complication following allo-HSCT that is most commonly caused by the reactivity of recipient T cells, natural killer (NK) cells or antibodies against donor grafted hematopoietic cells. The increasing use of allo-HSCT following reduced-intensity conditioning (RIC) and the increasing use of alternative donors (unrelated cord blood and human leukocyte antigen (HLA)-mismatched donor) have resulted in higher frequency of GF. This review describes the pathogenesis and current prevention and treatment of GF as well as agents in development for GF prevention or treatment. The risk of GF may be reduced in the future by optimizing the conditioning regimens and post-grafting immunosuppression, increasing the number of hematopoietic stem cells (HSCs) and/or immune cells transplanted, optimizing HSC homing and better detecting patients at high risk of GF by searching for pre-transplant donor-specific anti-HLA antibodies in patients given grafts from HLA-mismatched donors, or by closely monitoring donor T- and/or NK-cell chimerism after allo-HSCT following RIC.

  20. Progress of Research on Allogeneic Hematopoietic Stem Cell Transplantation with Reduced-intensity Conditioning Regimen for Treatment of Myelodysplastic Syndrome-Review%低强度预处理异基因造血干细胞移植治疗骨髓增生异常综合征研究进展

    Institute of Scientific and Technical Information of China (English)

    张征; 李晓

    2008-01-01

    异基因造血干细胞移植(allo-HSCT)是治疗骨髓增生异常综合征(MDS)的有效手段,MDS发病率随年龄增加而增加,尽管近年来传统清髓性移植治疗MDS取得可喜的成绩,但对于年龄大于60岁的MDS患者,allo-HSCT预后差,低强度预处理异基因造血干细胞移植(RIC allo-HSCT)使老年MDS患者进行allo-HSCT成为可能,利用供者淋巴细胞的移植物抗肿瘤作用显著降低移植相关器官毒性及非复发死亡率.本文就RIC-HSCT治疗MDS的问题诸如RIC allo-HSCT治疗MDS可行性,MDS病例选择,RIC allo-HSCT的时机干细胞来源,RIC预处理方案,疗效及预后评价,GVHD与移植物抗MDS效应等的研究进展做一综述及展望.

  1. [Successful treatment with reduced-intensity cord blood transplantation for acute myeloid leukemia with complete tetraploidy (92, XXXX)].

    Science.gov (United States)

    Iwasaki, Junko; Onozawa, Masahiro; Takahashi, Shojiro; Okada, Kohei; Takahata, Mutsumi; Shigematsu, Akio; Kahata, Kaoru; Kondo, Takeshi; Hashino, Satoshi; Imamura, Masahiro; Asaka, Masahiro

    2011-03-01

    A 56-year-old female was diagnosed with acute myeloid leukemia (FAB: AML-M1). G-banding karyotype of her bone marrow showed complete tetraploidy (92, XXXX [24/24]). Although she achieved complete remission (CR) after induction therapy and maintained CR during consolidation therapy, relapse occurred only 2 months after discharge. When the relapse occurred, bone marrow karyotypic analysis showed complete tetraploidy again. The patient received reduced-intensity cord blood transplantation (RI-CBT), which induced CR for the second time. The patient is currently alive 24 months after transplantation and there have not been any signs of recurrence to date. There have been a few reports of AML with near-tetraploidy, but cases of AML with complete tetraploidy are extremely rare. Tetraploid AML has been reported to have a poor prognosis and there have been very few cases maintaining CR over the long term after chemotherapy alone. This is the first case of complete tetraploid AML successfully treated by RI-CBT. The clinical course of this case suggests that hematopoietic stem cell transplantation during the first CR phase should be considered a treatment option for tetraploid AML.

  2. Reduced-intensity stem cell transplantation from an HLA-identical sibling donor in patients with myeloid malignancies.

    Science.gov (United States)

    Hamaki, T; Kami, M; Kim, S-W; Onishi, Y; Kishi, Y; Murashige, N; Hori, A; Kojima, R; Sakiyama, M; Imataki, O; Heike, Y; Tanosaki, R; Masuo, S; Miyakoshi, S; Taniguchi, S; Tobinai, K; Takaue, Y

    2004-05-01

    The purpose of this study was to evaluate the feasibility and efficacy of allogeneic hematopoietic stem cell transplantation with a reduced-intensity regimen (RIST) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In all, 36 patients (median age 55 years) underwent RIST from an HLA-matched related donor between September 1999 and December 2002. The diagnoses included AML (n=14), leukemia evolving from MDS (n=10), and MDS (refractory anemia with excess blasts n=6, refractory anemia n=6). The RIST regimen consisted of purine analog (cladribine or fludarabine)/busulfan, with or without antithymocyte globulin. The regimen was well tolerated, and 34 patients achieved durable engraftment and most achieved remission after RIST. A total of 17 patients developed grade II-IV acute GVHD, and 27 developed chronic GVHD. Eight patients relapsed, and five of them received antithymocyte globulin (ATG) as part of the preparative regimen. A total of 12 patients died (four disease progression, six transplantation-related complications, and two others). Estimated 1-year disease-free survival (DFS) in low- and high-risk groups was 85 and 64%, respectively. We conclude that RIST can be performed safely in elderly patients with myeloid malignancies, and has therapeutic potential for those who fail conventional chemotherapy. In view of the significant association between GVHD or ATG and DFS, defined management of GVHD following RIST should become a major target of clinical research.

  3. Intra-hematopoietic cell fusion as a source of somatic variation in the hematopoietic system.

    Science.gov (United States)

    Skinner, Amy M; Grompe, Markus; Kurre, Peter

    2012-06-15

    Cell fusion plays a well-recognized, physiological role during development. Bone-marrow-derived hematopoietic cells have been shown to fuse with non-hematopoietic cells in a wide variety of tissues. Some organs appear to resolve the changes in ploidy status, generating functional and mitotically-competent events. However, cell fusion exclusively involving hematopoietic cells has not been reported. Indeed, genomic copy number variation in highly replicative hematopoietic cells is widely considered a hallmark of malignant transformation. Here we show that cell fusion occurs between cells of the hematopoietic system under injury as well as non-injury conditions. Experiments reveal the acquisition of genetic markers in fusion products, their tractable maintenance during hematopoietic differentiation and long-term persistence after serial transplantation. Fusion events were identified in clonogenic progenitors as well as differentiated myeloid and lymphoid cells. These observations provide a new experimental model for the study of non-pathogenic somatic diversity in the hematopoietic system.

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

    Science.gov (United States)

    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.

  5. Two pregnancies shortly after transplantation with reduced intensity conditioning in chronic myeloid leukemia.

    Science.gov (United States)

    Faraci, Maura; Matthes-Martin, Susanne; Lanino, Edoardo; Morreale, Giuseppe; Ferretti, Marta; Giardino, Stefano; Micalizzi, Concetta; Balduzzi, Adriana

    2016-02-01

    POI is a relevant late complication after HSCT and occurring more frequently after MAC than after RIC regimens. Reports on the frequency of POI after RIC in a large pediatric and adolescent population are lacking. In this study, we describe a girl affected by CML diagnosed at the age of 15 yr and treated with oncarbide and interferon followed by imatinib and dasatinib. She had two pregnancies shortly after RIC performed according to the CML-SCT I-BFM protocol including TT, FLU, and MEL. Hypergonadotropic hypogonadism occurred four months after HSCT; menstruations resumed regularly six months after HSCT. Eight and 20 months after HSCT, the patient became pregnant and then delivered, respectively, two babies at term by cesarean section. Both newborns had no neonatal complications. Donor chimerism at time of two pregnancies and five yr after transplantation demonstrated complete donor engraftment. These findings suggest that I-BFM CML-SCT protocol could be a promising treatment option for adolescents or young adults with CML eligible for HSCT.

  6. Safety and efficacy of total body irradiation, cyclophosphamide, and cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with acute lymphoblastic leukemia.

    Science.gov (United States)

    Mori, Takehiko; Aisa, Yoshinobu; Kato, Jun; Yamane, Akiko; Nakazato, Tomonori; Shigematsu, Naoyuki; Okamoto, Shinichiro

    2012-04-01

    Disease relapse still greatly interferes with the success of allogeneic hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL). This study retrospectively evaluated the long-term safety and efficacy of a conditioning regimen consisting of total body irradiation (TBI; 12 Gy), cyclophosphamide (CY; 60 mg kg(-1) , two doses), and high-dose cytarabine (Ara-C; 2 g m(-2) ; four doses) for patients with ALL. Fifty-five patients (median age: 31-years old) were evaluated. Stem cells were from human leukocyte antigen-identical siblings in 22 patients and from alternative donors in 33. There were no cases of early death before engraftment, and 100-day transplant-related mortality was 7.3%. With a median follow-up period of 9.6 years, 5-year overall and disease-free survival were 63.2% (95% CI: 46.5-79.9%) and 63.6% (95% CI: 47.1-80.1%) in patients with complete remission, respectively, both of which were significantly higher than the values of 27.3% (95% CI: 8.7-46.0%) and 22.7% (95% CI: 5.3-40.1%) for patients in advanced stages (P < 0.01). These results suggest that TBI and CY (TBI-CY) plus Ara-C could be a feasible and effective conditioning regimen for adult patients with ALL both in remission and in advanced stages, and a future study to compare this combination therapy with TBI-CY is required.

  7. Lentiviral hematopoietic stem cell gene therapy in patients with Wiskott-Aldrich syndrome.

    Science.gov (United States)

    Aiuti, Alessandro; Biasco, Luca; Scaramuzza, Samantha; Ferrua, Francesca; Cicalese, Maria Pia; Baricordi, Cristina; Dionisio, Francesca; Calabria, Andrea; Giannelli, Stefania; Castiello, Maria Carmina; Bosticardo, Marita; Evangelio, Costanza; Assanelli, Andrea; Casiraghi, Miriam; Di Nunzio, Sara; Callegaro, Luciano; Benati, Claudia; Rizzardi, Paolo; Pellin, Danilo; Di Serio, Clelia; Schmidt, Manfred; Von Kalle, Christof; Gardner, Jason; Mehta, Nalini; Neduva, Victor; Dow, David J; Galy, Anne; Miniero, Roberto; Finocchi, Andrea; Metin, Ayse; Banerjee, Pinaki P; Orange, Jordan S; Galimberti, Stefania; Valsecchi, Maria Grazia; Biffi, Alessandra; Montini, Eugenio; Villa, Anna; Ciceri, Fabio; Roncarolo, Maria Grazia; Naldini, Luigi

    2013-08-23

    Wiskott-Aldrich syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative, but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and reinfused the cells after a reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical scores. Vector integration analyses revealed highly polyclonal and multilineage haematopoiesis resulting from the gene-corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes, and no aberrant clonal expansion was observed after 20 to 32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS.

  8. Effect of endothelial progenitor cell on hematopoietic reconstitution in allogeneic hematopoietic stem cell transplantation mouse model

    Institute of Scientific and Technical Information of China (English)

    化静

    2013-01-01

    Objective To examine the effects of endothelial progenitor cell (EPC) on hematopoietic reconsititution in allogeneic hematopoietic stem cell transplantation (alloHSCT) mouse model.Methods Allo-HSCT mouse model was established with condition of BU/CY,in which C57BL/6 (H-2b) and BABL/c (H-2d) mice were used

  9. A HIGHER INCIDENCE OF RELAPSE FOR ACUTE LYMPHOCYTIC LEUKEMIA TREATED WITH ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION CONDITIONED WITH BU-CY2 REGIMEN

    Institute of Scientific and Technical Information of China (English)

    朱康儿; 钟隽; 张涛; 曾慧兰

    2003-01-01

    Objective: To analyze long-term outcome in sixty leukemia patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT) following busulfan and cyclophosphamide (BU-CY2) between 1994 and 2000. Methods: BU-CY2 was used as the conditioning regimen and allo-HSCT was performed for all patients. All the patients were followed-up until August 2001 or death. The leukemia-free survival, relapse and transplant-related mortality were discussed. Results: All 60 patients had sustained engraftment. Acute GVHD occurred in 22 out of 60 patients (36.7%), and the incidence of acute GVHD was 48% in the patients with CML, 30% in AML and 26.7% in ALL. 38 patients are still alive in continuous remission with a median follow-up of 30 months (range 12-84) and 22 patients have died. The main causes of death were acute GVHD in 3 patients, CMV-IP in 7 patients and relapse in 11 patients, the remaining one died of pulmonary infection. Among 11 patients who died of relapse, 8 patients with ALL relapsed in the early stage post transplant (8/15, 53.3%), relapse was observed in the remaining 3 patients with AML, and however, no relapse was observed in CML. The probability of disease-free survival at 3 years for CML. AML and ALL patients was 80%, 70% and 26.7%, respectively. Conclusion: This results suggests that BU-CY2 is an effective conditioning regimen in patients with AML and CML, resulting in a low relapse rate and high long-term survival rate, but not as effective in patients with ALL, with a higher incidence of relapse and therefore, not recommended for ALL patients.

  10. Allogeneic Hematopoietic Stem Cell Transplantation after Conditioning Regimens with Fludarabine/melphalan or Fludarabine/busulfan for Patients with Hematological Malignancies: A Single-center Analysis.

    Science.gov (United States)

    Yamamoto, Wataru; Andou, Taiki; Itabashi, Megumi; Koyama, Satoshi; Ishii, Yoshimi; Numata, Ayumi; Motohashi, Kenji; Hagihara, Maki; Matsumoto, Kenji; Fujisawa, Shin

    2016-01-01

    Objective Fludarabine plus melphalan (FM) and fludarabine plus busulfan (FB) are two major conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods We retrospectively analyzed patients who underwent allo-HSCT after a conditioning regimen consisting of FM or FB with/without total body irradiation for hematological malignancies between 2005 and 2014. Results There were 41 patients who met the criteria. The median follow-up time for the survivors was 3 years. Thirty-two patients received allo-HSCT after the FM regimen and nine patients received allo-HSCT after the FB regimen. Patients who received FB were older than those who received FM (p=0.041). There was no significant difference in the 3-year overall survival between patients who had received FB and those who had received FM (29.6% vs. 56.5%, p=0.267). The 3-year cumulative incidence of relapse was significantly higher in patients who had received FB than that in patients who had received FM (66.7% vs. 17.8%, p=0.004), and FB was an independent prognostic factor for relapse by a multivariate analysis (hazard ratio, 9.8; 95% confidential interval, 2.5-39.3; p=0.001). When we restricted the evaluation to patients with acute myeloid leukemia and myelodysplastic syndrome, the 3-year cumulative incidence of relapse was also significantly higher in patients who had received FB than that in patients who had received FM (75.0% vs. 16.1%, p=0.004). Conclusion The results suggest that FM may provide better disease control than FB.

  11. Hematopoietic Stem Cell Cytokines and Fibroblast Growth factor-2 Stimulate Human Endothelial Cell-Pericyte Tube Co-Assembly in 3D Fibrin Matrices under Serum-Free Defined Conditions

    Science.gov (United States)

    Smith, Annie O.; Bowers, Stephanie L. K.; Stratman, Amber N.; Davis, George E.

    2013-01-01

    We describe a novel 3D fibrin matrix model using recombinant hematopoietic stem cell cytokines under serum-free defined conditions which promotes the assembly of human endothelial cell (EC) tubes with co-associated pericytes. Individual ECs and pericytes are randomly mixed together and EC tubes form that is accompanied by pericyte recruitment to the EC tube abluminal surface over a 3-5 day period. These morphogenic processes are stimulated by a combination of the hematopoietic stem cell cytokines, stem cell factor, interleukin-3, stromal derived factor-1α, and Flt-3 ligand which are added in conjunction with fibroblast growth factor (FGF)-2 into the fibrin matrix. In contrast, this tube morphogenic response does not occur under serum-free defined conditions when VEGF and FGF-2 are added together in the fibrin matrices. We recently demonstrated that VEGF and FGF-2 are able to prime EC tube morphogenic responses (i.e. added overnight prior to the morphogenic assay) to hematopoietic stem cell cytokines in collagen matrices and, interestingly, they also prime EC tube morphogenesis in 3D fibrin matrices. EC-pericyte interactions in 3D fibrin matrices leads to marked vascular basement membrane assembly as demonstrated using immunofluorescence and transmission electron microscopy. Furthermore, we show that hematopoietic stem cell cytokines and pericytes stimulate EC sprouting in fibrin matrices in a manner dependent on the α5β1 integrin. This novel co-culture system, under serum-free defined conditions, allows for a molecular analysis of EC tube assembly, pericyte recruitment and maturation events in a critical ECM environment (i.e. fibrin matrices) that regulates angiogenic events in postnatal life. PMID:24391990

  12. A trial of plerixafor adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency.

    Science.gov (United States)

    Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M; Czechowicz, Agnieszka; Shizuru, Judy A; Ko, Rose M; Cowan, Morton J

    2014-09-01

    For infants with SCID, the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with G-CSF plus plerixafor given to the host to mobilize HSC from their niches. We enrolled six patients who received CD34-selected haploidentical cells and one who received T-replete matched unrelated BM. All patients receiving G-CSF and plerixafor had generally poor CD34(+) cell and Lin(-) CD34(+) CD38(-) CD90(+) CD45RA(-) HSC mobilization, and developed donor T cells, but no donor myeloid or B-cell engraftment. Although well tolerated, G-CSF plus plerixafor alone failed to overcome physical barriers to donor engraftment.

  13. A trial of alemtuzumab adjunctive therapy in allogeneic hematopoietic cell transplantation with minimal conditioning for severe combined immunodeficiency.

    Science.gov (United States)

    Dvorak, Christopher C; Horn, Biljana N; Puck, Jennifer M; Adams, Stuart; Veys, Paul; Czechowicz, Agnieszka; Cowan, Morton J

    2014-09-01

    For infants with SCID the ideal conditioning regimen before allogeneic HCT would omit cytotoxic chemotherapy to minimize short- and long-term complications. We performed a prospective pilot trial with alemtuzumab monotherapy to overcome NK-cell mediated immunologic barriers to engraftment. We enrolled four patients who received CD34-selected haploidentical cells, two of whom failed to engraft donor T cells. The two patients who engrafted had delayed T-cell reconstitution, despite rapid clearance of circulating alemtuzumab. Although well-tolerated, alemtuzumab failed to overcome immunologic barriers to donor engraftment. Furthermore, alemtuzumab may slow T-cell development in patients with SCID in the setting of a T-cell depleted graft.

  14. Donor-derived mycosis fungoides following reduced intensity haematopoietic stem cell transplantation from a matched unrelated donor

    Science.gov (United States)

    Kinsella, Francesca A M; Amel Kashipaz, Mohammad Rasoul; Scarisbrick, Julia; Malladi, Ram

    2017-01-01

    A 46-year-old woman with a history of dasatinib-resistant chronic myeloid leukaemia, clonal evolution and monosomy 7 underwent reduced intensity conditioned in vivo T-cell-depleted allogeneic haematopoietic stem cell transplantation (HSCT) from a matched unrelated donor. Following the transplantation, she developed recurrent cutaneous graft versus host disease (GvHD), which required treatment with systemic immunosuppression and electrocorporeal photophoresis. Concurrently, she developed a lichenoid rash with granulomatous features suggestive of cutaneous sarcoidosis. Additional treatment with hydroxychloroquine was initially successful, but 2 months later, she developed erythroderma with palpable lymphadenopathy. Repeated histological analysis established a diagnosis of folliculotropic mycosis fungoides stage IVA2, and the malignant clone was confirmed to be of donor origin. A positive response to brentuximab has been shown. This is the first reported case of primary mycosis fungoides after matched unrelated donor HSCT, and in a patient still undergoing treatment for GvHD. PMID:28073814

  15. TRANSIENT AND PERMANENT ENGRAFTMENT POTENTIAL OF MURINE HEMATOPOIETIC STEM-CELL SUBSETS - DIFFERENTIAL-EFFECTS OF HOST CONDITIONING WITH GAMMA-RADIATION AND CYTOTOXIC DRUGS

    NARCIS (Netherlands)

    DOWN, JD; PLOEMACHER, RE

    1993-01-01

    Transplant of sorted donor (BG-Gpi-1(a)) hematopoietic stem cell subsets and host (BG-Gpi-1(b)) treatment with total body irradiation (TBI) or cytotoxic drugs were compared for induction of short- and long-term engraftment in a murine chimera model of congenic bone marrow transplantation (BMT). Para

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Graft failure following reduced-intensity cord blood transplantation for adult patients.

    Science.gov (United States)

    Narimatsu, Hiroto; Kami, Masahiro; Miyakoshi, Shigesaburo; Murashige, Naoko; Yuji, Koichiro; Hamaki, Tamae; Masuoka, Kazuhiro; Kusumi, Eiji; Kishi, Yukiko; Matsumura, Tomoko; Wake, Atsushi; Morinaga, Shinichi; Kanda, Yoshinobu; Taniguchi, Shuichi

    2006-01-01

    We reviewed the medical records of 123 adult reduced-intensity cord blood transplantation (RI-CBT) recipients to investigate the clinical features of graft failure after RI-CBT. Nine (7.3%) had graft failure, and were classified as graft rejection rather than primary graft failure; they showed peripheral cytopenia with complete loss of donor-type haematopoiesis, implying destruction of donor cells by immunological mechanisms rather than poor graft function. Three of them died of bacterial or fungal infection during neutropenia. Two recovered autologous haematopoiesis. The remaining four patients underwent a second RI-CBT and developed severe regimen-related toxicities. One died of pneumonia on day 8, and the other three achieved engraftment. Two of them died of transplant-related mortality, and the other survived without disease progression for 9.0 months after the second RI-CBT. In total, seven of the nine patients with graft failure died. The median survival of those with graft failure was 3.8 months (range, 0.9-15.4). Graft failure is a serious complication of RI-CBT. As host T cells cannot completely be eliminated by reduced-intensity preparative regimens, we need to be aware of the difficulty in differentiating graft rejection from other causes of graft failure following RI-CBT. Further studies are warranted to establish optimal diagnostic and treatment strategies.

  18. Exogenous endothelial cells as accelerators of hematopoietic reconstitution

    Directory of Open Access Journals (Sweden)

    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.

  19. Epo and other hematopoietic factors

    OpenAIRE

    2007-01-01

    The growth factors erythropoietin and granulocyte-colony stimulating factor have hematopoietic and non-hematopoietic functions. Both are used clinically in their recombinant forms. Both also have interesting tissue-protective effects in other organs, which are unrelated to their hematopoietic functions. They have clinical hematopoietic uses in neonatal populations and in experimental non-hematopoietic research, and clinical potential as neuroprotective or tissue-protective agents.

  20. A comparative study of reduced dose alemtuzumab in matched unrelated donor and related donor reduced intensity transplants.

    Science.gov (United States)

    Jardine, Laura; Publicover, Amy; Bigley, Venetia; Hale, Geoff; Pearce, Kim; Dickinson, Anne; Jackson, Graham; Collin, Matthew

    2015-03-01

    In vivo T cell depletion with 100 mg alemtuzumab prevents graft-versus-host disease (GVHD) in reduced intensity conditioned transplants but is associated with delayed immune reconstitution, a higher risk of infection and relapse. De-escalation studies have shown that a reduced dose of 30 mg is as effective as 100 mg in preventing GVHD in matched related donor (MRD) transplants. Dose reduction in matched unrelated donor (MUD) transplants is feasible but the comparative efficacy of alemtuzumab in this setting is not known and opinions vary widely concerning the optimal level of GVHD prophylaxis that should be achieved. Through retrospective analysis we made an objective comparison of MUD transplants receiving an empirically reduced dose of 60 mg, with MRD transplants receiving a 30 mg dose. We observed proportionate levels of alemtuzumab according to dose but an inverse relationship with body surface area particularly in MRD transplants. MUD transplants experienced more acute and chronic GVHD, higher T cell chimerism, more sustained use of ciclosporin and less need for donor lymphocyte infusion than MRD transplants. Thus, doubling the dose of alemtuzumab to 60 mg did not provide equivalent prevention of GVHD after MUD transplant although there was no difference in non-relapse mortality or survival compared with MRD transplants.

  1. Infectious complications following allogeneic HLA-identical sibling transplantation with antithymocyte globulin-based reduced intensity preparative regimen.

    Science.gov (United States)

    Mohty, M; Jacot, W; Faucher, C; Bay, J O; Zandotti, C; Collet, L; Choufi, B; Bilger, K; Tournilhac, O; Vey, N; Stoppa, A M; Coso, D; Gastaut, J A; Viens, P; Maraninchi, D; Olive, D; Blaise, D

    2003-11-01

    In the setting of reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (allo-SCT), the epidemiology of transplant-related infections is still poorly defined. In 101 high-risk patients who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan and antithymocyte globulin (ATG), we report during the first 6 months a cumulative incidence of positive CMV antigenemia of 42% (95% CI 32-52%), developing at a median of 37 (range 7-116) days without evidence of CMV disease (median follow-up, 434 days). The cumulative incidence of bacteremia was 25% (95% CI 17-33%), occurring at a median of 67 (range 7-172) days, while patients had recovered a full neutrophil count. In all, 65% of the bacteremia (95% CI 49-81%) were gram negative. The cumulative incidence of fungal infections was 8% (95% CI 3-13%), with a median onset of 89 (range 7-170) days. In multivariate analysis, stem cell source (bone marrow; P=0.0002) was significantly associated with the risk of positive CMV antigenemia, while higher doses of prednisone (>2 mg/kg) represented the major risk factor for bacteremia (P=0.0001). Infectious-related mortality was 5% (95% CI 1-9%), with aspergillosis being the principal cause. Collectively, these results suggest that prospective efforts are warranted to develop optimal antimicrobial preventive strategies after RIC allo-SCT.

  2. Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores.

    Science.gov (United States)

    Burt, Richard K; Cohen, Bruce A; Russell, Eric; Spero, Kenneth; Joshi, Akash; Oyama, Yu; Karpus, William J; Luo, Kehuan; Jovanovic, Borko; Traynor, Ann; Karlin, Karyn; Stefoski, Dusan; Burns, William H

    2003-10-01

    There were 21 patients with rapidly progressive multiple sclerosis (MS) treated on a phase 1/2 study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no 1-year mortality. Following transplantation, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pretransplantation EDSS of 6.0 or less. In 8 of 12 patients with high pretransplantation disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1-point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. There were 2 patients with a pretransplantation EDSS of 7.0 and 8.0 who died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression using a total body irradiation (TBI)-based regimen and hematopoietic stem cell transplantation (HSCT) are not effective for patients with progressive disease and high pretransplantation disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. Specifically, more patients and longer follow-up would be required in patients with an EDSS of 6.0 or less before drawing conclusions on this subgroup.

  3. Early central nervous system complications after reduced-intensity stem cell transplantation.

    Science.gov (United States)

    Kishi, Yukiko; Miyakoshi, Shigesaburo; Kami, Masahiro; Ikeda, Masayuki; Katayama, Yuta; Murashige, Naoko; Kusumi, Eiji; Yuji, Koichiro; Kobayashi, Kazuhiko; Kato, Daisuke; Hamaki, Tamae; Matsumura, Tomoko; Kim, Sung-Won; Morinaga, Shinichi; Mori, Shinichiro; Kanemaru, Mineo; Hayashi, Tatsuyuki; Takaue, Yoichi; Taniguchi, Shuichi

    2004-08-01

    To investigate clinical characteristics of early central nervous system (CNS) complications after reduced-intensity stem cell transplantation (RIST), we reviewed the medical records of 232 patients who had undergone RIST for hematologic diseases at our institutions between September 1999 and June 2003. All patients had received purine analog-based preparative regimens. Stem cell sources comprised granulocyte colony-stimulating factor-mobilized blood from HLA-identical or 1 locus-mismatched related donors (n = 151), unrelated bone marrow (n = 44), or unrelated cord blood (n = 37). Graft-versus-host disease prophylaxis incorporated cyclosporine with or without methotrexate. Diagnosis of CNS complications was based on clinical, radiologic, and microbiological findings. CNS complications occurred in 18 patients (7.8%), with a median onset of 22 days, and were infectious (n = 1), metabolic (n = 15), or cerebrovascular (n = 2). Symptoms included seizures (n = 7), visual disturbance (n = 2), headache (n = 8), nausea (n = 8), vomiting (n = 6), impaired consciousness (n = 16), and hemiparesis (n = 3). Complications improved promptly in 10 patients, and 8 patients died without improvement within 30 days. Multivariate analysis with logistic regression identified umbilical cord blood transplantation as a significant risk factor for early CNS complications (odds ratio, 14.5; 95% confidence interval, 3.7-56.9; P <.0001). CNS complications are a significant problem after RIST, particularly with umbilical cord blood. Limbic encephalopathy is an unrecognized subtype of neurotoxicity after umbilical cord blood transplantation.

  4. Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma.

    Science.gov (United States)

    Yuji, Koichiro; Miyakoshi, Shigesaburo; Kato, Daisuke; Miura, Yuji; Myojo, Tomohiro; Murashige, Naoko; Kishi, Yukiko; Kobayashi, Kazuhiro; Kusumi, Eiji; Narimatsu, Hiroto; Hamaki, Tamae; Matsumura, Tomoko; Kami, Masahiro; Fukuda, Takahiro; Masuo, Shigeru; Masuoka, Kazuhiro; Wake, Atsushi; Ueyama, Junichi; Yoneyama, Akiko; Miyamoto, Ko; Nagoshi, Haruhisa; Matsuzaki, Michio; Morinaga, Shinichi; Muto, Yoshitomo; Takeue, Yoichi; Taniguchi, Shuichi

    2005-04-01

    We report the results of reduced-intensity unrelated cord blood transplantation (RI-UCBT) in patients with advanced malignant lymphoma. Twenty patients (median age, 46.5 years; range, 27-66 years) underwent RI-UCBT with a preparative regimen consisting of fludarabine 125 mg/m2 , melphalan 80 mg/m 2 , and 4 Gy of total body irradiation. The median infused total cell dose was 2.75 x 10(7)/kg (range, 2.3-3.4 x 10(7)/kg). Graft-versus-host disease (GVHD) prophylaxis was composed of cyclosporine or tacrolimus alone. Fifteen patients achieved primary neutrophil engraftment after a median of 20 days. Eight patients developed grade II to IV acute GVHD, and 2 developed chronic GVHD. Of the 16 patients with evaluable disease, 10 achieved a complete response. Primary disease recurred in 1 patient, and transplant-related mortality within 100 days occurred in 8 of 20 patients. The estimated 1-year probability of progression-free survival was 50%. These data suggest that RI-UCBT is a feasible option for patients with refractory lymphoma who lack an HLA-matched donor.

  5. Busulfan plus fludarabine as a myeloablative conditioning regimen compared with busulfan plus cyclophosphamide for acute myeloid leukemia in first complete remission undergoing allogeneic hematopoietic stem cell transplantation: a prospective and multicenter study

    Directory of Open Access Journals (Sweden)

    Liu Hui

    2013-02-01

    Full Text Available Abstract Objective We conducted a prospective, randomized, open-label, multicenter study to compare busulfan plus fludarabine (BuFlu with busulfan plus cyclophosphamide (BuCy as the conditioning regimen in allogeneic hematopoietic stem cell transplantation (allo-HSCT for acute myeloid leukemia (AML in first complete remission (CR1. Methods Totally 108 AML-CR1 patients undergoing allo-HSCT were randomized into BuCy (busulfan 1.6 mg/kg, q12 hours, -7 ~ -4d; cyclophosphamide 60 mg/kg.d, -3 ~ -2d or BuFlu (busulfan 1.6 mg/kg, q12 hours, -5 ~ -2d; fludarabine 30 mg/m2.d, -6 ~ -2d group. Hematopoietic engraftment, regimen-related toxicity (RRT, graft-versus-host disease (GVHD, transplant related mortality (TRM, and overall survival were compared between the two groups. Results All patients achieved hematopoietic reconstitution except for two patients who died of RRT during conditioning. All patients obtained complete donor chimerism by day +30 post-transplantation. The incidence of total and III-IV RRT were 94.4% and 81.5% (P = 0.038, and 16.7% and 0.0% (P = 0.002, respectively, in BuCy and BuFlu group. With a median follow up of 609 (range, 3–2130 days after transplantation, the 5-year cumulative incidence of TRM were 18.8 ± 6.9% and 9.9 ± 6.3% (P = 0.104; the 5-year cumulative incidence of leukemia relapse were 16.5 ± 5.8% and 16.2 ± 5.3% (P = 0.943; the 5-year disease-free survival and overall survival were 67.4 ± 7.6% and 75.3 ± 7.2% (P = 0.315, and 72.3 ± 7.5% and 81.9 ± 7.0% (P = 0.177, respectively in BuCy and BuFlu group. Conclusion Compared with BuCy, BuFlu as a myeloablative condition regimen was associated with lower toxicities and comparable anti-leukemic activity in AML-CR1 patients undergoing allo-HSCT.

  6. Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen.

    Science.gov (United States)

    Faucher, Catherine; Mohty, Mohamad; Vey, Norbert; Gaugler, Béatrice; Bilger, Karin; Moziconnacci, Marie-Joelle; Stoppa, Anne-Marie; Coso, Diane; Ladaique, Patrick; Chabannon, Christian; Reviron, Denis; Maraninchi, Dominique; Gastaut, Jean-Albert; Olive, Daniel; Blaise, Didier

    2003-10-01

    Reduced-intensity conditioning regimens (RIC) and peripheral blood stem cells (PBSC) are increasingly used for allogeneic stem cell transplantation (allo-BMT). RIC has been shown to allow engraftment with minimal early transplant-related mortality (TRM). However, in the context of RIC, the use of bone marrow (BM) as stem cell source is still little evaluated. In this report, we analyzed the outcome of 32 high-risk patients with hematological malignancies who received an HLA-identical sibling allo-BMT after RIC including fludarabine, busulfan, and anti-thymocyte globulin (ATG). Sustained neutrophil and platelet recovery occurred at a median of 13 days (range, 10-19) and 17 days (range, 0-45) respectively. Early and durable full donor chimerism could be established as soon as the first month after allo-BMT. Also, a sustained and early CD8(+) T-cell recovery was observed, but the CD4(+) T-cell compartment remained profoundly low. The cumulative incidences of grade II-IV acute GVHD and chronic GVHD were 26% (95% CI, 11-41%) and 31% (95% CI, 15-47%) respectively. The overall cumulative incidence of TRM was 28% (95% CI, 12-44%) occurring mainly in patients aged over 50. In this setting, GVHD showed a protective effect on disease progression or relapse with better progression-free survival for patients with GVHD as compared to patients without GVHD (p=0.03). Collectively, these results confirm that the use of BM grafts for RIC is feasible with durable donor engraftment and no detrimental GVHD.

  7. Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency.

    Science.gov (United States)

    De Ravin, Suk See; Wu, Xiaolin; Moir, Susan; Anaya-O'Brien, Sandra; Kwatemaa, Nana; Littel, Patricia; Theobald, Narda; Choi, Uimook; Su, Ling; Marquesen, Martha; Hilligoss, Dianne; Lee, Janet; Buckner, Clarissa M; Zarember, Kol A; O'Connor, Geraldine; McVicar, Daniel; Kuhns, Douglas; Throm, Robert E; Zhou, Sheng; Notarangelo, Luigi D; Hanson, I Celine; Cowan, Mort J; Kang, Elizabeth; Hadigan, Coleen; Meagher, Michael; Gray, John T; Sorrentino, Brian P; Malech, Harry L

    2016-04-20

    X-linked severe combined immunodeficiency (SCID-X1) is a profound deficiency of T, B, and natural killer (NK) cell immunity caused by mutations inIL2RGencoding the common chain (γc) of several interleukin receptors. Gamma-retroviral (γRV) gene therapy of SCID-X1 infants without conditioning restores T cell immunity without B or NK cell correction, but similar treatment fails in older SCID-X1 children. We used a lentiviral gene therapy approach to treat five SCID-X1 patients with persistent immune dysfunction despite haploidentical hematopoietic stem cell (HSC) transplant in infancy. Follow-up data from two older patients demonstrate that lentiviral vector γc transduced autologous HSC gene therapy after nonmyeloablative busulfan conditioning achieves selective expansion of gene-marked T, NK, and B cells, which is associated with sustained restoration of humoral responses to immunization and clinical improvement at 2 to 3 years after treatment. Similar gene marking levels have been achieved in three younger patients, albeit with only 6 to 9 months of follow-up. Lentiviral gene therapy with reduced-intensity conditioning appears safe and can restore humoral immune function to posthaploidentical transplant older patients with SCID-X1.

  8. 2013 report from the Center for International Blood and Marrow Transplant Research (CIBMTR): current uses and outcomes of hematopoietic cell transplants for blood and bone marrow disorders.

    Science.gov (United States)

    Pasquini, Marcelo; Wang, Zhiwei; Horowitz, Mary M; Gale, Robert Peter

    2013-01-01

    Data reported herein indicate increasing use of hematopoietic cell transplants for persons with blood and bone marrow disorders. Recent trends include increasing use of alternative donors including human leukocyte antigen (HLA)-matched unrelated persons and HLA-matched umbilical cord blood cells, increasing use of blood cell rather than bone marrow grafts, and increasing use of reduced-intensity pretransplant conditioning regimens. Many of these shifts are driven by logistical considerations such as the need for donors in persons without an HLA-identical sibling or expanding use of allotransplants to older persons. Many changes in transplant practices are not supported by results of large randomized trials. More data are needed to critically-assess the impact of these changes.

  9. Lack of autophagy in the hematopoietic system leads to loss of hematopoietic stem cell function and dysregulated myeloid proliferation.

    Science.gov (United States)

    Mortensen, Monika; Watson, Alexander Scarth; Simon, Anna Katharina

    2011-09-01

    The regulated lysosomal degradation pathway of autophagy prevents cellular damage and thus protects from malignant transformation. Autophagy is also required for the maturation of various hematopoietic lineages, namely the erythroid and lymphoid ones, yet its role in adult hematopoietic stem cells (HSCs) remained unexplored. While normal HSCs sustain life-long hematopoiesis, malignant transformation of HSCs or early progenitors leads to leukemia. Mechanisms protecting HSCs from cellular damage are therefore essential to prevent hematopoietic malignancies. By conditionally deleting the essential autophagy gene Atg7 in the hematopoietic system, we found that autophagy is required for the maintenance of true HSCs and therefore also of downstream hematopoietic progenitors. Loss of autophagy in HSCs leads to the expansion of a progenitor cell population in the bone marrow, giving rise to a severe, invasive myeloproliferation, which strongly resembles human acute myeloid leukemia (AML).

  10. Hematopoietic Cell Transplantation Outcomes in Monosomal Karyotype Myeloid Malignancies.

    Science.gov (United States)

    Pasquini, Marcelo C; Zhang, Mei-Jie; Medeiros, Bruno C; Armand, Philippe; Hu, Zhen-Huan; Nishihori, Taiga; Aljurf, Mahmoud D; Akpek, Görgün; Cahn, Jean-Yves; Cairo, Mitchell S; Cerny, Jan; Copelan, Edward A; Deol, Abhinav; Freytes, César O; Gale, Robert Peter; Ganguly, Siddhartha; George, Biju; Gupta, Vikas; Hale, Gregory A; Kamble, Rammurti T; Klumpp, Thomas R; Lazarus, Hillard M; Luger, Selina M; Liesveld, Jane L; Litzow, Mark R; Marks, David I; Martino, Rodrigo; Norkin, Maxim; Olsson, Richard F; Oran, Betul; Pawarode, Attaphol; Pulsipher, Michael A; Ramanathan, Muthalagu; Reshef, Ran; Saad, Ayman A; Saber, Wael; Savani, Bipin N; Schouten, Harry C; Ringdén, Olle; Tallman, Martin S; Uy, Geoffrey L; Wood, William A; Wirk, Baldeep; Pérez, Waleska S; Batiwalla, Minoo; Weisdorf, Daniel J

    2016-02-01

    The presence of monosomal karyotype (MK+) in acute myeloid leukemia (AML) is associated with dismal outcomes. We evaluated the impact of MK+ in AML (MK+AML, n = 240) and in myelodysplastic syndrome (MDS) (MK+MDS, n = 221) on hematopoietic cell transplantation outcomes compared with other cytogenetically defined groups (AML, n = 3360; MDS, n = 1373) as reported to the Center for International Blood and Marrow Transplant Research from 1998 to 2011. MK+ AML was associated with higher disease relapse (hazard ratio, 1.98; P < .01), similar transplantation-related mortality (TRM) (hazard ratio, 1.01; P = .90), and worse survival (hazard ratio, 1.67; P < .01) compared with those outcomes for other cytogenetically defined AML. Among patients with MDS, MK+ MDS was associated with higher disease relapse (hazard ratio, 2.39; P < .01), higher TRM (hazard ratio, 1.80; P < .01), and worse survival (HR, 2.02; P < .01). Subset analyses comparing chromosome 7 abnormalities (del7/7q) with or without MK+ demonstrated higher mortality for MK+ disease in for both AML (hazard ratio, 1.72; P < .01) and MDS (hazard ratio, 1.79; P < .01). The strong negative impact of MK+ in myeloid malignancies was observed in all age groups and using either myeloablative or reduced-intensity conditioning regimens. Alternative approaches to mitigate disease relapse in this population are needed. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  11. Feasibility of early tapering of cyclosporine following reduced-intensity stem cell transplantation for advanced hematologic or solid malignancies.

    Science.gov (United States)

    Hori, Akiko; Kami, Masahiro; Ohnishi, Mutsuko; Murashige, Naoko; Kojima, Rie; Takaue, Yoichi

    2005-07-01

    Although some researchers have reported that early tapering of cyclosporine is feasible and beneficial to augment graft-versus-leukemia effects after conventional stem-cell transplantation, there is little information on the feasibility of this strategy following reduced-intensity stem cell transplantation (RIST). We summarized outcomes of 17 patients who underwent early tapering of cyclosporine following RIST from HLA-identical siblings.

  12. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation.

    NARCIS (Netherlands)

    Kroger, N.; Shimoni, A.; Schilling, G.; Schwerdtfeger, R.; Bornhauser, M.; Nagler, A.; Zander, A.R.; Heinzelmann, M.; Brand, R.; Gahrton, G.; Morris, C.; Niederwieser, D.; Witte, T.J.M. de

    2010-01-01

    From 2002 to 2007, 49 myeloma patients who relapsed following autologous SCT were included in a prospective multicenter trial to determine the efficacy of a reduced melphalan/fludarabine regimen followed by allogeneic SCT from unrelated donors. All patients showed leucocyte and platelet engraftment

  13. Reduced Intensity Conditioning With Clofarabine, Antithymocyte Globulin (ATG), Total Lymphoid Irradiation (TLI) Followed by Allogeneic Stem Cell Transplant

    Science.gov (United States)

    2016-01-21

    Acute Myeloid Leukemia; Myelodysplastic Syndrome; Acute Lymphocytic Leukemia; Relapsed/Refractory Chronic Lymphocytic Leukemia; Relapsed/Refractory Non Hodgkin's Lymphoma; Hodgkins Disease; Relapsed Refractory Multiple Myeloma

  14. Unrelated stem cell transplantation after reduced intensity conditioning for patients with multiple myeloma relapsing after autologous transplantation.

    NARCIS (Netherlands)

    Kroger, N.; Shimoni, A.; Schilling, G.; Schwerdtfeger, R.; Bornhauser, M.; Nagler, A.; Zander, A.R.; Heinzelmann, M.; Brand, R.; Gahrton, G.; Morris, C.; Niederwieser, D.; Witte, T.J.M. de

    2010-01-01

    From 2002 to 2007, 49 myeloma patients who relapsed following autologous SCT were included in a prospective multicenter trial to determine the efficacy of a reduced melphalan/fludarabine regimen followed by allogeneic SCT from unrelated donors. All patients showed leucocyte and platelet engraftment

  15. Hematopoietic stem cell transplantation for follicular lymphoma: optimal timing and indication.

    Science.gov (United States)

    Kim, Sung Won

    2014-01-01

    The definitive management of advanced follicular lymphoma (FL) remains controversial due to various treatment options, including watchful waiting, single-agent or combination chemotherapy, monoclonal antibody, and radioimmunotherapy. These options can provide prolonged progression-free survival. However, they cannot cure advanced FL. Allogeneic hematopoietic stem cell transplantation (allo-SCT) remains the sole curative therapy for FL. Allo-SCT has had a major impact with the use of reduced-intensity conditioning regimens because of its lower associated nonrelapse mortality compared with myeloablative regimens. Autologous SCT (auto-SCT) shows high response rates and extends progression-free survival in patients with chemosensitive relapse. In the rituximab era, however, associated comorbidities, risk of secondary cancers, and presence of refractory disease have become problematic in the auto-SCT population. On the basis of results from large-scale randomized trials, upfront auto-SCT is not recommended. Novel conditioning regimens including radioimmunotherapy followed by either auto-SCT or allo-SCT are likely to show efficacy even in chemorefractory disease. Consequently, the optimal timing for SCT remains a matter of opinion, except for patients in first remission. However, the outcomes of allo-SCT and auto-SCT keep on improving. Physicians should note that there is no therapy with a track record equivalent to that of SCT for relapsed or refractory FL.

  16. [Commonly used cre transgenic mice and their applications in hematopoietic system].

    Science.gov (United States)

    Peng, Lu-Yun; Cheng, Tao; Yuan, Wei-Ping

    2014-10-01

    Cre-lox recombination system consists of two elements: Cre recombinase enzyme and lox sites. Cre recombinase can recombine the lox site sequences by specifically detecting and cutting them. The direction and position of lox sites determine the functional effects of Cre enzyme such as deletion, inversion or chromosomal translocation. The hematopoietic system of mouse consists of multi-lineages and various developmental stage hematopoietic cells that are differentiated from hematopoietic stem cells (hematopoietic stem cells, HSC). The hematopoietic stem cells are maintained in the bone marrow microenvironment (niche). Currently, a variety of floxed conditional-knockout mice, recognized by Cre-lox recombination system, are used for the study of the hematopoietic system. This review summarizes the commonly used Cre transgenic mice and their applications in the study of hematopoietic system.

  17. Comparison of Outcomes for Pediatric Patients With Acute Myeloid Leukemia in Remission and Undergoing Allogeneic Hematopoietic Cell Transplantation With Myeloablative Conditioning Regimens Based on Either Intravenous Busulfan or Total Body Irradiation: A Report From the Japanese Society for Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Ishida, Hiroyuki; Kato, Motohiro; Kudo, Kazuko; Taga, Takashi; Tomizawa, Daisuke; Miyamura, Takako; Goto, Hiroaki; Inagaki, Jiro; Koh, Katsuyoshi; Terui, Kiminori; Ogawa, Atsushi; Kawano, Yoshifumi; Inoue, Masami; Sawada, Akihisa; Kato, Koji; Atsuta, Yoshiko; Yamashita, Takuya; Adachi, Souichi

    2015-12-01

    Pediatric patients with acute myeloid leukemia (AML) mainly receive myeloablative conditioning regimens based on busulfan (BU) or total body irradiation (TBI) before allogeneic hematopoietic cell transplantation (allo-HCT); however, the optimal conditioning regimen remains unclear. To identify which of these regimens is better for pediatric patients, we performed a retrospective analysis of nationwide registration data collected in Japan between 2006 and 2011 to assess the outcomes of patients receiving these regimens before a first allo-HCT. Myeloablative conditioning regimens based on i.v. BU (i.v. BU-MAC) (n = 69) or TBI (TBI-MAC) (n = 151) were compared in pediatric AML patients in first or second complete remission (CR1/CR2). The incidences of sinusoid obstruction syndrome, acute and chronic graft-versus-host disease, and early nonrelapse mortality (NRM) before day 100 were similar for both conditioning groups; however, the incidence of bacterial infection during the acute period was higher in the TBI-MAC group (P = .008). Both groups showed a similar incidence of NRM, and there was no significant difference in the incidence of relapse between the groups. Univariate and multivariate analyses revealed no significant differences in the 2-year relapse-free survival rates for the i.v. BU-MAC and TBI-MAC groups in the CR1/CR2 setting (71% versus 67%, P = .36; hazard ratio, .73; 95% CI, .43 to 1.24, respectively). TBI-MAC was no better than i.v. BU-MAC for pediatric AML patients in remission. Although this retrospective registry-based analysis has several limitations, i.v. BU-MAC warrants further evaluation in a prospective trial.

  18. Allogeneic hematopoietic stem-cell transplantation for leukocyte adhesion deficiency

    DEFF Research Database (Denmark)

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

    2009-01-01

    therapeutic option if a suitable HLA-matched stem-cell donation is available. Reduced-intensity conditioning was particularly safe, and mixed-donor chimerism seems sufficient to prevent significant symptoms, although careful long-term monitoring will be required for these patients....... Blood and Marrow Transplant Research. RESULTS: At a median follow-up of 62 months (extending to 14 years), the overall survival rate was 75%. Myeloablative conditioning regimens were used in 28 patients, and reduced-intensity conditioning in 8 patients, with no deaths in this subgroup. Survival rates...

  19. Other hematopoietic disorders

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008475 The significance of dynamic detection of WT1 expression on patients of hematologic malignancy following allogeneic hematopoietic stem cell transplantation. JIN Song(金松), et al. Instit Hematol, People’s Hosp, Peking Univ, Beijing 100044, Chin J Intern Med 2008;47(7):578-581. Objective To evaluate preliminarily the significance of dynamic detection of Wilms’ tumor gene (WT1) expression level on monitoring minimal

  20. Other hematopoietic disorders

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    2010371 The incidence and risk factors of late-onset non-infectious pulmonary complications after allogeneic hematopoietic stem cell transplantation. WU Tao(吴涛),et al.Dept Hematol,Nanfang Hosp,Nanfang Med Univ,Guangzhou 510515.Chin J Hematol 2010;31(4):249-252. Objective To analyze the incidence and the risk factors of late-onset non-infectious

  1. [A medical-pharmaceutical partnership model as a contributor to the success in conditioning regimen for allogenic hematopoietic stem cell transplantation in adults: a cross-reflection on our organizations].

