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Sample records for b-chronic lymphocytic leukemia

  1. Turmeric and green tea: a recipe for B-Chronic Lymphocytic Leukemia

    OpenAIRE

    Angelo, Laura S.; Kurzrock, Razelle

    2009-01-01

    Two naturally-occurring compounds--curcumin (the active ingredient in the spice turmeric) and the green tea extract epigallocatechin-3-gallate (EGCG) have marked effects on the apoptotic machinery in chronic lymphocytic leukemia (CLL). These results provide a preclinical foundation for future clinical use of these compounds in this disease.

  2. Apoptosis induced by Magnolia Grandiflora extract in chlorambucil-resistant B-chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Marin Gustavo

    2010-01-01

    Full Text Available Background: B-cell chronic lymphocitic leukemia (B-CLL still remains as an uncurable disease. Even the newest antineoplastic agents have demonstrated limitations in their efficacy. For this reason, further research of new compounds must be done. New pharmacological properties can be obtained from a great diversity botanical species. Among these products, Magnolia Grandiflora receives our attention since it mainly contains Honokiol which had demonstrated effect against B-CLL cells activating different cell death pathways. Aim: To test the ability of Magnolia Grandiflora extracts to induce apoptosis of B-CLL cells in vitro. Materials and Methods: Herb′s extraction: Twenty grams of powdered material were submitted to three consecutives decoctions with 500 ml of distilled water (96 °C, filtered and followed by ultrafiltration with cellulose membrane, lyophilized and reconstituted in AIM-V medium at a final concentration of 10 mg/ml solution. B-CLL chlorambucil- resistant cells were separated and cultivated in the presence of Magnolia′s extract. Samples of cells were taken from the cultures at 24, 48 and 72 h for apoptosis analysis by flow cytometry measuring positive annexin V (0.1 μg/ml cells. Statistics: Apoptosis values were represented by the mean plus or minus SD (± SD for five independent experiments. Statistical significance was determined by Student′s t -test. A P value of 0.05 or less was considered as significant. Results and Conclusion: This article discusses the apoptosis properties of Magnolia on B-CLL cells. The evidence suggests a potentially effective repertoire for B-CLL treatment. This herb extract might have promising therapy strategies in treating B-CLL or other hematological disease resistant to alkylating agents in clinical practice.

  3. Stages of Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Lymphocytic Leukemia Go to Health Professional Version Key Points Chronic ...

  4. What Is Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... Topic Normal bone marrow, blood, and lymphoid tissue What is chronic lymphocytic leukemia? Cancer starts when cells ... body, including the lymph nodes, liver, and spleen. What is leukemia? Leukemia is a cancer that starts ...

  5. Fludarabine Phosphate and Total-Body Irradiation Before Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia

    Science.gov (United States)

    2016-07-18

    B-Cell Prolymphocytic Leukemia; Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia

  6. [Chronic lymphocytic leukemia].

    Science.gov (United States)

    Aoki, Sadao

    2016-03-01

    Currently, several novel drugs are available for chronic lymphocytic leukemia (CLL) in Western countries. Of these drugs, those that inhibit the B-cell receptor (BCR) signaling pathway are the most promising. Ibrutinib inhibits BTK in the BCR pathway and can be administered orally. The results of several clinical trials suggest that ibrutinib is highly effective against relapsed/resistant (RR) and treatment-naïve CLL. Furthermore, ibrutinib shows equivalent efficacy on CLL with the 17p deletion. Idelalisib, which also blocks the BCR pathway, inhibits PIK3delta and induces CLL cell death. Clinical trials have shown outstanding efficacy of idelalisib against RR-CLL, especially when administered with antiCD20 antibodies. This drug is also effective against CLL with the 17p deletion. ABT-199 is another novel drug; it inhibits BCL2 signaling, not the BCR pathway, and can be administered orally. The efficacy of ABT-199 against RR-CLL has been demonstrated in a number of clinical trials. These drugs have only mild toxicity and can be used for patients in poor general condition. Unfortunately, none of these drugs have yet been approved in Japan. Rapid resolution of the 'drug lag' problem is necessary. PMID:27076234

  7. Acute Lymphocytic Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  8. Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  9. Cyclophosphamide, Alvocidib, and Rituximab in Treating Patients With High Risk B-Cell Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2015-11-10

    Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  10. Treatment Options by Stage (Chronic Lymphocytic Leukemia)

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Lymphocytic Leukemia Go to Health Professional Version Key Points Chronic ...

  11. Treatment Option Overview (Chronic Lymphocytic Leukemia)

    Science.gov (United States)

    ... ALL Treatment Childhood AML Treatment Research Chronic Lymphocytic Leukemia Treatment (PDQ®)–Patient Version General Information About Chronic Lymphocytic Leukemia Go to Health Professional Version Key Points Chronic ...

  12. Vorinostat, Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Previously Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-05-04

    Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma

  13. Curcumin and Cholecalciferol in Treating Patients With Previously Untreated Stage 0-II Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-02-16

    Contiguous Stage II Small Lymphocytic Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Stage 0 Chronic Lymphocytic Leukemia; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia

  14. Monoclonal Antibody Therapy in Treating Patients With Chronic Lymphocytic Leukemia, Lymphocytic Lymphoma, Acute Lymphoblastic Leukemia, or Acute Myeloid Leukemia

    Science.gov (United States)

    2013-06-03

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Noncontiguous Stage II Marginal Zone Lymphoma; Noncontiguous Stage II Small Lymphocytic Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Marginal Zone Lymphoma; Stage IV Small Lymphocytic Lymphoma

  15. Cancer Statistics: Acute Lymphocytic Leukemia (ALL)

    Science.gov (United States)

    ... population data for older age groups are available. Statistics at a Glance Show More At a Glance ... acute lymphocytic leukemia in the United States. Survival Statistics Show More How Many People Survive 5 Years ...

  16. Congenital acute lymphocytic leukemia associated with hyperleucocytic leukemia syndrome

    International Nuclear Information System (INIS)

    A two-month-old female infant had congenital acute lymphocytic leukemia 39 days after birth. Cranial CT showed many small high dense spots over the whole brain. The mechanism of occurrence of central neurologic symptoms and the association of hyperleucocytic leukemia are discussed with a review of the literature. (Namekawa, K.)

  17. Ibrutinib or Idelalisib in Treating Patients With Persistent or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Non-Hodgkin Lymphoma After Donor Stem Cell Transplant

    Science.gov (United States)

    2016-04-08

    Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Non-Hodgkin Lymphoma; Recurrent Small Lymphocytic Lymphoma; Small Lymphocytic Lymphoma

  18. Do We Know What Causes Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... Topic Can chronic lymphocytic leukemia be prevented? Do we know what causes chronic lymphocytic leukemia? The exact ... genes -- the instructions for how our cells function. We look like our parents because they are the ...

  19. What Should You Ask Your Doctor about Acute Lymphocytic Leukemia?

    Science.gov (United States)

    ... treatment for acute lymphocytic leukemia? What should you ask your doctor about acute lymphocytic leukemia? It is ... with your doctor. You should feel free to ask any question that’s on your mind, no matter ...

  20. Fungal natural products targeting chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Kildgaard, Sara; Knudsen, Peter Boldsen;

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults from the western world. No curative treatments of CLL are presently known so the treatment strategy today is primarily to prolong patient survival,1 why we have initiated new activities towards discovery of novel compounds....../compounds.2,3 This includes analysis of the spectroscopic data generated from LC-DAD-MS to reveal whether the active principles are either structurally known compounds or are likely to be novel compounds. This paper will illustrate our integrated discovery approaches and recent findings of anti-leukemia...

  1. Ibrutinib (PCI-32765) in Chronic Lymphocytic Leukemia

    OpenAIRE

    Jain, Nitin; O’Brien, Susan

    2013-01-01

    B-cell receptor (BCR) signaling is essential for chronic lymphocytic leukemia (CLL) cell survival. Many kinases in the BCR signaling pathway are currently being studied as potential therapeutic targets. These include Lyn, Syk, PI3 and Bruton tyrosine (BTK). Ibrutinib (PCI-32765) is a novel first-in-class selective inhibitor of BTK. Preclinical evidence suggests that ibrutinib inhibits CLL cell survival and proliferation. In addition, it also affects CLL cell migration and homing. Early clinic...

  2. What Are the Risk Factors for Acute Lymphocytic Leukemia?

    Science.gov (United States)

    ... both ALL and acute myeloid leukemia (AML). Japanese atomic bomb survivors had a greatly increased risk of developing ... cell acute lymphocytic leukemia. Most cases occur in Japan and the Caribbean area. This disease is not ...

  3. Ibrutinib and Rituximab Compared With Fludarabine Phosphate, Cyclophosphamide, and Rituximab in Treating Patients With Untreated Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma

    Science.gov (United States)

    2016-08-31

    Anemia; Fever, Sweat, and Hot Flashes; Stage I Chronic Lymphocytic Leukemia; Stage I Small Lymphocytic Lymphoma; Stage II Chronic Lymphocytic Leukemia; Stage II Small Lymphocytic Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Small Lymphocytic Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Small Lymphocytic Lymphoma; Weight Change

  4. Fungal natural products targeting chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Bladt, Tanja Thorskov; Kildgaard, Sara; Knudsen, Peter Boldsen; Gotfredsen, Charlotte Held; Duerr, C.; Seiffert, M.; Larsen, Thomas Ostenfeld

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults from the western world. No curative treatments of CLL are presently known so the treatment strategy today is primarily to prolong patient survival,1 why we have initiated new activities towards discovery of novel compounds...... with potential tumor specificity. Our starting point is a diverse fungal collection of thousands of Penicillium and Aspergillus species. These fungi have proven to be a very rich source of various bioactive compounds and yet our dereplication investigations have demonstrated that there are still...... numerous unknown compounds to be identified within these species. Until now we have found that 11 out of 289 fungal extracts are active against CLL cells. Using our established chemotaxonomic discovery approach we have dereplicated and fractionated these extracts to track the activity into single fractions/compounds...

  5. The molecular basis of familial chronic lymphocytic leukemia

    OpenAIRE

    Crowther-Swanepoel, Dalemari; Houlston, Richard S.

    2009-01-01

    Our understanding of the genetic basis of chronic lymphocytic leukemia is only just starting to be recognized. This perspective article by Drs. Crowther-Swanepoel and Houlston provides an up-to-date review the molecular epidemiology of chronic lymphocytic leukemia, with emphasis on the integration of biology and genomics. See related paper on page 647.