    Science.gov (United States)

    Bourget, Philippe; Falaschi, Ludivine; Suarez, Felipe; Galland, Valérie; Blot, Dominique; Trompette, Caroline; Sibon, David; Fontbrune, Flore Sicre de; Merlette, Christophe; Vidal, Fabrice; Corriol, Odile; Giraud, Bérénice; Broissand, Christine; Clement, Rozenn; Hermine, Olivier

    2012-06-01

    Allogeneic hematopoietic stem-cell transplant (allo-SCT) remains the only cure for many hematological malignancies and some benign and congenital diseases. Busulfan, proposed in its injectable form, has quickly become a mainstay of pharmacological and myeloablative (or non-myeloablative) conditioning. This is following the outbreak in 2010 of a multicenter international clinical phase II trial, we tested the robustness and reliability of our organization in a complex model of organization and multifactorial partnership. In this type "BuCy2" protocol based on a classical treatment duration of 4 consecutive days, the administration of IV busulfan is given in one single daily infusion instead of the conventional 16 infusions, while keeping the same total dose. Under these conditions, the treatment is totally secured using a therapeutic drug monitoring of busulfan, applied in real-time. The process is technically complex and requires the very close cooperation of the teams involved. A strength, weakness, opportunity and threat (SWOT) analysis has been constructed; it fully supports continuous quality improvement to the triple benefit of the nursing chain, the patients and their environment. Several critical points were identified and corrected. The experiment strongly contributes to the safety and security of the medication circuit at the hospital and, improves the performance of allo-SCT. It also contributes to the protection of all actors in the health field and their working environment via a well-functioning quality management system.

  2. Therapy-related acute myeloid leukemia and myelodysplastic syndrome after hematopoietic cell transplantation for lymphoma.

    Science.gov (United States)

    Yamasaki, S; Suzuki, R; Hatano, K; Fukushima, K; Iida, H; Morishima, S; Suehiro, Y; Fukuda, T; Uchida, N; Uchiyama, H; Ikeda, H; Yokota, A; Tsukasaki, K; Yamaguchi, H; Kuroda, J; Nakamae, H; Adachi, Y; Matsuoka, K-I; Nakamura, Y; Atsuta, Y; Suzumiya, J

    2017-04-03

    Therapy-related acute myeloid leukemia and myelodysplastic syndrome (t-AML/MDS) represent severe late effects in patients receiving hematopoietic cell transplantation (HCT) for lymphoma. The choice between high-dose therapy with autologous HCT and allogeneic HCT with reduced-intensity conditioning remains controversial in patients with relapsed lymphoma. We retrospectively analyzed incidence and risk factors for the development of t-AML/MDS in lymphoma patients treated with autologous or allogeneic HCT. A total of 13 810 lymphoma patients who received autologous (n=9963) or allogeneic (n=3847) HCT between 1985 and 2012 were considered. At a median overall survival (OS) of 52 and 46 months in autologous and allogeneic HCT groups, respectively, lymphoma patients receiving autologous HCT (1.38% at 3 years after autologous HCT) had a significant risk for developing t-AML/MDS compared to allogeneic HCT (0.37% at 3 years after allogeneic HCT, Pafter autologous and allogeneic HCT were high-stage risk at HCT (P=0.04) or secondary malignancies (P<0.001) and receiving cord blood stem cell (P=0.03) or involved field radiotherapy (P=0.002), respectively. Strategies that carefully select lymphoma patients for autologous HCT, by excluding lymphoma patients with high-stage risk at HCT, may allow the identification of individual lymphoma patients at particular high risk for t-AML/MDS.Bone Marrow Transplantation advance online publication, 3 April 2017; doi:10.1038/bmt.2017.52.

  3. Lentivirus-based Gene Therapy of Hematopoietic Stem Cells in Wiskott-Aldrich Syndrome

    Science.gov (United States)

    Aiuti, Alessandro; Biasco, Luca; Scaramuzza, Samantha; Ferrua, Francesca; Cicalese, Maria Pia; Baricordi, Cristina; Dionisio, Francesca; Calabria, Andrea; Giannelli, Stefania; Castiello, Maria Carmina; Bosticardo, Marita; Evangelio, Costanza; Assanelli, Andrea; Casiraghi, Miriam; Di Nunzio, Sara; Callegaro, Luciano; Benati, Claudia; Rizzardi, Paolo; Pellin, Danilo; Di Serio, Clelia; Schmidt, Manfred; Von Kalle, Christof; Gardner, Jason; Mehta, Nalini; Neduva, Victor; Dow, David J.; Galy, Anne; Miniero, Roberto; Finocchi, Andrea; Metin, Ayse; Banerjee, Pinaki; Orange, Jordan; Galimberti, Stefania; Valsecchi, Maria Grazia; Biffi, Alessandra; Montini, Eugenio; Villa, Anna; Ciceri, Fabio; Roncarolo, Maria Grazia; Naldini, Luigi

    2015-01-01

    Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by mutations in the gene encoding WASP, a protein regulating the cytoskeleton. Hematopoietic stem/progenitor cell (HSPC) transplants can be curative but, when matched donors are unavailable, infusion of autologous HSPCs modified ex vivo by gene therapy is an alternative approach. We used a lentiviral vector encoding functional WASP to genetically correct HSPCs from three WAS patients and re-infused the cells after reduced-intensity conditioning regimen. All three patients showed stable engraftment of WASP-expressing cells and improvements in platelet counts, immune functions, and clinical score. Vector integration analyses revealed highly polyclonal and multi-lineage haematopoiesis resulting from the gene corrected HSPCs. Lentiviral gene therapy did not induce selection of integrations near oncogenes and no aberrant clonal expansion was observed after 20–32 months. Although extended clinical observation is required to establish long-term safety, lentiviral gene therapy represents a promising treatment for WAS. PMID:23845947

  4. Comparison of Outcomes of HLA-Matched Related, Unrelated, or HLA-Haploidentical Related Hematopoietic Cell Transplantation following Nonmyeloablative Conditioning for Relapsed or Refractory Hodgkin Lymphoma

    National Research Council Canada - National Science Library

    Burroughs, Lauri M; O'Donnell, Paul V; Sandmaier, Brenda M; Storer, Barry E; Luznik, Leo; Symons, Heather J; Jones, Richard J; Ambinder, Richard F; Maris, Michael B; Blume, Karl G; Niederwieser, Dietger W; Bruno, Benedetto; Maziarz, Richard T; Pulsipher, Michael A; Petersen, Finn B; Storb, Rainer; Fuchs, Ephraim J; Maloney, David G

    2008-01-01

    ...) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n=38, unrelated, n...

  5. Addressing the questions of tomorrow: melphalan and new combinations as conditioning regimens before autologous hematopoietic progenitor cell transplantation in multiple myeloma.

    Science.gov (United States)

    Martino, Massimo; Olivieri, Attilio; Offidani, Massimo; Vigna, Ernesto; Moscato, Tiziana; Fedele, Roberta; Montanari, Mauro; Console, Giuseppe; Gentile, Massimo; Messina, Giuseppe; Irrera, Giuseppe; Morabito, Fortunato

    2013-05-01

    The role of high-dose chemotherapy (HDC) followed by autologous-progenitor cell transplantation (auto-HPCT) in the treatment of multiple myeloma (MM) continues to evolve in the novel agent era. Administration of high-dose melphalan (HDM) is considered the standard conditioning regimen. Nevertheless, several attempts have recently been made to improve the conditioning phase of the HDC procedure. We reviewed all the reported experiences and illustrated current knowledge in the field of conditioning regimens. For fit MM patients, HDC followed by auto-HPCT remains the standard of care. The available data confirm that melphalan (MEL) 200 mg/m(2) should continue to be considered the gold standard conditioning regimen, with dose reduction based on age and renal function. Targeting exposure to MEL by using area under the curve is a particularly appealing approach that could be explored to maximize efficacy and minimize toxicity of this drug. Other strategies are currently being evaluated in different trials, and the most interesting areas of research involve the incorporation of newer agents like bortezomib (BOR) into conditioning regimens. Moreover, intravenous busulfan has become available and this formulation may reduce toxicity and result in greater efficacy in association with MEL-based conditioning.

  6. Effects of priming with recombinant human granulocyte colony-stimulating factor on conditioning regimen for high-risk acute myeloid leukemia patients undergoing human leukocyte antigen-haploidentical hematopoietic stem cell transplantation: a multicenter randomized controlled study in southwest China.

    Science.gov (United States)

    Gao, Lei; Wen, Qin; Chen, Xinghua; Liu, Yao; Zhang, Cheng; Gao, Li; Kong, Peiyan; Zhang, Yanqi; Li, Yunlong; Liu, Jia; Wang, Qingyu; Su, Yi; Wang, Chunsen; Wang, Sanbin; Zeng, Yun; Sun, Aihua; Du, Xin; Zeng, Dongfeng; Liu, Hong; Peng, Xiangui; Zhang, Xi

    2014-12-01

    HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is an effective and immediate treatment for high-risk acute myeloid leukemia (HR-AML) patients lacking matched donors. Relapse remains the leading cause of death for HR-AML patients after haplo-HSCT. Accordingly, the prevention of relapse remains a challenge in the treatment of HR-AML. In a multicenter randomized controlled trial in southwestern China, 178 HR-AML patients received haplo-HSCT with conditioning regimens involving recombinant human granulocyte colony-stimulating factor (rhG-CSF) or non-rhG-CSF. The cumulative incidences of relapse and graft-versus-host disease (GVHD), 2-year leukemia-free survival (LFS), and overall survival (OS) were evaluated. HR-AML patients who underwent the priming conditioning regimen with rhG-CSF had a lower relapse rate than those who were treated with non-rhG-CSF (38.2%; 95% confidence interval [CI], 28.1% to 48.3% versus 60.7%, 95% CI, 50.5% to 70.8%; P priming group and 31 patients in the non-rhG-CSF-priming group were still alive at the median follow-up time of 42 months (range, 24 to 80 months). The 2-year probabilities of LFS and OS in the rhG-CSF-priming and non-rhG-CSF-priming groups were 55.1% (95% CI, 44.7% to 65.4%) versus 32.6% (95% CI, 22.8% to 42.3%) (P priming group (67.4%; 95% CI, 53.8% to 80.9% versus 41.9%; 95% CI, 27.1% to 56.6%; P priming conditioning regimen is an acceptable choice for HR-AML patients, especially for the patients with no M4/M5/M6 subtype who achieved CR before transplantation.

  7. Very low frequency radio events with a reduced intensity observed by the low-altitude DEMETER spacecraft

    Science.gov (United States)

    Záhlava, J.; Němec, F.; Santolík, O.; Kolmašová, I.; Parrot, M.; Rodger, C. J.

    2015-11-01

    We present results of a systematic study of unusual very low frequency (VLF) radio events with a reduced intensity observed in the frequency-time spectrograms measured by the low-orbiting Detection of Electro-Magnetic Emissions Transmitted from Earthquake Regions (DEMETER) spacecraft. They occur exclusively on the nightside. During these events, the intensity of fractional hop whistlers at specific frequencies is significantly reduced. These frequencies are usually above about 3.4 kHz (second Earth-ionosphere waveguide cutoff frequency), but about 20% of events extend down to about 1.7 kHz (first Earth-ionosphere waveguide cutoff frequency). The frequencies of a reduced intensity vary smoothly with time. We have inspected 6.5 years of DEMETER data, and we identified in total 1601 such events. We present a simple model of the event formation based on the wave propagation in the Earth-ionosphere waveguide. We apply the model to two selected events, and we demonstrate that the model is able to reproduce both the minimum frequencies of the events and their approximate frequency-time shapes. The overall geographic distribution of the events is shifted by about 3000 km westward and slightly southward with respect to the areas with high long-term average lightning activity. We demonstrate that this shift is related to the specific DEMETER orbit, and we suggest its qualitative explanation by the east-west asymmetry of the wave propagation in the Earth-ionosphere waveguide.

  8. Induction of embryonic stem cells to hematopoietic cells in vitro

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    In order to get hematopoietic cells from embryonic stem (ES) cells and to study development mechanisms of hematopoietic cells, the method of inducing embryonic stem cells to hematopoietic cells was explored by differenciating mouse ES cells and human embryonic cells in three stages. The differentiated cells were identified by flow cytometry, immunohistochemistry and Wright's staining. The results showed that embryoid bodies (EBs) could form when ES cells were cultured in the medium with 2-mercaptoethanol (2-ME). However, cytokines, such as stem cell factor (SCF), thrombopoietin (TPO), interleukin-3 (IL-3), interleukin-6 (IL-6), erythropoietin (EPO) and granular colony stimulating factor (G-CSF), were not helpful for forming EBs. SCF, TPO and embryonic cell conditional medium were useful for the differentiation of mouse EBs to hematopoietic progenitors. Eighty-six percent of these cells were CD34+ after 6-d culture. Hematopoietic progenitors differentiated to B lymphocytes when they were cocultured with primary bone marrow stroma cells in the DMEM medium with SCF and IL-6. 14 d later, most of the cells were CD34-CD38+. Wright's staining and immunohistochemistry showed that 80% of these cells were plasma-like morphologically and immunoglubolin positive. The study of hematopoietic cells from human embryonic cells showed that human embryonic cell differentiation was very similar to that of mouse ES cells. They could form EBs in the first stage and the CD34 positive cells account for about 48.5% in the second stage.

  9. Intravenous application of busulfan in the conditioning regimen of hematopoietic stem cell transplantation%造血干细胞移植预处理中静脉马利兰的应用

    Institute of Scientific and Technical Information of China (English)

    姚志娟; 孟庆祥; 张宏宇; 王钧; 张文丽; 温娟娟; 郭乃榄

    2011-01-01

    BACKGROUND: Busulfan is commonly used in bone marrow or peripheral blood stem cell transplantation pretreatment, which ismainly metabolized in the liver.OBJECTIVE: To evaluate the efficacy and safety of the conditioning regimen using intravenous busulfan in hematopoieticstemcell transplantation for malignant hematopathy.METHODS: A total of 43 patients receiving intravenous busulfan as conditioning regimen were included to observeregimen-related toxicity (hepatotoxicity, neurotoxicity, mucositis), engraftment time, acute graft-versus-hostdisease (aGVHD),overall survival, and leukemia relapse.RESULTS AND CONCLUSION: Thirty-one patients (72%) had a rise in the level of alanine aminotransferase. Untypical hepaticveno-occlusive syndrome occurred in 2 patients (5%). One patient had numbness on a couple of hands. Twenty-six patients(60%) had mucositis. The engraftment time of neutrophil was 16 days and that of platelet was 12 days. Delayed plateletengraftment was in 2 cases of autologous hematopoietic stem cell transplantation. The occurrence of aGVHD I -II was63%(24/38). The overall survival was 72% (31/43). The relapsed rate was 23% (10/43). The conditioning regimen with intravenousbusulfan in hematopoietic stem cell transplantation was effective and safe, and patients had better tolerance.%背景:马利兰常用于骨髓或外周血干细胞移植预处理,其主要在肝脏代谢.目的:评价静脉应用马利兰预处理在造血干细胞移植治疗恶性血液病中的有效性及安全性.方法:纳入43例患者预处理方案采用静脉剂型马利兰,观察其造血干细胞移植预处理中马利兰治疗相关毒性(肝脏、神经系统、口腔黏膜炎)造血干细胞植活时间、急性移植物抗宿主病、总生存率、白血病复发情况.结果与结论:静脉应用马利兰后,谷丙转氨酶升高72%(31/43),发生不典型肝静脉闭塞综合征5%(2/43),有1例发生双手麻木.口腔黏膜炎发生率60%(26/43).

  10. Hematopoietic stem cells and the aging hematopoietic system.

    Science.gov (United States)

    Gazit, Roi; Weissman, Irving L; Rossi, Derrick J

    2008-10-01

    The etiology of the age-associated pathophysiological changes of the hematopoietic system including the onset of anemia, diminished adaptive immune competence, and myelogenous disease development are underwritten by the loss of normal homeostatic control. As tissue and organ homeostasis in adults is primarily mediated by the activity of stem and progenitor cells, it has been suggested that the imbalances accompanying aging of the hematopoietic system may stem from alterations in the prevalence and/or functional capacity of hematopoietic stem cells (HSCs) and progenitors. In this review, we examine evidence implicating a role for stem cells in the aging of the hematopoietic system, and focus on the mechanisms suggested to contribute to stem cell aging.

  11. National Institutes of Health classification for chronic graft-versus-host disease predicts outcome of allo-hematopoietic stem cell transplant after fludarabine-busulfan-antithymocyte globulin conditioning regimen.

    Science.gov (United States)

    Saillard, Colombe; Crocchiolo, Roberto; Furst, Sabine; El-Cheikh, Jean; Castagna, Luca; Signori, Alessio; Oudin, Claire; Faucher, Catherine; Lemarie, Claude; Chabannon, Christian; Granata, Angela; Blaise, Didier

    2014-05-01

    Abstract In 2005, the National Institutes of Health (NIH) proposed standard criteria for diagnosis, organ scoring and global assessment of chronic graft-versus-host disease (cGvHD) severity. We retrospectively reclassified cGvHD with NIH criteria in a monocentric cohort of 130 consecutive adult patients with hematological malignancies presenting cGvHD after receiving allo-hematopoietic stem cell transplant (HSCT) with a fludarabine-busulfan-antithymocyte globulin (ATG) conditioning regimen, among 313 consecutive HSCT recipients. We compared NIH and Seattle classifications to correlate severity and outcome. The follow up range was effectively 2-120 months. Forty-four percent developed Seattle-defined cGvHD (22% limited, 78% extensive forms). Using NIH criteria, there were 23%, 40% and 37% mild, moderate and severe forms, respectively, and 58%, 32% and 8% classic cGvHD, late acute GvHD and overlap syndrome. Five-year overall survival was 55% (49-61), and cumulative incidences of non-relapse mortality (NRM) and relapse/progression at 2 years were 19% (14-23) and 19% (14-24). NIH mild and moderate forms were associated with better survival compared to severe cGvHD (hazard ratio [HR] = 3.28, 95% confidence interval [CI]: 1.38-7.82, p = 0.007), due to higher NRM among patients with severe cGvHD (HR = 3.04, 95% CI: 1.05-8.78, p = 0.04) but comparable relapse risk (p = NS). In conclusion, the NIH classification appears to be more accurate in predicting outcome mostly by the reclassification of old-defined extensive forms into NIH-defined moderate or severe.

  12. New drugs and allogeneic hematopoietic stem cell transplantation for hematological malignancies: do they have a role in bridging, consolidating or conditioning transplantation treatment?

    Science.gov (United States)

    Patriarca, Francesca; Giaccone, Luisa; Onida, Francesco; Castagna, Luca; Sarina, Barbara; Montefusco, Vittorio; Mussetti, Alberto; Mordini, Nicola; Maino, Elena; Greco, Raffaella; Peccatori, Jacopo; Festuccia, Moreno; Zaja, Francesco; Volpetti, Stefano; Risitano, Antonio; Bassan, Renato; Corradini, Paolo; Ciceri, Fabio; Fanin, Renato; Baccarani, Michele; Rambaldi, Alessandro; Bonifazi, Francesca; Bruno, Benedetto

    2017-07-01

    Novel targeted therapies and monoclonal antibodies can be combined with allogeneic stem cell transplantation (allo-SCT) at different time-points: 1) before the transplant to reduce tumour burden, 2) as part of the conditioning in place of or in addition to conventional agents 3) after the transplant to allow long-term disease control. Areas covered: This review focuses on the current integration of new drugs with allo-SCT for the treatment of major hematological malignancies for which allo-SCT has been a widely-adopted therapy. Expert opinion: After having been used as single agent salvage treatments in relapsed patients after allo-SCT or in combination with donor lymphocyte infusions, many new drugs have also been safely employed before allo-SCT as a bridge to transplantation or after it as planned consolidation/maintenance. This era of new drugs has opened new important opportunities to 'smartly' combine 'targeted drugs and cell therapies' in new treatment paradigms that may lead to higher cure rates or longer disease control in patients with hematological malignancies.

  13. Fludarabine and 2-Gy TBI is superior to 2 Gy TBI as conditioning for HLA-matched related hematopoietic cell transplantation: a phase III randomized trial.

    Science.gov (United States)

    Kornblit, Brian; Maloney, David G; Storb, Rainer; Storek, Jan; Hari, Parameswaran; Vucinic, Vladan; Maziarz, Richard T; Chauncey, Thomas R; Pulsipher, Michael A; Bruno, Benedetto; Petersen, Finn B; Bethge, Wolfgang A; Hübel, Kai; Bouvier, Michelle E; Fukuda, Takahiro; Storer, Barry E; Sandmaier, Brenda M

    2013-09-01

    The risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m(2) fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P < .0001) and 84 (68% versus 92%; P < .0001), as was NK cell chimerism on day 28 (75% versus 96%; P = .0005). In conclusion, this randomized trial demonstrates the importance of fludarabine in augmenting the graft-versus-tumor effect by ensuring prompt and durable high-level donor engraftment early after transplantation.

  14. Plerixafor (a CXCR4 antagonist following myeloablative allogeneic hematopoietic stem cell transplantation enhances hematopoietic recovery

    Directory of Open Access Journals (Sweden)

    Michael M. B. Green

    2016-08-01

    Full Text Available Abstract Background The binding of CXCR4 with its ligand (stromal-derived factor-1 maintains hematopoietic stem/progenitor cells (HSPCs in a quiescent state. We hypothesized that blocking CXCR4/SDF-1 interaction after hematopoietic stem cell transplantation (HSCT promotes hematopoiesis by inducing HSC proliferation. Methods We conducted a phase I/II trial of plerixafor on hematopoietic cell recovery following myeloablative allogeneic HSCT. Patients with hematologic malignancies receiving myeloablative conditioning were enrolled. Plerixafor 240 μg/kg was administered subcutaneously every other day beginning day +2 until day +21 or until neutrophil recovery. The primary efficacy endpoints of the study were time to absolute neutrophil count >500/μl and platelet count >20,000/μl. The cumulative incidence of neutrophil and platelet engraftment of the study cohort was compared to that of a cohort of 95 allogeneic peripheral blood stem cell transplant recipients treated during the same period of time and who received similar conditioning and graft-versus-host disease prophylaxis. Results Thirty patients received plerixafor following peripheral blood stem cell (n = 28 (PBSC or bone marrow (n = 2 transplantation. Adverse events attributable to plerixafor were mild and indistinguishable from effects of conditioning. The kinetics of neutrophil and platelet engraftment, as demonstrated by cumulative incidence, from the 28 study subjects receiving PBSC showed faster neutrophil (p = 0.04 and platelet recovery >20 K (p = 0.04 compared to the controls. Conclusions Our study demonstrated that plerixafor can be given safely following myeloablative HSCT. It provides proof of principle that blocking CXCR4 after HSCT enhances hematopoietic recovery. Larger, confirmatory studies in other settings are warranted. Trial registration ClinicalTrials.gov NCT01280955

  15. Allogeneic hematopoietic cell transplant for acute myeloid leukemia: Current state in 2013 and future directions.

    Science.gov (United States)

    Kanate, Abraham S; Pasquini, Marcelo C; Hari, Parameswaran N; Hamadani, Mehdi

    2014-04-26

    Acute myeloid leukemia (AML) represents a heterogeneous group of high-grade myeloid neoplasms of the elderly with variable outcomes. Though remission-induction is an important first step in the management of AML, additional treatment strategies are essential to ensure long-term disease-free survival. Recent pivotal advances in understanding the genetics and molecular biology of AML have allowed for a risk-adapted approach in its management based on relapse-risk. Allogeneic hematopoietic cell transplantation (allo-HCT) represents an effective therapeutic strategy in AML providing the possibility of cure with potent graft-versus-leukemia reactions, with a demonstrable survival advantage in younger patients with intermediate- or poor-risk cytogenetics. Herein we review the published data regarding the role of allo-HCT in adults with AML. We searched MEDLINE/PubMed and EMBASE/Ovid. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases. We discuss the role of allo-HCT in AML patients stratified by cytogenetic- and molecular-risk in first complete remission, as well as allo-HCT as an option in relapsed/refractory AML. Besides the conventional sibling and unrelated donor allografts, we review the available data and recent advances for alternative donor sources such as haploidentical grafts and umbilical cord blood. We also discuss conditioning regimens, including reduced intensity conditioning which has broadened the applicability of allo-HCT. Finally we explore recent advances and future possibilities and directions of allo-HCT in AML. Practical therapeutic recommendations have been made where possible based on available data and expert opinion.

  16. A prospective study of an alemtuzumab containing reduced-intensity allogeneic stem cell transplant program in patients with poor-risk and advanced lymphoid malignancies.

    Science.gov (United States)

    Sauter, Craig S; Chou, Joanne F; Papadopoulos, Esperanza B; Perales, Miguel-Angel; Jakubowski, Ann A; Young, James W; Scordo, Michael; Giralt, Sergio; Castro-Malaspina, Hugo

    2014-12-01

    Reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplant (allo-SCT) have used alemtuzumab to abrogate the risk of graft-versus-host disease (GVHD). Thirty-eight patients with advanced lymphoma underwent a prospective phase II study of melphalan, fludarabine and alemtuzumab containing RIC allo-SCT from 20 matched related and 18 unrelated donors with cyclosporine-A as GVHD prophylaxis. The cumulative incidence of grade II-IV acute GVHD at 3 months was 10.5% and three evaluable patients experienced chronic GVHD. Progression-free (PFS) and overall (OS) survival at 5 years was 25% (95% confidence interval [CI]: 13-40%) and 44% (95% CI: 28-59%), respectively. Previous high-dose therapy and autologous stem cell transplant (HDT-ASCT) and elevated lactate dehydrogenase (LDH) at the time of allo-SCT resulted in inferior OS. Within this cohort of patients with high-risk lymphoma, alemtuzumab containing RIC resulted in a low risk of GVHD and a high incidence of progression of disease, especially in those with poor-risk features defined by elevated LDH pre-allo-SCT and previous HDT-ASCT.

  17. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial.

    Science.gov (United States)

    Armand, Philippe; Kim, Haesook T; Sainvil, Marie-Michele; Lange, Paulina B; Giardino, Angela A; Bachanova, Veronika; Devine, Steven M; Waller, Edmund K; Jagirdar, Neera; Herrera, Alex F; Cutler, Corey; Ho, Vincent T; Koreth, John; Alyea, Edwin P; McAfee, Steven L; Soiffer, Robert J; Chen, Yi-Bin; Antin, Joseph H

    2016-04-01

    Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-IV acute GVHD (9% vs. 25%, P = 0·015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).

  18. Reduced-intensity stem-cell transplantation for adult acute lymphoblastic leukemia: a retrospective study of 33 patients.

    Science.gov (United States)

    Hamaki, T; Kami, M; Kanda, Y; Yuji, K; Inamoto, Y; Kishi, Y; Nakai, K; Nakayama, I; Murashige, N; Abe, Y; Ueda, Y; Hino, M; Inoue, T; Ago, H; Hidaka, M; Hayashi, T; Yamane, T; Uoshima, N; Miyakoshi, S; Taniguchi, S

    2005-03-01

    Efficacy of reduced-intensity stem-cell transplantation (RIST) for acute lymphoblastic leukemia (ALL) was investigated in 33 patients (median age, 55 years). RIST sources comprised 20 HLA-identical related donors, five HLA-mismatched related, and eight unrelated donors. Six patients had undergone previous transplantation. Disease status at RIST was first remission (n=13), second remission (n=6), and induction failure or relapse (n=14). All patients tolerated preparatory regimens and achieved neutrophil engraftment (median, day 12.5). Acute and chronic graft-versus-host disease (GVHD) developed in 45 and 64%, respectively. Six patients received donor lymphocyte infusion (DLI), for prophylaxis (n=1) or treatment of recurrent ALL (n=5). Nine patients died of transplant-related mortality, with six deaths due to GVHD. The median follow-up of surviving patients was 11.6 months (range, 3.5-37.3 months). The 1-year relapse-free and overall survival rates were 29.8 and 39.6%, respectively. Of the 14 patients transplanted in relapse, five remained relapse free for longer than 6 months. Cumulative rates of progression and progression-free mortality at 3 years were 50.9 and 30.4%, respectively. These findings suggest the presence of a graft-versus-leukemia effect for ALL. RIST for ALL is worth considering for further evaluation.

  19. Successful engraftment of mismatched unrelated cord blood transplantation following reduced intensity preparative regimen using fludarabine and busulfan.

    Science.gov (United States)

    Komatsu, Tsunehiko; Narimatsu, Hiroto; Yoshimi, Ai; Kurita, Naoki; Kusakabe, Manabu; Hori, Akiko; Murashige, Naoko; Matsumura, Tomoko; Kobayashi, Kazuhiko; Yuji, Koichiro; Tanaka, Yuji; Kami, Masahiro

    2007-01-01

    We conducted a pilot study to evaluate the feasibility of reduced-intensity cord blood transplantation (RI-CBT) using a non-total body irradiation (TBI) regimen in adult patients with advanced hematologic malignancies. Seventeen patients with a median age of 58 years (range, 38-74) underwent RI-CBT at Tsukuba Memorial Hospital between April 2004 and November 2005. Preparative regimens were fludarabine 30 mg/m(2) for 6 days, and busulfan 4 mg/kg for 2 days. Tacrolimus was used for prophylaxis of graft-vs-host disease (GVHD). Median numbers of infused total nucleated were 2.6 x 10(7)/kg (range, 2.0-3.3). HLA disparity was found in 2/6 antigens (n=16) and 1/6 antigens (n=1). Underlying diseases progressed despite preparative regimens in four patients. Of the remaining 13 patients, nine patients achieved engraftment at a median of day 18 (range, 17-28). Six of the nine patients with engraftment achieved complete donor-type chimerism by day 100. Six patients were alive in remission at median follow-up of 13.1 months (range, 1.0-19.0). This study demonstrated the feasibility of RI-CBT using a non-TBI regimen in adults. When disease progression is controlled by the preparative regimen, RI-CBT carries a clinically significant graft-vs-tumor effect. Further studies are required to identify patients who benefit from this regimen.

  20. Reduced dose of foscarnet as preemptive therapy for cytomegalovirus infection following reduced-intensity cord blood transplantation.

    Science.gov (United States)

    Narimatsu, H; Kami, M; Kato, D; Matsumura, T; Murashige, N; Kusumi, E; Yuji, K; Hori, A; Shibata, T; Masuoka, K; Wake, A; Miyakoshi, S; Morinaga, S; Taniguchi, S

    2007-03-01

    Although foscarnet is a promising alternative for the treatment of cytomegalovirus (CMV) infection, its toxicity can be significant in patients with advanced age. We retrospectively reviewed medical records of 123 patients (median age of 55; range, 17-79) who received reduced-intensity cord blood transplantation (RI-CBT). Patients preemptively received reduced-dose foscarnet 30 mg/kg twice daily when CMV antigenemia exceeded 10/50,000. Sixty-three patients developed CMV antigenemia on a median of day 34, and 29 received foscarnet preemptively. The median level of CMV antigenemia at the initiation of foscarnet was 30. Median duration of foscarnet administration was 24 days. Adverse effects included electrolyte abnormalities (n=19), renal impairment (n=13), and skin eruption requiring discontinuation of foscarnet (n=1). Preemptive therapy of foscarnet was completed in 18 patients. Seven patients died during foscarnet use without developing CMV disease. The remaining 3 developed CMV enterocolitis 5, 14, and 17 days after initiation of foscarnet. All of them were successfully treated with ganciclovir or foscarnet. Reduced dose of foscarnet is beneficial to control CMV reactivation following RI-CBT; however, it has considerable toxicities in RI-CBT recipients with advanced age. Further studies are warranted to minimize toxicities and identify optimal dosages.

  1. Bloodstream infection after umbilical cord blood transplantation using reduced-intensity stem cell transplantation for adult patients.

    Science.gov (United States)

    Narimatsu, Hiroto; Matsumura, Tomoko; Kami, Masahiro; Miyakoshi, Shigesaburo; Kusumi, Eiji; Takagi, Shinsuke; Miura, Yuji; Kato, Daisuke; Inokuchi, Chiho; Myojo, Tomohiro; Kishi, Yukiko; Murashige, Naoko; Yuji, Koichiro; Masuoka, Kazuhiro; Yoneyama, Akiko; Wake, Atsushi; Morinaga, Shinichi; Kanda, Yoshinobu; Taniguchi, Shuichi

    2005-06-01

    Bloodstream infection (BSI) is a significant problem after cord blood transplantation (CBT). However, little information has been reported on BSI after reduced-intensity CBT (RI-CBT). We retrospectively reviewed the medical records of 102 patients. The median age of the patients was 55 years (range, 17-79 years). Preparative regimens comprised fludarabine 125 to 150 mg/m 2 , melphalan 80 to 140 mg/m 2 , or busulfan 8 mg/kg and total body irradiation 2 to 8 Gy. Prophylaxis against graft-versus-host disease comprised cyclosporin or tacrolimus. BSI developed within 100 days of RI-CBT in 32 patients. The cumulative incidence of BSI was 25% at day 30 and 32% at day 100. The median onset was day 15 (range, 1-98 days). Causative organisms included Pseudomonas aeruginosa (n = 12), Staphylococcus epidermidis (n = 11), Staphylococcus aureus (n = 6), Enterococcus faecium (n = 4), Enterococcus faecalis (n = 4), Stenotrophomonas maltophilia (n = 4), and others (n = 7). Of the 32 patients with BSI, 25 (84%) died within 100 days after RI-CBT. BSI was the direct cause of death in 8 patients (25%). Univariate analysis failed to identify any significant risk factors. BSI clearly represents a significant and fatal complication after RI-CBT. Further studies are warranted to determine clinical characteristics, identify patients at high risk of BSI, and establish therapeutic strategies.

  2. Autologous transplantation followed closely by reduced-intensity allogeneic transplantation as consolidative immunotherapy in advanced lymphoma patients: a feasibility study.

    Science.gov (United States)

    Gutman, J A; Bearman, S I; Nieto, Y; Sweetenham, J W; Jones, R B; Shpall, E J; Zeng, C; Baron, A; McSweeney, P A

    2005-09-01

    We report outcomes in advanced lymphoma patients (n = 32) who enrolled in a trial of prospectively planned combined autologous/reduced-intensity transplantation (RIT) (n = 25) or who received RIT shortly after prior autografting because of high relapse risk or progressive disease (n = 7). Nine patients on the autologous/RIT transplant protocol did not proceed to planned RIT because of patient choice (n = 4), disease progression (n = 3), toxicity (n = 1), or no adequate donor (n = 1). Among the 23 other patients, RIT was started a median of 59 days (range 31-123) after autologous transplant. Fifteen patients had related donors, five patients had unrelated donors, and three patients had cord blood donors. Among all patients completing RIT, the median overall survival time was 385 days (95% CI 272-792), and the median relapse-free survival time was 157 days (95% CI 119-385). At the time of reporting, six patients (26%) remain alive and three patients (13%) remain alive without relapse. The 100-day transplant-related mortality (TRM) was 9% among all patients and was 0% among matched sibling donors. Overall TRM was 43%. Tandem transplant is feasible in advanced lymphoma with low early TRM. However, practical challenges associated with the strategy were significant and high levels of late TRM due to graft-versus-host disease and infections suggest that modifications of the procedure will be needed to improve outcomes and patient retention.

  3. Mechanisms of Tolerance Induction by Hematopoietic Chimerism: The Immune Perspective.

    Science.gov (United States)

    Yolcu, Esma S; Shirwan, Haval; Askenasy, Nadir

    2017-03-01

    Hematopoietic chimerism is one of the effective approaches to induce tolerance to donor-derived tissue and organ grafts without administration of life-long immunosuppressive therapy. Although experimental efforts to develop such regimens have been ongoing for decades, substantial cumulative toxicity of combined hematopoietic and tissue transplants precludes wide clinical implementation. Tolerance is an active immunological process that includes both peripheral and central mechanisms of mutual education of coresident donor and host immune systems. The major stages include sequential suppression of early alloreactivity, establishment of hematopoietic chimerism and suppressor cells that sustain the state of tolerance, with significant mechanistic and temporal overlap along the tolerization process. Efforts to devise less toxic transplant strategies by reduction of preparatory conditioning focus on modulation rather than deletion of residual host immunity and early reinstitution of regulatory subsets at the central and peripheral levels. Stem Cells Translational Medicine 2017;6:700-712.

  4. Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia

    Science.gov (United States)

    Zimdahl, Bryan; Ito, Takahiro; Blevins, Allen; Bajaj, Jeevisha; Konuma, Takaaki; Weeks, Joi; Koechlein, Claire S.; Kwon, Hyog Young; Arami, Omead; Rizzieri, David; Broome, H. Elizabeth; Chuah, Charles; Oehler, Vivian G.; Sasik, Roman; Hardiman, Gary; Reya, Tannishtha

    2014-01-01

    Cell fate can be controlled through asymmetric division and segregation of protein determinants. But the regulation of this process in the hematopoietic system is poorly understood. Here we show that the dynein binding protein Lis1 (Pafah1b1) is critically required for blood formation and hematopoietic stem cell function. Conditional deletion of Lis1 in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, the loss of Lis1 accelerated cell differentiation, in part through defects in spindle positioning and inheritance of cell fate determinants. Finally, deletion of Lis1 blocked propagation of myeloid leukemia and led to a marked improvement in animal survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells, and mark the directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development. PMID:24487275

  5. Toll-like receptor polymorphisms in allogeneic hematopoietic cell transplantation

    DEFF Research Database (Denmark)

    Kornblit, Brian; Enevold, Christian; Wang, Tao;

    2014-01-01

    To assess the impact of the genetic variation in toll-like receptors (TLRs) on outcome after allogeneic myeloablative conditioning hematopoietic cell transplantation (HCT), we investigated 29 single nucleotide polymorphisms across 10 TLRs in 816 patients and donors. Only donor genotype of TLR8 rs...

  6. Primary Immunodeficiency Diseases and Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Ayse Ozkan

    2014-02-01

    Full Text Available Hematopoietic stem cell transplantation (HSCT is the only curative therapy for primary immunodeficiency diseases. Early diagnosis, including prenatally, and early transplantation improve HSCT outcomes. Survival rates improve with advances in the methods of preparing hosts and donor cells, and in supportive and conditioning regimes.

  7. Hematopoietic derived cells do not contribute to osteogenesis as osteoblasts.

    Science.gov (United States)

    Otsuru, Satoru; Overholt, Kathleen M; Olson, Timothy S; Hofmann, Ted J; Guess, Adam J; Velazquez, Victoria M; Kaito, Takashi; Dominici, Massimo; Horwitz, Edwin M

    2017-01-01

    Despite years of extensive investigation, the cellular origin of heterotopic ossification (HO) has not been fully elucidated. We have previously shown that circulating bone marrow-derived osteoblast progenitor cells, characterized by the immunophenotype CD45-/CD44+/CXCR4+, contributed to the formation of heterotopic bone induced by bone morphogenetic protein (BMP)-2. In contrast, other reports have demonstrated the contribution of CD45+ hematopoietic derived cells to HO. Therefore, in this study, we developed a novel triple transgenic mouse strain that allows us to visualize CD45+ cells with red fluorescence and mature osteoblasts with green fluorescence. These mice were generated by crossing CD45-Cre mice with Z/RED mice that express DsRed, a variant of red fluorescent protein, after Cre-mediated recombination, and then crossing with Col2.3GFP mice that express green fluorescent protein (GFP) in mature osteoblasts. Utilizing this model, we were able to investigate if hematopoietic derived cells have the potential to give rise to mature osteoblasts. Analyses of this triple transgenic mouse model demonstrated that DsRed and GFP did not co-localize in either normal skeletogenesis, bone regeneration after fracture, or HO. This indicates that in these conditions hematopoietic derived cells do not differentiate into mature osteoblasts. Interestingly, we observed the presence of previously unidentified DsRed positive bone lining cells (red BLCs) which are derived from hematopoietic cells but lack CD45 expression. These red BLCs fail to produce GFP even under in vitro osteogenic conditions. These findings indicate that, even though both osteoblasts and hematopoietic cells are developmentally derived from mesoderm, hematopoietic derived cells do not contribute to osteogenesis in fracture healing or HO. Copyright © 2016 Elsevier Inc. All rights reserved.

  8. Graft-versus-host disease following allogeneic transplantation from HLA-identical sibling with antithymocyte globulin-based reduced-intensity preparative regimen.

    Science.gov (United States)

    Mohty, Mohamad; Bay, Jacques-Olivier; Faucher, Catherine; Choufi, Bachra; Bilger, Karin; Tournilhac, Olivier; Vey, Norbert; Stoppa, Anne-Marie; Coso, Diane; Chabannon, Christian; Viens, Patrice; Maraninchi, Dominique; Blaise, Didier

    2003-07-15

    Reduced-intensity conditioning (RIC) regimens are increasingly used for allogeneic stem cell transplantation (allo-SCT). RIC has been shown to allow engraftment with minimal early transplantation-related mortality (TRM). However, in the context of RIC, predictive factors for acute and chronic graft-versus-host disease (aGVHD and cGVHD, respectively) and their effect on outcome remain unknown. In this report, we analyzed the outcome of 101 high-risk patients (70 hematologic and 31 nonhematologic malignancies) who received an HLA-identical sibling allo-SCT after RIC, including fludarabine, busulfan, and antithymocyte globulin (ATG). The cumulative incidence of grade II-IV aGVHD was 36% (95% confidence interval [CI], 27%-45%), whereas the cumulative incidence of cGVHD at 2 years was 43% (95% CI, 33%-53%). In multivariate analysis, the incidence of aGVHD was significantly associated with the ATG dose infused during conditioning (P =.0005), whereas peripheral blood as stem cell source was the only predictive factor for the development of cGVHD (P =.0007). The 1-year cumulative incidences of disease progression or relapse in patients with (n = 69) and without (n = 31) GVHD (whatever its form or grade) were 30% (95% CI, 19%-41%) and 55% (95% CI, 37%-72%), respectively (P =.02), suggesting that a potent graft-versus-tumor (GVT) effect can be achieved in high-risk patients following RIC. Moreover, the GVT effect was closely associated with GVHD without an increased risk of TRM (cumulative incidence of TRM, 18% [95% CI, 10%-25%]). Collectively, these results provide a framework for the refinement of RIC approaches designed to enhance the GVT effect with an acceptable risk of GVHD.

  9. Hematopoietic-supportive effect of (2S, 3R)-ent-catechin on marrow-depressed mice

    Institute of Scientific and Technical Information of China (English)

    CHEN Yi-hong; WANG Dong-xiao; LIU Ping; CHEN Ruo-yun; CHEN Meng-li; CHENG Liu-fang; YIN Jian-fen; CHEN Gui-yun

    2005-01-01

    @@ Hematopoiesis is an active process of cell proliferation, differentiation and release. It is the process during which hematopoietic stem cells (HSCs) proliferate and differentiate to mature blood cells under the effect of hemetopoietic growth factors (HGFs) in certain hematopoietic microenvironment. HSCs are sources of hematopoiesis of a body that can self-renew, differentiate to blood cells of every lineage and maintain the constancy of them. As the major tissue of hematopoiesis bone marrow is filled with all kinds of blood cells in various developmental stages. Under the normal conditions, the ordered proliferation and differentiation of hematopoietic stem cells/hematopoietic progenitor cells (HSC/HPC) depend on the regulation of cytokine network.

  10. Long-term survival outcomes of reduced-intensity allogeneic or autologous transplantation in relapsed grade 3 follicular lymphoma

    Science.gov (United States)

    Klyuchnikov, Evgeny; Bacher, Ulrike; Ahn, Kwang Woo; Carreras, Jeanette; Kröger, Nicolaus M.; Hari, Parameswaran N.; Ku, Grace H.; Ayala, Ernesto; Chen, Andy I.; Chen, Yi-Bin; Cohen, Jonathon B.; Freytes, César O.; Gale, Robert Peter; Kamble, Rammurti T.; Kharfan-Dabaja, Mohamed A.; Lazarus, Hillard M.; Martino, Rodrigo; Mussetti, Alberto; Savani, Bipin N.; Schouten, Harry C.; Usmani, Saad Z.; Wiernik, Peter H.; Wirk, Baldeep; Smith, Sonali M.; Sureda, Anna; Hamadani, Mehdi

    2015-01-01

    Grade-3 follicular lymphoma (FL) has aggressive clinical behavior. To evaluate the optimal first transplantation approach in relapsed/refractory grade-3 FL patients, we compared the long-term outcomes after allogeneic (allo-) vs. autologous hematopoietic cell transplantation (auto-HCT) in the rituximab-era. A total of 197 patients undergoing first RIC allo-HCT or first auto-HCT during 2000-2012 were included. Rituximab-naïve patients were excluded. Allo-HCT recipients were younger; more heavily pretreated, and had a longer interval between diagnosis and HCT. The 5-year probabilities of non-relapse mortality (NRM), relapse/progression, progression-free survival (PFS) and overall survival (OS) for auto-HCT vs. allo-HCT groups were 4% vs. 27% (p<0.001); 61% vs. 20% (p<0.001); 36% vs. 51% (p=0.07) and 59% vs. 54% (p=0.7), respectively. On multivariate analysis auto-HCT was associated with reduced risk of NRM (RR=0.20; p=0.001). Within the first 11months post-HCT auto- and allo-HCT had similar risks of relapse/progression and PFS. Beyond 11months, auto-HCT was associated with higher risk of relapse/progression (RR=21.3; p=0.003) and inferior PFS (RR=3.2; p=0.005). In the first 24 months post-HCT, auto-HCT was associated with improved OS (RR=0.42; p=0.005), but in long-time survivors (beyond 24 months) it was associated with inferior OS (RR=3.6; p=0.04). RIC allo-HCT as the first transplant approach can provide improved PFS and OS, in long-term survivors. PMID:26437062

  11. Methotrexate Reduces the Incidence of Severe Acute Graft-versus-Host Disease without Increasing the Risk of Relapse after Reduced-Intensity Allogeneic Stem Cell Transplantation from Unrelated Donors.

    Science.gov (United States)

    Vigouroux, Stéphane; Tabrizi, Reza; Melot, Cyril; Coiffard, Joelle; Lafarge, Xavier; Marit, Gérald; Bouabdallah, Krimo; Pigneux, Arnaud; Leguay, Thibaut; Dilhuydy, Marie-Sarah; Schmitt, Anna; Boiron, Jean-Michel; Milpied, Noël

    2011-01-01

    Optimized prophylaxis against graft-versus-host disease (GVHD) after unrelated reduced-intensity allogeneic transplantation when preceded by a conditioning regimen utilizing antithymocyte globulin (ATG) is poorly defined. To investigate the effects of methotrexate (MTX) in this treatment setting, we conducted a retrospective analysis. Sixty-three patients were selected based on the administration of a total dose of 5 mg/kg of ATG in the conditioning regimen and then separated into either group M+ (n = 39), which received MTX or group M- (n = 24), which did not. All patients received cyclosporine. In the M- and M+ groups, cumulative incidences (CI) of grade III-IV acute GVHD (aGVHD) were 43% and 10%, respectively (P = .002). Multivariate analysis indicated that grade III-IV aGVHD was favored by both the absence of MTX and the provision of a female donor for a male recipient. At 2 years, the M+ and M- groups exhibited, respectively: overall survival of 69% and 40% (P = .06), disease-free survival of 57% and 43% (P = .2), nonrelapse mortality of 20% and 44% (P = .1), and incidence of relapse of 27% and 35% (P = .6). These data suggest that MTX reduces the incidence of severe aGVHD without increasing the risk of relapse but with an accompanying trend toward improved survival after unrelated reduced-intensity transplantation with ATG in the conditioning regimen.

  12. Hematopoietic Stem Cell Transplantation in Adult Sickle Cell Disease: Problems and Solutions

    Directory of Open Access Journals (Sweden)

    Hakan Özdoğu

    2015-09-01

    Full Text Available Sickle cell disease-related organ injuries cannot be prevented despite hydroxyurea use, infection prophylaxis, and supportive therapies. As a consequence, disease-related mortality reaches 14% in adolescents and young adults. Hematopoietic stem cell transplantation is a unique curative therapeutic approach for sickle cell disease. Myeloablative allogeneic hematopoietic stem cell transplantation is curative for children with sickle cell disease. Current data indicate that long-term disease-free survival is about 90% and overall survival about 95% after transplantation. However, it is toxic in adults due to organ injuries. In addition, this curative treatment approach has several limitations, such as difficulties to find donors, transplant-related mortality, graft loss, graft-versus-host disease (GVHD, and infertility. Engraftment effectivity and toxicity for transplantations performed with nonmyeloablative reduced-intensity regimens in adults are being investigated in phase 1/2 trials at many centers. Preliminary data indicate that GVHD could be prevented with transplantations performed using reduced-intensity regimens. It is necessary to develop novel regimens to prevent graft loss and reduce the risk of GVHD.

  13. Comparison of cyclosporine and tacrolimus combined with mycophenolate mofetil in prophylaxis for graft-versus-host disease after reduced-intensity umbilical cord blood transplantation.

    Science.gov (United States)

    Miyamoto, Toshihiro; Takashima, Shuichiro; Kato, Koji; Takase, Ken; Yoshimoto, Goichi; Yoshida, Shuro; Henzan, Hideho; Osaki, Koichi; Kamimura, Tomohiko; Iwasaki, Hiromi; Eto, Tetsuya; Teshima, Takanori; Nagafuji, Koji; Akashi, Koichi

    2017-01-01

    Umbilical cord blood transplantation with a reduced-intensity conditioning regimen (RIC-UCBT) is used increasingly in patients who have comorbid organ functions and lack human leukocyte antigen-identical donors. We compared the outcomes in 35 patients who received mycophenolate mofetil plus cyclosporine (MMF/CSP, n = 17) or MMF plus tacrolimus (MMF/TAC, n = 18) for graft-versus-host disease (GVHD) prophylaxis after RIC-UCBT. Cumulative incidence of neutrophil engraftment was 94 and 89 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.34). The incidence of pre-engraftment immune reaction did not differ between the MMF/CSP (41 %) and MMF/TAC (39 %, p = 1.00) groups; however, patients in the MMF/TAC group tended to have a lower incidence of grade II-IV acute GVHD than those in MMF/CSP group (28 vs 53 %, p = 0.11). Overall survival (OS) at 1 year was 43 and 60 % in MMF/CSP and MMF/TAC groups, respectively (p = 0.39). Progression-free survival, non-relapse mortality, and relapse rate were comparable between the two groups (p = 0.76, 0.59, and 0.88, respectively). In multivariate analyses, MMF/TAC GVHD prophylaxis was closely associated with improved OS, but not with incidence of engraftment and acute GVHD. These results suggest that more intensive GVHD prophylaxis with MMF/TAC decreased acute GVHD without affecting other clinical outcomes, resulting in improved OS after RIC-UCBT.