  6. The lymph node in chronic lymphocytic leukemia.

    Science.gov (United States)

    Dick, F R; Maca, R D

    1978-01-01

    Lymph nodes were examined from 41 cases of typical chronic lymphocytic leukemia (CLL). Degree of immaturity was graded as absent to minimal (Grade I), moderate (Grade II) and marked (Grade III). A moderate degree of immaturity was found in the lymph node in 14 of 41 cases even though the cells seen on the initial bone marrow and peripheral blood smears obtained from these patients were essentially all mature. The morphology of these nodes could be confused with poorly differentiated lymphocytic or mixed lymphocytic-histiocytic lymphoma in terms of the degree of immaturity present. A marked degree of immaturity present. A marked degree of immaturity was found in 5 cases; the morphology of these cases resembled histiocytic lymphoma. In the remaining 22 cases immaturity was essentially absent. The morphology of these cases was similar to that of diffuse well differentiated lymphocytic lymphoma. Our studies suggest that a moderate degree of immaturity in the lymph node of patients with CLL does not indicate that these patients will have a marked shortening of their survival. PMID:580071

  7. Autoimmune Cytopenias in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available The clinical course of chronic lymphocytic leukemia (CLL may be complicated at any time by autoimmune phenomena.The most common ones are hematologic disorders, such as autoimmune hemolytic anemia (AIHA and immune thrombocytopenia (ITP. Pure red cell aplasia (PRCA and autoimmune agranulocytosis (AG are, indeed, more rarely seen. However, they are probably underestimated due to the possible misleading presence of cytopenias secondary to leukemic bone marrow involvement or to chemotherapy cytotoxicity. The source of autoantibodies is still uncertain, despite the most convincing data are in favor of the involvement of resting normal B-cells. In general, excluding the specific treatment of underlying CLL, the managementof these complications is not different from that of idiopathic autoimmune cytopenias or of those associated to other causes. Among different therapeutic approaches, monoclonal antibody rituximab, given alone or in combination, has shown to be very effective.

  8. [The genetic landscape of chronic lymphocytic leukemia].

    Science.gov (United States)

    Marosvári, Dóra; Alpár, Donát; Király, Attila Péter; Rajnai, Hajnalka; Reiniger, Lilla; Bödör, Csaba

    2016-06-01

    Chronic lymphocytic leukemia (CLL) is the most frequent mature B-cell non-Hodgkin's lymphoma in the Western countries. The recent next-generation sequencing (NGS) studies lead to an exponential increase in our knowledge of the pathogenesis and progression of CLL. Whole genome and exome sequencing studies revealed a remarkable inter- and intra-patient genetic heterogeneity with a significant therapy-induced clonal evolution in the majority of the patients. Driver mutations were identified in components of various signalling pathways and cellular processes with notable prognostic and therapeutic relevance. Interestingly, these studies revealed only a few genes mutated in at least 15-20% of the patients with a larger number of genes mutated in a smaller proportion of patients. This improved understanding of the genomic landscape of CLL has opened new avenues for a more precise patient stratification and rational application of novel, more effective targeted therapies. PMID:27275638

  9. Initial therapy of chronic lymphocytic leukemia.

    Science.gov (United States)

    Eichhorst, Barbara; Cramer, Paula; Hallek, Michael

    2016-04-01

    Only chronic lymphocytic leukemia (CLL) patients with active or symptomatic disease or with advanced Binet or Rai stages require therapy. Prognostic risk factor profile and comorbidity burden are most relevant for the choice of treatment. For physically fit patients, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab remains the current standard therapy. For unfit patients, treatment with an anti-CD20 antibody (obinutuzumab or rituximab or ofatumumab) plus milder chemotherapy (chlorambucil) may be applied. Patients with a del(17p) or TP53 mutation should be treated with the kinase inhibitors ibrutinib or a combination of idelalisib and rituximab. Clinical trials over the next several years will determine, whether kinase inhibitors, other small molecules, immunotherapeutics, or combinations thereof will further improve outcomes for patients with CLL. PMID:27040702

  10. What Is Acute Lymphocytic Leukemia (ALL)?

    Science.gov (United States)

    ... White blood cells help the body fight infections. Lymphocytes These are the main cells that make up ... B cells) and T lymphocytes (T cells). B lymphocytes: B lymphocytes protect the body from invading germs ...

  11. Diagnosis of large granular lymphocytic leukemia in a patient previously treated for acute myeloblastic leukemia

    OpenAIRE

    Sinem Civriz Bozdag; Sinem Namdaroglu; Omur Kayikci; Gülsah Kaygusuz; Itir Demiriz; Murat Cinarsoy; Emre Tekgunduz; Fevzi Altuntas

    2013-01-01

    Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disease characterized by the clonal expansion of cytotoxic T or natural killer cells. We report on a patient diagnosed with T-cell LGL leukemia two years after the achievement of hematologic remission for acute myeloblastic leukemia.

  12. Prognostic significance of serum immunoglobulin pareprotein in chronic lymphocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    杨舒

    2012-01-01

    Objective To investigate the incidence of serum immunoglobulin (Ig) paraprotein in chronic lymphocytic leukemia(CLL) ,and to explore its clinical associated laboratory features and prognostic implication. Methods Serum protein electrophoresis and immunofixation

  13. Evolution of ibrutinib resistance in chronic lymphocytic leukemia (CLL)

    OpenAIRE

    Komarova, Natalia L.; Burger, Jan A.; Wodarz, Dominik

    2014-01-01

    Chronic ymphocytic leukemia is the most common leukemia, mostly arising in patients over the age of 50. The disease has been treated with chemo-immunotherapies with varying outcomes, depending on the genetic make-up of the tumor cells. Recently, a promising new tyrosine kinase inhibitor, ibrutinib, has been developed, which resulted in successful responses in clinical trials, even for the most aggressive chronic lymphocytic leukemia types. The crucial current questions include how long diseas...

  14. Stromal control of chronic lymphocytic leukemia cells

    Directory of Open Access Journals (Sweden)

    Seke Etet PF

    2013-09-01

    Full Text Available Paul Faustin Seke Etet,1 Armel Herve Nwabo Kamdje,2 Jeremie Mbo Amvene,2 Yousef Aldebasi,3 Mohammed Farahna,1 Lorella Vecchio41Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 2Department of Medicine, University of Ngaoundere, Ngaoundere, Cameroon; 3Department of Optometry, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 4Laboratory of Cytometry, Institute of Molecular Genetics, CNR, University of Pavia, Pavia, ItalyAbstract: In the ongoing efforts to develop therapies against chronic lymphocytic leukemia (CLL, stromal factors allowing malignant cells to escape spontaneous and chemotherapy-mediated apoptosis, giving way to relapses, have been abundantly investigated. Bone marrow adherent cell types, collectively referred to as stromal cells, appear to be key players in such escape, mainly because CLL malignant cells, which rapidly undergo spontaneous apoptosis when cultured in vitro, survive, migrate, and resist cytotoxic agents in co-culture with bone marrow stromal cells. CLL displays variable clinical courses according to well-defined prognostic factors induced on malignant B-cells (CLL cells or expressed by the transformed bone marrow stromal microenvironment. Particularly, a critical pathogenic role is played by proinflammatory factors, adhesion molecules, and signaling molecules involved in cell fate and stemness, such as Notch, Wnt, sonic Hedgehog, phosphoinositide 3-kinase (PI3K, protein kinase B (Akt, and the B-cell CLL/lymphoma 2 (Bcl-2 family of regulator proteins. As herein discussed, these molecules probably form a complex network favoring CLL cell survival, proliferation, and chemoresistance to anticancer therapy. Characterizing the sets of signaling pathways involved in the interactions between stromal cells and CLL cells may provide new tools for CLL clinical phenotyping and for re-sensitizing chemotherapy resistant cells

  15. ALLOGENEIC TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Patrizia Chiusolo

    2010-05-01

    Full Text Available

    Even if Chronic lymphocytic leukemia (CLL often has an indolent behavior with good responsiveness to cytoreductive treatment, about 20% of the patients, so called "poor-risk" patients, show an aggressive course and die within a few years despite early intensive therapies. Criteria for poor-risk disease according to the European Bone Marrow Transplantation (EBMT CLL Transplant Consensus are: purine analogue refractoriness, early relapse after purine analogue combination therapy, CLL with p53 lesion requiring treatment.

    Allogeneic transplant has potential curative role in CLL, however burden with very  high transplant related mortality (TRM rates of 38-50%:

    A major advance in reducing the short-term morbidity and mortality of allogeneic stem cell transplantation (SCT has been the introduction of non-myeloablative or reduced intensity conditioning (RIC regimens to allow engraftment of allogeneic stem cells. There is no doubt that the crucial therapeutic principle of allo-SCT in CLL is graft versus leukemia (GVL activity.

    The major complications of allogeneic SCT in CLL are: chronic graft-versus-host-disease (GVHD affecting quality of life, high graft rejection and infection rates rates correlated with preexisting immunosuppression. Disease relapse remains the major cause of failure after RIC allo-HCT in CLL patients.

    Sensitive minimal residual disease (MRD quantification has strong prognostic impact after transplant.

     

  16. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Herman, S E M; Niemann, C U; Farooqui, M;

    2014-01-01

    Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further...

  17. Targeted treatment for chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Masood A

    2011-11-01

    Full Text Available Aisha Masood1, Taimur Sher2, Aneel Paulus2, Kena C Miller2, Kasyapa S Chitta3, Asher Chanan-Khan4 1The Tisch Cancer Institute, Bone Marrow Transplant Unit, Mount Sinai School of Medicine, 2Department of Medicine, Roswell Park Cancer Institute, 3Department of Molecular Targets and Experimental Therapeutics, Roswell Park Cancer Institute, New York, NY, 4Division of Hematology/Oncology, Mayo Clinic, Jacksonville, FL, USA Abstract: The treatment of chronic lymphocytic leukemia (CLL has evolved over the last few decades. Recognition has increased of several key components of CLL biology currently manipulated for therapeutics. A milestone in the treatment of CLL was reached with the incorporation of immunotherapy with conventional chemotherapy. The fludarabine/cyclophosphamide/rituximab combination has demonstrated survival advantage for the first time in the treatment of CLL. Several other biological compounds are being explored with the hope of improving responses, impacting survival, and ultimately curing CLL. Important agents being tested are targeted on CLL surface molecules and their ligands, signal transduction protein and oncogenes. This review provides a brief summary of the recent advances made in preclinical and clinical investigation of selected promising therapeutic agents, which lead the target-directed therapeutic approach. Keywords: CLL, Akt inhibitors, Bcl-2 inhibitors, cyclin d kinase inhibitors, heat shock protein inhibitors, immunomodulatory drugs, monoclonal antibodies

  18. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-11-01

    Full Text Available Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles. Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  19. INFECTIOUS COMPLICATIONS IN CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    AnnaMaria Nosari

    2012-01-01

    Full Text Available

    Infectious complications have been known to be a major cause of morbidity and mortality in CLL patients who are predisposed to infections because of both the humoral immunodepression inherent to hematologic disease, which is related to stage and duration of CLL, and to further immunosuppression related to therapy. The majority of infections in CLL patients treated with alkilating agents is of bacterial origin. The immunodeficiency and natural infectious history of alkylator-resistant, corticosteroid-treated patients appears to have changed with the administration of purine analogs, which has been complicated by very severe and unusual infections and also more viral infections due to sustained reduction of CD4-positive T lymphocytes. The following introduction of monoclonal antibody therapies, in particular alemtuzumab, further increased the immunodepression, increasing also infections which appeared more often in patients with recurrent neutropenia due to chemotherapy cycles.

    Epidemiological data regarding fungal infections in lymphoproliferative disorders are scarce. Italian SEIFEM group in a retrospective multicentre study regarding CLL patients reported an incidence of mycoses 0.5%; however, chronic lymphoproliferative disorders emerged as second haematological underlying disease after acute leukemia in a French study on aspergillosis; in particular CLL with aspergillosis accounted for a third of these chronic lymphoproliferative diseases presenting mould infection.

  20. Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia

    OpenAIRE

    Bhattacharyya, Pritish K

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia′s. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML) on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and ...

  1. What's New in Adult Acute Lymphocytic Leukemia (ALL) in Adults Research?

    Science.gov (United States)

    ... Learn About Cancer » Leukemia - Acute Lymphocytic (ALL) in Adults » Detailed Guide » What’s new in acute lymphocytic leukemia ... What`s New in Leukemia - Acute Lymphocytic (ALL) in Adults Research? TOPICS Document Topics GO » SEE A LIST » ...

  2. Quantification of newly produced B and T lymphocytes in untreated chronic lymphocytic leukemia patients

    Directory of Open Access Journals (Sweden)

    Caimi Luigi

    2010-11-01

    Full Text Available Abstract Background The immune defects occurring in chronic lymphocytic leukemia are responsible for the frequent occurrence of infections and autoimmune phenomena, and may be involved in the initiation and maintenance of the malignant clone. Here, we evaluated the quantitative defects of newly produced B and T lymphocytes. Methods The output of B and T lymphocytes from the production and maturation sites was analyzed in chronic lymphocytic leukemia patients and healthy controls by quantifying kappa-deleting recombination excision circles (KRECs and T-cell receptor excision circles (TRECs by a Real-Time PCR assay that simultaneously detects both targets. T-lymphocyte subsets were analyzed by six-color flow cytometric analysis. Data comparison was performed by two-sided Mann-Whitney test. Results KRECs level was reduced in untreated chronic lymphocytic leukemia patients studied at the very early stage of the disease, whereas the release of TRECs+ cells was preserved. Furthermore, the observed increase of CD4+ lymphocytes could be ascribed to the accumulation of CD4+ cells with effector memory phenotype. Conclusions The decreased number of newly produced B lymphocytes in these patients is likely related to a homeostatic mechanism by which the immune system balances the abnormal B-cell expansion. This feature may precede the profound defect of humoral immunity characterizing the later stages of the disease.

  3. Safety and Tolerability Study of PCI-32765 in B Cell Lymphoma and Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2016-04-26

    B-cell Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma; Diffuse Well-differentiated Lymphocytic Lymphoma; B Cell Lymphoma; Follicular Lymphoma,; Mantle Cell Lymphoma; Non-Hodgkin's Lymphoma; Waldenstrom Macroglobulinemia; Burkitt Lymphoma; B-Cell Diffuse Lymphoma

  4. Protein profiles distinguish stable and progressive chronic lymphocytic leukemia.

    Science.gov (United States)

    Huang, Pauline Y; Mactier, Swetlana; Armacki, Natalie; Giles Best, O; Belov, Larissa; Kaufman, Kimberley L; Pascovici, Dana; Mulligan, Stephen P; Christopherson, Richard I

    2016-05-01

    Patients with a stable chronic lymphocytic leukemia (CLL) double their blood lymphocyte count in >5 years, but may develop progressive disease with lymphocytes doubling in selected reaction monitoring) using extracts of purified CD19(+) CLL cells from patients (n = 50). Hierarchical clustering of these protein profiles showed two clusters of patients that correlated with progressive and stable CLL, providing signatures that should be useful for triaging patients. Some of the proteins in the progressive cluster have not been linked with CLL, for example, glutamate dehydrogenase 1 and transcription intermediary factor 1-beta. PMID:26422656

  5. Acute lymphocytic Leukemia masquerading as acute osteomyelitis

    International Nuclear Information System (INIS)

    Two children each developed a focal destructive bone lesion accompanied by intermittent fever, swelling, tenderness and elevated ESR. Blood counts were normal; bone marrow aspiration showed acute leukemia. The bone lesions healed in both patients after anti-leukemic therapy. We suggest that the similar roentgenographic appearance of osteomyelitis, bone infarction and focal destructive lesions in leukemia probably reflects a common, basically ischemic process of bone. (orig.)

  6. Hodgkin lymphoma transformation of chronic lymphocytic leukemia/small lymphocytic lymphoma

    OpenAIRE

    Krause, John R.; Drinkard, Lee C.; Keglovits, Latoya C.

    2013-01-01

    Transformation to a large cell lymphoma may occur during the course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in approximately 5% of the cases. This is known as Richter's transformation. A much less frequent transformation to Hodgkin lymphoma may occur. We report a case of CLL/SLL in which a transformation to Hodgkin lymphoma occurred, and we review previously published reports of this transformation. Transformation to Hodgkin lymphoma in CLL/SLL has a poor outcome ...

  7. Sweet Syndrome in a Patient with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Curious Lymphocyte/Neutrophil Fluctuations

    OpenAIRE

    Çiğdem Usul Afşar; Semra Paydaş; Meral Günaldı; Berna Bozkurt Duman; Vehbi Erçolak; Suzan Zorludemir; Arbil Açıkalın

    2013-01-01

    Sweet syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by tender, red inflammatory nodules or papules that occur in association with infection, malignancy, connective tissue disease, or following exposure to certain drugs. Here, we present Sweet syndrome in a case with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL) which is a relatively rare co-occurrence. Conflict of interest:None declared.

  8. Sweet Syndrome in a Patient with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Curious Lymphocyte/Neutrophil Fluctuations

    Directory of Open Access Journals (Sweden)

    Çiğdem Usul Afşar

    2013-12-01

    Full Text Available Sweet syndrome, also referred to as acute febrile neutrophilic dermatosis, is characterized by tender, red inflammatory nodules or papules that occur in association with infection, malignancy, connective tissue disease, or following exposure to certain drugs. Here, we present Sweet syndrome in a case with small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL which is a relatively rare co-occurrence.

  9. Rituximab for the treatment of patients with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    M Gentile

    2010-03-01

    Full Text Available M Gentile, E Vigna, C Mazzone, E Lucia, AG Recchia, L Morabito2, MG Bisconte, C Gentile, F Morabito1UOC di Ematologia, Azienda Ospedaliera di Cosenza, Italy; 2Servicio de Hematología y Hemoterapia, Hospital Universitario de Canarias, La Laguna, Tenerife, SpainAbstract: Chronic lymphocytic leukemia (CLL is a lymphoproliferative disorder that originates from antigen-experienced B lymphocytes that do not die and hence accumulate due to external survival signals or undergo apoptosis and are replenished by proliferating precursors. These neoplastic lymphocytes exhibit a characteristic immunophenotype of CD5+/CD19+/CD20+/HLA-DR+/CD23+/sIgdim. Thus, the CD20 antigen has been an appealing target for therapy. The introduction of the monoclonal antibody rituximab (anti-CD20 enabled an outstanding advance in CLL treatment. The introduction of this monoclonal antibody into chemotherapy regimens has dramatically improved complete response rates and progression-free survival in patients with both untreated and relapsed CLL. Although only preliminary data from phase III confirmatory trials have been reported, the FCR regimen, which combines fludarabine and cyclophosphamide with rituximab, is currently the most effective treatment regimen for CLL patients, and has also been demonstrated to significantly improve overall survival . The success of rituximab and the identification of other CLL lymphocyte surface antigens have spurred the development of a multitude of monoclonal antibodies targeting distinct proteins and epitopes in an attempt to target CLL cells more effectively.Keywords: rituximab, chronic lymphocytic leukemia, chemotherapy

  10. Chromosomal study for prognostic grouping in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    To determine the frequency of various cytogenetic aberrations in newly diagnosed chronic lymphocytic leukemia (CLL) patients, and their detection rate by cytogenetic and fluorescent In situ hybridization (FISH) technique separately. Analysis was made on 100 diagnosed chronic lymphocytic leukemia patients. Cytogenetics and FISH technique were performed on blood or bone marrow samples. Nineteen out of 100 cases (19%) showed karyotype abnormalities; whereas 55 showed abnormalities using the CLL - specific FISH probes. The most frequent abnormality detected by standard cytogenetics was trisomy 12. The most common abnormality detected by FISH was a deletion of 13q14 (40 out of 55 cases; 72% of the abnormal). For prognostic grouping of CLL patients, FISH must always be requested which may even replace standard karyotyping. These chromosomal markers help in choosing the therapeutic options. (author)

  11. Lenalidomide in the treatment of chronic lymphocytic leukemia

    OpenAIRE

    Agostino Cortelezzi; Mariarita Sciumè; Gianluigi Reda

    2012-01-01

    The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL). However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently be...

  12. Aureobasidium pullulans infection in a patient with chronic lymphocytic leukemia

    OpenAIRE

    Leonardo Rodrigues de Oliveira; Helio Moraes-Souza; Andre Luiz Maltos; Keila Cristina dos Santos; Rodrigo Juliano Molina; Cristina Hueb Barata

    2013-01-01

    Saprophytic fungi are being increasingly recognized as etiologic agents of mycoses in immunosuppressed patients. We report a case of subcutaneous infiltration by Aureobasidium pullulans, likely due to traumatic inoculation, in a neutropenic patient during chemotherapy for chronic lymphocytic leukemia. The patient was treated with amphotericin B deoxycholate but was subsequently switched to itraconazole, which improved the lesion. This case highlights the importance of considering unusual fung...

  13. Chronic Lymphocytic Leukemia: Inception to Cure: Are We There?

    OpenAIRE

    Lad, Deepesh P.; Malhotra, Pankaj; Varma, Subhash

    2012-01-01

    There have been remarkable advances in our understanding of the biology and therapeutics of chronic lymphocytic leukemia. B cell receptor signaling and micro-environment in CLL biology have been the most modern areas of research. In CLL therapeutics, we have come a long way from alkylating agents to chemo-immunotherapy. Despite this there remain significant lacunae in the disease biology that has hindered our quest to achieve the ultimate in CLL: Cure. This review aims to summarize the past, ...

  14. Immunological aspects in chronic lymphocytic leukemia (CLL) development

    OpenAIRE

    García-Muñoz, Ricardo; Galiacho, Verónica Roldan; Llorente, Luis

    2012-01-01

    Chronic lymphocytic leukemia (CLL) is unique among B cell malignancies in that the malignant clones can be featured either somatically mutated or unmutated IGVH genes. CLL cells that express unmutated immunoglobulin variable domains likely underwent final development prior to their entry into the germinal center, whereas those that express mutated variable domains likely transited through the germinal center and then underwent final development. Regardless, the cellular origin of CLL remains ...

  15. Ibrutinib Improves Survival in Patients with Previously Treated Chronic Lymphocytic Leukemia

    Science.gov (United States)

    A summary of results from an international phase III trial that compared ibrutinib (Imbruvica®) and ofatumumab (Arzerra®) for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL).

  16. Occurrence of chronic lymphocytic leukemia in patients with chronic myelogenous leukemia

    Directory of Open Access Journals (Sweden)

    Pritish K Bhattacharyya

    2013-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is the most common leukemia of adults in the western world and constitutes about 33% of all leukemia′s. The incidence of CLL increases with age and are more common in older population. Chronic myeloid leukemia (CML on the contrary occurs in both young adults and elderly and is a chronic myeloproliferative disease that originates from abnormal pluripotent stem cells and results in involvement of multiple hematopoietic lineages, but predominantly myeloid and less commonly lymphoid. Association between CLL and myeloid malignancies (CML, acute myeloid leukemia and MDS, myelodysplastic syndrome is rare. In literature documenting CLL and CML in same patients, occur either simultaneously or CML is preceded by CLL.