  14. Characterizing the human hematopoietic CDome

    DEFF Research Database (Denmark)

    Barnkob, Mike Stein; Simon, Christian; Olsen, Lars Rønn

    2014-01-01

    , we seek to give a preliminary characterization of the "human hematopoietic CDome." We encountered severe gaps in the knowledge of CD protein expression, mostly resulting from incomplete and unstructured data generation, which we argue inhibit both basic research as well as therapies seeking to target...

  15. Sexual Health in Hematopoietic Stem Cell Transplant Recipients

    OpenAIRE

    2015-01-01

    Hematopoietic stem cell transplantation (HSCT) plays a central role in patients with malignant and, increasingly, nonmalignant conditions. As the number of transplants increases and the survival rate improves, long-term complications are important to recognize and treat to maintain quality of life. Sexual dysfunction is a commonly described but relatively often underestimated complication after HSCT. Conditioning regimens, generalized or genital graft-versus-host disease, medications, and car...

  16. Fetal hepatic progenitors support long-term expansion of hematopoietic stem cells.

    Science.gov (United States)

    Chou, Song; Flygare, Johan; Lodish, Harvey F

    2013-05-01

    We have developed a coculture system that establishes DLK(+) fetal hepatic progenitors as the authentic supportive cells for expansion of hematopoietic stem (HSCs) and progenitor cells. In 1-week cultures supplemented with serum and supportive cytokines, both cocultured DLK(+) fetal hepatic progenitors and their conditioned medium supported rapid expansion of hematopoietic progenitors and a small increase in HSC numbers. In 2- and 3-week cultures DLK(+) cells, but not their conditioned medium, continuously and significantly (>20-fold) expanded both hematopoietic stem and progenitor cells. Physical contact between HSCs and DLK(+) cells was crucial to maintaining this long-term expansion. Similar HSC expansion (approximately sevenfold) was achieved in cocultures using a serum-free, low cytokine- containing medium. In contrast, DLK(-) cells are incapable of expanding hematopoietic cells, demonstrating that hepatic progenitors are the principle supportive cells for HSC expansion in the fetal liver.

  17. Hematopoietic Processes in Eosinophilic Asthma.

    Science.gov (United States)

    Salter, Brittany M; Sehmi, Roma

    2017-01-24

    Airway eosinophilia is a hallmark of allergic asthma and understanding mechanisms that promote increases in lung eosinophil numbers is important for effective pharmaco-therapeutic development. It has become evident that expansion of hemopoietic compartments in the bone marrow promotes differentiation and trafficking of mature eosinophils to the airways. Hematopoietic progenitor cells egress the bone marrow and home to the lungs, where in-situ differentiative processes within the tissue provide an ongoing source of pro-inflammatory cells. In addition, hematopoietic progenitor cells in the airways can respond to locally-derived alarmins, to produce a panoply of cytokines thereby themselves acting as effector pro-inflammatory cells that potentiate type 2 responses in eosinophilic asthma. In this review, we will provide evidence for these findings and discuss novel targets for modulating eosinophilopoietic processes, migration and effector function of precursor cells.

  18. Successful treatment with intravesical cidofovir for virus-associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation: A case report and a review of the literature.

    Science.gov (United States)

    Sakurada, Maki; Kondo, Tadakazu; Umeda, Masayuki; Kawabata, Hiroshi; Yamashita, Kouhei; Takaori-Kondo, Akifum

    2016-07-01

    Virus-associated hemorrhagic cystitis (VAHC) is a formidable complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The standard management of severe VAHC after allo-HSCT has not been established. Intravenous administration of cidofovir (CDV), an acyclic nucleoside analogue with broad-spectrum activity against DNA viruses, has been reported to be effective for VAHC, but it can cause severe renal toxicity. Here we report four cases who achieved clinical responses with intravesical instillation of CDV for severe VAHC after allo-HSCT. Median age was 57 years (40-63), and all were male. The underlying diseases were hematological malignancies. Three had received bone marrow transplantation, and one received cord blood transplantation twice. Conditioning regimen was myeloablative for one, and reduced-intensity for three. The viral types were BK virus and/or adenovirus. Two patients had received CDV intravenously prior to the intravesical therapy. A dose of intravesical CDV was 2-5 mg/kg. In all cases, symptoms of cystitis improved dramatically within a few days without showing any systemic adverse effects. The virological response was observed in two cases. This local therapy was effective even in the cases refractory to the intravenous CDV and a case with severe renal failure. Along with the review of literature, we propose that the intravesical instillation of CDV can be a therapeutic option for severe VAHC after allo-HSCT.

  19. Differential requirements for hematopoietic commitment between human and rhesus embryonic stem cells.

    Science.gov (United States)

    Rajesh, Deepika; Chinnasamy, Nachimuthu; Mitalipov, Shoukhrat M; Wolf, Don P; Slukvin, Igor; Thomson, James A; Shaaban, Aimen F

    2007-02-01

    Progress toward clinical application of ESC-derived hematopoietic cellular transplantation will require rigorous evaluation in a large animal allogeneic model. However, in contrast to human ESCs (hESCs), efforts to induce conclusive hematopoietic differentiation from rhesus macaque ESCs (rESCs) have been unsuccessful. Characterizing these poorly understood functional differences will facilitate progress in this area and likely clarify the critical steps involved in the hematopoietic differentiation of ESCs. To accomplish this goal, we compared the hematopoietic differentiation of hESCs with that of rESCs in both EB culture and stroma coculture. Initially, undifferentiated rESCs and hESCs were adapted to growth on Matrigel without a change in their phenotype or karyotype. Subsequent differentiation of rESCs in OP9 stroma led to the development of CD34(+)CD45(-) cells that gave rise to endothelial cell networks in methylcellulose culture. In the same conditions, hESCs exhibited convincing hematopoietic differentiation. In cytokine-supplemented EB culture, rESCs demonstrated improved hematopoietic differentiation with higher levels of CD34(+) and detectable levels of CD45(+) cells. However, these levels remained dramatically lower than those for hESCs in identical culture conditions. Subsequent plating of cytokine-supplemented rhesus EBs in methylcellulose culture led to the formation of mixed colonies of erythroid, myeloid, and endothelial cells, confirming the existence of bipotential hematoendothelial progenitors in the cytokine-supplemented EB cultures. Evaluation of four different rESC lines confirmed the validity of these disparities. Although rESCs have the potential for hematopoietic differentiation, they exhibit a pause at the hemangioblast stage of hematopoietic development in culture conditions developed for hESCs.

  20. Allogeneic hematopoietic stem cell transplantation: transfusion issues

    Directory of Open Access Journals (Sweden)

    Akkök ÇA

    2016-05-01

    Full Text Available Çiğdem Akalın Akkök,1,21Department of Immunology and Transfusion Medicine, Oslo University Hospital, Ullevaal, Oslo, Norway; 2Department of Clinical Immunology and Transfusion Medicine, Lund University Hospital, Lund, Sweden Abstract: Allogeneic hematopoietic stem cell transplantation (AHSCT is an intention-to-cure treatment strategy in several malignancies and nonmalignancies. The number of patients receiving AHSCT is increasing due to new indications, and more elderly patients with comorbidities are included in the protocols. Survival of the patients undergoing AHSCT has improved owing to better patient care, including optimization of transfusion support, which has a major contribution. However, transfusion can also be hazardous. Increasing awareness about transfusion and finding the balance between avoiding unnecessary transfusions and transfusing the correct component when needed are the key issues. Myeloablative conditioning results in pancytopenia, and the patients are prone to infections, anemia, and bleeding both before and after transplantation. Until red cell and platelet engraftment, the patients are usually transfusion dependent needing red cell and/or platelet components. Physicians dealing with AHSCT patients should be well informed about the attributes of the blood components they order. Knowledge about transfusion indications, triggers, and how to prevent and manage eventual transfusion complications is also required. The clinical picture can be challenging, and transplantation/treatment-related toxicity/complications can sometimes be difficult to distinguish from a transfusion complication, especially if the latter one took place, for instance, several days or weeks ago. ABO compatibility between the patient and the donor is not a prerequisite when choosing human leukocyte antigen-matched hematopoietic stem cell donor. Consequently, ABO incompatibility exists in ~40% of the cases and brings some immunohematological issues

  1. Estimating the treatment effect from non-randomized studies: The example of reduced intensity conditioning allogeneic stem cell transplantation in hematological diseases

    Directory of Open Access Journals (Sweden)

    Resche-Rigon Matthieu

    2012-08-01

    Full Text Available Abstract Background In some clinical situations, for which RCT are rare or impossible, the majority of the evidence comes from observational studies, but standard estimations could be biased because they ignore covariates that confound treatment decisions and outcomes. Methods Three observational studies were conducted to assess the benefit of Allo-SCT in hematological malignancies of multiple myeloma, follicular lymphoma and Hodgkin’s disease. Two statistical analyses were performed: the propensity score (PS matching approach and the inverse probability weighting (IPW approach. Results Based on PS-matched samples, a survival benefit in MM patients treated by Allo-SCT, as compared to similar non-allo treated patients, was observed with an HR of death at 0.35 (95%CI: 0.14-0.88. Similar results were observed in HD, 0.23 (0.07-0.80 but not in FL, 1.28 (0.43-3.77. Estimated benefits of Allo-SCT for the original population using IPW were erased in HR for death at 0.72 (0.37-1.39 for MM patients, 0.60 (0.19-1.89 for HD patients, and 2.02 (0.88-4.66 for FL patients. Conclusion Differences in estimated benefits rely on whether the underlying population to which they apply is an ideal randomized experimental population (PS or the original population (IPW. These useful methods should be employed when assessing the effects of innovative treatment in non-randomized experiments.

  2. Novel strategies for improving hematopoietic reconstruction after allogeneic hematopoietic stem cell transplantation or intensive chemotherapy.

    Science.gov (United States)

    Baron, Frédéric; Nagler, Arnon

    2017-02-01

    High-dose conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT) as well as intensive poly-chemotherapy for acute myeloid leukemia (AML) induce prolonged periods of neutropenia. The duration of the neutropenia is particularly long following umbilical cord blood transplantation (UCBT). Areas covered: After briefly reviewing the impact of hematopoietic growth factors administration to hasten hematologic reconstitution after allo-HCT or intensive AML chemotherapy, this article summarizes recent approaches that have been investigated to prompt hematologic reconstruction after UCBT or intensive AML chemotherapy. Expert opinion: In the allo-HCT setting, administration of G-CSF or GM-CSF shortened the duration of the neutropenia but failed to decrease infection-related mortality or to improve survival. Novel approaches to hasten hematological reconstruction after UCBT such as double UCBT with expansion of one of the 2 UCB units with Notch ligand, mesenchymal stromal cells, nicotinamide, or StemRegenin 1, co-transplanting a single UCB unit with HLA-haploidentical CD34+ cells, or increasing UCB HSC homing to marrow niches via direct intra bone UCB administration, pulse treatment with dmPGE2 or enforced fucosylation are promising and deserve further investigations in prospective phase III studies. In the AML setting, G-CSF or GM-CSF administration after intensive chemotherapy decreased the duration of the neutropenia without improving survival.

  3. Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease

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    Atila Tanyeli

    2014-02-01

    Full Text Available Sickle cell anemia is one of the most common hemoglobinopathies in the worldwide. Sickle cell anemia characterized by crises and organ failure develops over time. Myeloablative stem cell transplantation is curative but it has been performed in children younger than 16 years of age. Modest modifications in the conditioning regimen and supportive care have improved outcome such that the majority of children with a suitable HLA-matched sibling donor can expect a cure from this approach. But nonmyeloablative protocols are crucial for the future of Hematopoietic Stem-Cell Transplantation for older sickle cell anemia patients with organ failure. A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor–recipient chimerism. Stem cell transplantation is recommended in the presence of HLA-matched siblings in patients at risk.

  4. Expansion of hematopoietic stem cells for transplantation: current perspectives

    Directory of Open Access Journals (Sweden)

    Schuster Jessica A

    2012-05-01

    Full Text Available Abstract Hematopoietic stem cells (HSCs are rare cells that have the unique ability to self-renew and differentiate into cells of all hematopoietic lineages. The expansion of HSCs has remained an important goal to develop advanced cell therapies for bone marrow transplantation and many blood disorders. Over the last several decades, there have been numerous attempts to expand HSCs in vitro using purified growth factors that are known to regulate HSCs. However, these attempts have been met with limited success for clinical applications. New developments in the HSC expansion field coupled with gene therapy and stem cell transplant should encourage progression in attractive treatment options for many disorders including hematologic conditions, immunodeficiencies, and genetic disorders.

  5. Fetal stromal niches enhance human embryonic stem cell-derived hematopoietic differentiation and globin switch.

    Science.gov (United States)

    Lee, King Yiu; Fong, Benny Shu Pan; Tsang, Kam Sze; Lau, Tze Kin; Ng, Pak Cheung; Lam, Audrey Carmen; Chan, Kathy Yuen Yee; Wang, Chi Chiu; Kung, Hsiang Fu; Li, Chi Kong; Li, Karen

    2011-01-01

    Hematopoiesis during mammalian embryonic development has been perceived as a migratory phenomenon, from the yolk sac blood island to the aorta-gonad-mesonephros (AGM) region, fetal liver (FL), and subsequently, the fetal bone marrow. In this study, we investigated the effects of primary stromal cells from fetal hematopoietic niches and their conditioned media (CM), applied singly or in sequential orders, on induction of human embryonic stem cells, H1, H9, and H14 lines, to hematopoietic cells. Our results demonstrated that stromal support of FL, AGM + FL, and AGM + FL + fetal bone marrow significantly increased the proliferation of embryoid bodies (EB) at day 18 of hematopoietic induction in the presence of thrombopoietin, stem cell factor, and Flt-3 ligand. AGM + FL also increased hematopoietic colony-forming unit (CFU) formation. CM did not enhance EB proliferation but CM of FL and AGM + FL significantly increased the density of total CFU and early erythroid (burst-forming unit) progenitors. Increased commitment to the hematopoietic lineage was demonstrated by enhanced expressions of CD45, alpha-, beta-, and gamma-globins in CFU at day 32, compared with EB at day 18. CM of FL significantly increased these globin expressions, indicating enhanced switches from embryonic to fetal and adult erythropoiesis. Over 50% and 10% of cells derived from CFU expressed CD45 and beta-globin proteins, respectively. Expressions of hematopoietic regulatory genes (Bmi-1, β-Catenin, Hox B4, GATA-1) were increased in EB or CFU cultures supported by FL or sequential CM. Our study has provided a strategy for derivation of hematopoietic cells from embryonic stem cells under the influence of primary hematopoietic niches and CM, particularly the FL.

  6. Histone acetyltransferase cofactor Trrap is essential for maintaining the hematopoietic stem/progenitor cell pool.

    Science.gov (United States)

    Loizou, Joanna I; Oser, Gabriela; Shukla, Vivek; Sawan, Carla; Murr, Rabih; Wang, Zhao-Qi; Trumpp, Andreas; Herceg, Zdenko

    2009-11-15

    The pool of hematopoietic stem/progenitor cells, which provide life-long reconstitution of all hematopoietic lineages, is tightly controlled and regulated by self-renewal and apoptosis. Histone modifiers and chromatin states are believed to govern establishment, maintenance, and propagation of distinct patterns of gene expression in stem cells, however the underlying mechanism remains poorly understood. In this study, we identified a role for the histone acetytransferase cofactor Trrap in the maintenance of hematopietic stem/progenitor cells. Conditional deletion of the Trrap gene in mice resulted in ablation of bone marrow and increased lethality. This was due to the depletion of early hematopoietic progenitors, including hematopoietic stem cells, via a cell-autonomous mechanism. Analysis of purified bone marrow progenitors revealed that these defects are associated with induction of p53-independent apoptosis and deregulation of Myc transcription factors. Together, this study has identified a critical role for Trrap in the mechanism that maintains hematopoietic stem cells and hematopoietic system, and underscores the importance of Trrap and histone modifications in tissue homeostasis.

  7. The role of the embryonic microenvironment in hematopoietic cell development

    NARCIS (Netherlands)

    E. Haak (Esther)

    2007-01-01

    textabstractThe adult hematopoietic system is comprised of a hierarchy of cells with the hematopoietic stem cell (HSC) at its foundation. HSCs give rise to progenitors that differentiate into mature hematopoietic cells, which perform the physiological functions of the hematopoietic system. The

  8. Cytokine receptors and hematopoietic differentiation.

    Science.gov (United States)

    Robb, L

    2007-10-15

    Colony-stimulating factors and other cytokines signal via their cognate receptors to regulate hematopoiesis. In many developmental systems, inductive signalling determines cell fate and, by analogy with this, it has been postulated that cytokines, signalling via their cognate receptors, may play an instructive role in lineage specification in hematopoiesis. An alternative to this instructive hypothesis is the stochastic or permissive hypothesis. The latter proposes that commitment to a particular hematopoietic lineage is an event that occurs independently of extrinsic signals. It predicts that the role of cytokines is to provide nonspecific survival and proliferation signals. In this review, we look at the role of cytokine receptor signalling in hematopoiesis and consider the evidence for both hypotheses. Data from experiments that genetically manipulate receptor gene expression in vitro or in vivo are reviewed. Experiments in which cytokine receptors were installed in multipotential cells showed that, in some cases, stimulation with the cognate ligand could lead to alterations in lineage output. The creation of genetically manipulated mouse strains demonstrated that cytokine receptors are required for expansion and survival of single lineages but did not reveal a role in lineage commitment. We conclude that hematopoietic differentiation involves mainly stochastic events, but that cytokine receptors also have some instructive role.

  9. Quercetin Inhibits Peripheral and Spinal Cord Nociceptive Mechanisms to Reduce Intense Acute Swimming-Induced Muscle Pain in Mice

    Science.gov (United States)

    Borghi, Sergio M.; Pinho-Ribeiro, Felipe A.; Fattori, Victor; Bussmann, Allan J. C.; Vignoli, Josiane A.; Camilios-Neto, Doumit; Casagrande, Rubia; Verri, Waldiceu A.

    2016-01-01

    The present study aimed to evaluate the effects of the flavonoid quercetin (3,3´,4´,5,7-pentahydroxyflavone) in a mice model of intense acute swimming-induced muscle pain, which resembles delayed onset muscle soreness. Quercetin intraperitoneal (i.p.) treatment dose-dependently reduced muscle mechanical hyperalgesia. Quercetin inhibited myeloperoxidase (MPO) and N-acetyl-β-D- glucosaminidase (NAG) activities, cytokine production, oxidative stress, cyclooxygenase-2 (COX-2) and gp91phox mRNA expression and muscle injury (creatinine kinase [CK] blood levels and myoblast determination protein [MyoD] mRNA expression) as well as inhibited NFκB activation and induced Nrf2 and HO-1 mRNA expression in the soleus muscle. Beyond inhibiting those peripheral effects, quercetin also inhibited spinal cord cytokine production, oxidative stress and glial cells activation (glial fibrillary acidic protein [GFAP] and ionized calcium-binding adapter molecule 1 [Iba-1] mRNA expression). Concluding, the present data demonstrate that quercetin is a potential molecule for the treatment of muscle pain conditions related to unaccustomed exercise. PMID:27583449

  10. Culture materials affect ex vivo expansion of hematopoietic progenitor cells.

    Science.gov (United States)

    LaIuppa, J A; McAdams, T A; Papoutsakis, E T; Miller, W M

    1997-09-01

    Ex vivo expansion of hematopoietic cells is important for applications such as cancer treatment, gene therapy, and transfusion medicine. While cell culture systems are widely used to evaluate the biocompatibility of materials for implantation, the ability of materials to support proliferation of primary human cells in cultures for reinfusion into patients has not been addressed. We screened a variety of commercially available polymer (15 types), metal (four types), and glass substrates for their ability to support expansion of hematopoietic cells when cultured under conditions that would be encountered in a clinical setting. Cultures of peripheral blood (PB) CD34+ cells and mononuclear cells (MNC) were evaluated for expansion of total cells and colony-forming unit-granulocyte monocyte (CFU-GM; progenitors committed to the granulocyte and/or monocyte lineage). Human hematopoietic cultures in serum-free medium were found to be extremely sensitive to the substrate material. The only materials tested that supported expansion at or near the levels of polystyrene were tissue culture polystyrene, Teflon perfluoroalkoxy, Teflon fluorinated ethylene propylene, cellulose acetate, titanium, new polycarbonate, and new polymethylpentene. MNC were less sensitive to the substrate materials than the primitive CD34+ progenitors, although similar trends were seen for expansion of the two cell populations on the substrates tested. CFU-GM expansion was more sensitive to substrate materials than was total cell expansion. The detrimental effects of a number of the materials on hematopoietic cultures appear to be caused by protein adsorption and/or leaching of toxins. Factors such as cleaning, sterilization, and reuse significantly affected the performance of some materials as culture substrates. We also used PB CD34+ cell cultures to examine the biocompatibility of gas-permeable cell culture and blood storage bags and several types of tubing commonly used with biomedical equipment

  11. 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.

  12. Fas transduces dual apoptotic and trophic signals in hematopoietic progenitors.

    Science.gov (United States)

    Pearl-Yafe, Michal; Stein, Jerry; Yolcu, Esma S; Farkas, Daniel L; Shirwan, Haval; Yaniv, Isaac; Askenasy, Nadir

    2007-12-01

    Stem cells and progenitors are often required to realize their differentiation potential in hostile microenvironments. The Fas/Fas ligand (FasL) interaction is a major effector pathway of apoptosis, which negatively regulates the expansion of differentiated hematopoietic cells. The involvement of this molecular interaction in the function of hematopoietic stem and progenitor cells is not well understood. In the murine syngeneic transplant setting, both Fas and FasL are acutely upregulated in bone marrow-homed donor cells; however, the Fas(+) cells are largely insensitive to FasL-induced apoptosis. In heterogeneous populations of lineage-negative (lin(-)) bone marrow cells and progenitors isolated by counterflow centrifugal elutriation, trimerization of the Fas receptor enhanced the clonogenic activity. Inhibition of caspases 3 and 8 did not affect the trophic signals mediated by Fas, yet it efficiently blocked the apoptotic pathways. Fas-mediated tropism appears to be of physiological significance, as pre-exposure of donor cells to FasL improved the radioprotective qualities of hematopoietic progenitors, resulting in superior survival of myeloablated hosts. Under these conditions, the activity of long-term reconstituting cells was not affected, as determined in sequential secondary and tertiary transplants. Dual caspase-independent tropic and caspase-dependent apoptotic signaling place the Fas receptor at an important junction of activation and death. This regulatory mechanism of hematopoietic homeostasis activates progenitors to promote the recovery from aplasia and converts into a negative regulator in distal stages of cell differentiation. Disclosure of potential conflicts of interest is found at the end of this article.

  13. Generation of axolotl hematopoietic chimeras

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    David Lopez

    2015-02-01

    Full Text Available Wound repair is an extremely complex process that requires precise coordination between various cell types including immune cells.  Unfortunately, in mammals this usually results in scar formation instead of restoration of the original fully functional tissue, otherwise known as regeneration.  Various animal models like frogs and salamanders are currently being studied to determine the intracellular and intercellular pathways, controlled by gene expression, that elicit cell proliferation, differentiation, and migration of cells during regenerative healing.  Now, the necessary genetic tools to map regenerative pathways are becoming available for the axolotl salamander, thus allowing comparative studies between scarring and regeneration.  Here, we describe in detail three methods to produce axolotl hematopoietic cell-tagged chimeras for the study of hematopoiesis and regeneration.

  14. Return to the hematopoietic stem cell origin

    Directory of Open Access Journals (Sweden)

    Igor M Samokhvalov

    2012-01-01

    Full Text Available Studying embryonic hematopoiesis is complicated by diversity of its locations in the constantly changing anatomy and by the mobility of blood cell precursors. Embryonic hematopoietic progenitors are identified in traditional in vivo and in vitro cell potential assays. Profound epigenetic plasticity of mammalian embryonic cells combined with significant inductive capacity of the potential assays suggest that our understanding of hematopoietic ontogenesis is substantially distorted. Non-invasive in vivo cell tracing methodology offers a better insight into complex processes of blood cell specification. In contrast to the widely accepted view based on the cell potential assays, the genetic tracing approach identified the yolk sac as the source of adult hematopoietic stem cell lineage. Realistic knowledge of the blood origin is critical for safe and efficient recapitulation of hematopoietic development in culture.

  15. Hematopoietic Stem Cells Expansionin Rotating Wall Vessel

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    1 IntroductionClinical trials have demonstrated that ex vivo expanded hematopoietic stem cells (HSCs) and progenitors offer great promise in reconstituting in vivo hematopoiesis in patients who have undergone intensive chemotherapy. It is therefore necessary to develop a clinical-scale culture system to provide the expanded HSCs and progenitors. Static culture systems such as T-flasks and gas-permeable blood bags are the most widely used culture devices for expanding hematopoietic cells. But they reveal sev...

  16. Hematopoietic progenitor migration to the adult thymus

    OpenAIRE

    Zlotoff, Daniel A.; Bhandoola, Avinash

    2011-01-01

    While most hematopoietic lineages develop in the bone marrow (BM), T cells uniquely complete their development in the specialized environment of the thymus. Hematopoietic stem cells with long-term self-renewal capacity are not present in the thymus. As a result, continuous T cell development requires that BM-derived progenitors be imported into the thymus throughout adult life. The process of thymic homing begins with the mobilization of progenitors out of the bone marrow, continues with thei...

  17. Hematopoietic stem cell gene therapy for adenosine deaminase deficient-SCID.

    Science.gov (United States)

    Aiuti, Alessandro; Brigida, Immacolata; Ferrua, Francesca; Cappelli, Barbara; Chiesa, Robert; Marktel, Sarah; Roncarolo, Maria-Grazia

    2009-01-01

    Gene therapy is a highly attractive strategy for many types of inherited disorders of the immune system. Adenosine deaminase (ADA) deficient-severe combined immunodeficiency (SCID) has been the target of several clinical trials based on the use of hematopoietic stem/progenitor cells engineered with retroviral vectors. The introduction of a low intensity conditioning regimen has been a crucial factor in achieving stable engrafment of hematopoietic stem cells and therapeutic levels of ADA-expressing cells. Recent studies have demonstrated that gene therapy for ADA-SCID has favorable safety profile and is effective in restoring normal purine metabolism and immune functions. Stem cell gene therapy combined with appropriate conditioning regimens might be extended to other genetic disorders of the hematopoietic system.

  18. SNP Array in Hematopoietic Neoplasms: A Review

    Directory of Open Access Journals (Sweden)

    Jinming Song

    2015-12-01

    Full Text Available Cytogenetic analysis is essential for the diagnosis and prognosis of hematopoietic neoplasms in current clinical practice. Many hematopoietic malignancies are characterized by structural chromosomal abnormalities such as specific translocations, inversions, deletions and/or numerical abnormalities that can be identified by karyotype analysis or fluorescence in situ hybridization (FISH studies. Single nucleotide polymorphism (SNP arrays offer high-resolution identification of copy number variants (CNVs and acquired copy-neutral loss of heterozygosity (LOH/uniparental disomy (UPD that are usually not identifiable by conventional cytogenetic analysis and FISH studies. As a result, SNP arrays have been increasingly applied to hematopoietic neoplasms to search for clinically-significant genetic abnormalities. A large numbers of CNVs and UPDs have been identified in a variety of hematopoietic neoplasms. CNVs detected by SNP array in some hematopoietic neoplasms are of prognostic significance. A few specific genes in the affected regions have been implicated in the pathogenesis and may be the targets for specific therapeutic agents in the future. In this review, we summarize the current findings of application of SNP arrays in a variety of hematopoietic malignancies with an emphasis on the clinically significant genetic variants.

  19. conditions

    Directory of Open Access Journals (Sweden)

    M. Venkatesulu

    1996-01-01

    Full Text Available Solutions of initial value problems associated with a pair of ordinary differential systems (L1,L2 defined on two adjacent intervals I1 and I2 and satisfying certain interface-spatial conditions at the common end (interface point are studied.

  20. The Hematopoietic Niche in Myeloproliferative Neoplasms

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    Annette H. Schmitt-Graeff

    2015-01-01

    Full Text Available Specialized microanatomical areas of the bone marrow provide the signals that are mandatory for the maintenance and regulation of hematopoietic stem cells (HSCs and progenitor cells. A complex microenvironment adjacent to the marrow vasculature (vascular niche and close to the endosteum (endosteal niche harbors multiple cell types including mesenchymal stromal cells and their derivatives such as CAR cells expressing high levels of chemokines C-X-C motif ligand 12 and early osteoblastic lineage cells, endothelial cells, and megakaryocytes. The characterization of the cellular and molecular networks operating in the HSC niche has opened new perspectives for the understanding of the bidirectional cross-talk between HSCs and stromal cell populations in normal and malignant conditions. A structural and functional remodeling of the niche may contribute to the development of myeloproliferative neoplasms (MPN. Malignant HSCs may alter the function and survival of MSCs that do not belong to the neoplastic clone. For example, a regression of nestin+ MSCs by apoptosis has been attributed to neuroglial damage in MPN. Nonneoplastic MSCs in turn can promote aggressiveness and drug resistance of malignant cells. In the future, strategies to counteract the pathological interaction between the niche and neoplastic HSCs may offer additional treatment strategies for MPN patients.

  1. Hematopoietic reconstitution on the prognosis of hematological malignancies after allogenceic hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    张燕

    2012-01-01

    Objective To analyze the impact of the time to hematopoietic reconstitution on the prognosis of hematological malignancies after allogeneic hematopoietic stem cell transplantation(allo-HSCT) . Methods 173 patients with hematological malignancies treated with allo-HSCT (excluding umbilical cord blood transplantation)

  2. ROLE AND TIMING OF HEMATOPOIETIC CELL TRANSPLANTATION FOR MYELODYSPLASTIC SYNDROME

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    Teresa L Field

    2010-07-01

    Full Text Available Allogeneic hematopoietic cell transplantation (HCT is the only curative treatment for patients with myelodysplastic syndromes (MDS.  Most patients with MDS are older than 60 years and age-associated morbidities limit the patients’ options for curative transplant therapy.  Since the development of conditioning regimens with reduced toxicity, the age limitations for HCT have waned for those patients with good performance status. This review will discuss the role of HCT for MDS based on prognostic features, the optimal timing of HCT, and outcomes based on patient age.

  3. Hematopoietic Stem Cell Transplantation for Severe Combined Immunodeficiency

    Science.gov (United States)

    Wahlstrom, Justin T.; Dvorak, Christopher C.; Cowan, Morton J.

    2015-01-01

    Hematopoietic stem cell transplantation (HSCT) is an effective approach for the treatment of severe combined immunodeficiency (SCID). However, SCID is not a homogeneous disease, and the treatment required for successful transplantation varies significantly between SCID subtypes and the degree of HLA mismatch between the best available donor and the patient. Recent studies are beginning to more clearly define this heterogeneity and how outcomes may vary. With a more detailed understanding of SCID, new approaches can be developed to maximize immune reconstitution, while minimizing acute and long-term toxicities associated with chemotherapy conditioning. PMID:25821657

  4. Runx1 is required for the endothelial to hematopoietic cell transition but not thereafter

    Science.gov (United States)

    Chen, Michael J.; Yokomizo, Tomomasa; Zeigler, Brandon; Dzierzak, Elaine; Speck, Nancy A.

    2009-01-01

    HSCs are the founder cells of the adult hematopoietic system, and thus knowledge of the molecular program directing their generation during development is important for regenerative hematopoietic strategies. Runx1 is a pivotal transcription factor required for HSC generation in the vascular regions of the mouse conceptus - the aorta, vitelline and umbilical arteries, yolk sac and placenta 1, 2. It is thought that HSCs emerge from vascular endothelial cells through the formation of intra-arterial clusters 3 and that Runx1 functions during the transition from ‘hemogenic endothelium’ to HSCs 4, 5. Here we show by conditional deletion that Runx1 activity in vascular endothelial cadherin (VEC) positive endothelial cells is indeed essential for intra-arterial cluster, hematopoietic progenitor, and HSC formation. In contrast, Runx1 is not required in cells expressing Vav, one of the first pan-hematopoietic genes expressed in HSCs. Collectively these data show that Runx1 function is essential in endothelial cells for hematopoietic progenitor and HSC formation from the vasculature, but its requirement ends once or before Vav is expressed. PMID:19129762

  5. In utero depletion of fetal hematopoietic stem cells improves engraftment after neonatal transplantation in mice.

    Science.gov (United States)

    Derderian, S Christopher; Togarrati, P Priya; King, Charmin; Moradi, Patriss W; Reynaud, Damien; Czechowicz, Agnieszka; Weissman, Irving L; MacKenzie, Tippi C

    2014-08-07

    Although in utero hematopoietic cell transplantation is a promising strategy to treat congenital hematopoietic disorders, levels of engraftment have not been therapeutic for diseases in which donor cells have no survival advantage. We used an antibody against the murine c-Kit receptor (ACK2) to deplete fetal host hematopoietic stem cells (HSCs) and increase space within the hematopoietic niche for donor cell engraftment. Fetal mice were injected with ACK2 on embryonic days 13.5 to 14.5 and surviving pups were transplanted with congenic hematopoietic cells on day of life 1. Low-dose ACK2 treatment effectively depleted HSCs within the bone marrow with minimal toxicity and the antibody was cleared from the serum before the neonatal transplantation. Chimerism levels were significantly higher in treated pups than in controls; both myeloid and lymphoid cell chimerism increased because of higher engraftment of HSCs in the bone marrow. To test the strategy of repeated HSC depletion and transplantation, some mice were treated with ACK2 postnatally, but the increase in engraftment was lower than that seen with prenatal treatment. We demonstrate a successful fetal conditioning strategy associated with minimal toxicity. Such strategies could be used to achieve clinically relevant levels of engraftment to treat congenital stem cell disorders.

  6. The effects of proliferation and DNA damage on hematopoietic stem cell function determine aging.

    Science.gov (United States)

    Khurana, Satish

    2016-07-01

    In most of the mammalian tissues, homeostasis as well as injury repair depend upon a small number of resident adult stem cells. The decline in tissue/organ function in aged organisms has been directly linked with poorly functioning stem cells. Altered function of hematopoietic stem cells (HSCs) is at the center of an aging hematopoietic system, a tissue with high cellular turnover. Poorly engrafting, myeloid-biased HSCs with higher levels of DNA damage accumulation are the hallmark features of an aged hematopoietic system. These cells show a higher proliferation rate than their younger counterparts. It was proposed that quiescence of these cells over long period of time leads to accumulation of DNA damage, eventually resulting in poor function/pathological conditions in hematopoietic system. However, various mouse models with premature aging phenotype also show highly proliferative HSCs. This review examines the evidence that links proliferation of HSCs with aging, which leads to functional changes in the hematopoietic system. Developmental Dynamics 245:739-750, 2016. © 2016 Wiley Periodicals, Inc.

  7. Activation of the canonical Wnt pathway leads to loss of hematopoietic stem cell repopulation and multilineage differentiation block

    DEFF Research Database (Denmark)

    Kirstetter, Peggy; Anderson, Kristina; Porse, Bo T;

    2006-01-01

    of hematopoietic stem cell function was associated with decreased expression of Cdkn1a (encoding the cell cycle inhibitor p21(cdk)), Sfpi1, Hoxb4 and Bmi1 (encoding the transcription factors PU.1, HoxB4 and Bmi-1, respectively) and altered integrin expression in Lin(-)Sca-1(+)c-Kit(+) cells, whereas PU.1......Wnt signaling increases hematopoietic stem cell self-renewal and is activated in both myeloid and lymphoid malignancies, indicating involvement in both normal and malignant hematopoiesis. We report here activated canonical Wnt signaling in the hematopoietic system through conditional expression...... of a stable form of beta-catenin. This enforced expression led to hematopoietic failure associated with loss of myeloid lineage commitment at the granulocyte-macrophage progenitor stage; blocked erythrocyte differentiation; disruption of lymphoid development; and loss of repopulating stem cell activity. Loss...

  8. Black hairy tongue associated with allo peripheral blood hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    LUO Yi; ZOU Ping; LI Qiu-bai; YOU Yong

    2010-01-01

    @@ Tongue lesions resulting from mucositis are a frequent complication of high-dose chemotherapy and irradiation. They are very common in patients with hematopoietic stem cell transplantation, and tongue lesions due to other causes have also been reported. Black hairy tongue (BHT) is a special tongue lesion, not rare in the population with tobacco abuse, but so far it has not been reported after allo peripheral blood hematopoietic stem cell transplantation (allo-PBHST). Here we presented a patient who developed BHT after allo-PBHST and discussed the factors that may cause this condition.

  9. Advance in hematopoietic stem cells transplantation for leukemia

    Institute of Scientific and Technical Information of China (English)

    HUANG Xiao-jun

    2008-01-01

    @@ During the past 50 years, intensive studies into the characteristics of hematopoietic stem cell transplantation immunology and the emergence of new immunosuppressant and anti-infective drugs have significantly improved the clinical result of hematopoietic stem cell transplantation (HSCT).

  10. HIF1α is a regulator of hematopoietic progenitor and stem cell development in hypoxic sites of the mouse embryo

    Directory of Open Access Journals (Sweden)

    Parisa Imanirad

    2014-01-01

    Full Text Available Hypoxia affects many physiologic processes during early stages of mammalian ontogeny, particularly placental and vascular development. In the adult, the hypoxic bone marrow microenvironment plays a role in regulating hematopoietic stem cell (HSC function. HSCs are generated from the major vasculature of the embryo, but whether the hypoxic response affects the generation of these HSCs is as yet unknown. Here we examined whether Hypoxia Inducible Factor1-alpha (HIF1α, a key modulator of the response to hypoxia, is essential for HSC development. We found hypoxic cells in embryonic tissues that generate and expand hematopoietic cells (aorta, placenta and fetal liver, and specifically aortic endothelial and hematopoietic cluster cells. A Cre/loxP conditional knockout (cKO approach was taken to delete HIF1α in Vascular Endothelial-Cadherin expressing endothelial cells, the precursors to definitive hematopoietic cells. Functional assays show that HSC and hematopoietic progenitor cells (HPCs are significantly reduced in cKO aorta and placenta. Moreover, decreases in phenotypic aortic hematopoietic cluster cells in cKO embryos indicate that HIF1α is necessary for generation and/or expansion of HPCs and HSCs. cKO adult BM HSCs are also affected under transplantation conditions. Thus, HIF1α is a regulator of HSC generation and function beginning at the earliest embryonic stages.

  11. Leukemia microvesicles affect healthy hematopoietic stem cells.

    Science.gov (United States)

    Razmkhah, Farnaz; Soleimani, Masoud; Mehrabani, Davood; Karimi, Mohammad Hossein; Amini Kafi-Abad, Sedigheh; Ramzi, Mani; Iravani Saadi, Mahdiyar; Kakoui, Javad

    2017-02-01

    Microvesicles are released by different cell types and shuttle mRNAs and microRNAs which have the possibility to transfer genetic information to a target cell and alter its function. Acute myeloid leukemia is a malignant disorder, and leukemic cells occupy all the bone marrow microenvironment. In this study, we investigate the effect of leukemia microvesicles on healthy umbilical cord blood hematopoietic stem cells to find evidence of cell information transferring. Leukemia microvesicles were isolated from acute myeloid leukemia patients and were co-incubated with healthy hematopoietic stem cells. After 7 days, cell count, hematopoietic stem cell-specific cluster of differentiation (CD) markers, colony-forming unit assay, and some microRNA gene expressions were assessed. Data showed a higher number of hematopoietic stem cells after being treated with leukemia microvesicles compared with control (treated with no microvesicles) and normal (treated with normal microvesicles) groups. Also, increased levels of microRNA-21 and microRNA-29a genes were observed in this group, while colony-forming ability was still maintained and high ranges of CD34(+), CD34(+)CD38(-), CD90(+), and CD117(+) phenotypes were observed as stemness signs. Our results suggest that leukemia microvesicles are able to induce some effects on healthy hematopoietic stem cells such as promoting cell survival and some microRNAs deregulation, while stemness is maintained.

  12. Graft-versus-host disease and graft-versus-tumor effects after allogeneic hematopoietic cell transplantation

    DEFF Research Database (Denmark)

    Storb, Rainer; Gyurkocza, Boglarka; Storer, Barry E

    2013-01-01

    We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the pures...

  13. The risk factors of post-transplant lymphoproliferative disorders following haploidentical hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    张春丽

    2014-01-01

    Objective Post-transplant lymphoproliferative disorder(PTLD)occurring after allogeneic hematopoietic stem cell transplantation(allo-HSCT)is rare but severe.Risk factors including pre-HSCT exposure variables,conditioning regimens,transplant-related complications,and post-HSCT immune reconstitution were investigated in the development of PTLD after allo-HSCT.Methods A

  14. Oral bacteria and yeasts in relationship to oral ulcerations in hematopoietic stem cell transplant recipients

    NARCIS (Netherlands)

    Laheij, A.M.G.A.; de Soet, J.J.; von dem Borne, P.A.; Kuijper, E.J.; Kraneveld, E.A.; van Loveren, C.; Raber-Durlacher, J.E.

    2012-01-01

    BACKGROUND: Oral mucositis is a serious and debilitating side effect of conditioning regimens for hematopoietic stem cell transplant (HSCT). Through HSCT, the homeostasis in the oral cavity is disrupted. The contribution of the oral microflora to mucositis remains to be clarified. The aim of our stu

  15. Impact of Pretransplantation 18F-fluorodeoxy Glucose—Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma

    Science.gov (United States)

    Bachanova, Veronika; Burns, Linda J.; Ahn, Kwang Woo; Laport, Ginna G.; Akpek, Görgün; Kharfan-Dabaja, Mohamed A.; Nishihori, Taiga; Agura, Edward; Armand, Philippe; Jaglowski, Samantha M.; Cairo, Mitchell S.; Cashen, Amanda F.; Cohen, Jonathon B.; D'Souza, Anita; Freytes, César O.; Gale, Robert Peter; Ganguly, Siddhartha; Ghosh, Nilanjan; Holmberg, Leona A.; Inward, David J.; Kanate, Abraham S.; Lazarus, Hillard M.; Malone, Adriana K.; Munker, Reinhold; Mussetti, Alberto; Norkin, Maxim; Prestidge, Tim D.; Rowe, Jacob M.; Satwani, Prakash; Siddiqi, Tanya; Stiff, Patrick J.; William, Basem M.; Wirk, Baldeep; Maloney, David G.; Smith, Sonali M.; Sureda, Anna M.; Carreras, Jeanette; Hamadani, Mehdi

    2015-01-01

    Assessment with 18F-fluorodeoxy glucose (FDG)—positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non—Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with worse OS (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), PFS (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL. PMID:25983043

  16. Allogeneic hematopoietic stem cell transplantation in patients with diffuse large B cell lymphoma relapsed after autologous stem cell transplantation: a GITMO study.

    Science.gov (United States)

    Rigacci, Luigi; Puccini, Bendetta; Dodero, Anna; Iacopino, Pasquale; Castagna, Luca; Bramanti, Stefania; Ciceri, Fabio; Fanin, Renato; Rambaldi, Alessandro; Falda, Michele; Milone, Giuseppe; Guidi, Stefano; Martelli, Massimo Fabrizio; Mazza, Patrizio; Oneto, Rosi; Bosi, Alberto

    2012-06-01

    Patients who relapse after an autologous hematopoietic stem cell transplantation (SCT) have a very poor prognosis. We have retrospectively analyzed diffuse large B cell lymphoma patients who underwent an allo-SCT after an auto-SCT relapse reported in the Gruppo Italiano Trapianto di Midollo Osseo (GITMO) database. From 1995 to 2008, 3449 autologous transplants were reported in the GITMO database. Eight hundred eighty-four patients relapsed or progressed after transplant; 165 patients, 19% of the relapsed patients, were treated with allo-transplant. The stem cell donor was related to the patient in 108 cases. A reduced intensity conditioning regimen was used in 116. After allo-SCT, 72 patients (43%) obtained a complete response and 9 obtained a partial response with an overall response rate of 49%; 84 patients (51%) experienced rapid progression of disease. Ninety-one patients died, 45 due to disease and 46 due to treatment-related mortality. Acute graft-versus-host disease was recorded in 57 patients and a chronic GvHD in 38 patients. With a median follow-up of 24 months (2-144) after allo, overall survival (OS) was 39%, and after a median of 21 months (2-138) after allo, progression-free survival (PFS) was 32%. Multivariate analysis indicated that the only factors affecting OS were status at allo-SCT, and those affecting PFS were status at allo-SCT and stem cell donor. This retrospective analysis shows that about one-fifth of patients with diffuse large B cell lymphoma who experience relapse after autologous transplantation may be treated with allogeneic transplantation. Moreover, the only parameter affecting either OS or PFS was the response status at the time of allo-SCT.

  17. Cord Blood Transplantation for Multiple Myeloma: A Study from the Multiple Myeloma Working Group of the Japan Society for Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Kawamura, Koji; Takamatsu, Hiroyuki; Ikeda, Takashi; Komatsu, Tsunehiko; Aotsuka, Nobuyuki; Amano, Itsuto; Yamamoto, Go; Watanabe, Kentaro; Ohno, Yuju; Matsue, Kosei; Kouzai, Yasuji; Tsukada, Nobuhiro; Ishiyama, Ken; Anzai, Naoyuki; Kato, Koji; Suzuki, Ritsuro; Sunami, Kazutaka; Kanda, Yoshinobu

    2015-07-01

    Cord blood has been investigated as an alternative source for hematopoietic stem cell transplantation, but information about its use for multiple myeloma is limited. The purpose of this study was to evaluate the feasibility of cord blood transplantation (CBT) for patients with multiple myeloma. Eighty-six patients with multiple myeloma who underwent a first CBT between 2001 and 2011 were included in this retrospective study. Sixty-two of them had received other types of stem cell transplantation before CBT. The cumulative incidences of neutrophil engraftment at day 50, grade II to IV acute graft-versus-host disease (GVHD), and chronic GVHD were 81.4%, 39.0%, and 19.5%, respectively. The incidence of nonrelapse mortality at 2 years was 39.0%, but it was only 6.2% in patients who underwent planned tandem autologous/reduced-intensity conditioning CBT (auto/RIC-CBT). Progression-free survival (PFS) and overall survival (OS) at 6 years were 13.0% and 15.2%, respectively. Less than a partial response before CBT and lack of prior transplantation were independent significant adverse factors for PFS, whereas the presence of prior transplantation and planned tandem transplantation were associated with better OS. OS at 6 years in patients who underwent auto/RIC-CBT was 45.9%. In addition, the development of chronic GVHD was associated with superior PFS. In conclusion, we demonstrated that cord blood is feasible as an alternative graft source for myeloma patients. Although CBT provided long-term survival for a fraction of patients, optimal use of this graft requires further clinical studies. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  18. Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients.

    Science.gov (United States)

    Kishi, Y; Murashige, N; Kami, M; Miyakoshi, S; Shibagaki, Y; Hamaki, T; Takaue, Y; Taniguchi, S

    2005-06-01

    Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

  19. 脐带间充质干细胞条件培养液促进人胚胎干细胞分化为造血细胞%Human umbilical cord mesenchymal stem cells conditioned medium promotes the hematopoietic differentiation of human embryonic stem cells

    Institute of Scientific and Technical Information of China (English)

    袁雅红; 李大哲; 于莉; 马石楠; 李东升

    2015-01-01

    Objective To optimize the scheme of human embryonic stem cell differentiation to hematopoietic cell by taking advantage of the characteristics of umbilical cord mesenchymal stem cells in supporting hematopoiesis . Method The umbilical cord mesenchymal stem cells were isolated and expanded with tissue block culture method and then the condition medium were collected routinely .Human embryonic stem cell were cultured on mouse embryonic fibroblasts ,and were induced to be embryoid bodies with embryoid bodies culture medium .The embryoid bodies were cultured with condition medium and embryoid bodies culture medium respectively .Finally ,the percentage of hematopoietic cell maker CD45 and CD34 were detected with flow cytometry .Result It is obtained a large number of homogeneous fibroblasts‐like umbilical cord mesenchymal stem cells which proliferated rapidly .After the embryoid bodies were cultured with condition medium 8 days ,the result shown that the percentage of CD45 were more than 60% and CD34 were more than 30% ,far higher than that of embryoidbodies cultured with embryoid bodies culture medium .Conclusion Human umbilical cord mesenchymal stem cells conditioned medium can promote thehematopoiet‐ic differentiation of human embryonic stem cells .And his method will avoid the mouse‐related disease and cut down the cost of experiment .%目的:利用人脐带间充质干细胞造血支持的特性,优化人胚胎干细胞造血分化方案。方法利用组织块培养法分离扩增人脐带间充质干细胞,收集条件培养液。以小鼠胚胎成纤维细胞为饲养层培养人胚胎干细胞,再用拟胚体培养液诱导拟胚体形成。分别用条件培养液和拟胚体培养液培养拟胚体,再用流式细胞术检测EB中造血标志CD45和CD34的表达。结果利用组织块培养法获得大量形态均一、增殖迅速的脐带间充质干细胞;间充质干细胞条件培养液诱导8 d后,拟胚体中的CD45表达60

  20. Hematopoietic stem cell transplantation for infantile osteopetrosis.

    Science.gov (United States)

    Orchard, Paul J; Fasth, Anders L; Le Rademacher, Jennifer; He, Wensheng; Boelens, Jaap Jan; Horwitz, Edwin M; Al-Seraihy, Amal; Ayas, Mouhab; Bonfim, Carmem M; Boulad, Farid; Lund, Troy; Buchbinder, David K; Kapoor, Neena; O'Brien, Tracey A; Perez, Miguel A Diaz; Veys, Paul A; Eapen, Mary

    2015-07-01

    We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from HLA-mismatched unrelated donors. The median age at transplantation was 12 months. Busulfan and cyclophosphamide was the most common conditioning regimen. Long-term survival was higher after HLA-matched sibling compared to alternative donor transplantation. There were no differences in survival after HLA-mismatched related, HLA-matched unrelated, or mismatched unrelated donor transplantation. The 5- and 10-year probabilities of survival were 62% and 62% after HLA-matched sibling and 42% and 39% after alternative donor transplantation (P = .01 and P = .002, respectively). Graft failure was the most common cause of death, accounting for 50% of deaths after HLA-matched sibling and 43% of deaths after alternative donor transplantation. The day-28 incidence of neutrophil recovery was 66% after HLA-matched sibling and 61% after alternative donor transplantation (P = .49). The median age of surviving patients is 7 years. Of evaluable surviving patients, 70% are visually impaired; 10% have impaired hearing and gross motor delay. Nevertheless, 65% reported performance scores of 90 or 100, and in 17%, a score of 80 at last contact. Most survivors >5 years are attending mainstream or specialized schools. Rates of veno-occlusive disease and interstitial pneumonitis were high at 20%. Though allogeneic transplantation results in long-term survival with acceptable social function, strategies to lower graft failure and hepatic and pulmonary toxicity are urgently needed.

  1. The Hematopoietic Stem Cell Therapy for Exploration of Space

    Science.gov (United States)

    Roach, Allana Nicole; Brezo, Jelena

    2002-01-01

    Astronauts experience severe/invasive disorders caused by space environments. These include hematological/cardiac abnormalities, bone and muscle losses, immunodeficiency, neurological disorders and cancer. While the cause of these symptoms are not yet fully delineated, one possible explanation could be the inhibition of hematopoietic stem cell (HSC) growth and hematopoiesis in space. HSCs differentiate into all types of blood cells, and growing evidence indicates that the HSCs also have the ability to transdifferentiate to various tissues, including muscle, skin, liver, neuronal cells and possibly bone. Therefore, a hypothesis was advanced in this laboratory that the hematopoietic stem cell-based therapy, herein called the hematopoietic stem cell therapy (HSCT), could mitigate some of the disorders described above. Due to the magnitude of this project our laboratory has subdivided it into 3 sections: a) HSCT for space anemia; b) HSCT for muscle and bone losses; and c) HSCT for immunodeficiency. Toward developing the HSCT protocol for space anemia, the HSC transplantation procedure was established using a mouse model of beta thalassemia. In addition, the NASA Rotating Wall Vessel (RWV) culture system was used to grow HSCs in space condition. To investigate the HSCT for muscle loss and bone loss, donor HSCs were genetically marked either by transfecting the beta-galactosidase-containing plasmid, pCMV.SPORT-beta-gal or by preparing from b-galactosidase transgenic mice. The transdifferentiation of HSCs to muscle is traced by the reporter gene expression in the hindlimb suspended mice with some positive outcome, as studied by the X-gal staining procedure. The possible structural contribution of HSCs against muscle loss is being investigated histochemically.

  2. Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells

    Science.gov (United States)

    Serafini, Marta; Dylla, Scott J.; Oki, Masayuki; Heremans, Yves; Tolar, Jakub; Jiang, Yuehua; Buckley, Shannon M.; Pelacho, Beatriz; Burns, Terry C.; Frommer, Sarah; Rossi, Derrick J.; Bryder, David; Panoskaltsis-Mortari, Angela; O'Shaughnessy, Matthew J.; Nelson-Holte, Molly; Fine, Gabriel C.; Weissman, Irving L.; Blazar, Bruce R.; Verfaillie, Catherine M.

    2007-01-01

    For decades, in vitro expansion of transplantable hematopoietic stem cells (HSCs) has been an elusive goal. Here, we demonstrate that multipotent adult progenitor cells (MAPCs), isolated from green fluorescent protein (GFP)-transgenic mice and expanded in vitro for >40–80 population doublings, are capable of multilineage hematopoietic engraftment of immunodeficient mice. Among MAPC-derived GFP+CD45.2+ cells in the bone marrow of engrafted mice, HSCs were present that could radioprotect and reconstitute multilineage hematopoiesis in secondary and tertiary recipients, as well as myeloid and lymphoid hematopoietic progenitor subsets and functional GFP+ MAPC-derived lymphocytes that were functional. Although hematopoietic contribution by MAPCs was comparable to control KTLS HSCs, approximately 103-fold more MAPCs were required for efficient engraftment. Because GFP+ host-derived CD45.1+ cells were not observed, fusion is not likely to account for the generation of HSCs by MAPCs. PMID:17227908

  3. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells

    Science.gov (United States)

    2013-01-01

    Pluripotent stem cells, both embryonic stem cells and induced pluripotent stem cells, are undifferentiated cells that can self-renew and potentially differentiate into all hematopoietic lineages, such as hematopoietic stem cells (HSCs), hematopoietic progenitor cells and mature hematopoietic cells in the presence of a suitable culture system. Establishment of pluripotent stem cells provides a comprehensive model to study early hematopoietic development and has emerged as a powerful research tool to explore regenerative medicine. Nowadays, HSC transplantation and hematopoietic cell transfusion have successfully cured some patients, especially in malignant hematological diseases. Owing to a shortage of donors and a limited number of the cells, hematopoietic cell induction from pluripotent stem cells has been regarded as an alternative source of HSCs and mature hematopoietic cells for intended therapeutic purposes. Pluripotent stem cells are therefore extensively utilized to facilitate better understanding in hematopoietic development by recapitulating embryonic development in vivo, in which efficient strategies can be easily designed and deployed for the generation of hematopoietic lineages in vitro. We hereby review the current progress of hematopoietic cell induction from embryonic stem/induced pluripotent stem cells. PMID:23796405

  4. Hematopoietic stem cell transplantation for infantile osteopetrosis

    NARCIS (Netherlands)

    Orchard, Paul J.; Fasth, Anders L.; Le Rademacher, Jennifer L.; He, Wensheng; Boelens, Jaap Jan; Horwitz, Edwin M.; Al-Seraihy, Amal; Ayas, Mouhab; Bonfim, Carmem M.; Boulad, Farid; Lund, Troy; Buchbinder, David K.; Kapoor, Neena; OBrien, Tracey A.; Perez, Miguel A Diaz; Veys, Paul A.; Eapen, Mary

    2015-01-01

    We report the international experience in outcomes after related and unrelated hematopoietic transplantation for infantile osteopetrosis in 193 patients. Thirty-four percent of transplants used grafts from HLA-matched siblings, 13% from HLA-mismatched relatives, 12% from HLA-matched, and 41% from HL

  5. Cellular memory and, hematopoietic stem cell aging

    NARCIS (Netherlands)

    Kamminga, Leonie M.; de Haan, Gerald

    Hematopoietic stem cells (HSCs) balance self-renewal and differentiation in order to sustain lifelong blood production and simultaneously maintain the HSC pool. However, there is clear evidence that HSCs are subject to quantitative and qualitative exhaustion. In this review, we briefly discuss

  6. Autonomous behavior of hematopoietic stem cells

    NARCIS (Netherlands)

    Kamminga, LM; Akkerman, [No Value; Weersing, E; Ausema, A; Dontje, B; Van Zant, G; de Haan, G

    2000-01-01

    Objective. Mechanisms that affect the function of primitive hematopoietic stem cells with long-term proliferative potential remain largely unknown. Here we assessed whether properties of stem cells are cell-extrinsically or cell-autonomously regulated. Materials and Methods. We developed a model in

  7. Ex vivo Expansion of Hematopoietic Stem Cells

    NARCIS (Netherlands)

    E. Farahbakhshian (Elnaz)

    2013-01-01

    textabstractHematopoiesis is a complex cellular differentiation process resulting in the formation of all blood cell types. In this process, hematopoietic stem cells (HSCs) reside at the top of the hematopoiesis hierarchy and have the capacity to differentiate into all blood cell lineages (multipote

  8. Autonomous behavior of hematopoietic stem cells

    NARCIS (Netherlands)

    Kamminga, LM; Akkerman, [No Value; Weersing, E; Ausema, A; Dontje, B; Van Zant, G; de Haan, G

    2000-01-01

    Objective. Mechanisms that affect the function of primitive hematopoietic stem cells with long-term proliferative potential remain largely unknown. Here we assessed whether properties of stem cells are cell-extrinsically or cell-autonomously regulated. Materials and Methods. We developed a model in

  9. Human hematopoietic cell culture, transduction, and analyses

    DEFF Research Database (Denmark)

    Bonde, Jesper; Wirthlin, Louisa; Kohn, Donald B;

    2008-01-01

    This unit provides methods for introducing genes into human hematopoietic progenitor cells. The Basic Protocol describes isolation of CD34(+) cells, transduction of these cells with a retroviral vector on fibronectin-coated plates, assaying the efficiency of transduction, and establishing long...

  10. Characterization of acute graft-versus-host disease following reduced-intensity stem-cell transplantation from an HLA-identical related donor.

    Science.gov (United States)

    Murashige, Naoko; Kami, Masahiro; Mori, Shin-ichiro; Katayama, Yuta; Kobayashi, Kazuhiko; Onishi, Yasushi; Hori, Akiko; Kishi, Yukiko; Hamaki, Tamae; Tajima, Kinuko; Kanda, Yoshinobu; Tanosaki, Ryuji; Takaue, Yoichi

    2008-08-01

    To investigate clinical features of acute graft-versus-host disease (GVHD) following reduced intensity stem-cell transplantation (RIST), we retrospectively investigated medical records of 65 patients with hematologic malignancies who underwent RIST from a matched related donor. Preparative regimen comprised fludarabine 30 mg/m(2) (n = 53) or cladribine 0.11 mg/kg (n = 12) for 6 days plus busulfan 4 mg/kg for 2 days. Twelve patients received rabbit antithymocyte globulin 2.5 mg/kg/day for 2-4 consecutive days. Grade II to IV acute GVHD was diagnosed in 36 patients (55%). Its median onset was day 58 (range, 17-109), while it was bimodal, peaking day 15-29 (early-onset GVHD, n = 18) and day 75-89 days (late-onset GVHD, n = 18). Variables that were more common in early-onset GVHD than late-onset GVHD included skin rash (89% vs. 61%) and noninfectious fevers (33% vs. 11%). Desaturation, pulmonary infiltrates and hyperbilirubinemia (>2.0 mg/dL) were more common in late-onset GVHD (6% vs. 22%, 0% vs. 17%, and 6% vs. 33%, respectively). All of the patients with early-onset GVHD given corticosteroid responded to it, while 5 of the 18 patients with late-onset GVHD failed to respond it. Patients with either early-onset or late-onset GVHD tended to have better progression-free survival (PFS) than those without it; however, there was no significant difference in PFS between patients with early-onset GVHD and those with late-onset GVHD. This study suggests that several etiologies might have contributed to the development of acute GVHD following RIST.

  11. Outcomes of patients with acute leukaemia who relapsed after reduced-intensity stem cell transplantation from HLA-identical or one antigen-mismatched related donors.

    Science.gov (United States)

    Kobayashi, Kazuhiko; Kami, Masahiro; Murashige, Naoko; Kusumi, Eiji; Kishi, Yukiko; Hamaki, Tamae; Hori, Akiko; Matsumura, Tomoko; Yuji, Koichiro; Masuo, Shigeru; Mori, Shinichiro; Miyakoshi, Shigesaburo; Tanosaki, Ryuji; Mitamura, Tadayuki; Takaue, Yoichi; Taniguchi, Shuichi

    2005-06-01

    The characteristics of relapse following reduced-intensity stem-cell transplantation (RIST) remain to be clarified. We reviewed the medical records of 19 patients with acute leukaemia [acute myeloid leukaemia (AML), 16; acute lymphoblastic leukaemia (ALL), 3] who relapsed after RIST from related donors using purine-analogue-based regimens. Their median age was 55 years (range, 29-65 years). Median interval between RIST and relapse was 4.9 months (range, 1.8-24.9 months). Three chose not to receive interventions. The remaining 16 patients received withdrawal of immunosuppression (n = 3), chemotherapy (n = 2), donor lymphocyte infusion (n = 10) and second transplantation (n = 7), alone (n = 9) or in combination (n = 7). Four are alive with a median follow-up of 27.6 months (range, 16.0-28.9 months); three in remission and one in relapse. The 2-year overall survival after relapse was 28.9%. Causes of death in 15 patients included progressive disease (n = 7), graft-versus-host disease (n = 5) and infections (n = 3). Cumulative incidences of relapse-related and non-relapse-related deaths at 2 years after relapse were 37% and 32% respectively. Two prognostic factors were identified on univariate analysis: age [P = 0.017; hazard ratio (HR), 1.16; 95% confidence interval (CI), 1.03-1.32], and ALL as underlying disease (P = 0.011; HR, 10.4; 95% CI, 1.73-62.4). Some AML patients who relapse after RIST achieve durable remission with allogeneic immunotherapy-based interventions; however they carry a significant risk of non-relapse mortality.

  12. The long-term outcome of reduced-intensity allogeneic stem cell transplantation from a matched related or unrelated donor, or haploidentical family donor in patients with leukemia: a retrospective analysis of data from the China RIC Cooperative Group.

    Science.gov (United States)

    Yu, Chang-Lin; Zheng-Dong; Qiao, Zhen-Hua; Wang, Jian-Min; Huang-He; Liang, Ying-Min; Wu, De-Pei; Chen, Bao-An; Bai-Hai; Shi, Bao-Fu; Sun, Wan-Jun; Qiao, Jun-Xiao; Guo, Mei; Qiao, Jian-Hui; Sun, Qi-Yun; Hu, Kai-Xun; Huang, Ya-Jing; Zuo, Hong-Li; Huang, Xiao-Jun; Ai, Hui-Sheng

    2017-02-01

    This study compared 6-year follow-up data from patients undergoing reduced-intensity conditioning (RIC) transplantation with an HLA-matched related donor (MRD), an HLA-matched unrelated donor (MUD), or an HLA-haploidentical donor (HID) for leukemia. Four hundred and twenty-seven patients from the China RIC Cooperative Group were enrolled, including 301 in the MRD, 79 in the HID, and 47 in the MUD groups. The conditioning regimen involved fludarabine combined with anti-lymphocyte globulin and cyclophosphamide. Graft-versus-host disease (GVHD) prophylaxis was administered using cyclosporin A (CsA) and mycophenolate mofetil (MMF). Four hundred and nineteen patients achieved stable donor chimerism. The incidence of stage II-IV acute GVHD in the HID group was 44.3 %, significantly higher than that in the MRD (23.6 %) and MUD (19.1 %) groups. The 1-year transplantation-related mortality (TRM) rates were 44.3, 17.6, and 21.3, respectively. Event-free survival (EFS) at 6 years in the HID group was 36.7 %, significantly lower than that of the MRD and MUD groups (59.1 and 66.0 %, P  0.05), respectively. RIC transplantation with MRD and MUD had similar outcome in leukemia which is better than that with HID. RIC transplantation with HID had lower relapsed with higher TRM and GVHD rate, particularly in advanced leukemias. RIC transplantation with MRD and MUD had similar outcomes in leukemia and they were better than those with HID. RIC transplantation with HID had a lower relapse rate but higher TRM and GVHD rates, particularly in cases of advanced leukemia.

  13. Immunological Basis of Bone Marrow Failure after Allogeneic Hematopoietic Stem Cell Transplantation

    Science.gov (United States)

    Masouridi-Levrat, Stavroula; Simonetta, Federico; Chalandon, Yves

    2016-01-01

    Bone marrow failure (BMF) syndromes are severe complications of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this paper, we distinguish two different entities, the graft failure (GF) and the poor graft function (PGF), and we review the current understanding of the interactions between the immune and hematopoietic compartments in these conditions. We first discuss how GF occurs as the result of classical alloreactive immune responses mediated by residual host cellular and humoral immunity persisting after conditioning and prevented by host and donor regulatory T cells. We next summarize the current knowledge about the contribution of inflammatory mediators to the development of PGF. In situations of chronic inflammation complicating allo-HSCT, such as graft-versus-host disease or infections, PGF seems to be essentially the result of a sustained impairment of hematopoietic stem cells (HSC) self-renewal and proliferation caused by inflammatory mediators, such as interferon-γ (IFN-γ) and tumor necrosis factor-α, and of induction of apoptosis through the Fas/Fas ligand pathway. Interestingly, the production of inflammatory molecules leads to a non-MHC restricted, bystander inhibition of hematopoiesis, therefore, representing a promising target for immunological interventions. Finally, we discuss immune-mediated impairment of bone marrow microenvironment as a potential mechanism hampering hematopoietic recovery. Better understanding of immunological mechanisms responsible for BMF syndromes after allo-HSCT may lead to the development of more efficient immunotherapeutic interventions. PMID:27695456

  14. Assessment of human multi-potent hematopoietic stem/progenitor cell potential using a single in vitro screening system.

    Directory of Open Access Journals (Sweden)

    Julien Calvo

    Full Text Available Hematopoietic stem cells are responsible for the generation of the entire blood system through life. This characteristic relies on their ability to self renew and on their multi-potentiality. Thus quantification of the number of hematopoietic stem cells in a given cell population requires to show both properties in the studied cell populations. Although xenografts models that support human hematopoietic stem cells have been described, such in vivo experimental systems remain restrictive for high throughput screening purposes for example. In this work we developed a conditional tetracycline inducible system controlling the expression of the human NOTCH ligand Delta-like 1 in the murine stromal MS5 cells. We cultured hematopoietic immature cells enriched in progenitor/stem cells in contact with MS5 cells that conditionally express Delta-like 1, in conditions designed to generate multipotential lineage differentiation. We show that upon induction or repression of DL1 expression during co-culture, human immature CD34(+CD38(-/low(CD45RA(-CD90(+ cells can express their B, T, NK, granulo/monocytic and erythroid potentials in a single well, and at the single cell level. We also document the interference of low NOTCH activation with human B and myelo/erythroid lymphoid differentiation. This system represents a novel tool to precisely quantify human hematopoietic immature cells with both lymphoid and myeloid potentials.

  15. ETS transcription factors in hematopoietic stem cell development.

    Science.gov (United States)

    Ciau-Uitz, Aldo; Wang, Lu; Patient, Roger; Liu, Feng

    2013-12-01

    Hematopoietic stem cells (HSCs) are essential for the maintenance of the hematopoietic system. However, these cells cannot be maintained or created in vitro, and very little is known about their generation during embryogenesis. Many transcription factors and signaling pathways play essential roles at various stages of HSC development. Members of the ETS ('E twenty-six') family of transcription factors are recognized as key regulators within the gene regulatory networks governing hematopoiesis, including the ontogeny of HSCs. Remarkably, although all ETS transcription factors bind the same DNA consensus sequence and overlapping tissue expression is observed, individual ETS transcription factors play unique roles in the development of HSCs. Also, these transcription factors are recurrently used throughout development and their functions are context-dependent, increasing the challenge of studying their mechanism of action. Critically, ETS factors also play roles under pathological conditions, such as leukemia and, therefore, deciphering their mechanism of action will not only enhance our knowledge of normal hematopoiesis, but also inform protocols for their creation in vitro from pluripotent stem cells and the design of new therapeutic approaches for the treatment of malignant blood cell diseases. In this review, we summarize the key findings on the roles of ETS transcription factors in HSC development and discuss novel mechanisms by which they could control hematopoiesis. © 2013.

  16. Oral changes in individuals undergoing hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    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.

  17. FGF signaling facilitates postinjury recovery of mouse hematopoietic system.

    Science.gov (United States)

    Zhao, Meng; Ross, Jason T; Itkin, Tomer; Perry, John M; Venkatraman, Aparna; Haug, Jeffrey S; Hembree, Mark J; Deng, Chu-Xia; Lapidot, Tsvee; He, Xi C; Li, Linheng

    2012-08-30

    Previous studies have shown that fibroblast growth factor (FGF) signaling promotes hematopoietic stem and progenitor cell (HSPC) expansion in vitro. However, it is unknown whether FGF promotes HSPC expansion in vivo. Here we examined FGF receptor 1 (FGFR1) expression and investigated its in vivo function in HSPCs. Conditional knockout (CKO) of Fgfr1 did not affect phenotypical number of HSPCs and homeostatic hematopoiesis, but led to a reduced engraftment only in the secondary transplantation. When treated with 5-fluorouracil (5FU), the Fgfr1 CKO mice showed defects in both proliferation and subsequent mobilization of HSPCs. We identified megakaryocytes (Mks) as a major resource for FGF production, and further discovered a novel mechanism by which Mks underwent FGF-FGFR signaling dependent expansion to accelerate rapid FGF production under stress. Within HSPCs, we observed an up-regulation of nuclear factor κB and CXCR4, a receptor for the chemoattractant SDF-1, in response to bone marrow damage only in control but not in Fgfr1 CKO model, accounting for the corresponding defects in proliferation and migration of HSPCs. This study provides the first in vivo evidence that FGF signaling facilitates postinjury recovery of the mouse hematopoietic system by promoting proliferation and facilitating mobilization of HSPCs.

  18. Sexual health in hematopoietic stem cell transplant recipients.

    Science.gov (United States)

    Li, Zhuoyan; Mewawalla, Prerna; Stratton, Pamela; Yong, Agnes S M; Shaw, Bronwen E; Hashmi, Shahrukh; Jagasia, Madan; Mohty, Mohamad; Majhail, Navneet S; Savani, Bipin N; Rovó, Alicia

    2015-12-01

    Hematopoietic stem cell transplantation (HSCT) plays a central role in patients with malignant and, increasingly, nonmalignant conditions. As the number of transplants increases and the survival rate improves, long-term complications are important to recognize and treat to maintain quality of life. Sexual dysfunction is a commonly described but relatively often underestimated complication after HSCT. Conditioning regimens, generalized or genital graft-versus-host disease, medications, and cardiovascular complications as well as psychosocial problems are known to contribute significantly to physical and psychological sexual dysfunction. Moreover, it is often a difficult topic for patients, their significant others, and health care providers to discuss. Early recognition and management of sexual dysfunction after HSCT can lead to improved quality of life and outcomes for patients and their partners. This review focuses on the risk factors for and treatment of sexual dysfunction after transplantation and provides guidance concerning how to approach and manage a patient with sexual dysfunction after HSCT.

  19. Gastrointestinal and hepatic complications of hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    Hande H Tuncer; Naveed Rana; Cannon Milani; Angela Darko; Samer A Al-Homsi

    2012-01-01

    Recognition and management of gastrointestinal and hepatic complications of hematopoietic stem cell transplantation has gained increasing importance as indications and techniques of transplantation have expanded in the last few years.The transplant recipient is at risk for several complications including conditioning chemotherapy related toxicities,infections,bleeding,sinusoidal obstruction syndrome,acute and chronic graftversus-host disease (GVHD) as well as other long-term problems.The severity and the incidence of many complications have improved in the past several years as the intensity of conditioning regimens has diminished and better supportive care and GVHD prevention strategies have been implemented.Transplant clinicians,however,continue to be challenged with problems arising from human leukocyte antigen-mismatched and unrelated donor transplants,expanding transplant indications and age-limit.This review describes the most commonly seen transplant related complications,focusing on their pathogenesis,differential diagnosis and management.

  20. Bussulfano e melfalano como regime de condicionamento para o transplante autogênico de células-tronco hematopoéticas na leucemia mielóide aguda em primeira remissão completa Busulfan and melphalan as conditioning regimen for autologous hematopoietic stem cell transplantation in acute myeloid leukemia in first complete remission

    Directory of Open Access Journals (Sweden)

    Nadjanara D. Bueno

    2008-10-01

    Full Text Available Vinte e dois pacientes consecutivos portadores de leucemia mielóide aguda (LMA em primeira remissão completa (1ªRC submetidos a transplante de células-tronco hematopoéticas autogênico (TCTH Auto condicionados com bussulfano e melfalano (Bu/Mel foram selecionados entre 1993 e 2006. A probabilidade de sobrevida global (SG pelo método de Kaplan-Meier foi de 57,5% após 36 meses, com "plateau" aos 20 meses após o transplante. Fatores como sexo, classificação Franco-Americana-Britânica (FAB da LMA, tratamento de indução, consolidação intensiva, remissão após o primeiro ciclo de indução e fonte de células não tiveram impacto na sobrevida. Pela análise citogenética, um paciente de mau prognóstico submetido ao procedimento, foi a óbito um ano após o transplante. Nove pacientes foram a óbito, oito por recidiva e um por hemorragia. Morte antes dos 100 dias ocorreu em dois pacientes, um por recidiva e outro por hemorragia decorrente da plaquetopenia refratária, relacionada ao procedimento. Concluímos que o regime de condicionamento Bu/Mel é opção válida ao uso de outros regimes de condicionamento, apresentando excelente taxa da sobrevida.Twenty-two consecutive patients with acute myeloid leukemia in first complete remission submitted to autologous hematopoietic stem cells transplantation conditioned with busulfan and melphalan were evaluated between 1993 and 2006. The overall survival, according to the Kaplan-Meier curve, was 57.5% at 36 months, with a "plateau" at 20 months after transplant. Factors such as gender, French-American-British (FAB classification of acute myeloid leukemia, induction therapy, intensive consolidation, remission after the first cycle of induction and source of cells had no impact on survival. One patient with poor prognosis before the procedure died a year after transplantation. Nine patients died, eight by relapse and one because of bleeding. Death before 100 days occurred for two patients, one

  1. Distinct roles for hematopoietic and extra-hematopoietic sphingosine kinase-1 in inflammatory bowel disease.

    Science.gov (United States)

    Snider, Ashley J; Ali, Wahida H; Sticca, Jonathan A; Coant, Nicolas; Ghaleb, Amr M; Kawamori, Toshihiko; Yang, Vincent W; Hannun, Yusuf A; Obeid, Lina M

    2014-01-01

    Sphingosine kinase 1 (SK1), one of two SK enzymes, is highly regulated and has been shown to act as a focal point for the action of many growth factors and cytokines. SK1 leads to generation of sphingosine-1-phosphate (S1P) and potentially the activation of S1P receptors to mediate biologic effects. Our previous studies implicated SK1/S1P in the regulation of inflammatory processes, specifically in inflammatory bowel disease (IBD). These studies were conducted using a total body knockout mouse for SK1 and were unable to determine the source of SK1/S1P (hematopoietic or extra-hematopoietic) involved in the inflammatory responses. Therefore, bone marrow transplants were performed with wild-type (WT) and SK1-/- mice and colitis induced with dextran sulfate sodium (DSS). Irrespective of the source of SK1/S1P, bone marrow or tissue, DSS induced colitis in all mice; however, mice lacking SK1 in both hematopoietic and extra-hematopoietic compartments exhibited decreased crypt damage. Systemic inflammation was assessed, and mice with WT bone marrow demonstrated significant neutrophilia in response to DSS. In the local inflammatory response, mice lacking SK1/S1P in either bone marrow or tissue exhibited decreased induction of cytokines and less activation of STAT3 (signal transducer and activator of transcription 3). Interestingly, we determined that extra-hematopoietic SK1 is necessary for the induction of cyclooxygenase 2 (COX2) in colon epithelium in response to DSS-induced colitis. Taken together our data suggest that hematopoietic-derived SK1/S1P regulates specific aspects of the systemic inflammatory response, while extra-hematopoietic SK1 in the colon epithelium is necessary for the autocrine induction of COX2 in DSS-induced colitis.

  2. Induction of hematopoietic and endothelial cell program orchestrated by ETS transcription factor ER71/ETV2.

    Science.gov (United States)

    Liu, Fang; Li, Daofeng; Yu, Yik Yeung Lawrence; Kang, Inyoung; Cha, Min-Ji; Kim, Ju Young; Park, Changwon; Watson, Dennis K; Wang, Ting; Choi, Kyunghee

    2015-05-01

    The ETS factor ETV2 (aka ER71) is essential for the generation of the blood and vascular system, as ETV2 deficiency leads to a complete block in blood and endothelial cell formation and embryonic lethality in the mouse. However, the ETV2-mediated gene regulatory network and signaling governing hematopoietic and endothelial cell development are poorly understood. Here, we map ETV2 global binding sites and carry out in vitro differentiation of embryonic stem cells, and germ line and conditional knockout mouse studies to uncover mechanisms involved in the hemangiogenic fate commitment from mesoderm. We show that ETV2 binds to enhancers that specify hematopoietic and endothelial cell lineages. We find that the hemangiogenic progenitor population in the developing embryo can be identified as FLK1(high)PDGFRα(-). Notably, these hemangiogenic progenitors are exclusively sensitive to ETV2-dependent FLK1 signaling. Importantly, ETV2 turns on other Ets genes, thereby establishing an ETS hierarchy. Consequently, the hematopoietic and endothelial cell program initiated by ETV2 is maintained partly by other ETS factors through an ETS switching mechanism. These findings highlight the critical role that transient ETV2 expression plays in the regulation of hematopoietic and endothelial cell lineage specification and stability. © 2015 The Authors.

  3. Flotillins are involved in the polarization of primitive and mature hematopoietic cells.

    Directory of Open Access Journals (Sweden)

    Lawrence Rajendran

    Full Text Available BACKGROUND: Migration of mature and immature leukocytes in response to chemokines is not only essential during inflammation and host defense, but also during development of the hematopoietic system. Many molecules implicated in migratory polarity show uniform cellular distribution under non-activated conditions, but acquire a polarized localization upon exposure to migratory cues. METHODOLOGY/PRINCIPAL FINDINGS: Here, we present evidence that raft-associated endocytic proteins (flotillins are pre-assembled in lymphoid, myeloid and primitive hematopoietic cells and accumulate in the uropod during migration. Furthermore, flotillins display a polarized distribution during immunological synapse formation. Employing the membrane lipid-order sensitive probe Laurdan, we show that flotillin accumulation in the immunological synapse is concomittant with membrane ordering in these regions. CONCLUSIONS: Together with the observation that flotillin polarization does not occur in other polarized cell types such as polarized epithelial cells, our results suggest a specific role for flotillins in hematopoietic cell polarization. Based on our results, we propose that in hematopoietic cells, flotillins provide intrinsic cues that govern segregation of certain microdomain-associated molecules during immune cell polarization.

  4. Cure for thalassemia major – from allogeneic hematopoietic stem cell transplantation to gene therapy

    Science.gov (United States)

    Srivastava, Alok; Shaji, Ramachandran V.

    2017-01-01

    Allogeneic hematopoietic stem cell transplantation has been well established for several decades as gene replacement therapy for patients with thalassemia major, and now offers very high rates of cure for patients who have access to this therapy. Outcomes have improved tremendously over the last decade, even in high-risk patients. The limited data available suggests that the long-term outcome is also excellent, with a >90% survival rate, but for the best results, hematopoietic stem cell transplantation should be offered early, before any end organ damage occurs. However, access to this therapy is limited in more than half the patients by the lack of suitable donors. Inadequate hematopoietic stem cell transplantation services and the high cost of therapy are other reasons for this limited access, particularly in those parts of the world which have a high prevalence of this condition. As a result, fewer than 10% of eligible patients are actually able to avail of this therapy. Other options for curative therapies are therefore needed. Recently, gene correction of autologous hematopoietic stem cells has been successfully established using lentiviral vectors, and several clinical trials have been initiated. A gene editing approach to correct the β-globin mutation or disrupt the BCL11A gene to increase fetal hemoglobin production has also been reported, and is expected to be introduced in clinical trials soon. Curative possibilities for the major hemoglobin disorders are expanding. Providing access to these therapies around the world will remain a challenge. PMID:27909215

  5. Hematopoietic stem cell origin of connective tissues.

    Science.gov (United States)

    Ogawa, Makio; Larue, Amanda C; Watson, Patricia M; Watson, Dennis K

    2010-07-01

    Connective tissue consists of "connective tissue proper," which is further divided into loose and dense (fibrous) connective tissues and "specialized connective tissues." Specialized connective tissues consist of blood, adipose tissue, cartilage, and bone. In both loose and dense connective tissues, the principal cellular element is fibroblasts. It has been generally believed that all cellular elements of connective tissue, including fibroblasts, adipocytes, chondrocytes, and bone cells, are generated solely by mesenchymal stem cells. Recently, a number of studies, including those from our laboratory based on transplantation of single hematopoietic stem cells, strongly suggested a hematopoietic stem cell origin of these adult mesenchymal tissues. This review summarizes the experimental evidence for this new paradigm and discusses its translational implications.

  6. Proteomic cornerstones of hematopoietic stem cell differentiation

    DEFF Research Database (Denmark)

    Klimmeck, Daniel; Hansson, Jenny; Raffel, Simon

    2012-01-01

    Regenerative tissues such as the skin epidermis, the intestinal mucosa or the hematopoietic system are organized in a hierarchical manner with stem cells building the top of this hierarchy. Somatic stem cells harbor the highest self-renewal activity and generate a series of multipotent progenitors...... related to immune defence mechanisms, centering around the RIG-I and type-1 interferon response systems, which are installed in multipotent progenitors but not evident in myeloid committed cells. This suggests that specific, and so far unrecognized, mechanisms protect these immature cells before...... they mature. In conclusion, this study indicates that the transition of hematopoietic stem/progenitors towards myeloid commitment is accompanied by a profound change in processing of cellular resources, adding novel insights into the molecular mechanisms at the interface between multipotency and lineage...

  7. Recent advances in hematopoietic stem cell biology

    DEFF Research Database (Denmark)

    Bonde, Jesper; Hess, David A; Nolta, Jan A

    2004-01-01

    PURPOSE OF REVIEW: Exciting advances have been made in the field of hematopoietic stem cell biology during the past year. This review summarizes recent progress in the identification, culture, and in vivo tracking of hematopoietic stem cells. RECENT FINDINGS: The roles of Wnt and Notch proteins...... in regulating stem cell renewal in the microenvironment, and how these molecules can be exploited in ex vivo stem cell culture, are reviewed. The importance of identification of stem cells using functional as well as phenotypic markers is discussed. The novel field of nanotechnology is then discussed...... in the context of stem cell tracking in vivo. This review concludes with a section on the unexpected potential of bone marrow-derived stem cells to contribute to the repair of damaged tissues. The contribution of cell fusion to explain the latter phenomenon is discussed. SUMMARY: Because of exciting discoveries...

  8. Emerging uses for pediatric hematopoietic stem cells.

    Science.gov (United States)

    Domen, Jos; Gandy, Kimberly; Dalal, Jignesh

    2012-04-01

    Many new therapies are emerging that use hematopoietic stem and progenitor cells. In this review, we focus on five promising emerging trends that are altering stem cell usage in pediatrics: (i) The use of hematopoietic stem cell (HSC) transplantation, autologous or allogeneic, in the treatment of autoimmune disorders is one. (ii) The use of cord blood transplantation in patients with inherited metabolic disorders such as Hurler syndrome shows great benefit, even more so than replacement enzyme therapy. (iii) Experience with the delivery of gene therapy through stem cells is increasing, redefining the potential and limitations of this therapy. (iv) It has recently been shown that human immunodeficiency virus (HIV) infection can be cured by the use of selected stem cells. (v) Finally, it has long been postulated that HSC-transplantation can be used to induce tolerance in solid-organ transplant recipients. A new approach to tolerance induction using myeloid progenitor cells will be described.

  9. DNA methylation profiling of hematopoietic stem cells.

    Science.gov (United States)

    Begtrup, Amber Hogart

    2014-01-01

    DNA methylation is a key epigenetic mark that is essential for properly functioning hematopoietic stem cells. Determining where functionally relevant DNA methylation marks exist in the genome is crucial to understanding the role that methylation plays in hematopoiesis. This chapter describes a method to profile DNA methylation by selectively enriching methylated DNA sequences that are bound in vitro by methyl-binding domain (MBD) proteins. The MBD-pulldown approach selects for DNA sequences that have the potential to be "read" by the endogenous machinery involved in epigenetic regulation. Furthermore, this approach is feasible with very small quantities of DNA, and is compatible with the use of any downstream high-throughput sequencing approach. This technique offers a reliable, simple, and powerful tool for exploration of the role of DNA methylation in hematopoietic stem cells.

  10. Inducing effects of macrophage stimulating protein on the expansion of early hematopoietic progenitor cells in liquid culture

    Institute of Scientific and Technical Information of China (English)

    MA Li-xia; HUANG Yan-hong; CHENG La-mei; LEI Jun; WANG Qi-ru

    2007-01-01

    Background Macrophage stimulating protein (MSP) is produced by human bone marrow endothelial cells. In this study,we sought to observe its effects on inducing the expansion of early hematopoietic progenitor cells which were cultured in a liquid culture system in the presence of the combination of stem cell factor (SCF), interleukin 3 (IL-3), interleukin 6 (IL-6), granulocyte macrophage-colony stimulating factor (GM-CSF), erythropoietin (EPO) (Cys) and MSP or of Cys and bone marrow endothelial cell conditioned medium (EC-CM).Methods Human bone marrow CD34+ cells were separated and cultured in a liquid culture system for 6 days.Granulocyte-macrophage colony forming unit (CFU-GM) and colony forming unit-granulocyte, erythrocyte, macrophage,megakaryocyte (CFU-GEMM) were employed to assay the effects of different treatment on the proliferation of hematopoeitic stem/progenitor cells. The nitroblue tetrazolium (NBT) reductive test and hoechest 33258 staining were employed to reflect the differentiation and apoptosis of the cells respectively.Results MSP inhibited the proliferation of CFU-GM and CFU-GEMM in semi-solid culture and the inhibitory effect on CFU-GEMM was stronger than on CFU-GM. MSP inhibited the differentiation of early hematopoietic progenitor cells induced by hematopoietic stimulators. Bone marrow (BM) CFU-GEMM was 2.3-fold or 1.7-fold increase or significantly decreased in either Cys+EC-CM, Cys+MSP or Cys compared with 0 hour control in liquid culture system after 6 days.Conclusion MSP, a hematopoietic inhibitor, inhibits the differentiation of early hematopoietic progenitor cells induced by hematopoietic stimulators and makes the early hematopoietic progenitor cells expand in a liquid culture system.

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    Lifescience Database Archive (English)

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    Lifescience Database Archive (English)

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  15. Placenta as a source of hematopoietic stem cells

    OpenAIRE

    Dzierzak, Elaine; Robin, Catherine

    2010-01-01

    The placenta is a large, highly vascularised hematopoietic tissue that functions during the embryonic and foetal development of eutherian mammals. Although recognised as the interface tissue important in the exchange of oxygen, nutrients and waste products between the foetus and mother, the placenta has increasingly become a focus of research concerning the ontogeny of the blood system. Here, we describe recent data showing the intrinsic hematopoietic potential and appearance of hematopoietic...

  16. Interleukin-1 regulates hematopoietic progenitor and stem cells in the midgestation mouse fetal liver

    OpenAIRE

    Orelio, Claudia; Peeters, Marian; Haak, Esther; van der Horn, Karin; Dzierzak, Elaine

    2009-01-01

    Hematopoietic progenitors are generated in the yolk sac and aorta-gonad-mesonephros region during early mouse development. At embryonic day 10.5 the first hematopoietic stem cells emerge in the aorta-gonad-mesonephros. Subsequently, hematopoietic stem cells and progenitors are found in the fetal liver. The fetal liver is a potent hematopoietic site, playing an important role in the expansion and differentiation of hematopoietic progenitors and hematopoietic stem cells. However, little is know...

  17. The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice

    Directory of Open Access Journals (Sweden)

    Qing-Shuo Zhang

    2015-07-01

    Full Text Available Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2−/− mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down-regulation of Egr1–p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes.

  18. The Sirt1 activator SRT3025 expands hematopoietic stem and progenitor cells and improves hematopoiesis in Fanconi anemia mice.

    Science.gov (United States)

    Zhang, Qing-Shuo; Deater, Matthew; Schubert, Kathryn; Marquez-Loza, Laura; Pelz, Carl; Sinclair, David A; Grompe, Markus

    2015-07-01

    Fanconi anemia is a genetic bone marrow failure syndrome. The current treatment options are suboptimal and do not prevent the eventual onset of aplastic anemia requiring bone marrow transplantation. We previously showed that resveratrol, an antioxidant and an activator of the protein deacetylase Sirt1, enhanced hematopoiesis in Fancd2 mutant mice and improved the impaired stem cell quiescence observed in this disease. Given that Sirt1 is important for the function of hematopoietic stem cells, we hypothesized that Sirt1 activation may improve hematopoiesis. Indeed, Fancd2(-/-) mice and wild-type mice treated with the selective Sirt1 activator SRT3025 had increased numbers of hematopoietic stem and progenitor cells, platelets and white blood cells. SRT3025 was also protective against acetaldehyde-induced hematopoietic damage. Unlike resveratrol, however, SRT3025 did not affect stem cell quiescence, suggesting distinct mechanisms of action. Conditional deletion of Sirt1 in hematopoietic cells did not abrogate the beneficial effects of SRT3025, indicating that the drug did not act by directly stimulating Sirt1 in stem cells, but must be acting indirectly via extra-hematopoietic effects. RNA-Seq transcriptome analysis revealed the down-regulation of Egr1-p21 expression, providing a potential mechanism for improved hematopoiesis. Overall, our data indicate that SRT3025 or related compounds may be beneficial in Fanconi anemia and other bone marrow failure syndromes.

  19. Hemorrhagic cystitis after hematopoietic stem cell trans-plantation: much progress and many remaining issues

    Institute of Scientific and Technical Information of China (English)

    Edmund K. Waller

    2007-01-01

    @@ The manuscript by Xu et al1 addresses an important question in the field of allogeneic hematopoietic progenitor cell transplantation (HPCT): how to identify those patients at risk for hemmoraghic cystitis. The authors performed a retrospective analysis of 250 patients undergoing allogeneic HPCT following myeloablative conditioning with busulfan and cyclophosphamide using a standard post-transplant immunoprophylaxis with cyclosporine, short-course methotrexate and mycophenylate.

  20. Microliter-bioreactor array with buoyancy-driven stirring for human hematopoietic stem cell culture

    OpenAIRE

    Luni, Camilla; Feldman, Hope C.; Pozzobon, Michela; De Coppi, Paolo; Meinhart, Carl D.; Elvassore, Nicola

    2010-01-01

    This work presents the development of an array of bioreactors where finely controlled stirring is provided at the microliter scale (100–300 μl). The microliter-bioreactor array is useful for performing protocol optimization in up to 96 parallel experiments of hematopoietic stem cell (HSC) cultures. Exploring a wide range of experimental conditions at the microliter scale minimizes cost and labor. Once the cell culture protocol is optimized, it can be applied to large-scale bioreactors for ste...

  1. Monitoring of WT1-specific cytotoxic T lymphocytes after allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Morita, Yuriko; Heike, Yuji; Kawakami, Mami; Miura, Osamu; Nakatsuka, Shin-Ichi; Ebisawa, Michiko; Mori, Shin-Ichiro; Tanosaki, Ryuji; Fukuda, Takahiro; Kim, Sung-Won; Tobinai, Kensei; Takaue, Yoichi

    2006-09-15

    Donor-derived cytotoxic T lymphocytes (CTL) that respond to tumor antigens emerge after hematopoietic stem cell transplantation (HSCT), particularly in association with the status of immune recovery. To analyze the frequency of CTL against PR1, PRAME and WT1 after HSCT, a tetramer-based analysis was performed in 97 samples taken from 35 patients (9 AML, 11 MDS, 2 CML, 4 ALL, 7 lymphoma and 2 renal cell carcinoma [RCC]) with the HLA-A02 phenotype. Regarding PR1, only 1 sample showed the presence of tetramer-positive cells (0.04%/lymphocyte). Similarly, in PRAME, only 10 of 97 samples were sporadically positive with low titers. For WT1, positive results were detected in 39 of 97 samples and 7 (2 CML, 1 ALL, 2 lymphoma and 2 RCC) patients clearly showed positive results more than once. On the basis of these results, we performed serial analyses of WT1-specific CTL during the clinical course in 2 patients with RCC, who underwent HSCT with a reduced-intensity regimen, to examine the precise correlation between the kinetics of CTL, the occurrence of GVHD and the observed clinical response. A higher positive rate for WT1-specific CTL and a correlation with the clinical response suggest that WT1 may be a useful antigen for a wider monitoring application.

  2. Consensus on the use of neutrophil-stimulating hematopoietic growth factors in clinical practice : An international viewpoint

    NARCIS (Netherlands)

    Rusthoven, JJ; deVries, EGE; Dale, DC; Piccart, M; Glaspy, J; Hamilton, A

    1997-01-01

    Hematopoietic growth factors (CSFs) are now available for use in patients with myelosuppression due to congenital, acquired and therapy-induced conditions. Variations in the use of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in differen

  3. Human Placenta Is a Potent Hematopoietic Niche Containing Hematopoietic Stem and Progenitor Cells throughout Development

    NARCIS (Netherlands)

    C. Robin (Catherine); K. Bollerot (Karine); S.C. Mendes (Sandra); E. Haak (Esther); M. Crisan (Mihaela); F. Cerisoli (Francesco); I. Lauw (Ivoune); P. Kaimakis (Polynikis); R.J.J. Jorna (Ruud); M. Vermeulen (Mark); M.H. Kayser (Manfred); R. van der Linden (Reinier); P. Imanirad (Parisa); M.M.A. Verstegen (Monique); H. Nawaz-Yousaf (Humaira); N. Papazian (Natalie); E.A.P. Steegers (Eric); T. Cupedo (Tom); E.A. Dzierzak (Elaine)

    2009-01-01

    textabstractHematopoietic stem cells (HSCs) are responsible for the life-long production of the blood system and are pivotal cells in hematologic transplantation therapies. During mouse and human development, the first HSCs are produced in the aorta-gonad-mesonephros region. Subsequent to this emerg

  4. Polycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms

    NARCIS (Netherlands)

    Radulovic, V.; de Haan, G.; Klauke, K.

    2013-01-01

    The equilibrium between self-renewal and differentiation of hematopoietic stem cells is regulated by epigenetic mechanisms. In particular, Polycomb-group (PcG) proteins have been shown to be involved in this process by repressing genes involved in cell-cycle regulation and differentiation. PcGs are

  5. Development of hematopoietic stem cell activity in the mouse embryo.

    NARCIS (Netherlands)

    A.M. Müller (Albrecht); A. Medvinsky; J. Strouboulis (John); F.G. Grosveld (Frank); E.A. Dzierzak (Elaine)

    1994-01-01

    textabstractThe precise time of appearance of the first hematopoietic stem cell activity in the developing mouse embryo is unknown. Recently the aorta-gonad-mesonephros region of the developing mouse embryo has been shown to possess hematopoietic colony-forming activity (CFU-S) in irradiated recipie

  6. Hematopoietic Stem Cell Transplantation in Patients with Beta Thalassemia Major

    Directory of Open Access Journals (Sweden)

    M. Akif Yesilipek

    2014-02-01

    Full Text Available Hemoglobinopathies include an enormous patient population in south part of Turkey. Allogeneic hematopoietic stem cell transplantation is only curative treatment in thalassemia. Optimal medical therapy is very important in the years before transplant to achieve a successful transplantation. In this study, the indications, risk factors, results and the situation related with hematopoietic stem cell transplantation in thalassemia in Turkey was reviewed.

  7. Allogeneic hematopoietic stem cell transplantation in children with aplastic anemia.

    Science.gov (United States)

    Xue, H-M; Xu, H-G; Huang, K; Guo, H-X; Li, Y; Zhou, D-H; Huang, S-L; Fang, J-P; Chen, C

    2015-05-18

    The aim of this study was to prospectively investigate the efficacy and safety of fully matched allogeneic hematopoietic stem cell transplants in children with severe aplastic anemia in China. A total of twenty patients with severe aplastic anemia were enrolled in our study. Thirteen cases underwent transplantation with fully human leukocyte antigen (HLA)-matched, granulocyte-colony stimulating factor (G-CSF)-primed bone marrow and peripheral blood stem cells (PBSCs) from matching sibling donors. One patient received fully HLA-matched bone marrow from an unrelated donor. Six patients received fully HLA-matched G-CSF-primed PBSCs from unrelated donors. The conditioning regimen included fludarabine, cyclophosphamide, and rabbit anti-thymocyte globulin. Graft-versus-host disease prophylaxis was conducted with cyclosporin A and short-course methotrexate. The median follow-up duration was 3.08 years (range, 0.83-8.41years). The median time of neutrophil recovery (>0.5 x 10(9)/L) was 14 days (range, 10-20 days), and the median time of platelet recovery (>20 x 10(9)/L) was 19 days (range, 14-31 days). The survival rate at the cutoff point of follow-up was 95.0% (19/20). Initial engraftment rate was 95% (19/20). Late graft failure (graft failures occurring 1 year or longer after transplantation) was observed in one patient. Only one patient developed Grade I acute graft-versus-host disease. Two cases suffered from Epstein- Barr virus (EBV)-associated post-transplant lymphoproliferative disorder and remitted after treatment with rituximab. One patient was diagnosed with hyperthyroidism 2.5 years after transplantation. Our study indicated that allogeneic hematopoietic stem cell transplantation is an effective and safe treatment for children with severe aplastic anemia in China.

  8. RESULTS OF HEMATOPOIETIC CELL TRANSPLANTATION IN PEDIATRIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    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.