  17. Aureobasidium pullulans infection in a patient with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Leonardo Rodrigues de Oliveira

    2013-09-01

    Full Text Available Saprophytic fungi are being increasingly recognized as etiologic agents of mycoses in immunosuppressed patients. We report a case of subcutaneous infiltration by Aureobasidium pullulans, likely due to traumatic inoculation, in a neutropenic patient during chemotherapy for chronic lymphocytic leukemia. The patient was treated with amphotericin B deoxycholate but was subsequently switched to itraconazole, which improved the lesion. This case highlights the importance of considering unusual fungal infections in critically ill patients such as those who are immunosuppressed due to chemotherapy. Diagnostic techniques and effective antifungal therapy have improved the prognosis of these cases.

  18. Reverse Pseudohyperkalemia: An Important Clinical Entity in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Sahar Mansoor

    2015-01-01

    Full Text Available Hyperkalemia is a potentially lethal electrolyte derangement commonly seen in patients with hematologic neoplasms with or without renal failure. Pseudohyperkalemia and reverse pseudohyperkalemia also can be seen in this patient population and early recognition and diagnosis of these conditions are vital. Here, we report a case of reverse pseudohyperkalemia in a patient with chronic lymphocytic leukemia (CLL and provide recommendations regarding diagnostic and therapeutic strategies for management of such patients. Further, we discuss the pathogenesis of this condition and its potential role as a surrogate of favorable prognostic features in patients with CLL.

  19. PARP1-Driven Apoptosis in Chronic Lymphocytic Leukemia

    OpenAIRE

    2014-01-01

    Chronic lymphocytic leukemia (CLL) is considered a malignancy resulting from defects in apoptosis. For this reason, targeting apoptotic pathways in CLL may be valuable for its management. Poly [ADP-ribose] polymerase 1 (PARP1) is the main member of a family of nuclear enzymes that act as DNA damage sensors. Through binding on DNA damaged structures, PARP1 recruits repair enzymes and serves as a survival factor, but if the damage is severe enough, its action may lead the cell to apoptosis thro...

  20. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Science.gov (United States)

    Barrientos, Jacqueline C

    2016-09-01

    Idelalisib is a first-in-class selective oral PI3Kδ inhibitor for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma, a predominantly elderly population with high comorbidity. The drug promotes apoptosis in primary CLL cells ex vivo, independent of common prognostic markers and inhibits CLL cell homing, migration and adhesion to cells in the microenvironment. Idelalisib has shown efficacy with acceptable safety as monotherapy and combination therapy in relapsed/refractory CLL. Idelalisib has clinical activity in patients with CLL with del(17p). The development of other novel B-cell-targeted agents provides the opportunity to evaluate additional idelalisib treatment combinations for their potential to further improve outcomes in CLL/small lymphocytic lymphoma. PMID:27324214

  1. FLT3 mutations in canine acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated protein in a variety of human acute leukemias. Mutations leading to constitutively active FLT3, including internal tandem duplications of the juxtamembrane domain (ITD), result in continuous cellular proliferation, resistance to apoptotic cell death, and a poorer prognosis. A better understanding of the molecular consequences of FLT3 activation would allow improved therapeutic strategies in these patients. Canine lymphoproliferative diseases, including lymphoma and acute leukemias, share evolutionarily conserved chromosomal aberrations and exhibit conserved mutations within key oncogenes when compared to their human counterparts. A small percentage of canine acute lymphocytic leukemias (ALL) also exhibit FLT3 ITD mutations. We molecularly characterized FLT3 mutations in two dogs and one cell line, by DNA sequencing, gene expression analysis via quantitative real-time PCR, and sensitivity to the FLT3 inhibitor lestaurtinib via in vitro proliferation assays. FLT 3 and downstream mediators of FLT3 activation were assessed by Western blotting. The canine B-cell leukemia cell line, GL-1, and neoplastic cells from 2/7 dogs diagnosed cytologically with ALL were found to have FLT3 ITD mutations and FLT3 mRNA up-regulation. Lestaurtinib, a small molecule FLT3 inhibitor, significantly inhibited the growth of GL-1 cells, while not affecting the growth of two other canine lymphoid cell lines without the FLT3 mutation. Finally, western blots were used to confirm the conserved downstream mediators of FLT3 activating mutations. These results show that ALL and FLT3 biology is conserved between canine and human patients, supporting the notion that canine ALL, in conjunction with the GL-1 cell line, will be useful in the development of a relevant large animal model to aid in the study of human FLT3 mutant leukemias

  2. Targeted treatment for chronic lymphocytic leukemia: clinical potential of obinutuzumab

    Directory of Open Access Journals (Sweden)

    Smolej L

    2014-12-01

    Full Text Available Lukáš Smolej 4th Department of Internal Medicine – Hematology, University Hospital Hradec Králové and Charles University in Prague, Faculty of Medicine in Hradec Králové, Hradec Králové, Czech Republic Abstract: Introduction of targeted agents revolutionized the treatment of chronic lymphocytic leukemia (CLL in the past decade. Addition of chimeric monoclonal anti-CD20 antibody rituximab to chemotherapy significantly improved efficacy including overall survival (OS in untreated fit patients; humanized anti-CD52 antibody alemtuzumab and fully human anti-CD20 antibody ofatumumab lead to improvement in refractory disease. Novel small molecule inhibitors such as ibrutinib and idelalisib demonstrated excellent activity and were very recently licensed in relapsed/refractory CLL. Obinutuzumab (GA101 is the newest monoclonal antibody approved for the treatment of CLL. This novel, glycoengineered, type II humanized anti-CD20 antibody is characterized by enhanced antibody-dependent cellular cytotoxicity and direct induction of cell death compared to type I antibodies. Combination of obinutuzumab and chlorambucil yielded significantly better OS in comparison to chlorambucil monotherapy in untreated comorbid patients. These results led to approval of obinuzutumab for the treatment of CLL. Numerous clinical trials combining obinutuzumab with other cytotoxic drugs and novel small molecules are currently under way. This review focuses on the role of obinutuzumab in the treatment of CLL. Keywords: chronic lymphocytic leukemia, anti-CD20 antibodies, chlorambucil, rituximab, ofatumumab, obinutuzumab, overall survival

  3. Allogeneic Transplantation for Patients With Acute Leukemia or Chronic Myelogenous Leukemia (CML)

    Science.gov (United States)

    2016-06-14

    Leukemia, Lymphocytic, Acute; Leukemia; Leukemia Acute Promyelocytic Leukemia (APL); Leukemia Acute Lymphoid Leukemia (ALL); Leukemia Chronic Myelogenous Leukemia (CML); Leukemia Acute Myeloid Leukemia (AML); Leukemia Chronic Lymphocytic Leukemia (CLL)

  4. A case of chronic lymphocytic leukemia with massive ascites

    Science.gov (United States)

    Yonal, Ipek; Nazlıgul, Esra; Tas, Gulsum; Agan, Mehmet Ramazan; Yenerel, Mustafa Nuri; Nalcaci, Meliha

    2012-01-01

    An 81-year old woman with a history of chronic lymphocytic leukemia (CLL) was admitted with night sweats and abdominal distension. A complete blood count showed hemoglobin 5 g/dL, white blood cell (WBC) count 28.5×109/L and platelets 38.4×109/L. Peripheral blood smear examination showed a large number of smudge cells and lymphocytosis composed of mature-looking lymphocytes with clumped nuclear chromatin. Computed tomography scan demonstrated enlarged cervical, axillary, paraaortic, retroperitoneal and mesenteric lymph nodes with concomitant omental thickening and ascites. Also, the liver and the spleen were enlarged in the presence of multiple ill-defined hypoechoic areas in the latter. Histopathological analysis of the cervical lymph node biopsy was consistent with CLL. Bone marrow examination showed diffuse infiltration of the marrow with small lymphocytes. Analysis of the ascitic fluid revealed an exudate with WBC 1220 cells/mL. Cytocentrifuge preparation of the ascitic fluid showed small mature lymphoid cells containing hyperchromatic nuclei with coarsely granular chromatin. On flow cytometric analysis of the ascitic fluid, expression of CD5, CD19, CD20, CD22, CD23, CD45 and HLA-DR was compatible with a diagnosis of CLL, in accordance with the results of the peripheral blood analysis. The patient was treated with chemotherapy consisting of cyclophosphamide, vincristine and prednisolone but died within one month after development of non-chylous ascites. PMID:23372915

  5. A case of chronic lymphocytic leukemia with massive ascites

    Directory of Open Access Journals (Sweden)

    Meliha Nalcaci

    2012-10-01

    Full Text Available An 81-year old woman with a history of chronic lymphocytic leukemia (CLL was admitted with night sweats and abdominal distension. A complete blood count showed hemoglobin 5 g/dL, white blood cell (WBC count 28.5x109/L and platelets 38.4x109/L. Peripheral blood smear examination showed a large number of smudge cells and lymphocytosis composed of mature-looking lymphocytes with clumped nuclear chromatin. Computed tomography scan demonstrated enlarged cervical, axillary, paraaortic, retroperitoneal and mesenteric lymph nodes with concomitant omental thickening and ascites. Also, the liver and the spleen were enlarged in the presence of multiple ill-defined hypoechoic areas in the latter. Histopathological analysis of the cervical lymph node biopsy was consistent with CLL. Bone marrow examination showed diffuse infiltration of the marrow with small lymphocytes. Analysis of the ascitic fluid revealed an exudate with WBC 1220 cells/mL. Cytocentrifuge preparation of the ascitic fluid showed small mature lymphoid cells containing hyperchromatic nuclei with coarsely gran- ular chromatin. On flow cytometric analysis of the ascitic fluid, expression of CD5, CD19, CD20, CD22, CD23, CD45 and HLA-DR was compatible with a diagnosis of CLL, in accordance with the results of the peripheral blood analysis. The patient was treated with chemotherapy consisting of cyclophosphamide, vincristine and prednisolone but died within one month after development of non-chylous ascites.

  6. Cranial radiation in childhood acute lymphocytic leukemia. Neuropsychologic sequelae

    International Nuclear Information System (INIS)

    A battery of neuropsychologic tests was administered ''blindly'' to 18 children with acute lymphocytic leukemia (ALL) who had been randomly assigned to treatment regimens with or without cranial radiation. These children were all in complete continuous remission for more than 3 1/2 years and were no longer receiving therapy. The results indicated no substantial differences between groups as a function of radiation therapy. However, decreased neuropsychologic performance was found when the entire sample was compared with population norms. These data do not support the hypothesis that cranial radiation therapy is responsible for the neuropsychologic sequelae seen in these survivors of ALL. Post hoc multiple regression analysis indicated that parental education levels accounted for more of the neuropsychologic variability seen in these children than other factors such as age at diagnosis, type of therapy, or sex of child

  7. Practical approach to management of chronic lymphocytic leukemia.

    Science.gov (United States)

    Smolej, Lukáš; Šimkovič, Martin

    2016-04-01

    Revolutionary progress has recently changed the landscape of chronic lymphocytic leukemia (CLL). Powerful prognostic factors, especially p53 mutation and/or deletion and IGHV mutation status, have refined individual patient prognosis. Purine analogs and monoclonal antibodies paved the way from palliative treatment to chemoimmunotherapy capable of eradication of minimal residual disease and prolongation of survival. Obinutuzumab (GA-101) and ofatumumab have been recently approved for the treatment of comorbid patients. Bendamustine is available for first-line treatment of patients ineligible for fludarabine, cyclophosphamide, and rituximab (FCR). High-dose glucocorticoids combined with rituximab represent a promising option for refractory CLL; ofatumumab is approved for fludarabine- and alemtuzumab-refractory patients. Allogeneic stem cell transplantation is the only curative option but is feasible in a highly selected group of patients only. The novel small molecule inhibitors ibrutinib and idelalisib have been recently approved for relapsed/refractory CLL. This review provides practical advice for diagnosis, prognostication and treatment of CLL. PMID:27186193

  8. Novel Therapies for Chronic Lymphocytic Leukemia: A Canadian Perspective.

    Science.gov (United States)

    Owen, Carolyn; Assouline, Sarit; Kuruvilla, John; Uchida, Cassandra; Bellingham, Catherine; Sehn, Laurie

    2015-11-01

    Chronic lymphocytic leukemia (CLL) is the most common adult lymphoproliferative disorder in Western countries. The current standard of care for CLL is chemoimmunotherapy, typically with fludarabine, cyclophosphamide, and rituximab (FCR). However, most patients with CLL are elderly with comorbidities and are unable to tolerate FCR. In order to choose the best treatment for each individual patient, physicians must balance efficacy with toxicity. In addition, most currently available treatments are ineffective in CLL patients with loss of TP53. Two groups of novel therapeutic agents-anti-CD20 monoclonal antibodies and small molecule inhibitors-are attempting to address these issues, and 5 of these agents have progressed to phase 3 trials: obinutuzumab, idelalisib, ibrutinib, venetoclax (ABT-199), and duvelisib (IPI-145). We present the current evidence for these novel agents in the treatment of CLL, along with the perspectives of 4 Canadian oncology experts. PMID:26416145

  9. Chronic lymphocytic leukemia (CLL)-Then and now.

    Science.gov (United States)

    Rai, Kanti R; Jain, Preetesh

    2016-03-01

    The field of chronic lymphocytic leukemia (CLL) has witnessed considerable change since the time clinical staging was introduced in clinical practice in 1975. Over the years, the prognostication in CLL has expanded with the addition in late 90s of mutational status of variable region of immunoglobulin heavy chain (IGHV), and chromosomal analyses using fluorescent in situ hybridization (FISH). More recently, stereotypy of BCR (B cell receptor) and whole exome sequencing (WES) based discovery of specific mutations such as NOTCH1, TP53, SF3B1, XPO-1, BIRC3, ATM, and RPS15 further refined the current prognostication system in CLL. In therapy, the field of CLL has seen major changes from oral chlorambucil and steroids prior to 1980s, to chemo-immunotherapy (CIT) with fludarabine, cyclophosphamide, rituximab (FCR) to the orally administered targeted therapeutic agents inhibiting kinases in the B cell receptor (BCR) signaling pathway such as Ibrutinib (BTK inhibitor) and Idelalisib (p110 PI3Kδ inhibitor) and novel anti-CD20 mAb's (monoclonal antibodies) such as obinutuzumab. This progress is continuing and other targeted therapeutics such as Bcl2 antagonists (Venetoclax or ABT-199) and finally chimeric antigen receptor against T cells (CART) are in the process of being developed. This review is an attempt to summarize the major benchmarks in the prognostication and in the therapy of CLL. The topic allocated to us by Dr Ayalew Tefferi and Dr Carlo Brugnara is very appropriate to reminisce what our understanding of chronic lymphocytic leukemia (CLL) was in 1976 and how rapidly have the advances occurring in this field affected the patients with CLL. Am. J. Hematol. 91:330-340, 2016. © 2015 Wiley Periodicals, Inc. PMID:26690614

  10. Triple cancer: chronic lymphocytic leukemia with bladder and prostate carcinoma.

    Science.gov (United States)

    Gajendra, Smeeta; Sharma, Rashi; Sahoo, Manas Kumar

    2015-08-01

    B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common lymphoproliferative disorder with an increased risk of developing subsequent neoplasms of epithelial and mesenchymal origin. The decreased immunity and B-cell dysfunction in CLL probably accounts for this emergence of second malignancies. We report a case of synchronous bladder transitional cell carcinoma (TCC) and prostatic carcinoma with CLL. A 74-year-old male who underwent transurethral resection of the prostate (TURP) for benign prostatic hyperplasia 2 years before, presented with recurrent urinary tract infection. Peripheral blood smear revealed leukocytosis with absolute lymphocytosis (absolute lymphocyte count: 37870 cells/mm³). Flow cytometric immunophenotyping revealed 75% abnormal lymphoid cells which were positive for CD 19, CD5, CD23, CD22, CD200, CD20 (moderate) with lambda light chain restriction and negative for CD3, CD10, FMC7, CD38, CD138, IgM, CD103, CD123. F Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) showed increased metabolic activity of the left lateral wall of the urinary bladder extending to the left UV junction, adjacent part of trigone and bladder neck region along with multiple heterogeneous enhancing areas with increased FDG avidity within the prostate. Transurethral resection of the bladder tumour by cystoscopy was performed. Histopathology showed high grade, muscle invasive urothelial carcinoma. Due to presence of uptake in the prostate, transurethral resection of the prostate was done and histopathology revealed adenocarcinoma of prostate (prostate specific antigen- positive), Gleason grade III+III and Gleason score 6. A high index of suspicion is required to detect synchronous and metachronous malignancies. Ancillary studies such as immunohistochemistry, flow cytometry and PET/CT are often essential for detection and an accurate diagnosis. PMID:26277675

  11. Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Agathangelidis, Andreas; Darzentas, Nikos; Hadzidimitriou, Anastasia;

    2012-01-01

    Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as...

  12. DNA repair initiated in chronic lymphocytic leukemia lymphocytes by 4-hydroperoxycyclophosphamide is inhibited by fludarabine and clofarabine.

    OpenAIRE

    Yamauchi, Takahiro; Nowak, Billie J.; Michael J Keating; Plunkett, William

    2001-01-01

    PURPOSE: Chronic lymphocytic leukemia (CLL) lymphocytes respond to DNA alkylation by excision repair, with the extent of repair increasing as the cells acquire resistance to alkylating agents. Because incorporation of nucleotide analogues into the repair patches elicits death signals in quiescent cells, the increased capacity for excision repair in alkylator-resistant cells could facilitate incorporation of nucleotide analogues. We hypothesized that the mechanism-based interaction of nucleosi...

  13. Paranasal Manifestations of Early Stage Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Ceren Günel

    2015-04-01

    Full Text Available OBJECTIVE: Chronic lymphocytic leukemia (CLL is the most common adult leukemia. A few studies have been reported about the relationship between CLL and paranasal sinuses. We aimed to investigate the paranasal manifestations of CLL and to determine the expression of nuclear factor-ĸB (NF-kB and tumor necrosis factor (TNF-α in the nasal mucosa in patients with CLL. MATERIALS AND METHODS: This study was a clinical trial that involved 40 patients. Group CLL (n=20 consisted of patients with early-stage CLL who were followed-up at the hematology clinic and who did not receive any treatment. The control group (n=20 consisted of patients who had undergone concha surgery because of nasal obstruction. Paranasal sinus computer tomography scans of all patients were taken, they were scored on the basis of the Lund–Mackay system, and sinusitis findings were recorded. The biopsy material taken from the inferior concha head of all patients was immunohistochemically stained with primary antibodies against NF-kB and TNF-α. RESULTS: There were no statistically significant differences between the two groups with respect to NF-κB (p=0.716 and TNF-α staining scores (p=1.000. The Lund–Mackay scores were significantly higher in the CLL group than in the control group (p=0.004. Fourteen patients had sinusitis at different locations, while the most common diagnosis was maxillary sinusitis (n=8 in the CLL group. CONCLUSION: This study showed that patients with early-stage CLL tend to have rhinosinusitis. However, NF-kB and TNF-α may not have a role in the inflammatory process involving the paranasal sinuses in patients with CLL.

  14. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia

    OpenAIRE

    Brown, Jennifer R; Barrientos, Jacqueline C.; Barr, Paul M.; Flinn, Ian W.; Burger, Jan A.; Tran, Anh; Clow, Fong; James, Danelle F; Graef, Thorsten; Friedberg, Jonathan W.; Rai, Kanti; O’Brien, Susan

    2015-01-01

    Ibrutinib was well tolerated when administered with BR CIT in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma.Ibrutinib added to CIT was associated with a high degree of clinical activity that compares favorably to historical reports of CIT alone.

  15. AUTOIMMUNE CYTOPENIAS IN CHRONIC LYMPHOCYTIC LEUKEMIA, FACTS AND MYTHS

    Directory of Open Access Journals (Sweden)

    Pavankumar Tandra

    2013-11-01

    Full Text Available CLL has been defined as presence of more than 5000 small mature appearing monoclonal B lymphocytes with a specific immunophenotype in peripheral blood. It is a well-known fact that CLL is associated with autoimmune cytopenias. CLL cells are CD5+ B lymphocytes, and usually are not the “guilty” cells which produce autoantibodies. T cell defect is another characteristic of CLL and the total number of T cells is increased, and there is inversion of the CD4/CD8 ratio. Autoimmune hemolytic anemia (AIHA is the most common autoimmune complication of CLL and has been reported in 10-25% of CLL patients. However, the stage-adjusted estimated rate of AIHA in CLL is about 5%. Conversely, CLL is three times more common in patients who present with AIHA. Direct agglutinin test (DAT is positive in 7-14% of CLL patients but AIHA may also occur in DAT negative patients. Autoimmune thrombocytopenia (AIT is the second most common complication of CLL and has been reported in 2-3% of patients. DAT is positive in AIT but presence of antiplatelet antibodies is neither diagnostic nor reliable. Autoimmune neutropenia (AIN and pure red cell aplasia (PRCA are very rare complications of CLL and like other autoimmune complications of CLL may occur at any clinical stage. It is believed that most case reports of AIN and PRCA in CLL actually belong to large granular lymphocytic leukemia (LGL. Non-hematologic autoimmune complications of CLL including cold agglutinin disease (CAD, paraneoplastic pemphigus (PNP, acquired angioedema, and anti-myelin associated globulin are rare. Before starting any treatment, clinicians should distinguish between autoimmune cytopenias and massive bone marrow infiltration since autoimmune complications of CLL are not necessarily equal to advanced disease with poor prognosis. According to IWCLL guideline, steroids are the mainstay of treatment of simple autoimmunity. Intravenous immunoglobulin (IVIg, cyclosporine, and rituximab are used in

  16. Granulomatous interstitial nephritis secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma.

    Science.gov (United States)

    Nasr, Samih H; Shanafelt, Tait D; Hanson, Curtis A; Fidler, Mary E; Cornell, Lynn D; Sethi, Sanjeev; Chaffee, Kari G; Morris, Joseph; Leung, Nelson