  9. Allogeneic hematopoietic stem cell transplantation for chronic lymphocytic leukemia%慢性淋巴细胞白血病的造血干细胞移植治疗

    Institute of Scientific and Technical Information of China (English)

    杨申淼; 江倩; 许兰平

    2013-01-01

      慢性淋巴细胞白血病(CLL)存在很大的临床异质性。尽管免疫化疗方案的进步带来了显著的疗效,部分患者仍可在短期内发生疾病进展,或处于疾病难治耐药的状态。由于移植物抗CLL效应的存在,异基因造血干细胞移植的根治性意义获得肯定。年轻CLL患者如具有高危因素,包括:嘌呤类似物耐药或治疗后早期复发,以及具有17p(TP53位点)缺失和TP53突变,异基因造血干细胞移植是合理的治疗选择。减低强度的预处理方案有效降低了患者的治疗相关死亡率。%Chronic lymphocytic leukemia(CLL) is an indolent lymphoproliferative disorder with great clinical heterogeneity. The immunochemotherapeutic regimens have improved the outcome of majority of the patients. Nonetheless, in some patients, the disease progresses shortly after the immunochemotherapy, while in others, it becomes refractory and drug resistant. Allogeneic hematopoietic stem cell transplantation(allo-SCT) potentially cures CLL due to the graft versus CLL effect. It has been wildly accepted that allo-SCT is a good option for young CLL patients with high risk factors, including purine analogue resistance, early relapse after purine analogue-based treatment, and 17p deletion and TP53 mutation. Reduced-intensity conditioning regimens effectively decrease the treatment-related mortality.

  10. Tuberculosis in Hematopoietic Stem Cell Transplant Recipients

    OpenAIRE

    Ramos, Jéssica Fernandes; Batista, Marjorie Vieira; Costa, Silvia Figueiredo

    2013-01-01

    Literature on tuberculosis (TB) occurring in recipients of Hematopoietic Stem Cell Transplant (HSCT) is scanty even in countries where TB is common. Most reports of TB in HSCT patients were from ASIA, in fact the TB incidence ranging from 0.0014 (USA) to 16% (Pakistan). There are few reports of TB diagnosis during the first two weeks after HSCT; most of cases described in the literature occurred after 90 days of HSCT, and the lung was the organ most involved. The mortality ranged from 0 to 50...

  11. Hematopoietic potential cells in skeletal muscle

    Institute of Scientific and Technical Information of China (English)

    Atsushi Asakura

    2007-01-01

    @@ During mouse embryogenesis,the formation of primi-tive hematopoiesis begins in the yolk sac on embryonic day 7.5(E7.5).Thereafter,definitive hematopoietic stem cell(HSC)activity is first detectable in the aorta-gonad-mesonephros(AGM)region on E10,followed by fetal liver and yolk sac.Subsequently,the fetal liver by E12 becomes the main tissue for definitive hematopoiesis.At a later time,HSC population in the fetal liver migrates to the bone marrow,which becomes the maior site of he-matopoiesis throughout normal adult life[1].

  12. Hospital Length of Stay in the First 100 Days After Allogeneic Hematopoietic Cell Transplantation for Acute Leukemia in Remission: Comparison among Alternative Graft Sources

    Science.gov (United States)

    Ballen, Karen K.; Joffe, Steven; Brazauskas, Ruta; Wang, Zhiwe; Aljurf, Mahmoud D.; Akpek, Görgün; Dandoy, Christopher; Frangoul, Haydar A.; Freytes, César O.; Khera, Nandita; Lazarus, Hillard M.; LeMaistre, Charles F.; Mehta, Paulette; Parsons, Susan K.; Szwajcer, David; Ustun, Celalettin; Wood, William A.; Majhail, Navneet S.

    2014-01-01

    Several studies have shown comparable survival outcomes among different graft sources, but the relative resource needs of hematopoietic cell transplantation (HCT) by graft source have not been well studied. We compared total hospital length of stay in the first 100 days after HCT in 1577 patients with acute leukemia in remission receiving umbilical cord blood (UCB), matched unrelated donor (MUD) or mismatched unrelated donors (MMUD) HCT from 2008–2011. To ensure a relatively homogenous study population, the analysis was limited to patients with acute myeloid leukemia and acute lymphoblastic leukemia in first or second complete remission who received HCT in the United States. To account for early deaths, we compared the number of days alive and out of hospital in the first 100 days. For children receiving myeloablative conditioning, median days alive and out of hospital in the first 100 days were 50, 54 and 60 days for single UCB, double UCB and MUD bone marrow (BM) recipients, respectively. In multivariate analysis, use of UCB was significantly associated with fewer days alive and out of the hospital compared to MUD BM. For adults receiving HCT using myeloablative conditioning, median days alive and out of hospital in first 100 days were 52 for single UCB, 55 for double UCB, 69 for MUD BM, 75 for MUD peripheral blood stem cells (PBSC), 63 for MMUD BM and 67 days MMUD PBSC recipients. In multivariate analysis, UCB and MMUD BM recipients had fewer days alive and out of the hospital compared to other graft sources. For adults receiving a reduced intensity preparative regimen, median days alive and out of hospital during the first 100 days for single UCB, double UCB, MUD PBSC and MMUD PBSC were 65, 63, 79, and 79, respectively. Similar to the other two groups, use of UCB was associated with a fewer days alive and out of the hospital. In conclusion, length of stay in the first 100 days varies by graft source and is greater for UCB HCT recipients. These data provide

  13. Autologous and allogeneic hematopoietic stem cell transplantation in follicular lymphoma.

    Science.gov (United States)

    Bhatt, V R; Armitage, J O

    2016-01-01

    High-dose chemotherapy and autologous stem cell transplantation (ASCT) improve survival in follicular lymphoma; however, relapse remains the most common cause of death. The lower risk of relapse with allogeneic SCT (alloSCT) is offset by a high transplant-related mortality (TRM). English articles indexed in the MEDLINE database were reviewed to discuss the role of graft purging, rituximab maintenance after ASCT, reduced-intensity conditioning (RIC) alloSCT, T-cell depletion, donor lymphocyte infusion (DLI) and alternate donor sources. Optimal salvage consolidation strategy may utilize ASCT following non-total body irradiation-based conditioning regimen in second remission. Rituximab maintenance after ASCT may improve molecular remission but is not yet shown to improve overall survival. RIC alloSCT permits its use in older and less-fit patients. Studies with T-cell depleted graft failed to reduce TRM despite a decline in graft-versus-host disease; however, these studies did demonstrate a therapeutic role of DLI in post-transplant relapses. In recent years, haploidentical and umbilical cord blood donors have emerged as alternative donor sources, with outcomes comparable to matched unrelated donor SCT. In the future, incorporation of novel therapeutic agents, improved risk-adapted treatment strategies, and advancement of transplant techniques may provide a better chance of survival.

  14. The Hematopoietic Stem Cell Therapy for Exploration of Space

    Science.gov (United States)

    Ohi, S.

    Departments of Biochemistry &Molecular Biology, Genetics &Human Genetics, Pediatrics &Child Long-duration space missions require countermeasures against severe/invasive disorders in astronauts that are caused by space environments, such as hematological/cardiac abnormalities, bone/muscle losses, immunodeficiency, neurological disorders, and cancer. Some, if not all, of these disorders may be amenable to hematopoietic stem cell therapy and gene therapy. Growing evidence indicates that hematopoietic stem cells (HSCs) possess extraordinary plasticity to differentiate not only to all types of blood cells but also to various tissues, including bone, muscle, skin, liver and neuronal cells. Therefore, our working hypothesis is that the hematopoietic stem cell-based therapy, herein called as the hematopoietic stem cell therapy (HSCT), might provide countermeasure/prevention for hematological abnormalities, bone and muscle losses in space, thereby maintaining astronauts' homeostasis. Our expertise lies in recombinant adeno-associated virus (rAAV)-mediated gene therapy for the hemoglobinopathies, -thalassemia and sickle cell disease (Ohi S, Kim BC, J Pharm Sci 85: 274-281, 1996; Ohi S, et al. Grav Space Biol Bull 14: 43, 2000). As the requisite steps in this protocol, we established procedures for purification of HSCs from both mouse and human bone marrow in 1 G. Furthermore, we developed an easily harvestable, long-term liquid suspension culture system, which lasts more than one year, for growing/expanding HSCs without stromal cells. Human globin cDNAs/gene were efficiently expressed from the rAAVs in the mouse HSCs in culture. Additionally, the NASA Rotating Wall Vessel (RWV) culture system is being optimized for the HSC growth/expansion. Thus, using these technologies, the above hypothesis is being investigated by the ground-based experiments as follows: 1) -thalassemic mice (C57BL/6-Hbbth/Hbbth, Hbd-minor) are transplanted with normal isologous HSCs to correct the

  15. Hormone Use for Therapeutic Amenorrhea and Contraception During Hematopoietic Cell Transplantation.

    Science.gov (United States)

    Chang, Katherine; Merideth, Melissa A; Stratton, Pamela

    2015-10-01

    There is a growing population of women who have or will undergo hematopoietic stem cell transplant for a variety of malignant and benign conditions. Gynecologists play an important role in addressing the gynecologic and reproductive health concerns for these women throughout the transplant process. As women undergo cell transplantation, they should avoid becoming pregnant and are at risk of uterine bleeding. Thus, counseling about and implementing hormonal treatments such as gonadotropin-releasing hormone agonists, combined hormonal contraceptives, and progestin-only methods help to achieve therapeutic amenorrhea and can serve as contraception during the peritransplant period. In this commentary, we summarize the timing, risks, and benefits of the hormonal options just before, during, and for the year after hematopoietic stem cell transplantation.

  16. Blockage of caspase-1 activation ameliorates bone marrow inflammation in mice after hematopoietic stem cell transplantation.

    Science.gov (United States)

    Qiao, Jianlin; Wu, Jinyan; Li, Yuanyuan; Xia, Yuan; Chu, Peipei; Qi, Kunming; Yan, Zhiling; Yao, Haina; Liu, Yun; Xu, Kailin; Zeng, Lingyu

    2016-01-01

    Conditioning regimens before hematopoietic stem cell transplantation (HSCT), cause damage to bone marrow and inflammation. Whether inflammasomes are involved in bone marrow inflammation remains unclear. The study aims to evaluate the role of inflammasomes in bone marrow inflammation after HSCT. On days 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of bone marrow inflammation, pro-inflammatory cytokines secretion, inflammasomes expression and caspase-1 activation. Bone marrow inflammation with neutrophils and macrophages infiltration was observed after HSCT. Secretion of IL-1β, IL-18, TNF-α and IL-6 were elevated, with increased caspase-1 activation and inflammasomes expression. Caspase-1 inhibitor administration after HSCT significantly reduced infiltration of neutrophils and macrophages into bone marrow and increased the numbers of megakaryocytes and platelets. In conclusion, inflammasomes activation is involved in bone marrow inflammation after HSCT and caspase-1 inhibition attenuates bone marrow inflammation and promoted hematopoietic reconstitution, suggesting targeting caspase-1 might be beneficial for improving HSCT outcomes.

  17. Roles of p53 in Various Biological Aspects of Hematopoietic Stem Cells

    Directory of Open Access Journals (Sweden)

    Takenobu Nii

    2012-01-01

    Full Text Available Hematopoietic stem cells (HSCs have the capacity to self-renew as well as to differentiate into all blood cell types, and they can reconstitute hematopoiesis in recipients with bone marrow ablation. In addition, transplantation therapy using HSCs is widely performed for the treatment of various incurable diseases such as hematopoietic malignancies and congenital immunodeficiency disorders. For the safe and successful transplantation of HSCs, their genetic and epigenetic integrities need to be maintained properly. Therefore, understanding the molecular mechanisms that respond to various cellular stresses in HSCs is important. The tumor suppressor protein, p53, has been shown to play critical roles in maintenance of “cell integrity” under stress conditions by controlling its target genes that regulate cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. In this paper, we summarize recent reports that describe various biological functions of HSCs and discuss the roles of p53 associated with them.

  18. Rare complications after second hematopoietic stem cell transplantation for thalassemia major.

    Science.gov (United States)

    Yanir, Asaf; Yatsiv, Ido; Braun, Jacques; Zilkha, Amir; Brooks, Rebecca; Bouhanna, Dalia; Weintraub, Michael; Stepensky, Polina

    2012-07-01

    We describe an 11-year-old girl with thalassemia major who underwent a second hematopoietic stem cell transplantation from a matched related donor and who subsequently developed posttransplant lymphoproliferative disorder complicated by severe ascending paralysis resembling Guillian-Barré syndrome. Six months later she developed a massive pericardial effusion. She received a multimodal treatment for these complications and currently, 18 months after transplantation, she is in a good clinical condition, is transfusion independent, with no evidence of graft-versus-host disease and off all treatment. This case highlights the dilemma surrounding second hematopoietic stem cell transplantations in hemoglobinopathies and the need for a careful, well informed, and collaborative decision-making process by patients, families, and medical professionals.

  19. Sleeping Beauty-Mediated Drug Resistance Gene Transfer in Human Hematopoietic Progenitor Cells

    Science.gov (United States)

    Hyland, Kendra A.; Olson, Erik R.; McIvor, R. Scott

    2015-01-01

    The Sleeping Beauty (SB) transposon system can insert sequences into mammalian chromosomes, supporting long-term expression of both reporter and therapeutic genes. Hematopoietic progenitor cells (HPCs) are an ideal therapeutic gene transfer target as they are used in therapy for a variety of hematologic and metabolic conditions. As successful SB-mediated gene transfer into human CD34+ HPCs has been reported by several laboratories, we sought to extend these studies to the introduction of a therapeutic gene conferring resistance to methotrexate (MTX), potentially providing a chemoprotective effect after engraftment. SB-mediated transposition of hematopoietic progenitors, using a transposon encoding an L22Y variant dihydrofolate reductase fused to green fluorescent protein, conferred resistance to methotrexate and dipyridamole, a nucleoside transport inhibitor that tightens MTX selection conditions, as assessed by in vitro hematopoietic colony formation. Transposition of individual transgenes was confirmed by sequence analysis of transposon–chromosome junctions recovered by linear amplification-mediated PCR. These studies demonstrate the potential of SB-mediated transposition of HPCs for expression of drug resistance genes for selective and chemoprotective applications. PMID:26176276

  20. Lentiviral gene therapy of murine hematopoietic stem cells ameliorates the Pompe disease phenotype.

    Science.gov (United States)

    van Til, Niek P; Stok, Merel; Aerts Kaya, Fatima S F; de Waard, Monique C; Farahbakhshian, Elnaz; Visser, Trudi P; Kroos, Marian A; Jacobs, Edwin H; Willart, Monique A; van der Wegen, Pascal; Scholte, Bob J; Lambrecht, Bart N; Duncker, Dirk J; van der Ploeg, Ans T; Reuser, Arnold J J; Verstegen, Monique M; Wagemaker, Gerard

    2010-07-01

    Pompe disease (acid alpha-glucosidase deficiency) is a lysosomal glycogen storage disorder characterized in its most severe early-onset form by rapidly progressive muscle weakness and mortality within the first year of life due to cardiac and respiratory failure. Enzyme replacement therapy prolongs the life of affected infants and supports the condition of older children and adults but entails lifelong treatment and can be counteracted by immune responses to the recombinant enzyme. We have explored the potential of lentiviral vector-mediated expression of human acid alpha-glucosidase in hematopoietic stem cells (HSCs) in a Pompe mouse model. After mild conditioning, transplantation of genetically engineered HSCs resulted in stable chimerism of approximately 35% hematopoietic cells that overexpress acid alpha-glucosidase and in major clearance of glycogen in heart, diaphragm, spleen, and liver. Cardiac remodeling was reversed, and respiratory function, skeletal muscle strength, and motor performance improved. Overexpression of acid alpha-glucosidase did not affect overall hematopoietic cell function and led to immune tolerance as shown by challenge with the human recombinant protein. On the basis of the prominent and sustained therapeutic efficacy without adverse events in mice we conclude that ex vivo HSC gene therapy is a treatment option worthwhile to pursue.

  1. Functions of TET Proteins in Hematopoietic Transformation.

    Science.gov (United States)

    Han, Jae-A; An, Jungeun; Ko, Myunggon

    2015-11-01

    DNA methylation is a well-characterized epigenetic modification that plays central roles in mammalian development, genomic imprinting, X-chromosome inactivation and silencing of retrotransposon elements. Aberrant DNA methylation pattern is a characteristic feature of cancers and associated with abnormal expression of oncogenes, tumor suppressor genes or repair genes. Ten-eleven-translocation (TET) proteins are recently characterized dioxygenases that catalyze progressive oxidation of 5-methylcytosine to produce 5-hydroxymethylcytosine and further oxidized derivatives. These oxidized methylcytosines not only potentiate DNA demethylation but also behave as independent epigenetic modifications per se. The expression or activity of TET proteins and DNA hydroxymethylation are highly dysregulated in a wide range of cancers including hematologic and non-hematologic malignancies, and accumulating evidence points TET proteins as a novel tumor suppressor in cancers. Here we review DNA demethylation-dependent and -independent functions of TET proteins. We also describe diverse TET loss-of-function mutations that are recurrently found in myeloid and lymphoid malignancies and their potential roles in hematopoietic transformation. We discuss consequences of the deficiency of individual Tet genes and potential compensation between different Tet members in mice. Possible mechanisms underlying facilitated oncogenic transformation of TET-deficient hematopoietic cells are also described. Lastly, we address non-mutational mechanisms that lead to suppression or inactivation of TET proteins in cancers. Strategies to restore normal 5mC oxidation status in cancers by targeting TET proteins may provide new avenues to expedite the development of promising anti-cancer agents.

  2. Epigenetic regulation of hematopoietic stem cell aging

    Energy Technology Data Exchange (ETDEWEB)

    Beerman, Isabel, E-mail: isabel.beerman@childrens.harvard.edu [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States); Rossi, Derrick J. [Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138 (United States); Department of Pediatrics, Harvard Medical School, Boston, MA 02115 (United States); Program in Cellular and Molecular Medicine, Division of Hematology/Oncology, Boston Children' s Hospital, MA 02116 (United States)

    2014-12-10

    Aging is invariably associated with alterations of the hematopoietic stem cell (HSC) compartment, including loss of functional capacity, altered clonal composition, and changes in lineage contribution. Although accumulation of DNA damage occurs during HSC aging, it is unlikely such consistent aging phenotypes could be solely attributed to changes in DNA integrity. Another mechanism by which heritable traits could contribute to the changes in the functional potential of aged HSCs is through alterations in the epigenetic landscape of adult stem cells. Indeed, recent studies on hematopoietic stem cells have suggested that altered epigenetic profiles are associated with HSC aging and play a key role in modulating the functional potential of HSCs at different stages during ontogeny. Even small changes of the epigenetic landscape can lead to robustly altered expression patterns, either directly by loss of regulatory control or through indirect, additive effects, ultimately leading to transcriptional changes of the stem cells. Potential drivers of such changes in the epigenetic landscape of aged HSCs include proliferative history, DNA damage, and deregulation of key epigenetic enzymes and complexes. This review will focus largely on the two most characterized epigenetic marks – DNA methylation and histone modifications – but will also discuss the potential role of non-coding RNAs in regulating HSC function during aging.

  3. Impact of Pretransplantation (18)F-fluorodeoxy Glucose-Positron Emission Tomography Status on Outcomes after Allogeneic Hematopoietic Cell Transplantation for Non-Hodgkin Lymphoma.

    Science.gov (United States)

    Bachanova, Veronika; Burns, Linda J; Ahn, Kwang Woo; Laport, Ginna G; Akpek, Görgün; Kharfan-Dabaja, Mohamed A; Nishihori, Taiga; Agura, Edward; Armand, Philippe; Jaglowski, Samantha M; Cairo, Mitchell S; Cashen, Amanda F; Cohen, Jonathon B; D'Souza, Anita; Freytes, César O; Gale, Robert Peter; Ganguly, Siddhartha; Ghosh, Nilanjan; Holmberg, Leona A; Inwards, David J; Kanate, Abraham S; Lazarus, Hillard M; Malone, Adriana K; Munker, Reinhold; Mussetti, Alberto; Norkin, Maxim; Prestidge, Tim D; Rowe, Jacob M; Satwani, Prakash; Siddiqi, Tanya; Stiff, Patrick J; William, Basem M; Wirk, Baldeep; Maloney, David G; Smith, Sonali M; Sureda, Anna M; Carreras, Jeanette; Hamadani, Mehdi

    2015-09-01

    Assessment with (18)F-fluorodeoxy glucose (FDG)-positron emission tomography (PET) before hematopoietic cell transplantation (HCT) for lymphoma may be prognostic for outcomes. Patients with chemotherapy-sensitive non-Hodgkin lymphoma (NHL) undergoing allogeneic HCT reported to the Center of International Blood and Marrow Transplantation Registry between 2007 and 2012 were included. Pre-HCT PET status (positive versus negative) was determined by the reporting transplantation centers. We analyzed 336 patients; median age was 55 years and 60% were males. Follicular lymphoma (n = 104) was more common than large cell (n = 85), mantle cell (n = 69), and mature natural killer or T cell lymphoma (n = 78); two thirds of the cohort received reduced-intensity conditioning; one half had unrelated donor grafts. Patients underwent PET scanning a median of 1 month (range, .07 to 2.83 months) before HCT; 159 were PET positive and 177 were PET negative. At 3 years, relapse/progression, progression-free survival (PFS), and overall survival (OS) in PET-positive versus PET-negative groups were 40% versus 26%; P = .007; 43% versus 47%; P = .47; and 58% versus 60%; P = .73, respectively. On multivariate analysis, a positive pretransplantation PET was associated with an increased risk of relapse/progression (risk ratio [RR], 1.86; P = .001) but was not associated with increased mortality (RR, 1.29, 95% confidence interval [CI], .96 to 1.7; P = .08), therapy failure (RR, 1.32; 95% CI, .95 to 1.84; P = .10), or nonrelapse mortality (RR, .75; 95% CI, .48 to 1.18; P = .22). PET status conferred no influence on graft-versus-host disease. A positive PET scan before HCT is associated with increased relapse risk but should not be interpreted as a barrier to a successful allograft. PET status does not appear to predict survival after allogeneic HCT for NHL. Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  4. FIP200 is required for the cell-autonomous maintenance of fetal hematopoietic stem cells.

    Science.gov (United States)

    Liu, Fei; Lee, Jae Y; Wei, Huijun; Tanabe, Osamu; Engel, James D; Morrison, Sean J; Guan, Jun-Lin

    2010-12-02

    Little is known about whether autophagic mechanisms are active in hematopoietic stem cells (HSCs) or how they are regulated. FIP200 (200-kDa FAK-family interacting protein) plays important roles in mammalian autophagy and other cellular functions, but its role in hematopoietic cells has not been examined. Here we show that conditional deletion of FIP200 in hematopoietic cells leads to perinatal lethality and severe anemia. FIP200 was cell-autonomously required for the maintenance and function of fetal HSCs. FIP200-deficient HSC were unable to reconstitute lethally irradiated recipients. FIP200 ablation did not result in increased HSC apoptosis, but it did increase the rate of HSC proliferation. Consistent with an essential role for FIP200 in autophagy, FIP200-null fetal HSCs exhibited both increased mitochondrial mass and reactive oxygen species. These data identify FIP200 as a key intrinsic regulator of fetal HSCs and implicate a potential role for autophagy in the maintenance of fetal hematopoiesis and HSCs.

  5. Low levels of allogeneic but not syngeneic hematopoietic chimerism reverse autoimmune insulitis in prediabetic NOD mice.

    Science.gov (United States)

    Kaminitz, Ayelet; Mizrahi, Keren; Yaniv, Isaac; Farkas, Daniel L; Stein, Jerry; Askenasy, Nadir

    2009-09-01

    The relative efficiencies of allogeneic and syngeneic bone marrow transplantation and the threshold levels of donor chimerism required to control autoimmune insulitis were evaluated in prediabetic NOD mice. Male and female NOD mice were conditioned by radiation and grafted with bone marrow cells from allogeneic and syngeneic sex-mismatched donors. Establishment of full allogeneic chimerism in peripheral blood reversed insulitis and restored glucose tolerance despite persistence of residual host immune cells. By contrast, sublethal total body irradiation (with or without syngeneic transplant) reduced the incidence and delayed the onset of diabetes. The latter pattern was also seen in mice that rejected the bone marrow allografts. Low levels of stable allogeneic hematopoietic chimerism (>1%) were sufficient to prevent the evolution of diabetes following allogeneic transplantation. The data indicate that immunomodulation attained at low levels of allogeneic, but not syngeneic, hematopoietic chimerism is effective in resolution of islet inflammation at even relatively late stages in the evolution of the prediabetic state in a preclinical model. However, our data question the efficacy and rationale behind syngeneic (autologous-like) immuno-hematopoietic reconstitution in type 1 diabetes.

  6. Effect of radiation dose-rate on hematopoietic cell engraftment in adult zebrafish.

    Directory of Open Access Journals (Sweden)

    Tiffany J Glass

    Full Text Available Although exceptionally high radiation dose-rates are currently attaining clinical feasibility, there have been relatively few studies reporting the biological consequences of these dose-rates in hematopoietic cell transplant (HCT. In zebrafish models of HCT, preconditioning before transplant is typically achieved through radiation alone. We report the comparison of outcomes in adult zebrafish irradiated with 20 Gy at either 25 or 800 cGy/min in the context of experimental HCT. In non-transplanted irradiated fish we observed no substantial differences between dose-rate groups as assessed by fish mortality, cell death in the kidney, endogenous hematopoietic reconstitution, or gene expression levels of p53 and ddb2 (damage-specific DNA binding protein 2 in the kidney. However, following HCT, recipients conditioned with the higher dose rate showed significantly improved donor-derived engraftment at 9 days post transplant (p ≤ 0.0001, and improved engraftment persisted at 31 days post transplant. Analysis for sdf-1a expression, as well as transplant of hematopoietic cells from cxcr4b -/- zebrafish, (odysseus, cumulatively suggest that the sdf-1a/cxcr4b axis is not required of donor-derived cells for the observed dose-rate effect on engraftment. Overall, the adult zebrafish model of HCT indicates that exceptionally high radiation dose-rates can impact HCT outcome, and offers a new system for radiobiological and mechanistic interrogation of this phenomenon. Key words: Radiation dose rate, Total Marrow Irradiation (TMI, Total body irradiation (TBI, SDF-1, Zebrafish, hematopoietic cell transplant.

  7. BAF180 regulates cellular senescence and hematopoietic stem cell homeostasis through p21.

    Science.gov (United States)

    Lee, Hyemin; Dai, Fangyan; Zhuang, Li; Xiao, Zhen-Dong; Kim, Jongchan; Zhang, Yilei; Ma, Li; You, M James; Wang, Zhong; Gan, Boyi

    2016-04-12

    BAF180 (also called PBRM1), a subunit of the SWI/SNF complex, plays critical roles in the regulation of chromatin remodeling and gene transcription, and is frequently mutated in several human cancers. However, the role of mammalian BAF180 in tumor suppression and tissue maintenance in vivo remains largely unknown. Here, using a conditional somatic knockout approach, we explored the cellular and organismal functions of BAF180 in mouse. BAF180 deletion in primary mouse embryonic fibroblasts (MEFs) triggers profound cell cycle arrest, premature cellular senescence, without affecting DNA damage response or chromosomal integrity. While somatic deletion of BAF180 in adult mice does not provoke tumor development, BAF180 deficient mice exhibit defects in hematopoietic system characterized by progressive reduction of hematopoietic stem cells (HSCs), defective long-term repopulating potential, and hematopoietic lineage developmental aberrations. BAF180 deletion results in elevated p21 expression in both MEFs and HSCs. Mechanistically, we showed that BAF180 binds to p21 promoter, and BAF180 deletion enhances the binding of modified histones associated with transcriptional activation on p21 promoter. Deletion of p21 rescues cell cycle arrest and premature senescence in BAF180 deficient MEFs, and partially rescues hematopoietic defects in BAF180 deficient mice. Together, our study identifies BAF180 as a critical regulator of cellular senescence and HSC homeostasis, which is at least partially regulated through BAF180-mediated suppression of p21 expression. Our results also suggest that senescence triggered by BAF180 inactivation may serve as a failsafe mechanism to restrain BAF180 deficiency-associated tumor development, providing a conceptual framework to further understand BAF180 function in tumor biology.

  8. Epo and non-hematopoietic cells: what do we know?

    Science.gov (United States)

    Ogunshola, Omolara O; Bogdanova, Anna Yu

    2013-01-01

    The hematopoietic growth factor erythropoietin (Epo) circulates in plasma and controls the oxygen carrying capacity of the blood (Fisher. Exp Biol Med (Maywood) 228:1-14, 2003). Epo is produced primarily in the adult kidney and fetal liver and was originally believed to play a role restricted to stimulation of early erythroid precursor proliferation, inhibition of apoptosis, and differentiation of the erythroid lineage. Early studies showed that mice with targeted deletion of Epo or the Epo receptor (EpoR) show impaired erythropoiesis, lack mature erythrocytes, and die in utero around embryonic day 13.5 (Wu et al. Cell 83:59-67, 1995; Lin et al. Genes Dev. 10:154-164, 1996). These animals also exhibited heart defects, abnormal vascular development as well as increased apoptosis in the brain suggesting additional functions for Epo signaling in normal development of the central nervous system and heart. Now, in addition to its well-known role in erythropoiesis, a diverse array of cells have been identified that produce Epo and/or express the Epo-R including endothelial cells, smooth muscle cells, and cells of the central nervous system (Masuda et al. J Biol Chem. 269:19488-19493, 1994; Marti et al. Eur J Neurosci. 8:666-676, 1996; Bernaudin et al. J Cereb Blood Flow Metab. 19:643-651, 1999; Li et al. Neurochem Res. 32:2132-2141, 2007). Endogenously produced Epo and/or expression of the EpoR gives rise to autocrine and paracrine signaling in different organs particularly during hypoxia, toxicity, and injury conditions. Epo has been shown to regulate a variety of cell functions such as calcium flux (Korbel et al. J Comp Physiol B. 174:121-128, 2004) neurotransmitter synthesis and cell survival (Velly et al. Pharmacol Ther. 128:445-459, 2010; Vogel et al. Blood. 102:2278-2284, 2003). Furthermore Epo has neurotrophic effects (Grimm et al. Nat Med. 8:718-724, 2002; Junk et al. Proc Natl Acad Sci U S A. 99:10659-10664, 2002), can induce an angiogenic phenotype in cultured

  9. Recent advances in hematopoietic stem cell transplantation.

    Science.gov (United States)

    Norkin, Maxim; Wingard, John R

    2017-01-01

    Hematopoietic cell transplantation (HCT), once used as a last-resort therapy, is now considered a lifesaving procedure for thousands of patients with life-threatening diseases worldwide and is frequently used early in the course of treatment for diseases destined to be uncontrollable by non-HCT therapies. Incremental advances leading to reduction of post-transplant morbidity and mortality by better control of graft versus host disease (GVHD), infections, and regimen-related toxicities, coupled with greater donor options, not only significantly increased the utilization and success of this procedure but also allowed many of these patients to enjoy healthy and productive lives after HCT. Emerging concepts in the field are now focused on the expansion of available donor options, further reduction of transplant-related toxicity, and decrease in post-transplant relapse.

  10. The Neuropsychiatry of Hematopoietic Stem Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Mitchell R. Levy

    2006-06-01

    Full Text Available BACKGROUND AND OBJECTIVES: Regimens incorporating hematopoietic stem cell transplantation (HSCT have become widely utilized in disease treatments, particularly for cancer. These complex treatment programs also expose patients to central nervous system (CNS toxicities from chemotherapy, irradiation, infection, metabolic effects and immunosuppression. METHODS: Relevant recent medical literature from Medline and bibliographies in pertinent publications are reviewed with a focus on those cases and studies pertaining to neuropsychiatric effects of HSCT. RESULTS: High rates of neuropsychiatric sequelae occur on a continuum from acute to chronic. Adverse outcomes include focal CNS deficits and severe global manifestations such as seizures, encephalopathy and delirium. More graduated effects on cognition, energy and mood are frequently seen, impacting patient function. CONCLUSIONS: Additional research on neuropsychiatric outcomes and treatment interventions is needed in the HSCT setting. Risks for neuropsychiatric deficits should be part of an ongoing informed consent discussion among treating physicians, patients and families.

  11. Interleukin-1 regulates hematopoietic progenitor and stem cells in the midgestation mouse fetal liver

    Science.gov (United States)

    Orelio, Claudia; Peeters, Marian; Haak, Esther; van der Horn, Karin; Dzierzak, Elaine

    2009-01-01

    Background Hematopoietic progenitors are generated in the yolk sac and aorta-gonad-mesonephros region during early mouse development. At embryonic day 10.5 the first hematopoietic stem cells emerge in the aorta-gonad-mesonephros. Subsequently, hematopoietic stem cells and progenitors are found in the fetal liver. The fetal liver is a potent hematopoietic site, playing an important role in the expansion and differentiation of hematopoietic progenitors and hematopoietic stem cells. However, little is known concerning the regulation of fetal liver hematopoietic stem cells. In particular, the role of cytokines such as interleukin-1 in the regulation of hematopoietic stem cells in the embryo has been largely unexplored. Recently, we observed that the adult pro-inflammatory cytokine interleukin-1 is involved in regulating aorta-gonad-mesonephros hematopoietic progenitor and hematopoietic stem cell activity. Therefore, we set out to investigate whether interleukin-1 also plays a role in regulating fetal liver progenitor cells and hematopoietic stem cells. Design and Methods We examined the interleukin-1 ligand and receptor expression pattern in the fetal liver. The effects of interleukin-1 on hematopoietic progenitor cells and hematopoietic stem cells were studied by FACS and transplantation analyses of fetal liver explants, and in vivo effects on hematopoietic stem cell and progenitors were studied in Il1r1−/− embryos. Results We show that fetal liver hematopoietic progenitor cells express the IL-1RI and that interleukin-1 increases fetal liver hematopoiesis, progenitor cell activity and promotes hematopoietic cell survival. Moreover, we show that in Il1r1−/− embryos, hematopoietic stem cell activity is impaired and myeloid progenitor activity is increased. Conclusions The IL-1 ligand and receptor are expressed in the midgestation liver and act in the physiological regulation of fetal liver hematopoietic progenitor cells and hematopoietic stem cells. PMID

  12. Gs signaling in osteoblasts and hematopoietic stem cells.

    Science.gov (United States)

    Kronenberg, Henry M

    2010-03-01

    The heterotrimeric G protein Gs is a major mediator of the actions of several G protein-coupled receptors that target cells of the osteoblast lineage. For this reason, we generated chimeric mice with normal host cells and cells derived from embryonic stem cells missing the gene encoding the alpha subunit of Gs. While the mutant cells contributed to cortical osteoblasts and to hematopoietic cells in the liver, the marrow space contained few if any osteoblasts or hematopoietic cells missing Gs. Subsequent studies using the Cre-lox approach to delete Gsalpha from early cells of the osteoblast lineage and from hematopoietic stem cells were performed. These studies demonstrated the crucial roles of Gsalpha in osteoblastic cells in regulating the differentiation of osteoblasts and in supporting B-cell development as well as the essential role for Gsalpha in hematopoietic stem cells in allowing the homing of these cells to the marrow.

  13. Gene editing in hematopoietic stem cells: a potential therapeutic approach for Fanconi anemia

    Energy Technology Data Exchange (ETDEWEB)

    Diez Cabezas, B.

    2015-07-01

    Gene therapy nowadays constitutes a safe and efficient treatment for a number of monogenic diseases affecting the hematopoietic system. Risks of insertional mutagenesis derived from the use of integrative vectors cannot, however, be completely excluded. Therefore, gene targeting has been proposed as a safer alternative, since the insertion of the herapeutic gene is driven to a specific locus in the genome. Gene targeting approaches are based on the use of specific nucleases which generate double strand breaks (DSBs) in a specific site of the genome,markedly enhancing the efficacy of homologous recombination (HR) with donor constructs harboring the gene of interest flanked by the corresponding homology arms. In this study we have optimized the conditions to target human lymphoblastic cell lines (LCLs) and also hematopoietic stem cells (HSCs) from healthy donors, with the final aim of correcting by gene editing the hematopoietic progenitor cells from Fanconi anemia subtype A (FA-A) patients. In particular, we have established a robust method to target both LCLs and HSCs in a safe harbor site in the genome, the AAVS1 locus. Our approach is based on the transduction of these cells with integrase-defective lentiviral vectors carrying a donor with the gene of interest, followed by the nucleofection of these cells with zinc finger nucleases used as mRNA. Using a control donor vector carrying the GFP reporter gene we have obtained, on average, 9.43% gene targeting efficiency in cord blood CD34+ cells from healthy donors. Moreover, we confirmed that gene targeting was also efficient in HSCs with long term and multipotent repopulation capacity, as demonstrated by transplants into immunodeficient mice. To improve the gene targeting efficiency, we investigated the feasibility of using gold nanoparticles, which were shown to improve the transduction efficiency of integrase-defective and competent lentiviral vectors in HSCs. This increment, however, did not lead to a higher gene

  14. Critical early events in hematopoietic cell seeding and engraftment.

    OpenAIRE

    Jerry Stein; Isaac Yaniv; Nadir Askenasy

    2005-01-01

    Durable hematopoietic stem cell engraftment requires efficient homing to and seeding in the recipient bone marrow. Dissection of cellular and molecular mechanisms by retrospective analysis of functional engraftment studies imposes severe limitations on the understanding of the early stages of this process. We have established an experimental approach for in vivo functional imaging of labeled cells at the level of recipient bone marrow in real time. The adhesive interaction of hematopoietic ce...

  15. Ischemic stroke activates hematopoietic bone marrow stem cells.

    Science.gov (United States)

    Courties, Gabriel; Herisson, Fanny; Sager, Hendrik B; Heidt, Timo; Ye, Yuxiang; Wei, Ying; Sun, Yuan; Severe, Nicolas; Dutta, Partha; Scharff, Jennifer; Scadden, David T; Weissleder, Ralph; Swirski, Filip K; Moskowitz, Michael A; Nahrendorf, Matthias

    2015-01-30

    The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood. To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells. Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (Pcell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19% to 7.32%±0.52% after tMCAO (Pstroke. The hematopoietic system's myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (Pstem cell quiescence. In mice with genetic deficiency of the β3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, P=0.51). Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6C(high) monocytes and neutrophils. © 2014 American Heart Association, Inc.

  16. Parathyroid hormone mediates hematopoietic cell expansion through interleukin-6.

    Directory of Open Access Journals (Sweden)

    Flavia Q Pirih

    Full Text Available Parathyroid hormone (PTH stimulates hematopoietic cells through mechanisms of action that remain elusive. Interleukin-6 (IL-6 is upregulated by PTH and stimulates hematopoiesis. The purpose of this investigation was to identify actions of PTH and IL-6 in hematopoietic cell expansion. Bone marrow cultures from C57B6 mice were treated with fms-like tyrosine kinase-3 ligand (Flt-3L, PTH, Flt-3L plus PTH, or vehicle control. Flt-3L alone increased adherent and non-adherent cells. PTH did not directly impact hematopoietic or osteoclastic cells but acted in concert with Flt-3L to further increase cell numbers. Flt-3L alone stimulated proliferation, while PTH combined with Flt-3L decreased apoptosis. Flt-3L increased blasts early in culture, and later increased CD45(+ and CD11b(+ cells. In parallel experiments, IL-6 acted additively with Flt-3L to increase cell numbers and IL-6-deficient bone marrow cultures (compared to wildtype controls but failed to amplify in response to Flt-3L and PTH, suggesting that IL-6 mediated the PTH effect. In vivo, PTH increased Lin(- Sca-1(+c-Kit(+ (LSK hematopoietic progenitor cells after PTH treatment in wildtype mice, but failed to increase LSKs in IL-6-deficient mice. In conclusion, PTH acts with Flt-3L to maintain hematopoietic cells by limiting apoptosis. IL-6 is a critical mediator of bone marrow cell expansion and is responsible for PTH actions in hematopoietic cell expansion.

  17. A promoter DNA demethylation landscape of human hematopoietic differentiation.

    Science.gov (United States)

    Calvanese, Vincenzo; Fernández, Agustín F; Urdinguio, Rocío G; Suárez-Alvarez, Beatriz; Mangas, Cristina; Pérez-García, Vicente; Bueno, Clara; Montes, Rosa; Ramos-Mejía, Verónica; Martínez-Camblor, Pablo; Ferrero, Cecilia; Assenov, Yassen; Bock, Christoph; Menendez, Pablo; Carrera, Ana Clara; Lopez-Larrea, Carlos; Fraga, Mario F

    2012-01-01

    Global mechanisms defining the gene expression programs specific for hematopoiesis are still not fully understood. Here, we show that promoter DNA demethylation is associated with the activation of hematopoietic-specific genes. Using genome-wide promoter methylation arrays, we identified 694 hematopoietic-specific genes repressed by promoter DNA methylation in human embryonic stem cells and whose loss of methylation in hematopoietic can be associated with gene expression. The association between promoter methylation and gene expression was studied for many hematopoietic-specific genes including CD45, CD34, CD28, CD19, the T cell receptor (TCR), the MHC class II gene HLA-DR, perforin 1 and the phosphoinositide 3-kinase (PI3K) and results indicated that DNA demethylation was not always sufficient for gene activation. Promoter demethylation occurred either early during embryonic development or later on during hematopoietic differentiation. Analysis of the genome-wide promoter methylation status of induced pluripotent stem cells (iPSCs) generated from somatic CD34(+) HSPCs and differentiated derivatives from CD34(+) HSPCs confirmed the role of DNA methylation in regulating the expression of genes of the hemato-immune system, and indicated that promoter methylation of these genes may be associated to stemness. Together, these data suggest that promoter DNA demethylation might play a role in the tissue/cell-specific genome-wide gene regulation within the hematopoietic compartment.

  18. Eicosanoid regulation of hematopoiesis and hematopoietic stem and progenitor trafficking.

    Science.gov (United States)

    Hoggatt, J; Pelus, L M

    2010-12-01

    Hematopoietic stem cell (HSC) transplantation is a potentially curative treatment for numerous hematological malignancies. The transplant procedure as performed today takes advantage of HSC trafficking; either egress of HSC from the bone marrow to the peripheral blood, that is, mobilization, for acquisition of the hematopoietic graft, and/or trafficking of HSC from the peripheral blood to bone marrow niches in the recipient patient, that is HSC homing. Numerous studies, many of which are reviewed herein, have defined hematopoietic regulatory mechanisms mediated by the 20-carbon lipid family of eicosanoids, and recent evidence strongly supports a role for eicosanoids in regulation of hematopoietic trafficking, adding a new role whereby eicosanoids regulate hematopoiesis. Short-term exposure of HSC to the eicosanoid prostaglandin E(2) increases CXCR4 receptor expression, migration and in vivo homing of HSC. In contrast, cannabinoids reduce hematopoietic progenitor cell (HPC) CXCR4 expression and induce HPC mobilization when administered in vivo. Leukotrienes have been shown to alter CD34(+) cell adhesion, migration and regulate HSC proliferation, suggesting that eicosanoids have both opposing and complimentary roles in the regulation of hematopoiesis. As numerous FDA approved compounds regulate eicosanoid signaling or biosynthesis, the utility of eicosanoid-based therapeutic strategies to improve hematopoietic transplantation can be rapidly evaluated.

  19. Stimulating effect of catechin,an active component of Spatholobus suberectu Dunn,on bioactivity of hematopoietic growth factor suberectus Dunn,on bioactivity of hematopoietic growth factor

    Institute of Scientific and Technical Information of China (English)

    WANG Dong-xiao; Liu Ping; CHEN Yi-hong; CHEN Ruo-yun; GUO Dai-hong; REN Hao-yang; CHEN Meng-li

    2008-01-01

    Background Hematopoietic growth factor(HGF)is indispensable to hematopoiesis in the body. The proliferation and differentiation of hematopoietic cells must rely on the existence and stimulation of HGE. This study investigated the effect of catechin, an active component extracted from Spatholobus suberectus Dunn (SSD), on bioactivity of granulocyte-macrophage colony-stimulating activity(GM-CSA), burst-promoting activity(BPA)and megakaryocyte colony-stimulating activity(MK-CSA)in spleen condition medium(SPCM)of mice to clarify the hematopoietic mechanism of catechin and SSD. Methods Spleen cells of mice were separated and spleen condition medium (SPCM)was prepared from spleen cell culture. Bone marrow cells of mice were separated and cultured in a culture system including 10%(v/v)SPCM(induced by catechin in vivo or ex vivo)for 6 days. Granulocyte-macrophage colony forming units(CFU-GM), erythrocyte burst-colony-forming units(BFU-E)and megakaryocyte colony-forming units(CFU-Meg)formation were employed to assay the effects of different treatment on the bioactivity of GM-CSA, BPA and MK-CSA in SPCM. Results SPCM induced by 1 00 mg/L catechin ex vivo could promote the growth of CFU-GM, BFU-E and CFU-Meg, which indicated that catechin could stimulate the production of GM-CSA, BPA and MK-CSA in SPCM. SPCM prepared at the fourth day of spleen cell culture showed the best stimulating activity. The bioactivity of GM-CSA, BPA and MK-CSA in the SPCM prepared after intraperitoneally injecting catechin into mice was also increased. The number of CFU-GM, BFU-E and CFU-Meg gradually increased as the dose of catechin increased and the time of administration prolonged. CFU-GM, BFU-E and CFU-Meg of the high-dose catechin group were significantly higher than those of the control group (P<0.01)and reached the maximum at the seventh day after administration. Conclusions This study suggests that catechin extracted from the active acetic ether part of Spatholobus suberectus Dunn can

  20. The mouse Runx1 +23 hematopoietic stem cell enhancer confers hematopoietic specificity to both Runx1 promoters

    National Research Council Canada - National Science Library

    Bee, Thomas; Ashley, Emma L K; Bickley, Sorrel R B; Jarratt, Andrew; Li, Pik-Shan; Sloane-Stanley, Jackie; Göttgens, Berthold; de Bruijn, Marella F T R

    2009-01-01

    The transcription factor Runx1 plays a pivotal role in hematopoietic stem cell (HSC) emergence, and studies into its transcriptional regulation should give insight into the critical steps of HSC specification...

  1. 氟达拉滨替代环磷酰胺的预处理方案用于单倍型造血干细胞移植%Conditioning regimen containing fludarabine instead of cyclophosphamide for haploidentical hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    陈惠仁; 何学鹏; 司英健; 杨凯; 胡波; 杜振兰; 张小妹; 张传仓

    2009-01-01

    目的 探讨含氟达拉滨的预处理方案对单倍型造血干细胞移植(HSCT)治疗的可行性和安全性.方法 对35例恶性血液病患者进行单倍型HSCT,其中标危4例,高危16例,复发未缓解15例,所有患者改良预处理用氟达拉滨取代静脉环磷酰胺,氟达拉滨用量为40 mg·m-2·d-1,连用5 d,供者接受rhG-CSF后采集造血干细胞,1例外周血HSCT,1例骨髓移植,33例骨髓加外周血造血干细胞联合移植,移植后观察预处理方案相关不良反应、植入、移植物抗宿主病(GVHD)发生和无病生存状况.结果 所有患者均植入成功,34例患者第1次取得持久植入;1例患者排斥母亲植入物后再进行父亲供髓移植后取得持久植入.所有患者均能较好耐受该预处理方案,无一例因预处理相关不良反应而早期死亡,无肝静脉闭塞病发生.Ⅲ~Ⅳ度急性GVHD 4例,Ⅲ度以上急性GVHD累计发生率为12.1%,慢性GVHD累汁发生率为31.7%.随访时间为8~25个月,死亡6例,复发死亡3例,而非疾病复发死亡3例,其中急性GVHD死亡例,真菌感染死亡1例,其余29例患者仍无病存活,Kaplan-Meier分析无病生存率达79.7%.结论 单倍型移植预处理用氟达拉滨取代静脉环磷酰胺安全可行,降低了方案相关不良反应,且未增加复发和感染率,有利于减少严重急性GVHD、提高移植成功率.%Objective To explore the feasibility and safety of conditioning regimen containing fludarabine (Flud) for haploidentieal hematopoietic stem cell transplantation (HSCT).Methods Preparative regimen containing Flud 40 mg·m-2·d-1 on day-7 to-3 in place of eyelophosphamide(CTX) for haploidentical HSCT was given to 35 patients with hematologic malignancies (4 standard risk,16 high risk,15 relapse with no remission).All donors received rhG-CSF followed by HSC harvest.One patient received peripheral blood HSCT(PBSCT),one bone marrow transplantation(BMT),and the others BM combination with PBSCT.The regimen

  2. Stepwise development of hematopoietic stem cells from embryonic stem cells.

    Directory of Open Access Journals (Sweden)

    Kenji Matsumoto

    Full Text Available The cellular ontogeny of hematopoietic stem cells (HSCs remains poorly understood because their isolation from and their identification in early developing small embryos are difficult. We attempted to dissect early developmental stages of HSCs using an in vitro mouse embryonic stem cell (ESC differentiation system combined with inducible HOXB4 expression. Here we report the identification of pre-HSCs and an embryonic type of HSCs (embryonic HSCs as intermediate cells between ESCs and HSCs. Both pre-HSCs and embryonic HSCs were isolated by their c-Kit(+CD41(+CD45(- phenotype. Pre-HSCs did not engraft in irradiated adult mice. After co-culture with OP9 stromal cells and conditional expression of HOXB4, pre-HSCs gave rise to embryonic HSCs capable of engraftment and long-term reconstitution in irradiated adult mice. Blast colony assays revealed that most hemangioblast activity was detected apart from the pre-HSC population, implying the early divergence of pre-HSCs from hemangioblasts. Gene expression profiling suggests that a particular set of transcripts closely associated with adult HSCs is involved in the transition of pre-HSC to embryonic HSCs. We propose an HSC developmental model in which pre-HSCs and embryonic HSCs sequentially give rise to adult types of HSCs in a stepwise manner.