    2015-06-01

    Granulomatous interstitial nephritis (GIN) is an uncommon pathologic lesion encountered in 0.5% to 5.9% of renal biopsies. Drugs, sarcoidosis, and infections are responsible for most cases of GIN. Malignancy is not an established cause of GIN. Here, we report a series of 5 patients with GIN secondary to chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Patients were mostly elderly white males with an established history of CLL/SLL who presented with severe renal impairment (median peak serum creatinine, 7.3 mg/dL), leukocyturia, and mild proteinuria. One had nephromegaly. In 2 patients, the development and relapse of renal insufficiency closely paralleled the level of lymphocytosis. Kidney biopsy in all patients showed GIN concomitant with CLL/SLL leukemic interstitial infiltration. Granulomas were nonnecrotizing and epithelioid and were associated with giant cells. One biopsy showed granulomatous arteritis. One patient had a granulomatous reaction in lymph nodes and skin. Steroids with/without CLL/SLL-directed chemotherapy led to partial improvement of kidney function in all patients except 1 who had advanced cortical scarring on biopsy. In conclusion, we report an association between CLL/SLL and GIN. Patients typically present with severe renal failure due to both GIN and leukemic interstitial infiltration, which tends to respond to steroids with/without CLL/SLL-directed chemotherapy. The pathogenesis of GIN in this clinical setting is unknown but may represent a local hypersensitivity reaction to the CLL/SLL tumor cells. PMID:25795422

  17. Chronic lymphocytic leukemia/small lymphocytic lymphoma: another neoplasm related to the B-cell follicle?

    Science.gov (United States)

    Tandon, Bevan; Swerdlow, Steven H; Hasserjian, Robert P; Surti, Urvashi; Gibson, Sarah E

    2015-01-01

    Although there has been increased attention paid to the critical nature of nodal involvement in chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), the B-cell compartment it is most closely related to and its relationship to the follicle remain uncertain. A clinicopathologic investigation of 60 extramedullary biopsies of LEF1+ CLL/SLL, including 29 cases with perifollicular/follicular (PF/F) growth, was therefore performed. A subset of PF/F cases demonstrated inner mantle zone preservation or intra-mantle zone growth. All PF/F and 16/31 other cases contained CD21+ follicular dendritic cells. No cytogenetic, IGHV mutational or gene usage differences were seen between PF/F and diffuse cases. PF/F cases were more often kappa positive (pa subset of bona fide CLL/SLL is related to the follicle, most likely the outer mantle zone, and that at least a subset of the diffuse cases may represent "later" disease. PMID:25860247

  18. Lenalidomide in the Treatment of Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Agostino Cortelezzi

    2012-01-01

    Full Text Available The application of nucleoside analogue-based chemotherapy and immunotherapy with rituximab or alemtuzumab has increased both response rate and survival in patients with Chronic Lymphocytic Leukemia (CLL. However, because none of these therapies is curative, sequential therapeutic regimens are required. The majority of patients with relapsed or refractory CLL carry poor prognostic factors and show shorter overall survival and resistance to standard treatment. Numerous drugs have recently been approved for CLL therapy and many novel agents are under clinical investigation. The role of the tumor microenvironment and of immune dysfunction in CLL have allowed to enlarge the therapeutic armamentarium for CLL patients. This article will provide a comprehensive summary regarding mechanism of action, efficacy and safety of lenalidomide in CLL patients. Relevant clinical trials using lenalidomide alone or in combinations are discussed. Lenalidomide shows good activity also in relapsed/refractory or treatment-naive CLL patients. Definitive data from ongoing studies are needed to validate overall and progression-free survival. The toxicity profile might limit lenalidomide use because it can result in serious side effects, but largely controlled by gradual dose escalation. Further understanding of the exact mechanism of action in CLL will allow more efficacious use of lenalidomide alone or in combination regimens.

  19. Chronic lymphocytic leukemia: a clinical review including Korean cohorts

    Science.gov (United States)

    Jeon, Young-Woo; Cho, Seok-Goo

    2016-01-01

    Only 5th decade ago, chronic lymphocytic leukemia (CLL) was only recognized as disease group of presenting features like peripheral lymphocytosis, organomegaly including of splenomegaly. As understanding of disease biology and molecular diagnostic tools are getting improved gradually, characterization of variation in CLL’s clinical courses was facilitated, resulting in better risk stratification and targeted treatments. Consequently multiple new targeted agents have been used in treatment of CLL, it makes improved clinical outcome. Rituximab containing chemoimmunotherapy (combination of rituximab, fludarabine, and cyclophosphamide) have shown better overall response rate and progression-free survival on fit patients’ group in front-line setting, result in standard first-line therapeutic option for CLL. Furthermore, after introducing that the B-cell receptor is crucial for the evolution and progression of CLL, emerging treatments targeting highly activated surface antigens and oncogenic signaling pathways have been associated with several successes in recent decades. These include new anti-CD 20 monoclonal antibody (obinutuzumab), the bruton tyrosine kinase inhibitor (ibrutinib), the phosphatidylinositol 3-kinase inhibitor (idelalisib), and B-cell CLL/lymphoma 2 inhibitor (ABT-199 and ABT-263). So, we discuss not only general pathophysiology of CLL, but also rapidly advancing treatment strategies that are being studied or approved for treatment of CLL. PMID:27044858

  20. Large granular lymphocyte leukemia: natural history and response to treatment.

    LENUS (Irish Health Repository)

    Fortune, Anne F

    2012-02-01

    Large granular lymphocyte leukemia (T-LGL) is an indolent T lymphoproliferative disorder that was difficult to diagnose with certainty until clonality testing of the T cell receptor gene became routinely available. We studied the natural history and response to treatment in 25 consecutive patients with T-LGL diagnosed between 2004 and 2008 in which the diagnosis was confirmed by molecular analysis, to define an effective treatment algorithm. The median age at diagnosis was 61 years (range 27-78), with a male to female ratio of 1:1.8 and presenting features of fatigue (n = 13), recurrent infections (n = 9), and\\/or abnormal blood counts (n = 5). Thirteen patients with symptomatic disease were treated as follows: pentostatin (nine patients), cyclosporine (six patients), methotrexate (three patients), and alemtuzumab in two patients in whom pentostatin was ineffective. Pentostatin was the single most effective therapy, with a response rate of 75% and minimal toxicity. The overall survival (OS) and progression-free survival (PFS) 37 months from diagnosis were 80% and 52%, respectively. Treatment of T-LGL should be reserved for patients with symptomatic disease, but in this series, pentostatin treatment was less toxic and more effective than cyclosporine or methotrexate.

  1. Flavopiridol in chronic lymphocytic leukemia: a concise review.

    Science.gov (United States)

    Christian, Beth A; Grever, Michael R; Byrd, John C; Lin, Thomas S

    2009-01-01

    Patients with chronic lymphocytic leukemia (CLL) with high-risk cytogenetic features such as del(17p13) have limited treatment options and decreased overall survival. Dysfunction of p53 leads to resistance to fludarabine-based therapies. Cyclin-dependent kinase inhibitors (CDKi) are a novel class of agents that induce apoptosis in CLL cells independent of p53 mutational status. The synthetic flavone flavopiridol demonstrated promising in vitro activity in CLL. In initial phase I studies using a continuous infusion dosing schedule in a variety of malignancies, no clinical activity was observed. Detailed pharmacokinetic modeling led to the development of a novel dosing schedule designed to achieve target drug concentrations in vivo. In phase I testing, this dosing schedule resulted in acute tumor lysis syndrome (TLS) as the dose-limiting toxicity. With the implementation of a standardized protocol to prevent severe TLS, flavopiridol was administered safely, and responses were observed in heavily pretreated, fludarabine-refractory patients, cytogenetically high-risk patients, and patients with bulky lymphadenopathy. In a pharmacokinetic analysis, flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome. Phase II studies are under way with encouraging preliminary results. Flavopiridol is currently under active investigation in combination with other agents and as a means to eradicate minimal residual disease in patients following cytoreductive chemotherapy. Several other investigational CDKi in preclinical and early clinical development are briefly discussed in this review. PMID:19778838

  2. Chronic lymphocytic leukemia: a clinical review including Korean cohorts.

    Science.gov (United States)

    Jeon, Young-Woo; Cho, Seok-Goo

    2016-05-01

    Only 5th decade ago, chronic lymphocytic leukemia (CLL) was only recognized as disease group of presenting features like peripheral lymphocytosis, organomegaly including of splenomegaly. As understanding of disease biology and molecular diagnostic tools are getting improved gradually, characterization of variation in CLL's clinical courses was facilitated, resulting in better risk stratification and targeted treatments. Consequently multiple new targeted agents have been used in treatment of CLL, it makes improved clinical outcome. Rituximab containing chemoimmunotherapy (combination of rituximab, fludarabine, and cyclophosphamide) have shown better overall response rate and progression-free survival on fit patients' group in front-line setting, result in standard first-line therapeutic option for CLL. Furthermore, after introducing that the B-cell receptor is crucial for the evolution and progression of CLL, emerging treatments targeting highly activated surface antigens and oncogenic signaling pathways have been associated with several successes in recent decades. These include new anti-CD 20 monoclonal antibody (obinutuzumab), the bruton tyrosine kinase inhibitor (ibrutinib), the phosphatidylinositol 3-kinase inhibitor (idelalisib), and B-cell CLL/lymphoma 2 inhibitor (ABT-199 and ABT-263). So, we discuss not only general pathophysiology of CLL, but also rapidly advancing treatment strategies that are being studied or approved for treatment of CLL. PMID:27044858

  3. PARP1-Driven Apoptosis in Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Panagiotis T. Diamantopoulos

    2014-01-01

    Full Text Available Chronic lymphocytic leukemia (CLL is considered a malignancy resulting from defects in apoptosis. For this reason, targeting apoptotic pathways in CLL may be valuable for its management. Poly [ADP-ribose] polymerase 1 (PARP1 is the main member of a family of nuclear enzymes that act as DNA damage sensors. Through binding on DNA damaged structures, PARP1 recruits repair enzymes and serves as a survival factor, but if the damage is severe enough, its action may lead the cell to apoptosis through caspase activation, or necrosis. We measured the PARP1 mRNA and protein pretreatment levels in 26 patients with CLL and the corresponding posttreatment levels in 15 patients after 3 cycles of immunochemotherapy, as well as in 15 healthy blood donors. No difference was found between the pre- and posttreatment levels of PARP1, but we found a statistically significant relative increase of the 89 kDa fragment of PARP1 that is cleaved by caspases in the posttreatment samples, indicating PARP1-related apoptosis in CLL patients after treatment. Our findings constitute an important step in the field, especially in the era of PARP1 inhibitors, and may serve as a base for future clinical trials with these agents in CLL.

  4. A role for oleoylethanolamide in chronic lymphocytic leukemia.

    Science.gov (United States)

    Masoodi, M; Lee, E; Eiden, M; Bahlo, A; Shi, Y; Ceddia, R B; Baccei, C; Prasit, P; Spaner, D E

    2014-07-01

    Oleoylethanolamide (OEA) is a bioactive lipid that stimulates nuclear and G protein-coupled receptors and regulates appetite and fat metabolism. It has not previously been shown to have a role in cancer. However, a mass spectrometry-based lipidomics platform revealed the presence of high amounts of OEA in the plasma of chronic lymphocytic leukemia (CLL) patients compared with normal donors. CLL cells produced OEA and the magnitude of plasma OEA levels was related directly to the circulating leukemic cell number. OEA from CLL cells was increased by URB-597, an inhibitor of fatty acid amide hydrolase (FAAH), and decreased by inflammatory mediators that downregulate expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD). These enzymes degrade and synthesize OEA, respectively. Nonphysiologic doses of OEA prevented spontaneous apoptosis of CLL cells in a receptor-independent manner that was mimicked by its free fatty acid (FFA) derivative oleate. However, OEA-containing supernatants from CLL cells induced lipolysis in adipocytes, lipid products from adipocytes protected CLL cells from cytotoxic chemotherapy, and increased levels of FFAs were found in CLL plasma that correlated with OEA. We suggest OEA is a lipolytic factor produced by CLL cells to fuel their growth with a potential role in drug resistance and cancer cachexia. PMID:24413323

  5. Vorinostat and Decitabine in Treating Patients With Advanced Solid Tumors or Relapsed or Refractory Non-Hodgkin's Lymphoma, Acute Myeloid Leukemia, Acute Lymphocytic Leukemia, or Chronic Myelogenous Leukemia

    Science.gov (United States)

    2014-08-26

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Secondary Acute Myeloid Leukemia; Splenic Marginal Zone Lymphoma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Adult Diffuse Mixed Cell Lymphoma; Stage IV Adult Diffuse Small Cleaved Cell Lymphoma; Stage IV Adult Immunoblastic Large Cell Lymphoma; Stage IV Adult Lymphoblastic Lymphoma; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma; Stage IV Marginal Zone Lymphoma

  6. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia

    Science.gov (United States)

    Levine, Ross L.; Loriaux, Marc; Huntly, Brian J. P.; Loh, Mignon L.; Beran, Miroslav; Stoffregen, Eric; Berger, Roland; Clark, Jennifer J.; Willis, Stephanie G.; Nguyen, Kim T.; Flores, Nikki J.; Estey, Elihu; Gattermann, Norbert; Armstrong, Scott; Look, A. Thomas; Griffin, James D.; Bernard, Olivier A.; Heinrich, Michael C.; Gilliland, D. Gary; Druker, Brian; Deininger, Michael W. N.

    2005-01-01

    Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML)/atypical chronic myelogenous leukemia (aCML), myelodysplastic syndrome (MDS), B-lineage acute lymphoblastic leukemia (ALL), T-cell ALL, and chronic lymphocytic leukemia (CLL). Analysis of 222 patients with AML identified JAK2V617F mutations in 4 patients with AML, 3 of whom had a preceding MPD. JAK2V617F mutations were identified in 9 (7.8%) of 116 CMML/a CML samples, and in 2 (4.2%) of 48 MDS samples. We did not identify the JAK2V617F disease allele in B-lineage ALL (n = 83), T-cell ALL (n = 93), or CLL (n = 45). These data indicate that the JAK2V617F allele is present in acute and chronic myeloid malignancies but not in lymphoid malignancies. PMID:16081687

  7. Safety, Tolerability, and Pharmacokinetics of Idelalisib in Japanese Adults With Relapsed or Refractory Indolent B-Cell Non-Hodgkin Lymphomas or Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2016-05-16

    Chronic Lymphocytic Leukemia; Indolent Non-Hodgkin Lymphoma; Follicular Lymphoma; Small Lymphocytic Lymphoma; Lymphoplasmacytic Lymphoma (With or Without Waldenstrom Macroglobulinemia); Marginal Zone Lymphoma

  8. Modern concepts in the treatment of chronic lymphocytic leukemia.

    Science.gov (United States)

    Smolej, Lukas

    2009-10-01

    There has been considerable progress in the treatment of chronic lymphocytic leukemia (CLL) during last 10 years. Purine analogs and monoclonal antibodies have enabled the shift from purely palliative treatment to intensive regimens aiming at complete remissions and possible prolongation of survival. Many patients have now been shown to achieve molecular responses in addition to their hematological remission. Despite this success, virtually all patients with CLL will eventually relapse and will become refractory to treatment. Allogeneic stem cell transplantation offers a chance of definite cure but is feasible in a minority of patients only. Therefore, considerable effort has been devoted to the further development of more conventional CLL management that is applicable to patient population generally affected by the disease. Emerging treatment concepts include novel combination of well-know agents such as rituximab and chlorambucil, fludarabine, cyclophosphamide and alemtuzumab, FCR with mitoxantrone amongst many. Consolidation regimens using mainly alemtuzumab are also increasingly used but are associated with a major increase in severe infections. High-dose steroids in combination with rituximab or alemtuzumab represent a promising option for refractory patients. Modern chemoimmunotherapy with the FCR regimen has also been tested in early stage patients with unfavourable prognostic factors. Finally, a there are a wide variety of novel drugs including bendamustine, a unique cytostatic with combined properties of an alkylating agent and purine analog, the monoclonal antibodies anti-CD20 ofatumumab and the anti-CD23 lumiliximab, thalidomide and its analog lenalidomide, the semi-synthetic flavonoid flavopiridol and other agents which are currently undergoing clinical trials with promising results. This article reviews the recent advances and future possibilities in the treatment of CLL. PMID:19843378

  9. Gene rearrangement study for minimal residual disease monitoring in children with acute lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Juliana Godoy Assumpcao

    2013-01-01

    Full Text Available OBJECTIVE To detect markers for minimal residual disease monitoring based on conventional polymerase chain reaction for immunoglobulin, T-cell receptor rearrangements and the Sil-Tal1 deletion in patients with acute lymphocytic leukemia. METHODS Fifty-nine children with acute lymphocytic leukemia from three institutions in Minas Gerais, Brazil, were prospectively studied. Clonal rearrangements were detected by polymerase chain reaction followed by homo/heteroduplex clonality analysis in DNA samples from diagnostic bone marrow. Follow-up samples were collected on Days 14 and 28-35 of the induction phase. The Kaplan-Meier and multivariate Cox methods were used for survival analysis. RESULTS Immunoglobulin/T-cell receptor rearrangements were not detected in 5/55 children screened (9.0%. For precursor-B acute lymphocytic leukemia, the most frequent rearrangement was IgH (72.7%, then TCRG (61.4%, and TCRD and IgK (47.7%; for T-acute lymphocytic leukemia, TCRG (80.0%, and TCRD and Sil-Tal deletion (20.0% were the most common. Minimal residual disease was detected in 35% of the cases on Day 14 and in 22.5% on Day 28-35. Minimal residual disease on Day 28-35, T-acute lymphocytic leukemia, and leukocyte count above 50 x 109/L at diagnosis were bad prognostic factors for leukemia-free survival in univariate analysis. Relapse risk for minimal residual disease positive relative to minimal residual disease negative children was 8.5 times higher (95% confidence interval: 1.02-70.7. CONCLUSION Immunoglobulin/T-cell receptor rearrangement frequencies were similar to those reported before. Minimal residual disease is an independent prognostic factor for leukemia-free survival, even when based on a non-quantitative technique, but longer follow-ups are needed.

  10. Renal complications in chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis: the Mayo Clinic experience.

    Science.gov (United States)

    Strati, Paolo; Nasr, Samih H; Leung, Nelson; Hanson, Curtis A; Chaffee, Kari G; Schwager, Susan M; Achenbach, Sara J; Call, Timothy G; Parikh, Sameer A; Ding, Wei; Kay, Neil E; Shanafelt, Tait D

    2015-09-01

    While the renal complications of plasma cell dyscrasia have been well-described, most information in patients with chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis is derived from case reports. This is a retrospective analysis of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who underwent kidney biopsy for renal insufficiency and/or nephrotic syndrome. Between January 1995 and June 2014, 49 of 4,024 (1.2%) patients with chronic lymphocytic leukemia (n=44) or monoclonal B-cell lymphocytosis (n=5) had a renal biopsy: 34 (69%) for renal insufficiency and 15 (31%) for nephrotic syndrome. The most common findings on biopsy were: membranoproliferative glomerulonephritis (n=10, 20%), chronic lymphocytic leukemia interstitial infiltration as primary etiology (n=6, 12%), thrombotic microangiopathy (n=6, 12%), and minimal change disease (n=5, 10%). All five membranoproliferative glomerulonephritis patients treated with rituximab, cyclophosphamide and prednisone-based regimens had recovery of renal function compared to 0/3 patients treated with rituximab with or without steroids. Chronic lymphocytic leukemia infiltration as the primary cause of renal abnormalities was typically observed in relapsed/refractory patients (4/6). Thrombotic microangiopathy primarily occurred as a treatment-related toxicity of pentostatin (4/6 cases), and resolved with drug discontinuation. All cases of minimal change disease resolved with immunosuppressive agents only. Renal biopsy plays an important role in the management of patients with chronic lymphocytic leukemia or monoclonal B-cell lymphocytosis who develop renal failure and/or nephrotic syndrome. PMID:26088927

  11. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292

    OpenAIRE

    Arnason JE; Brown JR

    2014-01-01

    Jon E Arnason,1 Jennifer R Brown21Beth Israel Deaconess Medical Center, 2CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL) is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatabl...

  12. Basal ganglia calcification on CT-scanning in children with acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    Calcification occurring in the basal ganglia in children with acute hympocytic leukemia following therapy is uncommon and to the best of our knowledge has not been reported prior to therapy. Eleven cases of bilateral symmetrical calcification in the basal ganglia were noted in 2350 CT scans, two being in children with acute lymphocytic leukemia. In one of the two cases, calcification was present prior to therapy. (orig.)

  13. Glioblastoma multiforme following prophylactic cranial irradiation and intrathecal methotrexate in a child with acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    Cases of radiation-induced glioma in humans are extremely rare. A 2-year-old boy with acute lymphocytic leukemia had received prophylactic cranial irradiation (2400 rad/2 1/2 weeks) and intrathecal methotrexate. Five years later he developed a glioblastoma multiforme on the left cerebral hemisphere while the leukemia was in remission. This is the first reported association of these disorders. It is possible that the glioma may have been induced by radiation and/or chemotherapy

  14. Genetic features of B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Stilgenbauer, S; Lichter, P; Döhner, H

    2000-03-01

    The genetic features of B-cell chronic lymphocytic leukemia (CLL) are currently being reassessed by molecular cytogenetic techniques such as fluorescence in situ hybridization (FISH). Conventional cytogenetic studies by chromosome banding are difficult in CLL mainly because of the low in vitro mitotic activity of the tumor cells, which leads to poor quantity and quality of metaphase spreads. Molecular genetic analyses are limited because candidate genes are known for only a few chromosomal aberrations that are observed in CLL. FISH was found to be a powerful tool for the genetic analysis of CLL as it overcomes both the low mitotic activity of the CLL cells and the lack of suitable candidate genes for analysis. Using FISH, the detection of chromosomal aberrations can be performed at the single cell level in both dividing and non-dividing cells, thus circumventing the need of metaphase preparations from tumor cells. Probes for the detection of trisomies, deletions and translocation breakpoints can be applied to the regions of interest with the growing number of clones available from genome-wide libraries. Using the interphase cytogenetic FISH approach with a disease specific set of probes, chromosome aberrations can be found in more than 80% of CLL cases. The most frequently observed abnormalities are losses of chromosomal material, with deletions in band 13q14 being the most common, followed by deletions in 11q22-q23, deletions in 17p13 and deletions in 6q21. The most common gains of chromosomal material are trisomies 12q, 8q and 3q. Translocation breakpoints, in particular involving the immunoglobulin heavy chain locus at 14q32, which are frequently observed in other types of non-Hodgkin's lymphoma, are rare events in CLL. Genes affected by common chromosome aberrations in CLL appear to be p53 in cases with 17p deletion and ataxia telangiectasia mutated (ATM), which is mutated in a subset of cases with 11q22-q23 aberrations. However, for the other frequently