  3. Vorinostat plus tacrolimus and mycophenolate to prevent graft-versus-host disease after related-donor reduced-intensity conditioning allogeneic haemopoietic stem-cell transplantation: a phase 1/2 trial

    NARCIS (Netherlands)

    Choi, S.W.; Braun, T.; Chang, L.; Ferrara, J.L.; Pawarode, A.; Magenau, J.M.; Hou, G.; Beumer, J.H.; Levine, J.E.; Goldstein, S.; Couriel, D.R.; Stockerl-Goldstein, K.; Krijanovski, O.I.; Kitko, C.; Yanik, G.A.; Lehmann, M.H.; Tawara, I.; Sun, Y; Paczesny, S.; Mapara, M.Y.; Dinarello, C.A.; Dipersio, J.F.; Reddy, P.

    2014-01-01

    BACKGROUND: Acute graft-versus-host disease (GVHD) remains a barrier to more widespread application of allogeneic haemopoietic stem-cell transplantation. Vorinostat is an inhibitor of histone deacetylases and was shown to attenuate GVHD in preclinical models. We aimed to study the safety and activit

  4. Allogeneic stem cell transplantation after reduced-intensity conditioning in patients with myelofibrosis: a prospective, multicenter study of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation.

    NARCIS (Netherlands)

    Kroger, N.; Holler, E.; Kobbe, G.; Bornhauser, M.; Schwerdtfeger, R.; Baurmann, H.; Nagler, A.; Bethge, W.; Stelljes, M.; Uharek, L.; Wandt, H.; Burchert, A.; Corradini, P.; Schubert, J.; Kaufmann, Martin; Dreger, P.; Wulf, G.G.; Einsele, H.; Zabelina, T.; Kvasnicka, H.M.; Thiele, J.; Brand, R.; Zander, A.R.; Niederwieser, D.; Witte, T.J.M. de

    2009-01-01

    From 2002 to 2007, 103 patients with primary myelofibrosis or postessential thrombocythemia and polycythemia vera myelofibrosis and a median age of 55 years (range, 32-68 years) were included in a prospective multicenter phase 2 trial to determine efficacy of a busulfan (10 mg/kg)/fludarabine (180 m

  5. Allogeneic hematopoietic cell transplantation for acute myeloid leukemia in older adults.

    Science.gov (United States)

    Sorror, Mohamed L; Estey, Elihu

    2014-12-01

    Acute myeloid leukemia (AML) is primarily a disease of the elderly and the numbers of these patients are increasing. Patients ≥60 years of age continue to have poor prognosis. Preliminary results suggest benefit from reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in selected patients 60-80 years of age. However, although patients in this age range comprise >50% of those with AML, they currently constitute only 17% of those offered HCT. In the absence of prospective randomized studies comparing HCT and chemotherapy, the decision to recommend HCT rests on retrospective analyses of the risks of relapse and nonrelapse mortality after each approach. There is strong evidence that pre-HCT comorbidities can predict HCT-related morbidity and mortality. Age alone does not appear predictive and, particularly if the risk of relapse with chemotherapy is high, should not be the sole basis for deciding against HCT. Use of geriatric assessment tools, inflammatory biomarkers, and genetic polymorphism data may further aid in predicting nonrelapse mortality after HCT. Disease status and pretreatment cytogenetics with FLT3-TID, NPM-1, and CEBP-α status are the main factors predicting relapse and these are likely to be supplemented by incorporation of other molecular markers and the level of minimal residual disease after chemotherapy. HLA-matched related and unrelated donor grafts seem preferable to those from other donor sources. Donor age is of no clear significance. Models combining comorbidities with AML risk factors are useful in risk assessment before HCT. In this chapter, we integrated information on AML-specific, HCT-specific, and patient-specific risk factors into a risk-adapted approach to guide decisions about HCT versus no HCT.

  6. Low-dose total body irradiation (TBI) and fludarabine followed by hematopoietic cell transplantation (HCT) from HLA-matched or mismatched unrelated donors and postgrafting immunosuppression with cyclosporine and mycophenolate mofetil (MMF) can induce durable complete chimerism and sustained remissions in patients with hematological diseases.

    Science.gov (United States)

    Niederwieser, Dietger; Maris, Michael; Shizuru, Judith A; Petersdorf, Effie; Hegenbart, Ute; Sandmaier, Brenda M; Maloney, David G; Storer, Barry; Lange, Thoralf; Chauncey, Thomas; Deininger, Michael; Pönisch, Wolfram; Anasetti, Claudio; Woolfrey, Ann; Little, Marie-Terese; Blume, Karl G; McSweeney, Peter A; Storb, Rainer F

    2003-02-15

    Toxicities of high-dose conditioning regimens have limited the use of conventional unrelated donor hematopoietic cell transplantation (HCT) to younger, medically fit patients. Based on preclinical studies, an HCT approach has been developed for elderly or medically infirm patients with HLA-matched or mismatched unrelated donors. In this study, 52 patients with hematological diseases were included. Most (88%) had preceding unsuccessful conventional HCT or refractory/advanced disease. Patients were treated with fludarabine 30 mg/m(2)/d from days -4 to -2, 2 Gy total body irradiation on day 0, cyclosporine at 6.25 mg/kg twice daily from day -3, and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Durable donor chimerism was attained in 88% of the patients. By day 28, a median of 100% of CD56(+) cells were of donor origin. Granulocyte and T-cell donor chimerism increased to medians of 100% on day 56 and day 180 (range, 55%-100%), respectively. Acute GVHD, grade II, was seen in 42% (CI, 29%-56%); grade III in 8% (CI, 0%-15%); and grade IV in 13% (CI, 4%-23%) of patients; it was fatal in 9%. The 100-day transplantation-related mortality was 11%. Complete remissions, including molecular remissions, were seen in 45% of patients with measurable disease before transplantation. Mortality from disease progression was 27% at one year. With a median follow-up of 19 months, 18 of the 52 patients (35%) were alive and 25% were in remission. HCT from HLA-matched or mismatched unrelated donors can be performed with a reduced intensity conditioning regimen in patients ineligible for conventional HCT.

  7. Hematopoietic tissue repair under chronic low daily dose irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Seed, T.M.

    1994-12-01

    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{minus}26.3 cGy d{sup {minus}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 & 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.

  8. Analysis of the hematopoietic tissue in Pleurodeles waltl newts exposed to 2 g hypergravity

    Science.gov (United States)

    Domaratskaya, Elena; Nikonova, Tatyana M.; Grigoryan, Eleonora N.; Dvorochkin, Natalya; Yousuf, Rukhsana; Almeida, Eduardo; Butorina, Nina N.

    2012-07-01

    Gravity is an important factor in creating biologically-relevant mechanical loads, and in spaceflight living organisms encounter both microgravity as well as hypergravity conditions. Here we studied the influence of hypergravity on the hematopoietic tissue of P. waltl newts in parallel with tissue regeneration experiments of the newt lens and tail. At day 9 post-surgery one group of newts was subjected to centrifugation at 2 g (2G, 12 days), while another was kept at 1 g. In addition, a basal control in wet mats, at 1g, (BC, 1G), and an aquarium control, neutrally buoyant, (AC, low G), were also performed. Differential blood counts and histological analysis of the spleen and liver were carried out in experimental and control groups of animals. At day 21 post-surgery in all groups (AC, 1G, and 2G), the number of neutrophils in the blood was significantly lower than in BC indicating a decrease in the inflammation induced by surgery. The 2G group however, showed numbers of neutrophils significantly higher than AC (neutrally buoyant) animals. This result suggests that post-operative inflammation can persist longer at 2 g that under unloaded aquarium conditions. In contrast we did not observe any significant differences in lymphocyte numbers between any experimental and control groups. Histological examination of the liver and spleen also did not show any significant morphological alterations due to hypergravity. These results indicate that 12 day exposure to hypergravity at 2 g, had only partial influence on newt hematopoiesis, possibly extending the duration of surgery-related inflammatory responses. Data obtained with newts in our previous experiments on Foton-M2 and Foton-M3 flights in microgravity also showed only slight effect on blood cells. Furthermore microgravity also did not cause any morphological changes in the hematopoietic and lymphoid tissues, and did not impair the proliferative capacity of newt hematopoietic cells. In sum these results indicate the

  9. Generation of hematopoietic humanized mice in the newborn BALB/c-Rag2null Il2rγnull mouse model: a multivariable optimization approach.

    Science.gov (United States)

    Lang, Julie; Weiss, Nicholas; Freed, Brian M; Torres, Raul M; Pelanda, Roberta

    2011-07-01

    Hematopoietic humanized mice generated via transplantation of human hematopoietic stem cells (hHSCs) into immunodeficient mice are a valuable tool for studying development and function of the human immune system. This study was performed to generate a protocol that improves development and quality of humanized mice in the BALB/c-Rag2(null)Il2rγ(null) strain, testing route of injection, in vitro culture and freezing of hHSCs, types of cytokines in the culture, and co-injection of lineage-depleted CD34(-) cells. Specific hHSC culturing conditions and the addition of support cells were found to increase the frequency, and human hematopoietic chimerism, of humanized mice. The optimized protocol resulted in BALB/c-Rag2(null)Il2rγ(null) humanized mice displaying more consistent human hematopoietic and lymphoid engraftment. Thus, hematopoietic humanized mice generated on a BALB/c immunodeficient background represent a useful model to study the human immune system.

  10. Hematopoietic stem cell characterization and isolation.

    Science.gov (United States)

    Rossi, Lara; Challen, Grant A; Sirin, Olga; Lin, Karen Kuan-Yin; Goodell, Margaret A

    2011-01-01

    Hematopoietic stem cells (HSCs) are defined by the capabilities of multi-lineage differentiation and long-term self-renewal. Both these characteristics contribute to maintain the homeostasis of the system and allow the restoration of hematopoiesis after insults, such as infections or therapeutic ablation. Reconstitution after lethal irradiation strictly depends on a third, fundamental property of HSCs: the capability to migrate under the influence of specific chemokines. Directed by a chemotactic compass, after transplant HSCs find their way to the bone marrow, where they eventually home and engraft. HSCs represent a rare population that primarily resides in the bone marrow with an estimated frequency of 0.01% of total nucleated cells. Separating HSCs from differentiated cells that reside in the bone marrow has been the focus of intense investigation for years. In this chapter, we will describe in detail the strategy routinely used by our laboratory to purify murine HSCs, by exploiting their antigenic phenotype (KSL), combined with the physiological capability to efficiently efflux the vital dye Hoechst 33342, generating the so-called Side Population, or SP.

  11. Hematopoietic Origin of Murine Lung Fibroblasts

    Directory of Open Access Journals (Sweden)

    Lindsay T. McDonald

    2015-01-01

    Full Text Available Multiple origins, including the bone marrow, have been suggested to contribute to fibroblast populations in the lung. Using bone marrow reconstitution strategies, the present study tested the hypothesis that the bone marrow hematopoietic stem cell (HSC gives rise to lung tissue fibroblasts in vivo. Data demonstrate that the nonadherent bone marrow fraction is enriched for CD45+ HSC-derived cells and was able to reconstitute hematopoiesis in lethally irradiated animals. Analysis of peripheral blood and lung tissues from engrafted mice demonstrated the ability of this population to give rise to CD45+/Discoidin-Domain Receptor-2+ (DDR2 circulating fibroblast precursors (CFPs in blood and fibroblast populations in lung. An HSC origin for lung fibroblasts was confirmed using a novel clonal cell transplantation method in which the bone marrow is reconstituted by a clonal population derived from a single HSC. Together, these findings provide evidence for an HSC contribution to lung fibroblasts and demonstrate a circulating intermediate through the CD45+/DDR2+ HSC-derived CFP.

  12. Polycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms.

    Science.gov (United States)

    Radulović, V; de Haan, G; Klauke, K

    2013-03-01

    The equilibrium between self-renewal and differentiation of hematopoietic stem cells is regulated by epigenetic mechanisms. In particular, Polycomb-group (PcG) proteins have been shown to be involved in this process by repressing genes involved in cell-cycle regulation and differentiation. PcGs are histone modifiers that reside in two multi-protein complexes: Polycomb Repressive Complex 1 and 2 (PRC1 and PRC2). The existence of multiple orthologs for each Polycomb gene allows the formation of a multitude of distinct PRC1 and PRC2 sub-complexes. Changes in the expression of individual PcG genes are likely to cause perturbations in the composition of the PRC, which affect PRC enzymatic activity and target selectivity. An interesting recent development is that aberrant expression of, and mutations in, PcG genes have been shown to occur in hematopoietic neoplasms, where they display both tumor-suppressor and oncogenic activities. We therefore comprehensively reviewed the latest research on the role of PcG genes in normal and malignant blood cell development. We conclude that future research to elucidate the compositional changes of the PRCs and methods to intervene in PRC assembly will be of great therapeutic relevance to combat hematological malignancies.

  13. Icing oral mucositis: Oral cryotherapy in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant.

    Science.gov (United States)

    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 < 0.001). The median oral mucositis severity, assessed using the WHO oral toxicity scale from grade 0-4, experienced in the no group was 2.5 vs. 2 in the 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.

  14. Cytokine combinations on the potential for ex vivo expansion of murine hematopoietic stem cells.

    Science.gov (United States)

    Lui, Wing Chi; Chan, Yuen Fan; Chan, Li Chong; Ng, Ray Kit

    2014-08-01

    Hematopoietic stem cell (HSC) is a rare cell population, which is capable of self-renewal and differentiation to all blood lineages. The clinical potential of HSCs for treating hematological disorders has led to the use of cytokine stimulation for ex vivo expansion. However, little is known about the molecular features of the HSC populations expanded under different cytokine combinations. We studied the expansion of murine HSCs cultured with six different cytokine combinations under serum-containing or serum-free conditions for 14days. We found that all the cytokine combinations promoted expansion of murine HSCs. Although SCF/IL-3/IL-6 induced the highest expansion of the immunophenotypic Lineage(-)Sca-1(+)c-Kit(+) (LSK) cells at day 14, over 90% of them were FcεRIα(+) mast cells. In contrast, the serum-free medium with SCF/Flt3-L/IL-11 effectively promoted the expansion of LSK/FcεRIα(-) HSCs by over 50-fold. HSCs expanded by SCF/Flt3-L/IL-11 combination formed compact hematopoietic colonies and demonstrated a higher degree of multipotency compared to the HSCs cultured with other cytokine combinations. Surprisingly, despite the same LSK/FcεRIα(-) immunophenotype, HSCs cultured with different cytokine combinations demonstrated differential patterns of hematopoietic gene expression. HSCs cultured with SCF/Flt3-L/IL-11 maintained a transcription profile resembling that of freshly isolated HSCs. We propose that serum-free medium supplemented with SCF/Flt3-L/IL-11 is the optimal culture condition to maintain the stemness of ex vivo expanded HSCs. This study used molecular characterization of cytokine-expanded murine HSCs to facilitate the selection of cytokine combinations that could induce fully competent HSC for clinical applications.

  15. AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN WITH SEVERE RESISTANT MULTIPLE SCLEROSIS

    Directory of Open Access Journals (Sweden)

    K. I. Kirgizov

    2013-01-01

    Full Text Available Unique experience of high-dose chemotherapy with consequent autologous hematopoietic stem cell transplantation in children with severe resistant multiple sclerosis (n=7 is shown in this article. At present time there is enough data on chemotherapy with consequent hematopoietic stem cell transplantation in children with severe resistant multiple sclerosis. This method was proved to be efficient and safe with immunoablative conditioning chemotherapy regimen. In patients included in this study the mean rate according to the Expanded Disability Status Scale was 5,94±0,2 (from 3 to 9 points. All the patients had disseminated demyelination loci, accumulating the contrast substance, in the brain and the spinal cord. After cyclophosphamide treatment in combination with anti-monocytes globulin the fast stabilization of the condition and prolonged (the observation period was 3-36 moths clinical and radiologic as well as immunophenotypic remission with marked positive dynamics according to the Expanded Disability Status Scale were noted. No pronounced side-effects and infectious complications were mentioned. The maximal improvement according to the Expanded Disability Status Scale (EDSS was 5,5 points, the mean — 2,7±0,1 (from 2 to 5,5 points accompanied with positive dynamics on the magneto-resonance imaging.  The efficacy of the treatment was also proved by the positive changes in the lymphocytes subpopulation status in peripheral blood. The timely performed high-dose chemotherapy with consequent hematopoietic stem cell transplantation is an effective and safe method to slowdown the autoimmune inflammatory process. This method can be recommended to use in treatment of children with severe resistant multiple sclerosis. 

  16. Essential roles of VLA-4 in the hematopoietic system.

    Science.gov (United States)

    Imai, Yoichi; Shimaoka, Motomu; Kurokawa, Mineo

    2010-05-01

    Integrins are one of the major families of adhesion molecules and make various kinds of biological effects by mediating cell-cell and cell-matrix interactions. Among integrins, VLA-4 is expressed on many types of hematopoietic cells including stem/progenitor cells and it is considered as a critical regulator of adult hematopoiesis. Recent studies revealed that VLA-4 is not necessarily required for the development or maintenance of adult hematopoietic cells. On the other hand, it was proved that VLA-4 is essential for homeostasis of distribution of hematopoietic stem/progenitor cells (HSPCs) and mature lymphocytes in the body. The dynamic regulation of VLA-4 function is mediated by its conformational change, which is strictly linked to the interaction between alpha and beta cytoplasmic domains. The study using knockin mice showed that GFFKR sequence, a well-preserved motif in the alpha cytoplasmic domain of VLA-4, is critical for binding of alpha and beta cytoplasmic domains as well as regulation of hematopoietic cell distribution. Small molecules targeting this cytoplasmic interaction or ligand-VLA-4 interaction may become good candidates of new drugs for mobilization of hematopoietic stem cells. Several studies have suggested the impact of VLA-4 on chemotherapy sensitivity and prognosis in hematological malignancies, which awaits further investigations.

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  15. Interleukin-1 regulates Hematopoietic progenitor and stem cells in the midgestation mouse fetal liver

    NARCIS (Netherlands)

    C. Orelio (Claudia); M. Peeters (Marian); E. Haak (Esther); K. van der Horn (Karin); E.A. Dzierzak (Elaine)

    2009-01-01

    textabstractBackground Hematopoietic progenitors are generated in the yolk sac and aorta-gonad-mesonephros region during early mouse development. At embryonic day 10.5 the first hematopoietic stem cells emerge in the aorta-gonad-mesonephros. Subsequently, hematopoietic stem cells and progenitors are

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  18. Interleukin-1 regulates Hematopoietic progenitor and stem cells in the midgestation mouse fetal liver

    NARCIS (Netherlands)

    C. Orelio (Claudia); M. Peeters (Marian); E. Haak (Esther); K. van der Horn (Karin); E.A. Dzierzak (Elaine)

    2009-01-01

    textabstractBackground Hematopoietic progenitors are generated in the yolk sac and aorta-gonad-mesonephros region during early mouse development. At embryonic day 10.5 the first hematopoietic stem cells emerge in the aorta-gonad-mesonephros. Subsequently, hematopoietic stem cells and progenitors are

  19. Proton MR spectroscopy of hyperplastic hematopoietic marrow in aplastic anemia

    Energy Technology Data Exchange (ETDEWEB)

    Amano, Yasuo; Kumazaki, Tatsuo [Nippon Medical School, Tokyo (Japan); Arai, Nobuyuki

    1997-04-01

    The purpose of this study was to compare the findings of magnetic resonance (MR) spectroscopy of hyperplastic hematopoietic marrow with those of normal bone marrow. Twenty-four samples of normal marrow from eight control subjects and 19 samples of hyperplastic marrow in aplastic anemia were examined with a 1.5 T MR unit. The former showed low intensity on opposed-phase T1-weighted images, while the latter showed high intensity on both fast STIR and opposed-phase T1-weighted images. MR spectroscopy quantitatively confirmed that the water; fat ratio was increased and the transverse relaxation time of water was changed in hyperplastic bone marrow, compared with normal bone marrow. In summary, MR imaging is able to detect hematopoietic regions among a wide range of bone marrow of aplastic anemia, while MR spectroscopy allowed us to quantitatively analyze the cell population of hyperplastic hematopoietic marrow in aplastic anemia. (author)

  20. The Genetic Landscape of Hematopoietic Stem Cell Frequency in Mice

    Directory of Open Access Journals (Sweden)

    Xiaoying Zhou

    2015-07-01

    Full Text Available Prior efforts to identify regulators of hematopoietic stem cell physiology have relied mainly on candidate gene approaches with genetically modified mice. Here we used a genome-wide association study (GWAS strategy with the hybrid mouse diversity panel to identify the genetic determinants of hematopoietic stem/progenitor cell (HSPC frequency. Among 108 strains, we observed ∼120- to 300-fold variation in three HSPC populations. A GWAS analysis identified several loci that were significantly associated with HSPC frequency, including a locus on chromosome 5 harboring the homeodomain-only protein gene (Hopx. Hopx previously had been implicated in cardiac development but was not known to influence HSPC biology. Analysis of the HSPC pool in Hopx−/− mice demonstrated significantly reduced cell frequencies and impaired engraftment in competitive repopulation assays, thus providing functional validation of this positional candidate gene. These results demonstrate the power of GWAS in mice to identify genetic determinants of the hematopoietic system.

  1. Notch signaling and development of the hematopoietic system.

    Science.gov (United States)

    Sandy, Ashley R; Jones, Morgan; Maillard, Ivan

    2012-01-01

    Notch signaling exerts multiple important functions in the hematopoietic system. Notch1-mediated signals are essential to induce the onset of definitive hematopoiesis within specialized domains of hemogenic endothelium in the fetal dorsal aorta. In contrast, Notch is dispensable for the subsequent maintenance of hematopoietic stem cells in the adult bone marrow. Notch is a key regulator of early T-cell development in the thymus. An expanding number of hematopoietic and lymphoid cell types have been reported to receive context-dependent inputs from the Notch pathway that regulate their differentiation and function. Progress in the field will continue to bring fundamental information about hematopoiesis and practical insights into the potential to modulate Notch signaling for therapeutic purposes.

  2. Obesity and inflammation and the effect on the hematopoietic system.

    Science.gov (United States)

    Benites, Bruno Deltreggia; Gilli, Simone Cristina Olenscki; Saad, Sara Teresinha Olalla

    2014-03-01

    Bone marrow is organized in specialized microenvironments known as 'marrow niches'. These are important for the maintenance of stem cells and their hematopoietic progenitors whose homeostasis also depends on other cell types present in the tissue. Extrinsic factors, such as infection and inflammatory states, may affect this system by causing cytokine dysregulation (imbalance in cytokine production) and changes in cell proliferation and self-renewal rates, and may also induce changes in the metabolism and cell cycle. Known to relate to chronic inflammation, obesity is responsible for systemic changes that are best studied in the cardiovascular system. Little is known regarding the changes in the hematopoietic system induced by the inflammatory state carried by obesity or the cell and molecular mechanisms involved. The understanding of the biological behavior of hematopoietic stem cells under obesity-induced chronic inflammation could help elucidate the pathophysiological mechanisms involved in other inflammatory processes, such as neoplastic diseases and bone marrow failure syndromes.

  3. Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation

    Science.gov (United States)

    Goode, Debbie K.; Obier, Nadine; Vijayabaskar, M.S.; Lie-A-Ling, Michael; Lilly, Andrew J.; Hannah, Rebecca; Lichtinger, Monika; Batta, Kiran; Florkowska, Magdalena; Patel, Rahima; Challinor, Mairi; Wallace, Kirstie; Gilmour, Jane; Assi, Salam A.; Cauchy, Pierre; Hoogenkamp, Maarten; Westhead, David R.; Lacaud, Georges; Kouskoff, Valerie; Göttgens, Berthold; Bonifer, Constanze

    2016-01-01

    Summary Metazoan development involves the successive activation and silencing of specific gene expression programs and is driven by tissue-specific transcription factors programming the chromatin landscape. To understand how this process executes an entire developmental pathway, we generated global gene expression, chromatin accessibility, histone modification, and transcription factor binding data from purified embryonic stem cell-derived cells representing six sequential stages of hematopoietic specification and differentiation. Our data reveal the nature of regulatory elements driving differential gene expression and inform how transcription factor binding impacts on promoter activity. We present a dynamic core regulatory network model for hematopoietic specification and demonstrate its utility for the design of reprogramming experiments. Functional studies motivated by our genome-wide data uncovered a stage-specific role for TEAD/YAP factors in mammalian hematopoietic specification. Our study presents a powerful resource for studying hematopoiesis and demonstrates how such data advance our understanding of mammalian development. PMID:26923725

  4. Salvage Second Hematopoietic Cell Transplantation in Myeloma

    Science.gov (United States)

    Michaelis, Laura C.; Saad, Ayman; Zhong, Xiaobo; Le-Rademacher, Jennifer; Freytes, Cesar O.; Marks, David I.; Lazarus, Hillard M.; Bird, Jennifer M.; Holmberg, Leona; Kamble, Rammurti T.; Kumar, Shaji; Lill, Michael; Meehan, Kenneth R.; Saber, Wael; Schriber, Jeffrey; Tay, Jason; Vogl, Dan T.; Wirk, Baldeep; Savani, Bipin N.; Gale, Robert P.; Vesole, David H.; Schiller, Gary J.; Abidi, Muneer; Anderson, Kenneth C.; Nishihori, Taiga; Kalaycio, Matt E.; Vose, Julie M.; Moreb, Jan S.; Drobyski, William; Munker, Reinhold; Roy, Vivek; Ghobadi, Armin; Holland, H. Kent; Nath, Rajneesh; To, L. Bik; Maiolino, Angelo; Kassim, Adetola A.; Giralt, Sergio A.; Landau, Heather; Schouten, Harry C.; Maziarz, Richard T.; Mikhael, Joseph; Kindwall-Keller, Tamila; Stiff, Patrick J.; Gibson, John; Lonial, Sagar; Krishnan, Amrita; Dispenzieri, Angela; Hari, Parameswaran

    2013-01-01

    Autologous hematopoietic cell transplantation (AHCT) as initial therapy of patients with multiple myeloma (MM) improves survival. However, data to support this approach for relapsed/progressive disease after initial AHCT (AHCT1) are limited. Using Center for International Blood and Marrow Transplant Research data, we report the outcomes of 187 patients who underwent a second AHCT (AHCT2) for the treatment of relapsed/progressive MM. Planned tandem AHCT was excluded. Median age at AHCT2 was 59 years (range, 28 to 72), and median patient follow-up was 47 months (range, 3 to 97). Nonrelapse mortality after AHCT2 was 2% at 1 year and 4% at 3 years. Median interval from AHCT1 to relapse/progression was 18 months, and median interval between transplantations was 32 months. After AHCT2, the incidence of relapse/progression at 1 and 3 years was 51% and 82%, respectively. At 3 years after AHCT2, progression-free survival was 13%, and overall survival was 46%. In multivariate analyses, those relapsing ≥36 months after AHCT1 had superior progression-free (P = .045) and overall survival (P = .019). Patients who underwent AHCT2 after 2004 had superior survival (P = .026). AHCT2 is safe and feasible for disease progression after AHCT1. In this retrospective study, individuals relapsing ≥36 months from AHCT1 derived greater benefit from AHCT2 compared with those with a shorter disease-free interval. Storage of an adequate graft before AHCT1 will ensure that the option of a second autologous transplantation is retained for patients with relapsed/progressive MM. PMID:23298856

  5. Characterizing human herpes virus 6 following hematopoietic stem cell transplantation.

    Science.gov (United States)

    Perissinotti, Anthony J; Gulbis, Alison; Shpall, Elizabeth J; Howell, Joshua

    2015-04-01

    Human herpes virus 6 reactivation occurs in approximately 50% of patients following hematopoietic stem cell transplant, however, the significance of human herpes virus 6 reactivation remains uncertain. A retrospective study was conducted analyzing clinical data of patients testing positive for human herpes virus 6 by quantitative polymerase chain reaction following hematopoietic stem cell transplant from 1 January 1998 to 1 October 2011. Data retrieved were used to describe the clinical course and outcome of human herpes virus 6 positive hematopoietic stem cell transplant patients. Sixty patients were identified who tested positive for human herpes virus 6 by polymerase chain reaction following hematopoietic stem cell transplant. A high proportion of patients were identified in this cohort with acute myeloid leukemia (28.3%), active disease (65%), transplanted with a matched unrelated donor (30%), ≥ 1 antigen mismatched (28.3%) matched unrelated donor, or an umbilical cord graft (25%), and those who received antithymocyte globulin (42.4%). Thirty-eight (63.3%) patients were treated for human herpes virus 6 with foscarnet alone or in combination with intravenous immunoglobulin, whereas 18 (30%) did not require treatment survival at Day 100 was 73.3%. This study suggests human herpes virus 6 reactivation occurs shortly after hematopoietic stem cell transplant (median of 25 days (interquartile range, 20-31.75) after hematopoietic stem cell transplant). Many potential risk factors are described in this report. Treatment of human herpes virus 6 predominately consisted of foscarnet with or without intravenous immunoglobulin; however, treatment of human herpes virus 6 was not always warranted. Furthermore, the effect of treatment on patient outcomes is uncertain. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  6. [Endothelial origin for hematopoietic stem cells: a visual proof].

    Science.gov (United States)

    Boisset, Jean-Charles; Robin, Catherine

    2011-10-01

    Hematopoietic stem cells (HSC) are the source of all blood cell types produced during the entire life of an organism. They appear during embryonic development, where they will transit through different successive hematopoietic organs, before to finally colonize the bone marrow. Nowadays, the precise origin of HSC remains a matter of controversy. Different HSC precursor candidates, located in different anatomical sites, have been proposed. Here, we summarize and discuss the different theories in light of the recent articles, especially those using in vivo confocal microscopy technology.

  7. Differential outcome of neurological HCMV infection in two hematopoietic stem cell transplant recipients

    Directory of Open Access Journals (Sweden)

    Colombo Anna

    2012-10-01

    Full Text Available Abstract Background Human cytomegalovirus (HCMV infection of the central nervous system (CNS is a rare but life threatening condition which may follow hematopoietic stem cell transplantation. Diagnosis, monitoring and treatment approaches rely on anecdotal reports. Case presentations The different outcomes of HCMV CNS disease in an adult and a pediatric T-cell depleted hematopoietic stem cell transplant (HSCT recipient are reported. In the first case, HCMV encephalitis emerged in the context of simultaneous impairment of the T- and B-cell immunity. Antiviral treatment only reduced viral load in peripheral blood and the patient died. In the second case, an HCMV radiculopathy was observed and antiviral treatment was adjusted on the basis of intrathecal drug level. In addition, donor HCMV-specific cytotoxic T lymphocytes (CTLs were infused. Viral load in the CNS decreased and the patient recovered from the acute event. In neither case were drug-resistant HCMV variants observed in blood or CNS samples. Conclusions T-cell depleted HSCT appears a predisposing condition for CNS HCMV infection since never observed in other HSCT recipients at our center in the last 15 years. Intensive diagnostic approaches and timely aggressive combination treatments might improve clinical outcome in these patients.

  8. Adult hematopoietic stem cells lacking Hif-1α self-renew normally.

    Science.gov (United States)

    Vukovic, Milica; Sepulveda, Catarina; Subramani, Chithra; Guitart, Amélie V; Mohr, Jasmine; Allen, Lewis; Panagopoulou, Theano I; Paris, Jasmin; Lawson, Hannah; Villacreces, Arnaud; Armesilla-Diaz, Alejandro; Gezer, Deniz; Holyoake, Tessa L; Ratcliffe, Peter J; Kranc, Kamil R

    2016-06-09

    The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance.

  9. Oral lorazepam prevents seizure during high-dose busulfan in children undergoing hematopoietic stem cell transplantation: a prospective study.

    Science.gov (United States)

    Hamidieh, Amir Ali; Hamedani, Ravak; Hadjibabaie, Molouk; Amini, Mohsen; Sadrai, Sima; Ghavamzadeh, Ardeshir

    2010-10-01

    High-dose Busulfan in combination chemotherapy has been used commonly for hematopoietic stem cell transplantation. It crosses the blood-brain barrier and could cause seizure. Benzodiazepines have been used as anticonvulsant prophylaxis. This is a prospective study using oral lorazepam together with busulfan-based conditioning regimen in 30 children undergoing hematopoietic stem cell transplantation. The dose of lorazepam used ranged from 0.017 to 0.039 mg/kg (median = 0.026 mg/kg) per dose. None of the patients developed seizure while receiving oral lorazepam or within 72 hours of the last dose of Busulfan. Oral lorazepam was tolerated by the patients, but all patients needed dose reduction due to some adverse effects. In the authors' experience, oral lorazepam is a useful anticonvulsant prophylaxis for children receiving high-dose busulfan.

  10. Allogeneic hematopoietic cell transplantation without fluconazole and fluoroquinolone prophylaxis.

    Science.gov (United States)

    Heidenreich, D; Kreil, S; Nolte, F; Reinwald, M; Hofmann, W-K; Klein, S A

    2016-01-01

    Fluoroquinolone (FQ) and fluconazole prophylaxis is recommended for patients undergoing allogeneic hematopoietic cell transplantation (alloHCT). However, due to an uncertain scientific basis and the increasing emergence of resistant germs, this policy should be questioned. Therefore, FQ and fluconazole prophylaxis was omitted in alloHCT at our center. In this retrospective analysis, all consecutive patients (n = 63) who underwent first alloHCT at our institution from September 2010 to September 2013 were included. Patients neither received FQ nor fluconazole prophylaxis. Day 100 mortality, incidence of febrile neutropenia, bacterial infections, and invasive fungal diseases (IFD) were assessed. Sixteen patients who started conditioning under antimicrobial treatment/prophylaxis due to pre-existing neutropenia (3/16), IFD (12/16), or aortic valve replacement (1/16) were excluded from the analysis. Finally, 47 patients were transplanted without prophylaxis as intended. Day 100 mortality was 9 %. Febrile neutropenia occurred in 62 % (29/47); 17/47 patients (36 %) experienced a blood stream infection (BSI) with detection of Gram-positive bacteria in 14 patients, Gram-negative bacteria in five patients, and candida in one patient, respectively. Coagulase-negative staphylococci were the most frequently isolated Gram-positive bacteria; 12/21 isolated Gram-positive and 3/6 Gram-negative bacteria were FQ resistant. In 21 % (10/47) of the patients, IFD (1x proven, 1x probable, and 8x possible) were diagnosed. To conclude, all three criteria, day 100 mortality, the incidence of IFD, and BSI, are in the range of published data for patients transplanted with FQ and fluconazole prophylaxis. These data demonstrate that alloHCT is feasible without FQ and fluconazole prophylaxis.

  11. Adult neurogenesis in the decapod crustacean brain: A hematopoietic connection?

    Science.gov (United States)

    Beltz, Barbara S.; Zhang, Yi; Benton, Jeanne L.; Sandeman, David C.

    2011-01-01

    New neurons are produced and integrated into circuits in the adult brains of many organisms, including crustaceans. In some crustacean species, the 1st- generation neuronal precursors reside in a niche exhibiting characteristics analogous to mammalian neurogenic niches. However, unlike mammalian niches where several generations of neuronal precursors coexist, the lineage of precursor cells in crayfish is spatially separated allowing the influence of environmental and endogenous regulators on specific generations in the neuronal precursor lineage to be defined. Experiments also demonstrate that the 1st-generation neuronal precursors in the crayfish Procambarus clarkii are not self-renewing. A source external to the neurogenic niche must therefore provide cells that replenish the 1st-generation precursor pool, because although these cells divide and produce a continuous efflux of 2nd-generation cells from the niche, the population of 1st-generation niche precursors is not diminished with growth and aging. In vitro studies show that cells extracted from the hemolymph, but not other tissues, are attracted to and incorporated into the neurogenic niche, a phenomenon that appears to involve serotonergic mechanisms. We propose that in crayfish, the hematopoietic system may be a source of cells that replenish the niche cell pool. These and other studies reviewed here establish decapod crustaceans as model systems in which the processes underlying adult neurogenesis, such as stem cell origins and transformation, can be readily explored. Studies in diverse species where adult neurogenesis occurs will result in a broader understanding of fundamental mechanisms and how evolutionary processes may have shaped the vertebrate/mammalian condition. PMID:21929622

  12. Reconstitution of mammary epithelial morphogenesis by murine embryonic stem cells undergoing hematopoietic stem cell differentiation.

    Directory of Open Access Journals (Sweden)

    Shuxian Jiang

    Full Text Available BACKGROUND: Mammary stem cells are maintained within specific microenvironments and recruited throughout lifetime to reconstitute de novo the mammary gland. Mammary stem cells have been isolated through the identification of specific cell surface markers and in vivo transplantation into cleared mammary fat pads. Accumulating evidence showed that during the reformation of mammary stem cell niches by dispersed epithelial cells in the context of the intact epithelium-free mammary stroma, non-mammary epithelial cells may be sequestered and reprogrammed to perform mammary epithelial cell functions and to adopt mammary epithelial characteristics during reconstruction of mammary epithelium in regenerating mammary tissue in vivo. METHODOLOGY/PRINCIPAL FINDINGS: To examine whether other types of progenitor cells are able to contribute to mammary branching morphogenesis, we examined the potential of murine embryonic stem (mES cells, undergoing hematopoietic differentiation, to support mammary reconstitution in vivo. We observed that cells from day 14 embryoid bodies (EBs under hematopoietic differentiation condition, but not supernatants derived from these cells, when transplanted into denuded mammary fat pads, were able to contribute to both the luminal and myoepithelial lineages in branching ductal structures resembling the ductal-alveolar architecture of the mammary tree. No teratomas were observed when these cells were transplanted in vivo. CONCLUSIONS/SIGNIFICANCE: Our data provide evidence for the dominance of the tissue-specific mammary stem cell niche and its role in directing mES cells, undergoing hematopoietic differentiation, to reprogram into mammary epithelial cells and to promote mammary epithelial morphogenesis. These studies should also provide insights into regeneration of damaged mammary gland and the role of the mammary microenvironment in reprogramming cell fate.

  13. Phenotypic and functional analysis of human fetal liver hematopoietic stem cells in culture.

    Science.gov (United States)

    Rollini, Pierre; Faes-Van't Hull, Eveline; Kaiser, Stefan; Kapp, Ursula; Leyvraz, Serge

    2007-04-01

    Steady-state hematopoiesis and hematopoietic transplantation rely on the unique potential of stem cells to undergo both self-renewal and multilineage differentiation. Fetal liver (FL) represents a promising alternative source of hematopoietic stem cells (HSCs), but limited by the total cell number obtained in a typical harvest. We reported that human FL nonobese diabetic/severe combined immunodeficient (NOD/SCID) repopulating cells (SRCs) could be expanded under simple stroma-free culture conditions. Here, we sought to further characterize FL HSC/SRCs phenotypically and functionally before and following culture. Unexpanded or cultured FL cell suspensions were separated into various subpopulations. These were tested for long-term culture potential and for in vivo repopulating function following transplantation into NOD/SCID mice. We found that upon culture of human FL cells, a tight association between classical stem cell phenotypes, such as CD34(+) /CD38(-) and/or side population, and NOD/SCID repopulating function was lost, as observed with other sources. Although SRC activity before and following culture consistently correlated with the presence of a CD34(+) cell population, we provide evidence that, contrary to umbilical cord blood and adult sources, stem cells present in both CD34(+) and CD34(-) FL populations can sustain long-term hematopoietic cultures. Furthermore, upon additional culture, CD34-depleted cell suspensions, devoid of SRCs, regenerated a population of CD34(+) cells possessing SRC function. Our studies suggest that compared to neonatal and adult sources, the phenotypical characteristics of putative human FL HSCs may be less strictly defined, and reinforce the accumulated evidence that human FL represents a unique, valuable alternative and highly proliferative source of HSCs for clinical applications.

  14. Deficiency of GRP94 in the hematopoietic system alters proliferation regulators in hematopoietic stem cells.

    Science.gov (United States)

    Luo, Biquan; Tseng, Chun-Chih; Adams, Gregor B; Lee, Amy S

    2013-12-01

    We have previously reported that acute inducible knockout of the endoplasmic reticulum chaperone GRP94 led to an expansion of the hematopoietic stem and progenitor cell pool. Here, we investigated the effectors and mechanisms for this phenomenon. We observed an increase in AKT activation in freshly isolated GRP94-null HSC-enriched Lin(-) Sca-1(+) c-Kit(+) (LSK) cells, corresponding with higher production of PI(3,4,5)P3, indicative of PI3K activation. Treatment of GRP94-null LSK cells with the AKT inhibitor MK2206 compromised cell expansion, suggesting a causal relationship between elevated AKT activation and increased proliferation in GRP94-null HSCs. Microarray analysis demonstrated a 97% reduction in the expression of the hematopoietic cell cycle regulator Ms4a3 in the GRP94-null LSK cells, and real-time quantitative PCR confirmed this down-regulation in the LSK cells but not in the total bone marrow (BM). A further examination comparing freshly isolated BM LSK cells with spleen LSK cells, as well as BM LSK cells cultured in vitro, revealed specific down-regulation of Ms4a3 in freshly isolated BM GRP94-null LSK cells. On examining cell surface proteins that are known to regulate stem cell proliferation, we observed a reduced expression of cell surface connexin 32 (Cx32) plaques in GRP94-null LSK cells. However, suppression of Cx32 hemichannel activity in wild-type LSK cells through mimetic peptides did not lead to increased LSK cell proliferation in vitro. Two other important cell surface proteins that mediate HSC-niche interactions, specifically Tie2 and CXCR4, were not impaired by Grp94 deletion. Collectively, our study uncovers novel and unique roles of GRP94 in regulating HSC proliferation.

  15. 重视造血干细胞移植中的造血微环境问题%Pay close attention to hematopoietic inductive microenvironment in hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    张曦; 张诚; 陈幸华

    2012-01-01

    Hematopoietic stem cell transplantation is a therapeutic method in treatment of various hematologic neoplastic disorders. Successful transplantion relies on the normal proliferation, differentiation of the transplanted hematopoietic stem cells in the recipients, and the low occurence of complications. In previous studies, more attention has been paid to the hematopoietic stem cells rather than the hematopoietic inductive microenvironment , which is actually necessary for the survival and function of the transplanted hematopoietic stem cells. Results from our studies indicate that the hematopoietic inductive microenvironment is as important as the hematopoietic stem cells in the transplantation therapy.

  16. 氟达拉滨替代环磷酰胺的清髓性预处理化疗联合异基因造血干细胞移植治疗急性白血病的对照研究%Control study of fludarabine instead of cyclophosphamide in modified busulfan-cyclophosphamide as a myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation for treatment of acute leukemia

    Institute of Scientific and Technical Information of China (English)

    胡凯; 王继军; 田磊; 万伟; 赵伟; 李其辉; 克晓燕

    2014-01-01

    目的 探讨氟达拉滨替代改良BuCy方案中环磷酰胺的预处理方案在异基因造血干细胞移植中的安全性及有效性.方法 对45例急性白血病患者进行异基因造血干细胞移植,其中23例采用改良BuCy预处理化疗,22例采用BuFlu方案(氟达拉滨每天40 mg/m2,用5d,来替代改良BuCy方案中的环磷酰胺)进行预处理化疗.移植均采用外周血造血干细胞移植.移植后观察比较两组预处理方案相关不良反应、植入、移植物抗宿主病(GVHD)、感染发生和长期随访下的无病生存情况.结果 除改良BuCy组1例患者死于预处理后脑出血,其余患者均获得成功植入.两组患者预处理不良反应发生率差异无统计学意义(P>0.05);BuFlu组患者病毒感染较改良BuCy组高(P=0.009),而Ⅲ~Ⅳ度急性GVHD发生率较低[26.1%(6/23)比4.5%(1/22),P=0.046].中位随访41个月,改良BuCy组非复发死亡4例(17.4%),BuFlu组非复发死亡2例(9.1%)(P=0.665).两组复发率分别为30.3%(7/23)和40.9%(9/22)(P=0.474);5年总生存率分别为(55.1±l 1.9)%和(61.4±10.8)%(P=0.659),无事件生存率分别为(44.5±12.1)%和(22.1±12.3)%(P=0.747).结论 氟达拉滨替代改良BuCy方案中环磷酰胺的预处理化疗耐受性较好,严重GVHD发生率低,总生存率无明显差异.应用时应注意移植中感染及复发的风险.%Objective To evaluate the fludarabine instead of cyclophosphamide in modified busulfancyclophosphamide (mBuCy) regimen as a new myeloablative conditioning regimen for the treatment of acute leukemia patients receiving allogeneic hematopoietic stem cell transplantation (HSCT).Methods The clinic data of 45 acute leukemia patients undergoing allogeneic HSCT were analyzed.Among them,23 patients received mBuCy as conditioning regimen and 22 patients received BuFlu regimen (fludarabine 40 mg·m-2·d-1 for 5 days,instead of cyclophosphamide in mBuCy).Hematopietic engraftment,regimen-related toxicity (RRT

  17. Involvement of the histamine H4 receptor in clozapine-induced hematopoietic toxicity: Vulnerability under granulocytic differentiation of HL-60 cells.

    Science.gov (United States)

    Goto, Aya; Mouri, Akihiro; Nagai, Tomoko; Yoshimi, Akira; Ukigai, Mako; Tsubai, Tomomi; Hida, Hirotake; Ozaki, Norio; Noda, Yukihiro

    2016-09-01

    Clozapine is an effective antipsychotic for treatment-resistant schizophrenia, but can cause fatal hematopoietic toxicity as agranulocytosis. To elucidate the mechanism of hematopoietic toxicity induced by clozapine, we developed an in vitro assay system using HL-60 cells, and investigated the effect on hematopoiesis. HL-60 cells were differentiated by all-trans retinoic acid (ATRA) into three states according to the following hematopoietic process: undifferentiated HL-60 cells, those undergoing granulocytic ATRA-differentiation, and ATRA-differentiated granulocytic cells. Hematopoietic toxicity was evaluated by analyzing cell survival, cell proliferation, granulocytic differentiation, apoptosis, and necrosis. In undifferentiated HL-60 cells and ATRA-differentiated granulocytic cells, both clozapine (50 and 100μM) and doxorubicin (0.2µM) decreased the cell survival rate, but olanzapine (1-100µM) did not. Under granulocytic differentiation for 5days, clozapine, even at a concentration of 25μM, decreased survival without affecting granulocytic differentiation, increased caspase activity, and caused apoptosis rather than necrosis. Histamine H4 receptor mRNA was expressed in HL-60 cells, whereas the expression decreased under granulocytic ATRA-differentiation little by little. Both thioperamide, a histamine H4 receptor antagonist, and DEVD-FMK, a caspase-3 inhibitor, exerted protection against clozapine-induced survival rate reduction, but not of live cell counts. 4-Methylhistamine, a histamine H4 receptor agonist, decreased the survival rate and live cell counts, as did clozapine. HL-60 cells under granulocytic differentiation are vulnerable under in vitro assay conditions to hematopoietic toxicity induced by clozapine. Histamine H4 receptor is involved in the development of clozapine-induced hematopoietic toxicity through apoptosis, and may be a potential target for preventing its occurrence through granulocytic differentiation.

  18. Bacterial foodborne infections after hematopoietic cell transplantation.

    Science.gov (United States)

    Boyle, Nicole M; Podczervinski, Sara; Jordan, Kim; Stednick, Zach; Butler-Wu, Susan; McMillen, Kerry; Pergam, Steven A

    2014-11-01

    Diarrhea, abdominal pain, and fever are common among patients undergoing hematopoietic cell transplantation (HCT), but such symptoms are also typical with foodborne infections. The burden of disease caused by foodborne infections in patients undergoing HCT is unknown. We sought to describe bacterial foodborne infection incidence after transplantation within a single-center population of HCT recipients. All HCT recipients who underwent transplantation from 2001 through 2011 at the Fred Hutchinson Cancer Research Center in Seattle, Washington were followed for 1 year after transplantation. Data were collected retrospectively using center databases, which include information from transplantation, on-site examinations, outside records, and collected laboratory data. Patients were considered to have a bacterial foodborne infection if Campylobacter jejuni/coli, Listeria monocytogenes, E. coli O157:H7, Salmonella species, Shigella species, Vibrio species, or Yersinia species were isolated in culture within 1 year after transplantation. Nonfoodborne infections with these agents and patients with pre-existing bacterial foodborne infection (within 30 days of transplantation) were excluded from analyses. A total of 12 of 4069 (.3%) patients developed a bacterial foodborne infection within 1 year after transplantation. Patients with infections had a median age at transplantation of 50.5 years (interquartile range [IQR], 35 to 57), and the majority were adults ≥18 years of age (9 of 12 [75%]), male gender (8 of 12 [67%]) and had allogeneic transplantation (8 of 12 [67%]). Infectious episodes occurred at an incidence rate of 1.0 per 100,000 patient-days (95% confidence interval, .5 to 1.7) and at a median of 50.5 days after transplantation (IQR, 26 to 58.5). The most frequent pathogen detected was C. jejuni/coli (5 of 12 [42%]) followed by Yersinia (3 of 12 [25%]), although Salmonella (2 of 12 [17%]) and Listeria (2 of 12 [17%]) showed equal frequencies; no cases of Shigella

  19. Evaluation of respiratory conditions in early phase of hematopoietic stem cell transplantation Avaliação das condições respiratórias na fase inicial do transplante de células tronco hematopoiéticas

    Directory of Open Access Journals (Sweden)

    Eliane Aparecida Bom

    2012-01-01

    Full Text Available OBJECTIVE: To investigate the effectiveness of respiratory physiotherapy based on clinical evidence and analyze the improvement in respiratory parameters. METHODS: A prospective study was carried out in the Bone Marrow Transplant Unit of the Universidade Estadual de Campinas (UNICAMP. Two different previously established respiratory physiotherapy protocols were applied from days D-1 to D+7 that aimed to improve airway clearance, pulmonary re-expansion and the strengthening of respiratory muscles. Group A were subjected to diaphragmatic proprioceptive stimulation, breathing exercises, incentive spirometry with Respiron®, inspiratory muscle training with the Threshold® Inspiratory Muscle Training device, bronchial hygienization with Shaker® and cough stimulation. Group B performed a protocol that only used incentive spirometry. The parameters analyzed were: tidal volume, minute volume, maximal inspiratory pressure, maximal expiratory pressure, oxygen saturation, heart rate and respiratory frequency. RESULTS: Sixty-seven patients submitted to myeloablative hematopoietic stem cell transplantation were included in this study. Among these, thirty-nine were evaluated and randomized in the two groups. There were significant differences between the groups for tidal volume at D+2 (p-value = 0.007 and maximal inspiratory pressure (p-value = 0.03, maximal expiratory pressure (p-value = 0.03 and tidal volume (p-value = 0.004 at D+7. CONCLUSION: On comparing Group A with Group B, the authors concluded that the protocol of respiratory physiotherapy applied in this study resulted in an improvement in ventilation and in respiratory muscle strength of patients submitted to hematopoietic stem cell transplantation.OBJETIVO: investigar a eficácia da fisioterapia respiratória (FR baseada em evidência clínica e nos parâmetros respiratórios. Estudo prospectivo realizado na Unidade de Transplante de Medula Óssea da Universidade Estadual de Campinas. Dois

  20. The role of CD44 in fetal and adult hematopoietic stem cell regulation.

    Science.gov (United States)

    Cao, Huimin; Heazlewood, Shen Y; Williams, Brenda; Cardozo, Daniela; Nigro, Julie; Oteiza, Ana; Nilsson, Susan K

    2016-01-01

    Throughout development, hematopoietic stem cells migrate to specific microenvironments, where their fate is, in part, extrinsically controlled. CD44 standard as a member of the cell adhesion molecule family is extensively expressed within adult bone marrow and has been previously reported to play important roles in adult hematopoietic regulation via CD44 standard-ligand interactions. In this manuscript, CD44 expression and function are further assessed and characterized on both fetal and adult hematopoietic stem cells. Using a CD44(-/-) mouse model, conserved functional roles of CD44 are revealed throughout development. CD44 is critical in the maintenance of hematopoietic stem and progenitor pools, as well as in hematopoietic stem cell migration. CD44 expression on hematopoietic stem cells as well as other hematopoietic cells within the bone marrow microenvironment is important in the homing and lodgment of adult hematopoietic stem cells isolated from the bone/bone marrow interface. CD44 is also involved in fetal hematopoietic stem cell migration out of the liver, via a process involving stromal cell-derived factor-1α. The absence of CD44 in neonatal bone marrow has no impact on the size of the long-term reconstituting hematopoietic stem cell pool, but results in an enhanced long-term engraftment potential of hematopoietic stem cells.

  1. Mutual Interference between Cytomegalovirus and Reconstitution of Protective Immunity after Hematopoietic Cell Transplantation

    Directory of Open Access Journals (Sweden)

    Matthias J. Reddehase

    2016-08-01

    Full Text Available Hematopoietic cell transplantation (HCT is a therapy option for aggressive forms of hematopoietic malignancies that are resistant to standard antitumoral therapies. Hematoablative treatment preceding HCT, however, opens a ‘window of opportunity’ for latent cytomegalovirus (CMV by releasing it from immune control with the consequence of reactivation of productive viral gene expression and recurrence of infectious virus. A ‘window of opportunity’ for the virus represents a ‘window of risk’ for the patient. In the interim between HCT and reconstitution of antiviral immunity, primarily mediated by CD8+ T cells, initially low amounts of reactivated virus can expand exponentially, disseminate to essentially all organs, and cause multiple organ CMV disease, with interstitial pneumonia (CMV-IP representing the most severe clinical manifestation. Here I will review predictions originally made in the mouse model of experimental HCT and murine CMV infection, some of which have already paved the way to translational preclinical research and promising clinical trials of a pre-emptive cytoimmunotherapy of human CMV disease. Specifically, the mouse model has been pivotal in providing ‘proof of concept’ for preventing CMV disease after HCT by adoptive transfer of preselected, virus epitope-specific effector and memory CD8+ T cells bridging the critical interim. CMV, however, is not a ‘passive antigen’ but is a pathogen that actively interferes with the reconstitution of protective immunity by infecting bone marrow stromal cells that otherwise form niches for hematopoiesis by providing the structural microenvironment and by producing hematopoietically active cytokines, the hemopoietins. Depending on the precise conditions of HCT, reduced homing of transplanted hematopoietic stem- and progenitor cells to infected bone marrow stroma and impaired colony growth and lineage differentiation can lead to ‘graft failure’. In consequence

  2. Placenta as a source of hematopoietic stem cells

    NARCIS (Netherlands)

    E.A. Dzierzak (Elaine); C. Robin (Catherine)

    2010-01-01

    textabstractThe placenta is a large, highly vascularised hematopoietic tissue that functions during the embryonic and foetal development of eutherian mammals. Although recognised as the interface tissue important in the exchange of oxygen, nutrients and waste products between the foetus and mother,

  3. Phylogeny of the infectious hematopoietic necrosis virus in European aquaculture

    NARCIS (Netherlands)

    Cieslak, Michael; Wahli, Thomas; Diserens, Nicolas; Haenen, Olga L.M.; Schütze, Heike

    2017-01-01

    Infectious hematopoietic necrosis (IHN) — a highly lethal infectious salmonid disease — has caused substantial economic losses in the European production of rainbow trout (Oncorhynchus mykiss) since the late 1980s. The causal agent of IHN is the IHN virus (IHNV) introduced from overseas. However,

  4. DNA Damage Response in Hematopoietic Stem Cell Ageing.

    Science.gov (United States)

    Li, Tangliang; Zhou, Zhong-Wei; Ju, Zhenyu; Wang, Zhao-Qi

    2016-06-01

    Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal) and progenitor progenies (differentiation), which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR) in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.

  5. DNA Damage Response in Hematopoietic Stem Cell Ageing

    Directory of Open Access Journals (Sweden)

    Tangliang Li

    2016-06-01

    Full Text Available Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal and progenitor progenies (differentiation, which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.

  6. Lentiviral hematopoietic stem cell gene therapy in inherited metabolic disorders

    NARCIS (Netherlands)

    G. Wagemaker (Gerard)

    2014-01-01

    textabstractAfter more than 20 years of development, lentiviral hematopoietic stem cell gene therapy has entered the stage of initial clinical implementation for immune deficiencies and storage disorders. This brief review summarizes the development and applications, focusing on the lysosomal enzyme

  7. Longitudinal Assessment of Hematopoietic Stem Cell Transplantation and Hyposalivation

    DEFF Research Database (Denmark)

    Laaksonen, Matti; Ramseier, Adrian; Rovó, Alicia

    2011-01-01

    Hyposalivation is a common adverse effect of anti-neoplastic therapy of head and neck cancer, causing impaired quality of life and predisposition to oral infections. However, data on the effects of hematopoietic stem cell transplantation (HSCT) on salivary secretion are scarce. The present study...

  8. 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...

  9. Placenta as a source of hematopoietic stem cells

    NARCIS (Netherlands)

    E.A. Dzierzak (Elaine); C. Robin (Catherine)

    2010-01-01

    textabstractThe placenta is a large, highly vascularised hematopoietic tissue that functions during the embryonic and foetal development of eutherian mammals. Although recognised as the interface tissue important in the exchange of oxygen, nutrients and waste products between the foetus and mother,

  10. Allo-Hematopoietic Stem Cell Transplant in China: 2014 Update.

    Science.gov (United States)

    Lv, Meng; Huang, Xiao-Jun

    2014-01-01

    Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides powerful curative weapons for patients with certain hematological diseases. Great improvements have been made within recent years, particularly in the fields of haploidentical HSCT, allo-HSCT for aplastic anemia, and strategies to overcome relapse and graft versus host disease. This review updates the current state of allo-HSCT in China.

  11. Dynamic changes in mouse hematopoietic stem cell numbers during aging

    NARCIS (Netherlands)

    de Haan, G; Van Zant, G

    1999-01-01

    To address the fundamental question of whether or not stem cell populations age, we performed quantitative measurements of the cycling status and frequency of hematopoietic stem cells in long-lived C57BL/6 (B6) and short-lived DBA/2 (DBA) mice at different developmental and aging stages. The frequen

  12. Fetal liver stromal cells promote hematopoietic cell expansion

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Kun; Hu, Caihong [Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China); Zhou, Zhigang [Shanghai 1st People Hospital, Shanghai Jiao Tong University, Shanghai 201620 (China); Huang, Lifang; Liu, Wenli [Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China); Sun, Hanying, E-mail: shanhum@163.com [Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030 (China)

    2009-09-25

    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.

  13. Cellular barcoding tool for clonal analysis in the hematopoietic system

    NARCIS (Netherlands)

    Gerrits, Alice; Dykstra, Brad; Kalmykowa, Olga J.; Klauke, Karin; Verovskaya, Evgenia; Broekhuis, Mathilde J. C.; de Haan, Gerald; Bystrykh, Leonid V.

    2010-01-01

    Clonal analysis is important for many areas of hematopoietic stem cell research, including in vitro cell expansion, gene therapy, and cancer progression and treatment. A common approach to measure clonality of retrovirally transduced cells is to perform integration site analysis using Southern blott

  14. Polycomb group proteins in hematopoietic stem cell aging and malignancies

    NARCIS (Netherlands)

    Klauke, Karin; de Haan, Gerald

    2011-01-01

    Protection of the transcriptional "stemness" network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many age-

  15. Expansion of human cord blood hematopoietic stem cells for transplantation.

    Science.gov (United States)

    Chou, Song; Chu, Pat; Hwang, William; Lodish, Harvey

    2010-10-08

    A recent Science paper reported a purine derivative that expands human cord blood hematopoietic stem cells in culture (Boitano et al., 2010) by antagonizing the aryl hydrocarbon receptor. Major problems need to be overcome before ex vivo HSC expansion can be used clinically.

  16. The hematopoietic system in the context of regenerative medicine.

    Science.gov (United States)

    Porada, Christopher D; Atala, Anthony J; Almeida-Porada, Graça

    2016-04-15

    Hematopoietic stem cells (HSC) represent the prototype stem cell within the body. Since their discovery, HSC have been the focus of intensive research, and have proven invaluable clinically to restore hematopoiesis following inadvertent radiation exposure and following radio/chemotherapy to eliminate hematologic tumors. While they were originally discovered in the bone marrow, HSC can also be isolated from umbilical cord blood and can be "mobilized" peripheral blood, making them readily available in relatively large quantities. While their ability to repopulate the entire hematopoietic system would already guarantee HSC a valuable place in regenerative medicine, the finding that hematopoietic chimerism can induce immunological tolerance to solid organs and correct autoimmune diseases has dramatically broadened their clinical utility. The demonstration that these cells, through a variety of mechanisms, can also promote repair/regeneration of non-hematopoietic tissues as diverse as liver, heart, and brain has further increased their clinical value. The goal of this review is to provide the reader with a brief glimpse into the remarkable potential HSC possess, and to highlight their tremendous value as therapeutics in regenerative medicine.

  17. Regulation of hematopoietic stem cells during mouse development

    NARCIS (Netherlands)

    C. Orelio (Claudia)

    2003-01-01

    textabstractThe hematopoietic system is comprised of many different cell types that fulfill important physiological functions throughout embryonic and adult stages of mouse development. As the mature blood cells have a limited life-span, the pool of blood cells needs constant replenishing. At the ba

  18. DNA Damage Response in Hematopoietic Stem Cell Ageing

    Institute of Scientific and Technical Information of China (English)

    Tangliang Li; Zhong-Wei Zhou; Zhenyu Ju; Zhao-Qi Wang

    2016-01-01

    Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal) and progenitor progenies (differentiation), which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR) in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employ-ing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically reg-ulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.

  19. Autologous hematopoietic stem cell transplantation for autoimmune diseases.

    NARCIS (Netherlands)

    Gratwohl, A.; Passweg, J.R.; Bocelli-Tyndall, C.; Fassas, A.; Laar, J.M. van; Farge, D.; Andolina, M.; Arnold, R.; Carreras, E.; Finke, J.; Kotter, I.; Kozak, T.; Lisukov, I.; Lowenberg, B.; Marmont, A.; Moore, J.; Saccardi, R.; Snowden, J.A.; Hoogen, F.H.J. van den; Wulffraat, N.M.; Zhao, X.; Tyndall, A.

    2005-01-01

    Experimental data and early phase I/II studies suggest that high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (HSCT) can arrest progression of severe autoimmune diseases. We have evaluated the toxicity and disease response in 473 patients with severe autoimmune

  20. Hematopoietic development from human induced pluripotent stem cells.

    Science.gov (United States)

    Lengerke, Claudia; Grauer, Matthias; Niebuhr, Nina I; Riedt, Tamara; Kanz, Lothar; Park, In-Hyun; Daley, George Q

    2009-09-01

    A decade of research on human embryonic stem cells (ESC) has paved the way for the discovery of alternative approaches to generating pluripotent stem cells. Combinatorial overexpression of a limited number of proteins linked to pluripotency in ESC was recently found to reprogram differentiated somatic cells back to a pluripotent state, enabling the derivation of isogenic (patient-specific) pluripotent stem cell lines. Current research is focusing on improving reprogramming protocols (e.g., circumventing the use of retroviral technology and oncoproteins), and on methods for differentiation into transplantable tissues of interest. In mouse ESC, we have previously shown that the embryonic morphogens BMP4 and Wnt3a direct blood formation via activation of Cdx and Hox genes. Ectopic expression of Cdx4 and HoxB4 enables the generation of mouse ESC-derived hematopoietic stem cells (HSC) capable of multilineage reconstitution of lethally irradiated adult mice. Here, we explore hematopoietic development from human induced pluripotent stem (iPS) cells generated in our laboratory. Our data show robust differentiation of iPS cells to mesoderm and to blood lineages, as shown by generation of CD34(+)CD45(+) cells, hematopoietic colony activity, and gene expression data, and suggest conservation of blood patterning pathways between mouse and human hematopoietic development.

  1. 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.

  2. Hematopoietic progenitor cell mobilization for autologous transplantation - a literature review

    Directory of Open Access Journals (Sweden)

    Marco Aurélio Salvino

    2016-02-01

    Full Text Available ABSTRACT The use of high-dose chemotherapy with autologous support of hematopoietic progenitor cells is an effective strategy to treat various hematologic neoplasms, such as non-Hodgkin lymphomas and multiple myeloma. Mobilized peripheral blood progenitor cells are the main source of support for autologous transplants, and collection of an adequate number of hematopoietic progenitor cells is a critical step in the autologous transplant procedure. Traditional strategies, based on the use of growth factors with or without chemotherapy, have limitations even when remobilizations are performed. Granulocyte colony-stimulating factor is the most widely used agent for progenitor cell mobilization. The association of plerixafor, a C-X-C Chemokine receptor type 4 (CXCR4 inhibitor, to granulocyte colony stimulating factor generates rapid mobilization of hematopoietic progenitor cells. A literature review was performed of randomized studies comparing different mobilization schemes in the treatment of multiple myeloma and lymphomas to analyze their limitations and effectiveness in hematopoietic progenitor cell mobilization for autologous transplant. This analysis showed that the addition of plerixafor to granulocyte colony stimulating factor is well tolerated and results in a greater proportion of patients with non-Hodgkin lymphomas or multiple myeloma reaching optimal CD34+ cell collections with a smaller number of apheresis compared the use of granulocyte colony stimulating factor alone.

  3. Regimen-related toxicity following reduced-intensity stem-cell transplantation (RIST): comparison between Seattle criteria and National Cancer Center Common Toxicity Criteria (NCI-CTC) version 2.0.

    Science.gov (United States)

    Sakiyama, M; Kami, M; Hori, A; Imataki, O; Hamaki, T; Murashige, N; Kobayashi, K; Kishi, Y; Kojima, R; Kim, S-W; Kusumi, E; Yuji, K; Miyakoshi, S; Mori, S; Tanosaki, R; Taniguchi, S; Takaue, Y

    2004-11-01

    Acute regimen-related toxicity (RRT) is minimal in reduced-intensity stem-cell transplantation (RIST). However, the Seattle RRT grading (Bearman et al), developed in the context of conventional-intensity transplantation, is frequently applied to RIST. We compared the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0 with the Seattle criteria after RIST in 86 patients. RRT within 30 days of transplant graded by both sets of criteria were significantly associated with the outcome confirming the predictive value of both the systems. A total of 15 patients died of disease progression, and 12 of transplant-related mortality: RRT (n = 2), graft-versus-host disease (GVHD) (n = 7), infection (n = 1), and others (n = 2). GVHD-related deaths primarily resulted from infections after steroid treatment (n = 6) and bronchiolitis obliterans (n = 1). This study shows that NCI-CTC is appropriate in toxicity evaluation of RIST, and that its application to RIST enables a toxicity comparison between RIST and other types of cancer treatments. Since GVHD is a significant problem in RIST, modifications are required to evaluate immunological complications following RIST.

  4. Symptoms after hospital discharge following hematopoietic stem cell transplantation

    Directory of Open Access Journals (Sweden)

    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.

  5. Gfi1.1 regulates hematopoietic lineage differentiation during zebrafish embryogenesis

    Institute of Scientific and Technical Information of China (English)

    Wei Wei; Shuo Lin; Lu Wen; Peng Huang; Zheng Zhang; Yuanyuan Chen; An Xiao; Haigen Huang; Zuoyan Zhu; Bo Zhang

    2008-01-01

    Growth factor independence 1 (GFI1) is important for maturation of mammalian lymphocytes and neutrophils and maintenance of adult hematopoietic stem cells (HSCs).The role of GFl1 in embryonic hematopoiesis is less well characterized.Through an enhancer trap screen and bioinformatics analysis,we identified a zebrafish homolog of Gfi1 (named gfi1.1) and analyzed its function during embryonic development.Expression of both an endogenous gfi1.1 gene and a GFP reporter gene inserted near its genomic locus was detected in hematopoietic cells of zebrafish embryos.Morpholino (MO) knockdown of gfi1.1 reduced expression of scl,lmo2,c-myb,mpo,rag1,gata1 and hemoglobin alpha embryonic-1 (hbael),as well as the total amount of embryonic hemoglobin,but increased expression of pu.1 and l-plastin.Under the same conditions,MO injection did not affect the markers involved in vascular and pronephric development.Conversely,overexpression of gfi1.1 via mRNA injection enhanced expression of gatal but inhibited expression ofpu.1.These findings suggest that Gfi1.1 plays a critical role in regulating the balance of embryonic erythroid and myeloid lineage determination,and is also required for the differentiation of lymphocytes and granulocytes during zebrafish embryogenesis.

  6. The transcriptional coactivator Cbp regulates self-renewal and differentiation in adult hematopoietic stem cells.

    Science.gov (United States)

    Chan, Wai-In; Hannah, Rebecca L; Dawson, Mark A; Pridans, Clare; Foster, Donna; Joshi, Anagha; Göttgens, Berthold; Van Deursen, Jan M; Huntly, Brian J P

    2011-12-01

    The transcriptional coactivator Cbp plays an important role in a wide range of cellular processes, including proliferation, differentiation, and apoptosis. Although studies have shown its requirement for hematopoietic stem cell (HSC) development, its role in adult HSC maintenance, as well as the cellular and molecular mechanisms underlying Cbp function, is not clear. Here, we demonstrate a gradual loss of phenotypic HSCs and differentiation defects following conditional ablation of Cbp during adult homeostasis. In addition, Cbp-deficient HSCs reconstituted hematopoiesis with lower efficiency than their wild-type counterparts, and this response was readily exhausted under replicative stress. This phenotype relates to an alteration in cellular fate decisions for HSCs, with Cbp loss leading to an increase in differentiation, quiescence, and apoptosis. Genome-wide analyses of Cbp occupancy and differential gene expression upon Cbp deletion identified HSC-specific genes regulated by Cbp, providing a molecular basis for the phenotype. Finally, Cbp binding significantly overlapped at genes combinatorially bound by 7 major hematopoietic transcriptional regulators, linking Cbp to a critical HSC transcriptional regulatory network. Our data demonstrate that Cbp plays a role in adult HSC homeostasis by maintaining the balance between different HSC fate decisions, and our findings identify a putative HSC-specific transcriptional network coordinated by Cbp.

  7. Hematopoietic cell crisis: An early stage of evolving myeloid leukemia following radiation exposure

    Energy Technology Data Exchange (ETDEWEB)

    Seed, T.M.

    1990-01-01

    Under select radiological conditions, chronic radiation exposure elicits a high incidence of myeloproliferative disease, principally myeloid leukemia (ML), in beagles. Previously we demonstrated that for full ML expression, a four-stage preclinical sequence is required, namely (1) suppression, (2) recovery, (3) accommodation, and (4) preleukemic transition. Within this pathological sequence, a critical early event has been identified as the acquisition of radioresistance by hematopoietic progenitors that serves to mediate a newfound regenerative hematopoietic capacity. As such, this event sets the stage'' for preleukemic progression by initiating progression from preclinical phase 1 to 2. Due to the nature of target cell suppression, the induction of crisis, and the outgrowth of progenitors with altered phenotypes, this preleukemic event resembles the immortalization'' step of the in vitro transformation sequence following induction with either physical and chemical carcinogens. The radiological, temporal, and biological dictates governing this event have been extensively evaluated and will be discussed in light of their role in the induction and progression of chronic radiation leukemia. 35 refs., 2 tabs.

  8. SLAM family markers resolve functionally distinct subpopulations of hematopoietic stem cells and multipotent progenitors.

    Science.gov (United States)

    Oguro, Hideyuki; Ding, Lei; Morrison, Sean J

    2013-07-03

    Hematopoietic stem cells (HSCs) and multipotent hematopoietic progenitors (MPPs) are routinely isolated using various markers but remain heterogeneous. Here we show that four SLAM family markers, CD150, CD48, CD229, and CD244, can distinguish HSCs and MPPs from restricted progenitors and subdivide them into a hierarchy of functionally distinct subpopulations with stepwise changes in cell-cycle status, self-renewal, and reconstituting potential. CD229 expression largely distinguished lymphoid-biased HSCs from rarely dividing myeloid-biased HSCs, enabling prospective enrichment of these HSC subsets. Differences in CD229 and CD244 expression resolved CD150(-)CD48(-/low)Lineage(-/low)Sca-1(+)c-Kit(+) cells into a hierarchy of highly purified MPPs that retained erythroid and platelet potential but exhibited progressive changes in mitotic activity and reconstituting potential. Use of these markers, and reconstitution assays, showed that conditional deletion of Scf from endothelial cells and perivascular stromal cells eliminated the vast majority of bone marrow HSCs, including nearly all CD229(-/low) HSCs, demonstrating that quiescent HSCs are maintained by a perivascular niche. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Bmi1 confers resistance to oxidative stress on hematopoietic stem cells.

    Directory of Open Access Journals (Sweden)

    Shunsuke Nakamura

    Full Text Available BACKGROUND: The polycomb-group (PcG proteins function as general regulators of stem cells. We previously reported that retrovirus-mediated overexpression of Bmi1, a gene encoding a core component of polycomb repressive complex (PRC 1, maintained self-renewing hematopoietic stem cells (HSCs during long-term culture. However, the effects of overexpression of Bmi1 on HSCs in vivo remained to be precisely addressed. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we generated a mouse line where Bmi1 can be conditionally overexpressed under the control of the endogenous Rosa26 promoter in a hematopoietic cell-specific fashion (Tie2-Cre;R26Stop(FLBmi1. Although overexpression of Bmi1 did not significantly affect steady state hematopoiesis, it promoted expansion of functional HSCs during ex vivo culture and efficiently protected HSCs against loss of self-renewal capacity during serial transplantation. Overexpression of Bmi1 had no effect on DNA damage response triggered by ionizing radiation. In contrast, Tie2-Cre;R26Stop(FLBmi1 HSCs under oxidative stress maintained a multipotent state and generally tolerated oxidative stress better than the control. Unexpectedly, overexpression of Bmi1 had no impact on the level of intracellular reactive oxygen species (ROS. CONCLUSIONS/SIGNIFICANCE: Our findings demonstrate that overexpression of Bmi1 confers resistance to stresses, particularly oxidative stress, onto HSCs. This thereby enhances their regenerative capacity and suggests that Bmi1 is located downstream of ROS signaling and negatively regulated by it.

  10. Oncolytic viral purging of leukemic hematopoietic stem and progenitor cells with Myxoma virus.

    Science.gov (United States)

    Rahman, Masmudur M; Madlambayan, Gerard J; Cogle, Christopher R; McFadden, Grant

    2010-01-01

    High-dose chemotherapy and radiation followed by autologous blood and marrow transplantation (ABMT) has been used for the treatment of certain cancers that are refractory to standard therapeutic regimes. However, a major challenge with ABMT for patients with hematologic malignancies is disease relapse, mainly due to either contamination with cancerous hematopoietic stem and progenitor cells (HSPCs) within the autograft or the persistence of residual therapy-resistant disease niches within the patient. Oncolytic viruses represent a promising therapeutic approach to prevent cancer relapse by eliminating tumor-initiating cells that contaminate the autograft. Here we summarize an ex vivo "purging" strategy with oncolytic Myxoma virus (MYXV) to remove cancer-initiating cells from patient autografts prior to transplantation. MYXV, a novel oncolytic poxvirus with potent anti-cancer properties in a variety of in vivo tumor models, can specifically eliminate cancerous stem and progenitor cells from samples obtained from acute myelogenous leukemia (AML) patients, while sparing normal CD34+ hematopoietic stem and progenitor cells capable of rescuing hematopoiesis following high dose conditioning. We propose that a broader subset of patients with intractable hematologic malignancies who have failed standard therapy could become eligible for ABMT when the treatment schema is coupled with ex vivo oncolytic therapy.

  11. Nephrotic syndrome after allogeneic hematopoietic stem cell transplantation: etiology and pathogenesis.

    Science.gov (United States)

    Luo, Xiao-dan; Liu, Qi-fa; Zhang, Yu; Sun, Jing; Wang, Guo-bao; Fan, Zhi-ping; Yi, Zheng-shan; Ling, Yi-wen; Wei, Yong-qiang; Liu, Xiao-li; Xu, Bing

    2011-02-15

    In this study we investigated the etiology and pathogenesis of nephrotic syndrome (NS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 257 patients with hematopoietic malignancies who survived more than 2 months post allo-HSCT. Associations of NS with the conditioning regimen, graft versus host disease (GVHD), and other variables were analyzed. Pathologic features of the kidney, regulatory T cells (Tregs), interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) were studied. NS was identified in 9 patients. The number of Tregs at day+30, 60, 90, and 180 was lower in NS patients than non-NS patients (P=0.001, 0.001, 0.007, 0.003). Serum levels of IFN-γ and TNF-α were higher in NS patients (P=0.032, 0.001, respectively). NS post allo-HSCT was associated with the occurrence of chronic GVHD (P=0.02). NS post-HSCT is an immune disorder that may involve immune complex deposition, Th1 cytokines, and Tregs.

  12. Regulatory functions of TRAIL in hematopoietic progenitors: human umbilical cord blood and murine bone marrow transplantation.

    Science.gov (United States)

    Mizrahi, K; Stein, J; Pearl-Yafe, M; Kaplan, O; Yaniv, I; Askenasy, N

    2010-07-01

    The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) signaling pathway has selective toxicity to malignant cells. The TRAIL receptors DR4 and DR5 are expressed at low levels in human umbilical cord blood cells (3-15%) and are upregulated by incubation with the cognate ligand, triggering apoptosis in 70-80% of receptor-positive cells (P<0.001). Apoptosis is not induced in hematopoietic progenitors, as determined from sustained severe combined immunodeficiency reconstituting potential and clonogenic activity. Furthermore, elimination of dead cells after incubation with TRAIL for 72 h results in a threefold enrichment in myeloid progenitors. Exposure to TRAIL in semisolid cultures showed synergistic activity of DR4 and granulocyte/macrophage colony-stimulating factor in recruiting lineage-negative (lin(-)) and CD34(+) progenitors and in promoting the formation of large colonies. In murine bone marrow, approximately 30% of lin(-) cells express TRAIL-R2 (the only murine receptor), and the receptor is upregulated after transplantation in cycling and differentiating donor cells that home to the host marrow. However, this receptor is almost ubiquitously expressed in the most primitive (lin(-)SCA-1(+)c-kit(+)) progenitors, and stimulates the clonogenic activity of lin(-) cells (P<0.001), suggesting a tropic function after transplantation. It is concluded that TRAIL does not trigger apoptosis in hematopoietic progenitors, and upregulation of its cognate receptors under stress conditions mediates tropic signaling that supports recovery from hypoplasia.

  13. Angiotensin-converting enzyme (CD143) marks hematopoietic stem cells in human embryonic, fetal, and adult hematopoietic tissues

    NARCIS (Netherlands)

    Jokubaitis, Vanta J.; Sinka, Lidia; Driessen, Rebecca; Whitty, Genevieve; Haylock, David N.; Bertoncello, Ivan; Smith, Ian; Peault, Bruno; Tavian, Manuela; Simmons, Paul J.

    2008-01-01

    Previous studies revealed that mAb BB9 reacts with a subset of CD34(+) human BM cells with hematopoietic stem cell (HSC) characteristics. Here we map B89 expression throughout hernatopoietic development and show that the earliest definitive HSCs that arise at the ventral wall of the aorta and surrou

  14. Erythropoietic Potential of CD34+ Hematopoietic Stem Cells from Human Cord Blood and G-CSF-Mobilized Peripheral Blood

    Directory of Open Access Journals (Sweden)

    Honglian Jin

    2014-01-01

    Full Text Available Red blood cell (RBC supply for transfusion has been severely constrained by the limited availability of donor blood and the emergence of infection and contamination issues. Alternatively, hematopoietic stem cells (HSCs from human organs have been increasingly considered as safe and effective blood source. Several methods have been studied to obtain mature RBCs from CD34+ hematopoietic stem cells via in vitro culture. Among them, human cord blood (CB and granulocyte colony-stimulating factor-mobilized adult peripheral blood (mPB are common adult stem cells used for allogeneic transplantation. Our present study focuses on comparing CB- and mPB-derived stem cells in differentiation from CD34+ cells into mature RBCs. By using CD34+ cells from cord blood and G-CSF mobilized peripheral blood, we showed in vitro RBC generation of artificial red blood cells. Our results demonstrate that CB- and mPB-derived CD34+ hematopoietic stem cells have similar characteristics when cultured under the same conditions, but differ considerably with respect to expression levels of various genes and hemoglobin development. This study is the first to compare the characteristics of CB- and mPB-derived erythrocytes. The results support the idea that CB and mPB, despite some similarities, possess different erythropoietic potentials in in vitro culture systems.

  15. Risk factors for mortality in patients with bloodstream infections during the pre-engraftment period after hematopoietic stem cell transplantation

    Science.gov (United States)

    Karpov, Igor; Milanovich, Natalia; Uss, Anatoly; Iskrov, Igor

    2016-01-01

    Background Bloodstream infections (BSI) remain a frequent complication during the pre-engraftment period after hematopoietic stem cell transplantation (HSCT), resulting in high mortality rates. This study evaluated risk factors for mortality in hematopoietic stem cell transplant recipients with BSI in the pre-engraftment period. Methods This prospective case control study was performed at the Center of Hematology and Bone Marrow Transplantation in Minsk, Republic of Belarus. Data relating to patient age and gender, date and type of transplantation, conditioning chemotherapy regimen, microorganisms isolated from blood, and antibacterial therapy were prospectively collected from all hematopoietic stem cell recipients with microbiologically proven cases of BSI in the pre-engraftment period. The primary outcome was all-cause 30-day mortality after onset of febrile neutropenia. Results A total of 135 adult patients with microbiologically proven BSI after HSCT were studied, with 65.2% of cases caused by gram-negative microorganisms and 21.5% by non-fermenting bacteria. Inadequate empiric antibacterial therapy and isolation of carbapenem-resistant non-fermenting gram-negative bacteria (Acinetobacter baumannii and Pseudomonas aeruginosa) were independently associated with increased all-cause 30-day mortality in these patients. Conclusion The risk factors for mortality in adult patients with BSI in the pre-engraftment period after HSCT were inadequacy of empirical antibacterial therapy and isolation of carbapenem-resistant A. baumannii or P. aeruginosa. PMID:27382554

  16. Prevention of γ-radiation induced cellular genotoxicity by tempol: protection of hematopoietic system.

    Science.gov (United States)

    Ramachandran, Lakshmy; Nair, Cherupally Krishnan Krishnan

    2012-09-01

    Tempol (TPL) under in vitro conditions reduced the extent of gamma radiation induced membrane lipid peroxidation and disappearance of covalently closed circular form of plasmid pBR322. TPL protected cellular DNA from radiation-induced damage in various tissues under ex vivo and in vivo conditions as evidenced by comet assay. TPL also prevented radiation induced micronuclei formation (in peripheral blood leucocytes) and chromosomal aberrations (in bone marrow cells) in whole body irradiated mice. TPL enhanced the rate of repair of cellular DNA (blood leucocytes and bone marrow cells) damage when administered immediately after radiation exposure as revealed from the increased Cellular DNA Repair Index (CRI). The studies thus provided compelling evidence to reveal the effectiveness of TPL to protect hematopoietic system from radiation injury.

  17. SIRT1 deficiency compromises mouse embryonic stem cell hematopoietic differentiation, and embryonic and adult hematopoiesis in the mouse

    Science.gov (United States)

    Ou, Xuan; Chae, Hee-Don; Wang, Rui-Hong; Shelley, William C.; Cooper, Scott; Taylor, Tammi; Kim, Young-June; Deng, Chu-Xia; Yoder, Mervin C.

    2011-01-01

    SIRT1 is a founding member of a sirtuin family of 7 proteins and histone deacetylases. It is involved in cellular resistance to stress, metabolism, differentiation, aging, and tumor suppression. SIRT1−/− mice demonstrate embryonic and postnatal development defects. We examined hematopoietic and endothelial cell differentiation of SIRT1−/− mouse embryonic stem cells (ESCs) in vitro, and hematopoietic progenitors in SIRT1+/++/−, and −/− mice. SIRT1−/− ESCs formed fewer mature blast cell colonies. Replated SIRT1−/− blast colony-forming cells demonstrated defective hematopoietic potential. Endothelial cell production was unaltered, but there were defects in formation of a primitive vascular network from SIRT1−/−-derived embryoid bodies. Development of primitive and definitive progenitors derived from SIRT1−/− ESCs were also delayed and/or defective. Differentiation delay/defects were associated with delayed capacity to switch off Oct4, Nanog and Fgf5 expression, decreased β-H1 globin, β-major globin, and Scl gene expression, and reduced activation of Erk1/2. Ectopic expression of SIRT1 rescued SIRT1−/− ESC differentiation deficiencies. SIRT1−/− yolk sacs manifested fewer primitive erythroid precursors. SIRT1−/− and SIRT1+/− adult marrow had decreased numbers and cycling of hematopoietic progenitors, effects more apparent at 5%, than at 20%, oxygen tension, and these progenitors survived less well in vitro under conditions of delayed growth factor addition. This suggests a role for SIRT1 in ESC differentiation and mouse hematopoiesis. PMID:20966168

  18. 异基因造血干细胞移植治疗骨髓增生异常综合征临床疗效分析%Clinical efficacy of allogeneic hematopoietic stem cell transplantation on myelodysplastic syndrome

    Institute of Scientific and Technical Information of China (English)

    皖湘; 孙自敏; 刘会兰; 耿良权; 王兴兵; 丁凯阳; 童娟; 汤宝林; 王祖贻

    2012-01-01

    The aim of the study was to analyze retrospectively the indication and timing of transplantation, choice of hematopoietic stem cell source, preparative regimens for treating myelodysplastic syndrome ( MDS ) by allogeneic hematopoietic stem cell transplantation ( Allo-HSCT ) and its efficacy. Details of myeloid recovery were available from 21 patients, only one adult patient failed to have engraftment in the first transplantation with unrelated cord blood, but obtained hematopoiesis recovery by 4/6 HLA-matched related peripheral blood stem cell transplantation ( PBSCT ) combined with bone marrow transplantation ( BMT ) from her mother in thirty-eight days. Three patients died at median time of 13 months after transplantation, but none of 22 patients relapsed. When to proceed HSCT for MDS patients is dependent on international prognostic scoring system( IPSS ), patients at high risk group shall transplant as soon as possible after the disease diagnosed, and low-risk group shall be transplanted after treated with other drugs while the effect is not well. Patients without a matched family donor or unrelated donor are referred to HLA-haploidentical unrelated cord blood transplantation ( UCBT ). Preparative regimens include myeloablative or reduced intensity conditioning ( RIC ), and the outcome of transplantation is comparable.%回顾性分析异基因造血干细胞移植(Allo-HSCT)治疗骨髓增生异常综合征(MDS)的适应证、治疗时机、移植物的选择、移植预处理方案的选择和移植疗效.22例患者中21例获得造血重建,1例非血缘脐血移植(UCBT)未获得植入的成人患者,于非血缘脐血移植(UCBT)后38 d进行母亲HLA4/6相合的外周血联合骨髓造血干细胞移植解救治疗获得植入.22例中死亡3例,无1例复发.MDS患者何时进行Allo-HSCT需依据国际预后积分系统(IPSS )对患者分组,评分属于高危组的患者宜在疾病确诊后尽早进行移植,而低危组的患者可在其他药物治

  19. Potent graft-versus-leukemia effect after reduced-intensity allogeneic SCT for intermediate-risk AML with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD.

    Science.gov (United States)

    Labouré, Gaëlle; Dulucq, Stéphanie; Labopin, Myriam; Tabrizi, Reza; Guérin, Estelle; Pigneux, Arnaud; Lafarge, Xavier; Leguay, Thibaut; Bouabdallah, Krimo; Dilhuydy, Marie-Sarah; Duclos, Cédric; Lascaux, Axelle; Marit, Gérald; Mahon, François-Xavier; Boiron, Jean-Michel; Milpied, Noël; Vigouroux, Stéphane

    2012-12-01

    To investigate the role of reduced-intensity allogeneic (RIC-allo) stem cell transplant (SCT) as postremission therapy in adult intermediate-risk patients with acute myelogenous leukemia (AML) with FLT3-ITD or wild-type NPM1 and CEBPA without FLT3-ITD, we conducted a single-center retrospective study between January 2001 and December 2010. Sixty-six patients were included: 37 treated with RIC-alloSCT and 29 with nonallogeneic SCT therapies. Both groups were comparable concerning age, WBC count at diagnosis, gender, karyotype, genotype, and number of courses of chemotherapy to reach complete remission (CR1). Median follow-up after CR1 was 37 months (range, 11-112 months) and 48 months (range, 9-83 months) in the allo and no-allo groups, respectively. In the allo versus no-allo groups, the 3-year cumulative incidence of relapse (CIR) rates were 25% ± 8% versus 61% ± 9%; P = .005. The 3-year nonrelapse mortality (NRM), overall survival (OS), and relapse-free survival (RFS) were 22% ± 7% versus 4% ± 4% (P = .005), 52% ± 9% versus 44% ± 10% (P = .75), and 53% ± 9% versus 35% ± 9% (P = .28), respectively. Multivariate analysis indicated that CIR was reduced by allo (hazard ratio [HR], 0.32; P = .01). A landmark analysis performed at day 185 after CR1 confirmed a lower CIR after allo. RIC-allo reduces the risk of relapse, suggesting a potent graft-versus-leukemia (GVL) effect in these patients at a high risk of relapse.

  20. Growth Factors: Production of Monocyte Chemotactic Protein-1 (MCP-1/JE) by Bone Marrow Stromal Cells: Effect on the Migration and Proliferation of Hematopoietic Progenitor Cells.

    Science.gov (United States)

    Xu, Y. X.; Talati, B. R.; Janakiraman, N.; Chapman, R. A.; Gautam, S. C.

    1999-01-01

    Recombinant chemotactic cytokines (chemokines) have been shown to modulate in vitro proliferation of hematopoietic progenitor cells. Whether bone marrow stromal cells produce chemokines and the physiological role they may have in the regulation of hematopoiesis has largely remained unexamined. We have examined the expression of monocyte chemoattractant protein-1 (MCP-1/JE) in bone marrow stromal cells and its effect on the migration and proliferation of murine hematopoietic progenitor cells. Freshly derived murine bone marrow stromal cells were found to secrete abundant amounts of MCP-1/JE, which was further increased upon stimulation of stromal cells with pro-inflammatory agents LPS, IL1-alpha, IFN-gamma, or TNF-alpha. Although culture supernatant conditioned by stromal cells exhibited chemotactic activity toward hematopoietic progenitor cells, the chemotactic activity was not due to MCP-1/JE. Furthermore, rMCP-1/JE also failed to induce migration of progenitor cells. MCP-1/JE, however, caused 20 to 30% increase in the clonal expansion of progenitor cells. Thus, although MCP-1/JE does not chemoattract hematopoietic progenitor cells it may have a role in their proliferation and clonal expansion.

  1. JAK2V617F expression in mice amplifies early hematopoietic cells and gives them a competitive advantage that is hampered by IFNα.

    Science.gov (United States)

    Hasan, Salma; Lacout, Catherine; Marty, Caroline; Cuingnet, Marie; Solary, Eric; Vainchenker, William; Villeval, Jean-Luc

    2013-08-22

    The acquired gain-of-function V617F mutation in the Janus Kinase 2 (JAK2(V617F)) is the main mutation involved in BCR/ABL-negative myeloproliferative neoplasms (MPNs), but its effect on hematopoietic stem cells as a driver of disease emergence has been questioned. Therefore, we reinvestigated the role of endogenous expression of JAK2(V617F) on early steps of hematopoiesis as well as the effect of interferon-α (IFNα), which may target the JAK2(V617F) clone in humans by using knock-in mice with conditional expression of JAK2(V617F) in hematopoietic cells. These mice develop a MPN mimicking polycythemia vera with large amplification of myeloid mature and precursor cells, displaying erythroid endogenous growth and progressing to myelofibrosis. Interestingly, early hematopoietic compartments [Lin-, LSK, and SLAM (LSK/CD48-/CD150+)] increased with the age. Competitive repopulation assays demonstrated disease appearance and progressive overgrowth of myeloid, Lin-, LSK, and SLAM cells, but not lymphocytes, from a low number of engrafted JAK2(V617F) SLAM cells. Finally, IFNα treatment prevented disease development by specifically inhibiting JAK2(V617F) cells at an early stage of differentiation and eradicating disease-initiating cells. This study shows that JAK2(V617F) in mice amplifies not only late but also early hematopoietic cells, giving them a proliferative advantage through high cell cycling and low apoptosis that may sustain MPN emergence but is lost upon IFNα treatment.

  2. Haemopedia: An Expression Atlas of Murine Hematopoietic Cells

    Directory of Open Access Journals (Sweden)

    Carolyn A. de Graaf

    2016-09-01

    Full Text Available Hematopoiesis is a multistage process involving the differentiation of stem and progenitor cells into distinct mature cell lineages. Here we present Haemopedia, an atlas of murine gene-expression data containing 54 hematopoietic cell types, covering all the mature lineages in hematopoiesis. We include rare cell populations such as eosinophils, mast cells, basophils, and megakaryocytes, and a broad collection of progenitor and stem cells. We show that lineage branching and maturation during hematopoiesis can be reconstructed using the expression patterns of small sets of genes. We also have identified genes with enriched expression in each of the mature blood cell lineages, many of which show conserved lineage-enriched expression in human hematopoiesis. We have created an online web portal called Haemosphere to make analyses of Haemopedia and other blood cell transcriptional datasets easier. This resource provides simple tools to interrogate gene-expression-based relationships between hematopoietic cell types and genes of interest.

  3. Aging, Clonality, and Rejuvenation of Hematopoietic Stem Cells.

    Science.gov (United States)

    Akunuru, Shailaja; Geiger, Hartmut

    2016-08-01

    Aging is associated with reduced organ function and increased disease incidence. Hematopoietic stem cell (HSC) aging driven by both cell intrinsic and extrinsic factors is linked to impaired HSC self-renewal and regeneration, aging-associated immune remodeling, and increased leukemia incidence. Compromised DNA damage responses and the increased production of reactive oxygen species (ROS) have been previously causatively attributed to HSC aging. However, recent paradigm-shifting concepts, such as global epigenetic and cytoskeletal polarity shifts, cellular senescence, as well as the clonal selection of HSCs upon aging, provide new insights into HSC aging mechanisms. Rejuvenating agents that can reprogram the epigenetic status of aged HSCs or senolytic drugs that selectively deplete senescent cells provide promising translational avenues for attenuating hematopoietic aging and, potentially, alleviating aging-associated immune remodeling and myeloid malignancies.

  4. Imaging Macrophage and Hematopoietic Progenitor Proliferation in Atherosclerosis

    DEFF Research Database (Denmark)

    Ye, Yu-Xiang; Calcagno, Claudia; Binderup, Tina

    2015-01-01

    RATIONALE: Local plaque macrophage proliferation and monocyte production in hematopoietic organs promote progression of atherosclerosis. Therefore, noninvasive imaging of proliferation could serve as a biomarker and monitor therapeutic intervention. OBJECTIVE: To explore (18)F-FLT positron emission...... tomography-computed tomography imaging of cell proliferation in atherosclerosis. METHODS AND RESULTS: (18)F-FLT positron emission tomography-computed tomography was performed in mice, rabbits, and humans with atherosclerosis. In apolipoprotein E knock out mice, increased (18)F-FLT signal was observed...... with atherosclerosis, (18)F-FLT signal significantly increased in the inflamed carotid artery and in the aorta. CONCLUSIONS: (18)F-FLT positron emission tomography imaging may serve as an imaging biomarker for cell proliferation in plaque and hematopoietic activity in individuals with atherosclerosis....

  5. Immature hematopoietic stem cells undergo maturation in the fetal liver.

    Science.gov (United States)

    Kieusseian, Aurelie; Brunet de la Grange, Philippe; Burlen-Defranoux, Odile; Godin, Isabelle; Cumano, Ana

    2012-10-01

    Hematopoietic stem cells (HSCs), which are defined by their capacity to reconstitute adult conventional mice, are first found in the dorsal aorta after 10.5 days post coitus (dpc) and in the fetal liver at 11 dpc. However, lympho-myeloid hematopoietic progenitors are detected in the dorsal aorta from 9 dpc, raising the issue of their role in establishing adult hematopoiesis. Here, we show that these progenitors are endowed with long-term reconstitution capacity, but only engraft natural killer (NK)-deficient Rag2γc(-/-) mice. This novel population, called here immature HSCs, evolves in culture with thrombopoietin and stromal cells, into HSCs, defined by acquisition of CD45 and MHC-1 expression and by the capacity to reconstitute NK-competent mice. This evolution occurs during ontogeny, as early colonization of fetal liver by immature HSCs precedes that of HSCs. Moreover, organ culture experiments show that immature HSCs acquire, in this environment, the features of HSCs.

  6. Polycomb group proteins in hematopoietic stem cell aging and malignancies.

    Science.gov (United States)

    Klauke, Karin; de Haan, Gerald

    2011-07-01

    Protection of the transcriptional "stemness" network is important to maintain a healthy hematopoietic stem cells (HSCs) compartment during the lifetime of the organism. Recent evidence shows that fundamental changes in the epigenetic status of HSCs might be one of the driving forces behind many age-related HSC changes and might pave the way for HSC malignant transformation and subsequent leukemia development, the incidence of which increases exponentially with age. Polycomb group (PcG) proteins are key epigenetic regulators of HSC cellular fate decisions and are often found to be misregulated in human hematopoietic malignancies. In this review, we speculate that PcG proteins balance HSC aging against the risk of developing cancer, since a disturbance in PcG genes and proteins affects several important cellular processes such as cell fate decisions, senescence, apoptosis, and DNA damage repair.

  7. Regulation of stem cells in the zebra fish hematopoietic system.

    Science.gov (United States)

    Huang, H-T; Zon, L I

    2008-01-01

    Hematopoietic stem cells (HSCs) have been used extensively as a model for stem cell biology. Stem cells share the ability to self-renew and differentiate into multiple cell types, making them ideal candidates for tissue regeneration or replacement therapies. Current applications of stem cell technology are limited by our knowledge of the molecular mechanisms that control their proliferation and differentiation, and various model organisms have been used to fill these gaps. This chapter focuses on the contributions of the zebra fish model to our understanding of stem cell regulation within the hematopoietic system. Studies in zebra fish have been valuable for identifying new genetic and signaling factors that affect HSC formation and development with important implications for humans, and new advances in the zebra fish toolbox will allow other aspects of HSC behavior to be investigated as well, including migration, homing, and engraftment.

  8. Mitophagy in hematopoietic stem cells: the case for exploration.

    Science.gov (United States)

    Joshi, Aashish; Kundu, Mondira

    2013-11-01

    Hematopoietic stem cells (HSCs) are inherently quiescent and self-renewing, yet can differentiate and commit to multiple blood cell types. Intracellular mitochondrial content is dynamic, and there is an increase in mitochondrial content during differentiation and lineage commitment in HSCs. HSCs reside in a hypoxic niche within the bone marrow and rely heavily on glycolysis, while differentiated and committed progenitors rely on oxidative phosphorylation. Increased oxidative phosphorylation during differentiation and commitment is not only due to increased mitochondrial content but also due to changes in mitochondrial cytosolic distribution and efficiency. These changes in the intracellular mitochondrial landscape contribute signals toward regulating differentiation and commitment. Thus, a functional relationship exists between the mitochondria in HSCs and the state of the HSCs (i.e., stemness vs. differentiated). This review focuses on how autophagy-mediated mitochondrial clearance (i.e., mitophagy) may affect HSC mitochondrial content, thereby influencing the fate of HSCs and maintenance of hematopoietic homeostasis.

  9. Rhizomucor and Scedosporium Infection Post Hematopoietic Stem-Cell Transplant

    Directory of Open Access Journals (Sweden)

    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.

  10. Mobilization of hematopoietic progenitor cells in patients with liver cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Ursula; M; Gehling; Marc; Willems; Kathleen; Schlagner; Ralf; A; Benndorf; Maura; Dandri; Jrg; Petersen; Martina; Sterneck; Joerg-Matthias; Pollok; Dieter; K; Hossfeld; Xavier; Rogiers

    2010-01-01

    AIM:To test the hypothesis that liver cirrhosis is associated with mobilization of hematopoietic progenitor cells. METHODS:Peripheral blood samples from 72 patients with liver cirrhosis of varying etiology were analyzed by flow cytometry.Identified progenitor cell subsets were immunoselected and used for functional assays in vitro. Plasma levels of stromal cell-derived factor-1(SDF-1) were measured using an enzyme linked immunosorbent assay.RESULTS:Progenitor cells with a CD133 + /CD45 + CD14 + phenotype we...

  11. Effects of endotoxin on proliferation of human hematopoietic cell precursors

    OpenAIRE

    Rinehart, John J.; Keville, Lisa

    1997-01-01

    In examining the effects of corticosteroids on hematopoiesis in vitro, we observed that results were highly dependent on the lot of commercial fetal calf serum (FCS) utilized. We hypothesized that this variability correlated with the picogram (pg) level of endotoxin contaminating the FCS. Randomly obtained commercial lots of FCS contained 0.39 to 187 pg/ml of lipopolysaccharide (LPS). Standard FCS concentrations in hematopoietic precursor proliferation assays (granulocyte-marcrophage colony f...

  12. Cholesterol and hematopoietic stem cells: inflammatory mediators of atherosclerosis.

    Science.gov (United States)

    Lang, Jennifer K; Cimato, Thomas R

    2014-05-01

    Atherosclerosis causing heart attack and stroke is the leading cause of death in the modern world. Therapy for end-stage atherosclerotic disease using CD34(+) hematopoietic cells has shown promise in human clinical trials, and the in vivo function of hematopoietic and progenitor cells in atherogenesis is becoming apparent. Inflammation plays a central role in the pathogenesis of atherosclerosis. Cholesterol is a modifiable risk factor in atherosclerosis, but in many patients cholesterol levels are only mildly elevated. Those with high cholesterol levels often have elevated circulating monocyte and neutrophil counts. How cholesterol affects inflammatory cell levels was not well understood. Recent findings have provided new insight into the interaction among hematopoietic stem cells, cholesterol, and atherosclerosis. In mice, high cholesterol levels or inactivation of cholesterol efflux transporters have multiple effects on hematopoietic stem cells (HSPCs), including promoting their mobilization into the bloodstream, increasing proliferation, and differentiating HSPCs to the inflammatory monocytes and neutrophils that participate in atherosclerosis. Increased levels of interleukin-23 (IL-23) stimulate IL-17 production, resulting in granulocyte colony-stimulating factor (G-CSF) secretion, which subsequently leads to HSPC release into the bloodstream. Collectively, these findings clearly link elevated cholesterol levels to increased circulating HSPC levels and differentiation to inflammatory cells that participate in atherosclerosis. Seminal questions remain to be answered to understand how cholesterol affects HSPC-mobilizing cytokines and the role they play in atherosclerosis. Translation of findings in animal models to human subjects may include HSPCs as new targets for therapy to prevent or regress atherosclerosis in patients.

  13. Leukemia in donor cells after allogeneic hematopoietic stem cell transplant

    OpenAIRE

    2002-01-01

    The development of leukemia in donor cells after allogeneic hematopoietic stem cell transplant is an extremely rare event. We report here the case of a patient who developed myelodysplastic syndrome/acute myeloid leukemia, in cells of donor origin 3.5 years after related donor HSCT for refractory chronic lymphocytic leukemia and therapy-induced myelodysplastic syndrome. The origin of the leukemia was determined by analysis of minisatillite polymorphism tested on CD34(+) cells.

  14. Formation of an adherent hematopoietic expansion culture using fucoidan.

    Science.gov (United States)

    Irhimeh, Mohammad R; Fitton, J Helen; Ko, Kap-Hyoun; Lowenthal, Ray M; Nordon, Robert E

    2011-09-01

    Expansion of transplantable cord blood (CB) progenitors using a stroma requires provision of an exogenous cell source because of the low frequency of stromal precursor cells in CB. A simpler approach from a clinical regulatory perspective would be to provide synthetic extracellular matrix. The aim of this study was to characterize the effect on hematopoietic cell culture of fucoidan. The modulation of cytokine-driven hematopoietic cell expansion by fucoidan was investigated using two-level fractional and full factorial experimental designs. Mobilized peripheral blood (PB) CD34(+) cells were grown over 10 days in various combinations of FL, SCF, TPO, G-CSF, and SDF-1. Cultures were analyzed by immunophenotype. The effect of fucoidan on the divisional recruitment of CD34(+) cells was studied by CFDA-SE division tracking. Fucoidan was adsorbed by polystyrene to tissue culture plates and promoted formation of an adherent hematopoietic culture. Factorial design experiments with mobilized PB-CD34(+) cells showed that fucoidan reduced the production of CD34(+) cells and CD34(+)CXCR4(+) ratio but did not affect the production of monocytic, granulocytic, or megakaryocytic cells. The inhibitory effect of fucoidan on expansion of CB-CD34(+) cells was greater than mobilized PB. Division tracking analysis showed that CD34(+) cell generation times were lengthened by fucoidan. Fucoidan binds growth factors via their heparin-binding domain. The formation of an adherent hematopoietic culture system by fucoidan is most likely mediated by the binding of L-selectin and integrin-αMβ2 on myeloids. Fucoidan deserves further investigation as glycan scaffold that is suitable for immobilization of other matrix molecules thought to comprise blood stem cell niche.

  15. Intestinal dysbiosis and allogeneic hematopoietic progenitor cell transplantation

    OpenAIRE

    Raghunathan, Vikram M.; Sheng, Iris; Lim, Seah H.

    2016-01-01

    The intestinal microbiota is a diverse and dynamic ecosystem that is increasingly understood to play a vital role in human health. Hematopoietic stem cell transplant recipients undergo prolonged exposure to antimicrobials, chemotherapeutic agents, and immunosuppressants, resulting in profound shifts in the gut microbiome. A growing body of research has revealed the ways in which these microbiologic shifts shape immune modulation, affecting susceptibility to infections and graft-versus-host di...

  16. Cell cycle regulation of hematopoietic stem or progenitor cells.

    Science.gov (United States)

    Hao, Sha; Chen, Chen; Cheng, Tao

    2016-05-01

    The highly regulated process of blood production is achieved through the hierarchical organization of hematopoietic stem cell (HSC) subsets and their progenies, which differ in self-renewal and differentiation potential. Genetic studies in mice have demonstrated that cell cycle is tightly controlled by the complex interplay between extrinsic cues and intrinsic regulatory pathways involved in HSC self-renewal and differentiation. Deregulation of these cellular programs may transform HSCs or hematopoietic progenitor cells (HPCs) into disease-initiating stem cells, and can result in hematopoietic malignancies such as leukemia. While previous studies have shown roles for some cell cycle regulators and related signaling pathways in HSCs and HPCs, a more complete picture regarding the molecular mechanisms underlying cell cycle regulation in HSCs or HPCs is lacking. Based on accumulated studies in this field, the present review introduces the basic components of the cell cycle machinery and discusses their major cellular networks that regulate the dormancy and cell cycle progression of HSCs. Knowledge on this topic would help researchers and clinicians to better understand the pathogenesis of relevant blood disorders and to develop new strategies for therapeutic manipulation of HSCs.

  17. SBR-Blood: systems biology repository for hematopoietic cells.

    Science.gov (United States)

    Lichtenberg, Jens; Heuston, Elisabeth F; Mishra, Tejaswini; Keller, Cheryl A; Hardison, Ross C; Bodine, David M

    2016-01-04

    Extensive research into hematopoiesis (the development of blood cells) over several decades has generated large sets of expression and epigenetic profiles in multiple human and mouse blood cell types. However, there is no single location to analyze how gene regulatory processes lead to different mature blood cells. We have developed a new database framework called hematopoietic Systems Biology Repository (SBR-Blood), available online at http://sbrblood.nhgri.nih.gov, which allows user-initiated analyses for cell type correlations or gene-specific behavior during differentiation using publicly available datasets for array- and sequencing-based platforms from mouse hematopoietic cells. SBR-Blood organizes information by both cell identity and by hematopoietic lineage. The validity and usability of SBR-Blood has been established through the reproduction of workflows relevant to expression data, DNA methylation, histone modifications and transcription factor occupancy profiles. Published by Oxford University Press on behalf of Nucleic Acids Research 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  18. Aging of hematopoietic stem cells: DNA damage and mutations?

    Science.gov (United States)

    Moehrle, Bettina M; Geiger, Hartmut

    2016-10-01

    Aging in the hematopoietic system and the stem cell niche contributes to aging-associated phenotypes of hematopoietic stem cells (HSCs), including leukemia and aging-associated immune remodeling. Among others, the DNA damage theory of aging of HSCs is well established, based on the detection of a significantly larger amount of γH2AX foci and a higher tail moment in the comet assay, both initially thought to be associated with DNA damage in aged HSCs compared with young cells, and bone marrow failure in animals devoid of DNA repair factors. Novel data on the increase in and nature of DNA mutations in the hematopoietic system with age, the quality of the DNA damage response in aged HSCs, and the nature of γH2AX foci question a direct link between DNA damage and the DNA damage response and aging of HSCs, and rather favor changes in epigenetics, splicing-factors or three-dimensional architecture of the cell as major cell intrinsic factors of HSCs aging. Aging of HSCs is also driven by a strong contribution of aging of the niche. This review discusses the DNA damage theory of HSC aging in the light of these novel mechanisms of aging of HSCs.

  19. Hematopoietic Stem Cells in Neural-crest Derived Bone Marrow.

    Science.gov (United States)

    Jiang, Nan; Chen, Mo; Yang, Guodong; Xiang, Lusai; He, Ling; Hei, Thomas K; Chotkowski, Gregory; Tarnow, Dennis P; Finkel, Myron; Ding, Lei; Zhou, Yanheng; Mao, Jeremy J

    2016-12-21

    Hematopoietic stem cells (HSCs) in the endosteum of mesoderm-derived appendicular bones have been extensively studied. Neural crest-derived bones differ from appendicular bones in developmental origin, mode of bone formation and pathological bone resorption. Whether neural crest-derived bones harbor HSCs is elusive. Here, we discovered HSC-like cells in postnatal murine mandible, and benchmarked them with donor-matched, mesoderm-derived femur/tibia HSCs, including clonogenic assay and long-term culture. Mandibular CD34 negative, LSK cells proliferated similarly to appendicular HSCs, and differentiated into all hematopoietic lineages. Mandibular HSCs showed a consistent deficiency in lymphoid differentiation, including significantly fewer CD229 + fractions, PreProB, ProB, PreB and B220 + slgM cells. Remarkably, mandibular HSCs reconstituted irradiated hematopoietic bone marrow in vivo, just as appendicular HSCs. Genomic profiling of osteoblasts from mandibular and femur/tibia bone marrow revealed deficiencies in several HSC niche regulators among mandibular osteoblasts including Cxcl12. Neural crest derived bone harbors HSCs that function similarly to appendicular HSCs but are deficient in the lymphoid lineage. Thus, lymphoid deficiency of mandibular HSCs may be accounted by putative niche regulating genes. HSCs in craniofacial bones have functional implications in homeostasis, osteoclastogenesis, immune functions, tumor metastasis and infections such as osteonecrosis of the jaw.

  20. [Latent infection of human herpes virus in hematopoietic system].

    Science.gov (United States)

    Wu, Ke-Fu; Ma, Xiao-Tong; Zheng, Guo-Guang; Song, Yu-Hua

    2008-12-01

    Up to date, eight types of human herpes viruses have been identified, all of which are ubiquitous, and usually establish latent infection in the host after primary infection. Since most of the herpes viruses are maintained in an asymptomatic form, they are often neglected. However, under some circumstances, these herpes viruses can cause fatal or severe diseases. Furthermore, the association of herpes viruses with hematopoietic malignancies is attracting researchers' attention. With the extensive development of hematopoietic stem cell and organ transplantation, reports regarding transplantation failure and complication caused by infection of human herpes virus has been increasing. Cytokine storm was firstly suggested as the mechanism of graft-versus-host diseases. In recent years, which has also been applied in the pathogenesis research of inflammation, and is supposed to play an important role in severe virus infection. In this paper, through discussing the possible role of latent infection of human herpes virus in the failure or complication of bone marrow or hematopoietic stem cell transplantation, and in refractory leukemia, the function and significance of latent infection of human herpes virus and the cytokine storm it caused were investigated.

  1. The Notch pathway in the developing hematopoietic system.

    Science.gov (United States)

    Bigas, Anna; Robert-Moreno, Alex; Espinosa, Lluís

    2010-01-01

    The main function of the Notch signaling pathway is to generate cell diversity during both embryonic development and adult tissue homeostasis. The extended use of this pathway, together with its conservation during evolution, is indicative of its importance. During embryonic development, the vascular and hematopoietic systems are intimately associated and Notch signals are responsible for the correct specification of both systems. More explicitly, Notch is required for the induction of the arterial program; however, it is simultaneously or consecutively also involved in the generation of hematopoietic stem cells. Although both genetic programs are different, they are both implemented in endothelial cells of the dorsal aorta in the midgestation embryo. This close association during the development of arteries and blood has hindered our understanding of Notch function in the generation of hematopoietic stem cells. Here, we will review the work from recent years showing how Notch participates in the embryonic development of hematopoiesis in the mouse, but also in other organisms such as chick, zebrafish and flies.

  2. Hematopoietic Stem Cells Expansion in Rotating Wall Vessel

    Institute of Scientific and Technical Information of China (English)

    Yang LIU; Tian-Qing LIU; Xiu-Bo FAN; Dan GE; Zhan-Feng CUI; Xue-Hu MA

    2005-01-01

    @@ 1 Introduction Clinical trials have demonstrated that ex vivo expanded hematopoietic stem cells (HSCs) and progenitors offer great promise in reconstituting in vivo hematopoiesis in patients who have undergone intensive chemotherapy.It is therefore necessary to develop a clinical-scale culture system to provide the expanded HSCs and progenitors.Static culture systems such as T-flasks and gas-permeable blood bags are the most widely used culture devices for expanding hematopoietic cells. But they reveal several inherent limitations: ineffective mixing, lack of control options for dissolved oxygen and pH and difficulty in continuous feeding, which restricts the usefulness of static systems. Several advanced bioreactors have been used in the field of HSCs expansion. But hematopoietic cells are extremely sensitive to shear, so cells in bioreactors such as stirred and perfusion culture systems may suffer physical damage. This problem will be improved by applying the rotating wall vessel (RWV) bioreactor in clinic because of its low shear and unique structure. In this research, cord blood (CB) HSCs were expanded by means of a cell-dilution feeding protocol in RWV.

  3. Generation of mature hematopoietic cells from human pluripotent stem cells.

    Science.gov (United States)

    Togarrati, Padma Priya; Suknuntha, Kran

    2012-06-01

    A number of malignant and non-malignant hematological disorders are associated with the abnormal production of mature blood cells or primitive hematopoietic precursors. Their capacity for continuous self-renewal without loss of pluripotency and the ability to differentiate into adult cell types from all three primitive germ layers make human embryonic stem cells and induced pluripotent stem cells (hiPSCs) attractive complementary cell sources for large-scale production of transfusable mature blood cell components in cell replacement therapies. The generation of patient-specific hematopoietic stem/precursor cells from iPSCs by the regulated manipulation of various factors involved in reprograming to ensure complete pluripotency, and developing innovative differentiation strategies for generating unlimited supply of clinically safe, transplantable, HLA-matched cells from hiPSCs to outnumber the inadequate source of hematopoietic stem cells obtained from cord blood, bone marrow and peripheral blood, would have a major impact on the field of regenerative and personalized medicine leading to translation of these results from bench to bedside.

  4. Experiments on Gene Transferring to Primary Hematopoietic Cells by Liposome

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Liposomes have showed many advantages in mediating exogenous gene into many cell types in vitro and in vivo. But few data are available concerning gene transfer into hematopoietic cells. In this report, we described two-marker genes (Neo R and Lac Z) co-transferred into hematopoietic cells of human and mouse by using liposome in vitro. The efficiency of gene transfer was tested by Xgal staining and observation of colony formation. The X-gal blue staining rate of transduced cells was about (13.33±2. 68) % in human and about (16. 28±2.95) % in mouse without G418 selection. After G418 selection, the blue cell rate was (46. 06±3.47)%in human and (43. 45±4. 1) % in mouse, which were markedly higher than those before selection, suggesting that high-efficiency gene transfer and expression could be attained in primary hematopoietic cells using this easy and harmless transduction protocol. At the same time, this protocol provided experimental data for clinicians to investigate the biology of marrow reconstitution and trace the origin of relapse after autologous bone marrow transplantation for the patients with leukemia.

  5. Critical early events in hematopoietic cell seeding and engraftment.

    Directory of Open Access Journals (Sweden)

    Jerry Stein

    2005-12-01

    Full Text Available Durable hematopoietic stem cell engraftment requires efficient homing to and seeding in the recipient bone marrow. Dissection of cellular and molecular mechanisms by retrospective analysis of functional engraftment studies imposes severe limitations on the understanding of the early stages of this process. We have established an experimental approach for in vivo functional imaging of labeled cells at the level of recipient bone marrow in real time. The adhesive interaction of hematopoietic cells with the bone marrow stroma evolves as the most important early event. Adhesion to the marrow, rather than the vascular endothelium, determines the efficiency of both homing and seeding, and is absolutely essential to maintain cell viability in the marrow. Seeding and engraftment may be improved either by bypassing homing or by localized transplant of a large number of cells in a relatively small marrow space. There is functional redundancy in the molecular pathways that mediate the cell-stroma interaction, such that blockage of a single pathway has only minor effect on homing and seeding. We hypothesize that successfully seeding-engrafting cells undergo extensive phenotypic changes as a consequence of interaction with the stroma, without engaging in rapid proliferation. Surprisingly, Fas-ligand appears to promote hematopoietic cell engraftment by immunomodulatory and trophic effects.

  6. Critical early events in hematopoietic cell seeding and engraftment.

    Science.gov (United States)

    Stein, Jerry; Yaniv, Isaac; Askenasy, Nadir

    2005-01-01

    Durable hematopoietic stem cell engraftment requires efficient homing to and seeding in the recipient bone marrow. Dissection of cellular and molecular mechanisms by retrospective analysis of functional engraftment studies imposes severe limitations on the understanding of the early stages of this process. We have established an experimental approach for in vivo functional imaging of labeled cells at the level of recipient bone marrow in real time. The adhesive interaction of hematopoietic cells with the bone marrow stroma evolves as the most important early event. Adhesion to the marrow, rather than the vascular endothelium, determines the efficiency of both homing and seeding, and is absolutely essential to maintain cell viability in the marrow. Seeding and engraftment may be improved either by bypassing homing or by localized transplant of a large number of cells in a relatively small marrow space. There is functional redundancy in the molecular pathways that mediate the cell-stroma interaction, such that blockage of a single pathway has only minor effect on homing and seeding. We hypothesize that successfully seeding-engrafting cells undergo extensive phenotypic changes as a consequence of interaction with the stroma, without engaging in rapid proliferation. Surprisingly, Fas-ligand appears to promote hematopoietic cell engraftment by immunomodulatory and trophic effects.

  7. Delivery of Genome Editing Reagents to Hematopoietic Stem/Progenitor Cells.

    Science.gov (United States)

    Hoban, Megan D; Romero, Zulema; Cost, Gregory J; Mendel, Matthew; Holmes, Michael; Kohn, Donald B

    2016-02-03

    This unit describes the protocol for the delivery of reagents for targeted genome editing to CD34(+) hematopoietic stem/progenitor cells (HSPCs). Specifically, this unit focuses on the process of thawing and pre-stimulating CD34(+) HSPCs, as well as the details of their electroporation with in vitro-transcribed mRNA-encoding site-specific nucleases [in this case zinc-finger nucleases (ZFNs)]. In addition, discussed is delivery of a gene editing donor template in the form of an oligonucleotide or integrase-defective lentiviral vector (IDLV). Finally, an analysis of cell survival following treatment and downstream culture conditions are presented. While optimization steps might be needed for each specific application with respect to nuclease and donor template amount, adherence to this protocol will serve as an excellent starting point for this further work.

  8. Fluorophore-conjugated iron oxide nanoparticle labeling and analysis of engrafting human hematopoietic stem cells

    DEFF Research Database (Denmark)

    Maxwell, Dustin J; Bonde, Jesper; Hess, David A

    2008-01-01

    The use of nanometer-sized iron oxide particles combined with molecular imaging techniques enables dynamic studies of homing and trafficking of human hematopoietic stem cells (HSC). Identifying clinically applicable strategies for loading nanoparticles into primitive HSC requires strictly defined...... culture conditions to maintain viability without inducing terminal differentiation. In the current study, fluorescent molecules were covalently linked to dextran-coated iron oxide nanoparticles (Feridex) to characterize human HSC labeling to monitor the engraftment process. Conjugating fluorophores...... or in vivo. Transplantation of purified primary human cord blood lineage-depleted and CD34(+) cells into immunodeficient mice allowed detection of labeled human HSC in the recipient bones. Flow cytometry was used to precisely quantitate the cell populations that had sequestered the nanoparticles...

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

    Directory of Open Access Journals (Sweden)

    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.

  10. In vivo imaging of hematopoietic stem cell development in the zebrafish

    Institute of Scientific and Technical Information of China (English)

    Panpan Zhang; Feng Liu

    2011-01-01

    In vivo imaging is crucial for developmental biology and can further help to follow cell development/differentiation in normal and pathological conditions.Recent advances in optical imaging techniques has facilitated tracing of the developmental dynamics of a specific organ,tissue,or even a single cell.The zebrafish is an excellent model for imaging of hematopoiesis due to its transparent embryo at early stage; moreover,different zebrafish hematopoietic stem cells (HSCs) transgenic lines have been demonstrated as very useful tools for illustrating the details of the HSC developmental process.In this review,we summarize recent studies related to the non-invasive in vivo imaging of HSC transgenics,to show that zebrafish transgenic lines are powerful tools for developmental biology and disease.At the end of the review,the perspective and some open questions in this field will be discussed.

  11. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells.

    Science.gov (United States)

    Yu, Vionnie W C; Yusuf, Rushdia Z; Oki, Toshihiko; Wu, Juwell; Saez, Borja; Wang, Xin; Cook, Colleen; Baryawno, Ninib; Ziller, Michael J; Lee, Eunjung; Gu, Hongcang; Meissner, Alexander; Lin, Charles P; Kharchenko, Peter V; Scadden, David T

    2016-11-17

    Stem cells determine homeostasis and repair of many tissues and are increasingly recognized as functionally heterogeneous. To define the extent of-and molecular basis for-heterogeneity, we overlaid functional, transcriptional, and epigenetic attributes of hematopoietic stem cells (HSCs) at a clonal level using endogenous fluorescent tagging. Endogenous HSC had clone-specific functional attributes over time in vivo. The intra-clonal behaviors were highly stereotypic, conserved under the stress of transplantation, inflammation, and genotoxic injury, and associated with distinctive transcriptional, DNA methylation, and chromatin accessibility patterns. Further, HSC function corresponded to epigenetic configuration but not always to transcriptional state. Therefore, hematopoiesis under homeostatic and stress conditions represents the integrated action of highly heterogeneous clones of HSC with epigenetically scripted behaviors. This high degree of epigenetically driven cell autonomy among HSCs implies that refinement of the concepts of stem cell plasticity and of the stem cell niche is warranted. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Embryonic Hematopoietic Progenitor Cells Reside in Muscle before Bone Marrow Hematopoiesis.

    Directory of Open Access Journals (Sweden)

    Yuka Tanaka

    Full Text Available In mice, hematopoietic cells home to bone marrow from fetal liver prenatally. To elucidate mechanisms underlying homing, we performed immunohistochemistry with the hematopoietic cell marker c-Kit, and observed c-Kit(+ cells localized inside muscle surrounding bone after 14.5 days post coitum. Flow cytometric analysis showed that CD45(+ c-Kit(+ hematopoietic cells were more abundant in muscle than in bone marrow between 14.5 and 17.5 days post coitum, peaking at 16.5 days post coitum. CD45(+ c-Kit(+ cells in muscle at 16.5 days post coitum exhibited higher expression of Gata2, among several hematopoietic genes, than did fetal liver or bone marrow cells. Colony formation assays revealed that muscle hematopoietic cells possess hematopoietic progenitor activity. Furthermore, exo utero transplantation revealed that fetal liver hematopoietic progenitor cells home to muscle and then to BM. Our findings demonstrate that hematopoietic progenitor cell homing occurs earlier than previously reported and that hematopoietic progenitor cells reside in muscle tissue before bone marrow hematopoiesis occurs during mouse embryogenesis.

  13. Meis1 Is Required for Adult Mouse Erythropoiesis, Megakaryopoiesis and Hematopoietic Stem Cell Expansion.

    Directory of Open Access Journals (Sweden)

    Michelle Erin Miller

    Full Text Available Meis1 is recognized as an important transcriptional regulator in hematopoietic development and is strongly implicated in the pathogenesis of leukemia, both as a Hox transcription factor co-factor and independently. Despite the emerging recognition of Meis1's importance in the context of both normal and leukemic hematopoiesis, there is not yet a full understanding of Meis1's functions and the relevant pathways and genes mediating its functions. Recently, several conditional mouse models for Meis1 have been established. These models highlight a critical role for Meis1 in adult mouse hematopoietic stem cells (HSCs and implicate reactive oxygen species (ROS as a mediator of Meis1 function in this compartment. There are, however, several reported differences between these studies in terms of downstream progenitor populations impacted and effectors of function. In this study, we describe further characterization of a conditional knockout model based on mice carrying a loxP-flanked exon 8 of Meis1 which we crossed onto the inducible Cre localization/expression strains, B6;129-Gt(ROSA26Sor(tm1(Cre/ERTNat/J or B6.Cg-Tg(Mx1-Cre1Cgn/J. Findings obtained from these two inducible Meis1 knockout models confirm and extend previous reports of the essential role of Meis1 in adult HSC maintenance and expansion and provide new evidence that highlights key roles of Meis1 in both megakaryopoiesis and erythropoiesis. Gene expression analyses point to a number of candidate genes involved in Meis1's role in hematopoiesis. Our data additionally support recent evidence of a role of Meis1 in ROS regulation.

  14. Cryopreservation of hematopoietic stem/progenitor cells for therapeutic use.

    Science.gov (United States)

    Watt, Suzanne M; Austin, Eric; Armitage, Sue

    2007-01-01

    To date, more than 25,000 hematopoietic transplants have been carried out across Europe for hematological disorders, the majority being for hematological malignancies. At least 70% of these are autologous transplants, the remaining 30% being allogeneic, which are sourced from related (70% of the allogeneic) or unrelated donors. Peripheral blood mobilized with granulocyte colony stimulating factor is the major source of stem cells for transplantation, being used in approx 95% of autologous transplants and in approx 65% of allogeneic transplants. Other cell sources used for transplantation are bone marrow and umbilical cord blood. One crucial advance in the treatment of these disorders has been the development of the ability to cryopreserve hematopoietic stem cells for future transplantation. For bone marrow and mobilized peripheral blood, the majority of cryopreserved harvests come from autologous collections that are stored prior to a planned infusion following further treatment of the patient or at the time of a subsequent relapse. Other autologous harvests are stored as backup or "rainy day" harvests, the former specifically being intended to rescue patients who develop graft failure following an allogeneic transplant or who may require this transplant at a later date. Allogeneic bone marrow and mobilized peripheral blood are less often cryopreserved than autologous harvests. This is in contrast to umbilical cord blood that may be banked for directed or sibling (related) hematopoietic stem cell transplants, for allogeneic unrelated donations, and for autologous donations. Allogeneic unrelated donations are of particular use for providing a source of hematopoietic stem cells for ethnic minorities, patients with rare human leukocyte antigen types, or where the patient urgently requires a transplant and cannot wait for the weeks to months required to prepare a bone marrow donor. There are currently more than 200,000 banked umbilical cord blood units registered with

  15. Ongoing graft-versus-host disease is a risk factor for azoospermia after allogeneic hematopoietic stem cell transplantation: a survey of the Late Effects Working Party of the European Group for Blood and Marrow Transplantation.

    Science.gov (United States)

    Rovó, Alicia; Aljurf, Mahmoud; Chiodi, Sandra; Spinelli, Simonetta; Salooja, Nina; Sucak, Gülsan; Hunter, Ann; Kim, Tan Swee; Socié, Gérard; van Lint, Maria Teresa; Passweg, Jakob R; Arat, Mutlu; Badoglio, Manuela; Tichelli, André

    2013-03-01

    The aim of this study was to assess the degree of spermatogenesis defects in sperm analysis in long-term male survivors after allogeneic hematopoietic stem cell transplantation in order to identify the risk factors related to potential infertility after hematopoietic stem cell transplantation and to provide data on longitudinal sperm recovery after hematopoietic stem cell transplantation. Here, the Late Effects Working Party of the European Group for Blood and Marrow Transplantation reports data of sperm analysis from 224 males who underwent hematopoietic stem cell transplantation. Median time between transplantation and sperm analysis was 63 months (8-275 months). At last sperm analysis, presence of any degree of spermatozoa was reported in 70 (31%) and complete azoospermia in 154 (69%) patients. In multivariate analysis, being conditioned with total body irradiation (RR 7.1; 95% CI: 3.4-14.8) and age over 25 years at transplantation (RR 2.4; 95% CI: 1.09-5.2) were significantly associated with higher risk for azoospermia. In patients not conditioned with total body irradiation, ongoing chronic graft-versus-host disease is the main adverse factor for sperm recovery (RR of 3.11; 95% CI: 1.02-9.47; P=0.045). Already established risk factors, such as total body irradiation and age older than 25 years at hematopoietic stem cell transplantation, were seen to be the most relevant adverse risk factor for sperm production after hematopoietic stem cell transplantation. Furthermore, for the first time, ongoing graft-versus-host disease has been shown to be the most relevant adverse factor for sperm recovery, particularly in patients conditioned without total body irradiation. We also introduce a useful scoring system to predict the probability of male long-term survivors' azoospermia.

  16. Toward revision of antimicrobial therapies in hematopoietic stem cell transplantation: target the pathogens, but protect the indigenous microbiota

    Science.gov (United States)

    KHORUTS, ALEXANDER; HIPPEN, KELI L.; LEMIRE, AMANDA M.; HOLTAN, SHERNAN G.; KNIGHTS, DAN; YOUNG, JO-ANNE H.

    2017-01-01

    Host microbiota plays important roles in providing colonization resistance to pathogens and instructing development and function of the immune system. Antibiotic treatments intended to target pathogens further weaken the host defenses and may paradoxically increase the risk of systemic infections. This consequence is especially problematic in patients undergoing hematopoietic stem cell transplantation, where the mucosal defenses are already weakened by the conditioning regimens. This review discusses the roles that indigenous microbiota plays in protecting the host and maintaining immune homeostasis. In addition, we highlight possible strategies that are being developed to allow targeted antimicrobial therapy against pathogens, while minimizing the harm to indigenous microbiota. PMID:27513211

  17. Mitigation of radiation-induced hematopoietic injury via regulation of cellular MAPK/phosphatase levels and increasing hematopoietic stem cells.

    Science.gov (United States)

    Patwardhan, R S; Sharma, Deepak; Checker, Rahul; Sandur, Santosh K

    2014-03-01

    Here we describe a novel strategy for mitigation of ionizing radiation-induced hematopoietic syndrome by suppressing the activity of MKP3, resulting in ERK activation and enhanced abundance of hematopoietic stem cells, using the antioxidant flavonoid baicalein (5,6,7-trihydroxyflavone). It offered complete protection to mouse splenic lymphocytes against radiation-induced cell death. Inhibitors of ERK and Nrf-2 could significantly abrogate baicalein-mediated radioprotection in lymphocytes. Baicalein inhibited phosphatase MKP3 and thereby enhanced phosphorylation of ERK and its downstream proteins such as Elk and Nrf-2. It also increased the nuclear levels of Nrf-2 and the mRNA levels of its dependent genes. Importantly, baicalein administration to mice before radiation exposure led to significant recovery of loss of bone marrow cellularity and also inhibited cell death. Administration of baicalein increased the hematopoietic stem cell frequency as measured by side-population assay and also by antibody staining. Further, baicalein offered significant protection against whole-body irradiation (WBI; 7.5Gy)-induced mortality in mice. Interestingly, we found that baicalein works by activating the same target molecules ERK and Nrf-2 both in vitro and in vivo. Finally, administration of all-trans-retinoic acid (inhibitor of Nrf-2) significantly abrogated baicalein-mediated protection against WBI-induced mortality in mice. Thus, in contrast to the generalized conception of antioxidants acting as radioprotectors, we provide a rationale that antioxidants exhibit pleiotropic effects through the activation of multiple cellular signaling pathways.

  18. Analysis of the hematopoietic effects of new dominant spotting (W) mutations of the mouse. I. Influence upon hematopoietic stem cells

    Energy Technology Data Exchange (ETDEWEB)

    Geissler, E.N.; Russell, E.S.

    1983-07-01

    Mice carrying two mutants W alleles usually have severe macrocytic anemias which result from deficiencies of hematopoietic stem cells (CFUs). Anemic W/sup 39//W/sup 39/ and W/sup 41//W/sup 41/ homozygotes have deficiencies in the numbers of femoral stem cells which correspond to the severities of their anemias. The non-anemic W/sup 44//W/sup 44/ homozygote has as few stem cells as the W/sup 41//W/sup 41/ mouse. Nevertheless, bone marrow implants from W/sup 44//W/sup 44/ donors cure the anemias of W/W/sup v/ recipients while implants from anemic W/sup 39//W/sup 39/ and W/sup 41//W/sup 41/ donors do not. The peripheral hematologic differences between W/sup 41//W/sup 41/ and W/sup 44//W/sup 44/ homozygotes probably arise from qualitative differences intrinsic to their stem cells rather than from extrinsic hematopoietic factors. The hematopoietic environments of all three W homozygotes are relatively normal in that they support normal erythropoiesis when injected with congenic +/+ marrow. Even non-anemic W/sup 44//W/sup 44/ recipients are repopulated with +/+ donor red cells, indicating that W/sup 44//W/sup 44/ stem cells are at a disadvantage when completing with normal counterparts. 14 references, 6 figures, 2 tables.

  19. Regression of the tumor after withdrawal of cyclosporine in relapsed extranodal natural killer/T cell lymphoma following allogeneic hematopoietic stem cell transplantation.

    Science.gov (United States)

    Kako, Shinichi; Izutsu, Koji; Oshima, Kumi; Sato, Hiroyuki; Kanda, Yoshinobu; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2007-10-01

    The prognosis of patients with advanced-stage extranodal natural killer/T cell lymphoma, nasal type (ENKL) has been generally poor, and several anecdotal reports have suggested the role of allogeneic hematopoietic stem cell transplantation (HSCT). A potential advantage of allogeneic HSCT may be the graft-versus-lymphoma (GVL) effect. The susceptibility to the GVL effect, however, has been shown to vary according to histologic subtypes, and it has been hardly documented yet whether ENKL is susceptible to the GVL effect. Here we report a patient with advanced-stage ENKL who underwent allogeneic HSCT from an HLA one-allele mismatched related donor, whose clinical course after HSCT suggested the potent GVL effect against ENKL. A 43-year-old female underwent allogeneic HSCT for advanced-stage, chemorefractory ENKL, and achieved complete response. In 4 months after the transplantation, however, the ENKL relapsed in multiple sites. These lesions markedly responded to the discontinuation of immunosuppressive agents and disappeared. Except for a temporal exacerbation of bronchiolitis obliterans organizing pneumonia, she has been free from disease for more than a year without other treatments against lymphoma. The clinical course of the current patient suggests the potent GVL effect against ENKL. Allogeneic HSCT, including that with reduced-intensity regimens, is a promising treatment option for high-risk ENKL.

  20. AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR LYMPHOMA: AN EVALUATION OF GRAFTS SOURCE AND MINIMAL RESIDUAL DISEASE

    Institute of Scientific and Technical Information of China (English)

    HOU Shu-ling; ZHANG Qiao-hua; HAN Wei-e; GUI Wei; WANG Yu-luan

    2005-01-01

    Objective: To determine whether the source of autologous hematopoietic stem cells altered the clinical outcomes of patients undergoing high dose chemotherapy and autologous hematopoietic stem cell transplantation (AHSCT) for aggressive lymphoma and to study the problem of minimal residual disease (MRD). Methods: 14 lymphoma patients who had lymphoma with high risk factors, relapsed lymphoma or refractory lymphoma received autologous bone marrow transplantation (ABMT). 14 lymphoma patients who were similar to ABMT group received autologous peripheral blood stem cells transplantation (APBSCT). Regimen of CBV (cyclophos phamide 50~60 mg/kg/d×2 d, carmustine 15 mg/kg/d×1 d,etoposide 45~60 mg/kg/d×1 d) was received by all the patients as conditioning regimen in the transplant pretreatment followed by ABMT or APBSCT. Autologous peripheral blood stem cell (APBSC) was mobilized by CTX 2g~3g/m2/d×2 d iv and G-CSF 5 μg/kg/d for five to seven days. MRD was continually supervised by PCR in bone marrow before and after transplantation. Cellular immunocyte function, such as natural killer cell (NK), CD3, CD4, CD8 and sIL-2R was tested before and twenty days after transplantation. Results: In ABMT group, the median time for hematopoietic recovery of absolute neutrophilia counts ≥0.5×109/L and platelet counts ≥20×109/L was +18 days and +20 days respectively. In contrast, the APBSCT group was both at 12 days. Patients who have undergone ABMT all got complete remission (CR), while 81.8% patients in APBSCT group got CR. The 3-year disease free survival (DFS) in APBSCT and ABMT group was 75% and 72.7% respectively (P>0.05). The mean days of immunity recovering in APBSCT was ±20 days. After transplantation, MRD in 11 patients were positive, in whom 6 patients died. Conclusion: Aggressive lymphoma patients' hemapoiesis recovered more rapidly in APBSCT group than that in ABMT group, but 3-year DFS had no statistical difference. Patients positive for IgH/TCR-γ by

  1. Tracking the Elusive Fibrocyte: Identification and Characterization of Collagen‐Producing Hematopoietic Lineage Cells During Murine Wound Healing

    National Research Council Canada - National Science Library

    Suga, Hirotaka; Rennert, Robert C; Rodrigues, Melanie; Sorkin, Michael; Glotzbach, Jason P; Januszyk, Michael; Fujiwara, Toshihiro; Longaker, Michael T; Gurtner, Geoffrey C

    2014-01-01

    .... In this study, to distinguish hematopoietic and nonhematopoietic cells without surface markers, we took advantage of the gene vav 1, which is expressed solely on hematopoietic cells but not on...

  2. Hematopoietic Stem Cell Transplantation and History

    Directory of Open Access Journals (Sweden)

    Atila Tanyeli

    2014-02-01

    Full Text Available Attemps to employ marrow stem cell for therapeutic purpose began in 1940’s. Marrow transplantation might be of use not only in irradiation protection, but also with therapeutic aim to marrow aplasia, leukemia and other diseases. The use and defining tissue antigens in humans were crucial to the improving of transplantation. The administration of methotrexate for GVHD improved the long term survival. Conditioning regimens for myeloablation designed according to diseases. Cord blood and peripheral blood stem cells were used for transplantion after 1980’s. Cord blood and bone marrow stem cell banks established to find HLA matched donor.

  3. A novel complex, RUNX1-MYEF2, represses hematopoietic genes in erythroid cells

    NARCIS (Netherlands)

    B. van Riel (Boet); T. Pakozdi (Tibor); R.W.W. Brouwer (Rutger); R. Monteiro (Rui); E. Tuladhar (Era); V. Franke (Vedran); J.C. Bryne; R.J.J. Jorna (Ruud); E.J. Rijkers; W.F.J. van IJcken (Wilfred); C. Andrieu-Soler (Charlotte); J.A.A. Demmers (Jeroen); R. Patient (Roger); E. Soler (Eric); B. Lenhard (Boris); F.G. Grosveld (Frank)

    2012-01-01

    textabstractRUNX1 is known to be an essential transcription factor for generating hematopoietic stem cells (HSC), but much less is known about its role in the downstream process of hematopoietic differentiation. RUNX1 has been shown to be part of a large transcription factor complex, together with

  4. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos

    NARCIS (Netherlands)

    T. Yokomizo (Tomomasa); E.A. Dzierzak (Elaine)

    2010-01-01

    textabstractHematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of w

  5. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo.

    NARCIS (Netherlands)

    M.F.T.R. de Bruijn (Marella); N.A. Speck; M.C. Peeters (Marian); E.A. Dzierzak (Elaine)

    2000-01-01

    textabstractThe aorta-gonad-mesonephros (AGM) region is a potent hematopoietic site within the mammalian embryo body, and the first place from which hematopoietic stem cells (HSCs) emerge. Within the complex embryonic vascular, excretory and reproductive tissues of the

  6. Fine-tuning Hematopoiesis: Microenvironmental factors regulating self-renewal and differentiation of hematopoietic stem cells

    NARCIS (Netherlands)

    T.C. Luis (Tiago)

    2010-01-01

    markdownabstract__Abstract__ Hematopoietic stem cells (HSCs) have the ability to self renew and generate all lineages of blood cells. Although it is currently well established that hematopoietic stem cells (HSCs) regenerate the blood compartment, it was only in the 1960s that was introduced the not

  7. Niche contributions to oncogenesis: Emerging concepts and implications for the hematopoietic system

    NARCIS (Netherlands)

    M.H.G.P. Raaijmakers (Marc H.G.P.)

    2011-01-01

    textabstractThe field of hematopoietic oncology has traditionally focused on the study of hematopoietic cell autonomous genetic events in an effort to understand malignant transformation and develop therapeutics. Although highly rewarding in both aspects, this cell autonomous approach has failed to

  8. Short and long-term repopulating hematopoietic stem cells in the mouse

    NARCIS (Netherlands)

    J.C.M. van der Loo

    1995-01-01

    textabstractThe formation and development of blood cells, or hematopoiesis, normally takes place in the bone marrow, which serves as the major hematopoietic organ during adult life. A small population of bone marrow cells (BMC), designated as hematopoietic stem cells, underlies the process of blood

  9. Estradiol increases hematopoietic stem and progenitor cells independent of its actions on bone

    NARCIS (Netherlands)

    Illing, Anett; Liu, Peng; Ostermay, Susanne; Schilling, Arndt; de Haan, Gerald; Krust, Andree; Amling, Michael; Chambon, Pierre; Schinke, Thorsten; Tuckermann, Jan P.

    2012-01-01

    Hematopoietic stem and progenitor cells reside in vascular and endosteal niches in the bone marrow. Factors affecting bone remodeling were reported to influence numbers and mobilization of hematopoietic stem cells. We therefore analyzed the effects of estradiol acting anabolic on bone integrity. Her

  10. Pharmacoeconomics of Hematopoietic Stem Cell Mobilization : An Overview of Current Evidence and Gaps in the Literature

    NARCIS (Netherlands)

    Shaughnessy, Paul; Chao, Nelson; Shapiro, Jamie; Walters, Kent; McCarty, John; Abhyankar, Sunil; Shayani, Sepideh; Helmons, Pieter; Leather, Helen; Pazzalia, Amy; Pickard, Simon

    2013-01-01

    Adequate hematopoietic stem cell (HSC) mobilization and collection is required prior to proceeding with high dose chemotherapy and autologous hematopoietic stem cell transplant. Cytokines such as G-CSF, GM-CSF, and peg-filgrastim, alone or in combination with plerixafor, and after chemotherapy have

  11. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization

    NARCIS (Netherlands)

    van Pel, M; van Os, R; Velders, GA; Hagoort, H; Heegaard, PMH; Lindley, IJD; Willemze, R; Fibbe, WE

    2006-01-01

    Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory

  12. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos

    Science.gov (United States)

    Yokomizo, Tomomasa; Dzierzak, Elaine

    2010-01-01

    Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit+CD31+SSEA1– cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis. PMID:20876651

  13. Improvement of Thymopoiesis after Hematopoietic Stem Cell Transplantation by Cytokines: Translational studies in experimental animal models

    NARCIS (Netherlands)

    E-J. Wils (Evert-Jan)

    2011-01-01

    textabstractAllogeneic hematopoietic stem cell transplantation (AlloHSCT) is a powerful treatment modality that is frequently applied as part of treatment of hematological malignancies, aplastic anemia and inborn errors of hematopoietic progenitor cells. A major drawback of alloHSCT is the treatment

  14. Three-dimensional cartography of hematopoietic clusters in the vasculature of whole mouse embryos.

    Science.gov (United States)

    Yokomizo, Tomomasa; Dzierzak, Elaine

    2010-11-01

    Hematopoietic cell clusters in the aorta of vertebrate embryos play a pivotal role in the formation of the adult blood system. Despite their importance, hematopoietic clusters have not been systematically quantitated or mapped because of technical limitations posed by the opaqueness of whole mouse embryos. Here, we combine an approach to make whole mouse embryos transparent, with multicolor marking, to allow observation of hematopoietic clusters using high-resolution 3-dimensional confocal microscopy. Our method provides the first complete map and temporal quantitation of all hematopoietic clusters in the mouse embryonic vasculature. We show that clusters peak in number at embryonic day 10.5, localize to specific vascular subregions and are heterogeneous, indicating a basal endothelial to non-basal (outer cluster) hematopoietic cell transition. Clusters enriched with the c-Kit(+)CD31(+)SSEA1(-) cell population contain functional hematopoietic progenitors and stem cells. Thus, three-dimensional cartography of transparent mouse embryos provides novel insight into the vascular subregions instrumental in hematopoietic progenitor/stem cell development, and represents an important technological advancement for comprehensive in situ hematopoietic cluster analysis.

  15. Expanded Hematopoietic Progenitor Cells Reselected for High Aldehyde Dehydrogenase Activity Demonstrate Islet Regenerative Functions.

    Science.gov (United States)

    Seneviratne, Ayesh K; Bell, Gillian I; Sherman, Stephen E; Cooper, Tyler T; Putman, David M; Hess, David A

    2016-04-01

    Human umbilical cord blood (UCB) hematopoietic progenitor cells (HPC) purified for high aldehyde dehydrogenase activity (ALDH(hi) ) stimulate islet regeneration after transplantation into mice with streptozotocin-induced β cell deletion. However, ALDH(hi) cells represent a rare progenitor subset and widespread use of UCB ALDH(hi) cells to stimulate islet regeneration will require progenitor cell expansion without loss of islet regenerative functions. Here we demonstrate that prospectively purified UCB ALDH(hi) cells expand efficiently under serum-free, xeno-free conditions with minimal growth factor supplementation. Consistent with the concept that ALDH-activity is decreased as progenitor cells differentiate, kinetic analyses over 9 days revealed the frequency of ALDH(hi) cells diminished as culture time progressed such that total ALDH(hi) cell number was maximal (increased 3-fold) at day 6. Subsequently, day 6 expanded cells (bulk cells) were sorted after culture to reselect differentiated progeny with low ALDH-activity (ALDH(lo) subset) from less differentiated progeny with high ALDH-activity (ALDH(hi) subset). The ALDH(hi) subset retained primitive cell surface marker coexpression (32.0% ± 7.0% CD34(+) /CD38(-) cells, 37.0% ± 6.9% CD34(+) /CD133(+) cells), and demonstrated increased hematopoietic colony forming cell function compared with the ALDH(lo) subset. Notably, bulk cells or ALDH(lo) cells did not possess the functional capacity to lower hyperglycemia after transplantation into streptozotocin-treated NOD/SCID mice. However, transplantation of the repurified ALDH(hi) subset significantly reduced hyperglycemia, improved glucose tolerance, and increased islet-associated cell proliferation and capillary formation. Thus, expansion and delivery of reselected UCB cells that retain high ALDH-activity after short-term culture represents an improved strategy for the development of cellular therapies to enhance islet regeneration in situ.

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  15. File list: InP.Bld.10.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Bld.10.AllAg.Hematopoietic_Stem_Cells mm9 Input control Blood Hematopoietic Ste...hive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Bld.10.AllAg.Hematopoietic_Stem_Cells.bed ...

  16. File list: InP.Bld.20.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Bld.20.AllAg.Hematopoietic_Stem_Cells hg19 Input control Blood Hematopoietic St...em Cells SRX038907 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/InP.Bld.20.AllAg.Hematopoietic_Stem_Cells.bed ...

  17. File list: Pol.Bld.05.AllAg.CD34_Hematopoietic_stem_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Bld.05.AllAg.CD34_Hematopoietic_stem_cells hg19 RNA polymerase Blood CD34 Hematopo...ietic stem cells http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Bld.05.AllAg.CD34_Hematopoietic_stem_cells.bed ...

  18. File list: InP.Bld.05.AllAg.Hematopoietic_Stem_Cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available InP.Bld.05.AllAg.Hematopoietic_Stem_Cells mm9 Input control Blood Hematopoietic Ste...hive.biosciencedbc.jp/kyushu-u/mm9/assembled/InP.Bld.05.AllAg.Hematopoietic_Stem_Cells.bed ...

  19. File list: Pol.Bld.50.AllAg.CD34_Hematopoietic_stem_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Pol.Bld.50.AllAg.CD34_Hematopoietic_stem_cells hg19 RNA polymerase Blood CD34 Hematopo...ietic stem cells http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/Pol.Bld.50.AllAg.CD34_Hematopoietic_stem_cells.bed ...

  20. File list: His.Bld.10.AllAg.CD34_Hematopoietic_stem_cells [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available His.Bld.10.AllAg.CD34_Hematopoietic_stem_cells hg19 Histone Blood CD34 Hematopoieti...c stem cells SRX026654 http://dbarchive.biosciencedbc.jp/kyushu-u/hg19/assembled/His.Bld.10.AllAg.CD34_Hematopoietic_stem_cells.bed ...