  15. Update in the management of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Lin Thomas S

    2009-07-01

    Full Text Available Abstract Advances in the treatment of chronic lymphocytic leukemia (CLL have improved initial overall response (OR rates, complete response (CR rates and progression free survival (PFS. Despite these advances, CLL remains incurable with standard therapies. Thus, there remains a need for more effective therapies in both the upfront and relapsed setting, particularly for patients with high-risk cytogenetic abnormalities such as del(11q22 and del(17p13. The 2008 American Society of Hematology (ASH Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL. The benefit of adding rituximab to purine analog therapy in the upfront setting was demonstrated by a large randomized study which showed that the addition of rituximab to fludarabine and cyclophosphamide (FCR significantly improved OR, CR and PFS. The improvement in PFS directly resulted from an improved ability to eliminate minimal residual disease (MRD in the peripheral blood, highlighting the importance of MRD eradication. However, a multi-center study suggested that the high CR rates to chemoimmunotherapy regimens such as FCR obtained in academic centers may not be reproducible when the same regimens are given in the community setting. The immunomodulatory drug lenalidomide is active in relapsed high-risk CLL, but two studies of lenalidomide in previously untreated CLL patients failed to achieve a CR and were associated with significant tumor lysis, tumor flare and hematologic toxicity. In the relapsed setting, a combination study of the bifunctional alkylator bendamustine and rituximab (BR demonstrated a high OR rate in patients with del(11q22 and del(17p13, indicating that further studies to define's bendamustine activity are warranted in high-risk CLL. Similarly, the CDK inhibitor flavopiridol demonstrated significant clinical activity and durable remissions in heavily treated, refractory CLL patients with high-risk cytogenetic features and bulky

  16. Serological analysis of cell surface antigens of null cell acute lymphocytic leukemia by mouse monoclonal antibodies.

    OpenAIRE

    Ueda, R; Tanimoto, M; Takahashi, T.; Ogata, S; Nishida, K; Namikawa, R.; Nishizuka, Y; Ota, K.

    1982-01-01

    Nine antigens systems were defined. Two were related to HLA-A,B,C and to Ia-like antigens; the others could be grouped into three categories. (i) NL-22, NL-1: NL-22 antibody reacted with leukemia cells from 12 to 16 cases of null cell acute lymphocytic leukemia (null-ALL) but not with any other type of leukemia tested or with lymphoid cells of various origins. Among cultured cell lines tested, one (NALM-6) of three null-ALL cell lines was positive, the others were negative. Absorption analysi...

  17. Cell surface antigens of radiation leukemia virus-induced BALB/c leukemias defined by syngeneic cytotoxic T lymphocytes

    International Nuclear Information System (INIS)

    Two cell surface antigens of mouse leukemias were defined by BALB/c cytotoxic T lymphocytes (CTL) generated against syngeneic radiation leukemia virus (RadLV)-induced leukemia, BALBRV1 or BALBRVD. Hyperimmunization of BALB/c mice with irradiated leukemias followed by in vitro sensitization of primed spleen cells resulted in the generation of CTL with high killing activity. The specificity of CTL was examined by direct cytotoxicity assays and competitive inhibition assays. A shared cell surface antigen, designated as BALBRV1 antigen, was detected by BALB/c anti-BALBRV1 CTL. BALBRV1 antigen was expressed not only on RadLV-induced BALB/c leukemias except for BALBRVD, but also on spontaneous or X-ray-induced BALB/c leukemias, chemically-induced leukemias with the H-2d haplotype and some chemically-induced BALB/c sarcomas. In contrast, a unique cell surface antigen, designated as BALBRVD antigen, was detected by BALB/c anti-BALBRVD CTL. BALBRVD antigen was expressed only on BALBRVD, but not on thirty-nine normal lymphoid or tumor cells. These two antigens could be distinguished from those previously defined on Friend, Moloney, Rauscher or Gross murine leukemia virus (MuLV) leukemias, or MuLV-related antigens. Both cytotoxic responses were blocked by antisera against H-2Kd, but not H-2Dd. The relationship of BALBRV1 antigen and BALBRVD antigen to endogenous MuLV is discussed with regard to the antigenic distribution on tumor cell lines. (author)

  18. miRNA expression profiles in chronic lymphocytic and acute lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    D.L. Zanette

    2007-11-01

    Full Text Available MicroRNAs (miRNAs are a class of small endogenous RNAs that play important regulatory roles by targeting mRNAs for cleavage or translational repression. miRNAs act in diverse biological processes including development, cell growth, apoptosis, and hematopoiesis, suggesting their association with cancer. We determined the miRNA expression profile of chronic and acute lymphocytic leukemias (CLL and ALL using the TaqMan® MicroRNA Assays Human Panel (Applied Biosystems. Pooled leukemia samples were compared to pooled CD19+ samples from healthy individuals (calibrator by the 2-DDCt method. Total RNA input was normalized based on the Ct values obtained for hsa-miR-30b. The five most highly expressed miRNAs were miR-128b, miR-204, miR-218, miR-331, and miR-181b-1 in ALL, and miR-331, miR-29a, miR-195, miR-34a, and miR-29c in CLL. To our knowledge, this is the first report associating miR-128b, miR-204 and miR-331 to hematological malignancies. The miR-17-92 cluster was also found to be up-regulated in ALL, as previously reported for some types of lymphomas. The differences observed in gene expression levels were validated for miR-331 and miR-128b in ALL and CD19+ samples. These miRNAs were up-regulated in ALL, in agreement with our initial results. A brief target analysis was performed for miR-331. One of its putative targets, SOCS1, promotes STAT activation, which is a known mediator of cell proliferation and survival, suggesting the possibility of an association between miR-331 and these processes. This initial screening provided information on miRNA differentially expressed in normal and malignant B-cells that could suggest the potential roles of these miRNAs in hematopoiesis and leukemogenesis.

  19. p53 mutations in human lymphoid malignancies: Association with Burkitt lymphoma and chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Gaidano, G.; Ballerini, P.; Gong, J.Z.; Inghirami, G.; Knowles, D.M.; Dalla-Favera, R. (Columbia Univ., New York, NY (United States)); Neri, A, (Columbia Univ., New York, NY (United States) Centro Malattie del Sangue G. Marcora, Milan (Italy)); Newcomb, E.W. (New York Univ. School of Medicine, New York (United States)); Magrath, I.T. (National Cancer Institute, Bethesda, MD (United States))

    1991-06-15

    The authors have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direst sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsoes; 17/27 cell lines) and its leukemic counterpart L{sub 3}-type B-cell acute lymphoblastic leukemia (5/9), both of which also carry activated c-myc oncogenes, and (ii) B-cell chronic lymphocytic leukemia (6/40) and, in particular, its stage of progression known as Richter's transformation (3/7). Mutations were not found at any significant frequency in other types of non-Hodgkin lymphoma or acute lymphoblastic leukemia. In many cases, only the mutated allele was detectable, implying loss of the normal allele. These results suggest that (1) significant differences in the frequency of p53 mutations are present among subtypes of neoplasms derived from the same tissue; (2) p53 may play a role in tumor progression in B-cell chronic lymphocytic leukemia; (3) the presence of both p53 loss/inactivation and c-myc oncogene activation may be important in the pathogenesis of Burkitt lymphoma and its leukemia form L{sub 3}-type B-cell acute lymphoblastic leukemia.

  20. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Strefford, J C; Sutton, L-A; Baliakas, P; Agathangelidis, A; Malčíková, J; Plevova, K; Scarfó, L; Davis, Zachary James; Stalika, E; Cortese, D; Cahill, N; Pedersen, L B; di Celle, P F; Tzenou, T; Geisler, C; Panagiotidis, P; Langerak, A W; Chiorazzi, N; Pospisilova, S; Oscier, D; Davi, F; Belessi, C; Mansouri, L; Ghia, P; Stamatopoulos, K; Rosenquist, R

    2013-01-01

    Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B...

  1. PHARMACOKINETICS OF VINCRISTINE IN CHILDREN AND ADOLESCENTS WITH ACUTE LYMPHOCYTIC-LEUKEMIA

    NARCIS (Netherlands)

    CROM, WR; DEGRAAF, SSN; SYNOLD, T; UGES, DRA; BLOEMHOF, H; RIVERA, G; CHRISTENSEN, ML; MAHMOUD, H; EVANS, WE

    1994-01-01

    We studied the pharmacokinetics of vincristine in children with acute lymphocytic leukemia by means of a specific high-performance liquid chromatographic assay with ultraviolet and electrochemical detection and a limited sampling strategy. Our objectives were to characterize the disposition of vincr

  2. Not all IGHV3-21 chronic lymphocytic leukemias are equal

    DEFF Research Database (Denmark)

    Baliakas, Panagiotis; Agathangelidis, Andreas; Hadzidimitriou, Anastasia;

    2015-01-01

    An unresolved issue in chronic lymphocytic leukemia (CLL) is whether IGHV3-21 gene usage, in general, or the expression of stereotyped B-cell receptor immunoglobulin defining subset #2 (IGHV3-21/IGLV3-21), in particular, determines outcome for IGHV3-21-utilizing cases. We reappraised this issue in...

  3. Array-based genomic screening at diagnosis and during follow-up in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Gunnarsson, Rebeqa; Mansouri, Larry; Isaksson, Anders;

    2011-01-01

    High-resolution genomic microarrays enable simultaneous detection of copy-number aberrations such as the known recurrent aberrations in chronic lymphocytic leukemia [del(11q), del(13q), del(17p) and trisomy 12], and copy-number neutral loss of heterozygosity. Moreover, comparison of genomic...

  4. Hemorrhagic cerebellar anaplastic glioma appearing 12 years after prophylactic cranial radiotherapy for acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    A radiation-induced cerebellar glioma is extremely rare, and the etiology of such a tumor is unknown. We report a rare case of hemorrhagic cerebellar anaplastic glioma occurring 12 years after prophylactic cranial radiotherapy for acute lymphocytic leukemia. We discuss the etiologies of the radiation-induced hemorrhagic cerebellar glioma as a secondary malignancy after radiotherapy. (author)

  5. Cranial radiotherapy predisposes to abdominal adiposity in survivors of childhood acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    Advances in treatment of acute lymphocytic leukemia increased the likelihood of developing late treatment-associated effects, such as abdominal adiposity, increasing the risk of cardiovascular disease in this population. Cranial radiotherapy is one of the factors that might be involved in this process. The aim of this study was to determine the effect of cranial radiotherapy on adiposity indexes in survivors of acute lymphocytic leukemia. A comparative cross-sectional study of 56 acute lymphocytic leukemia survivors, chronological age between 15 and 24 years, assigned into two groups according to the exposure to cranial radiotherapy (25 irradiated and 31 non-irradiated), assessed according to body fat (dual energy X-ray absorptiometry), computed tomography scan-derived abdominal adipose tissue, lipid profile, and insulin resistance. Cranial radiotherapy increased body fat and abdominal adipose tissue and altered lipid panel. Yet, lipids showed no clinical relevance so far. There were significantly more obese patients among those who received cranial radiotherapy (52% irradiated versus 22.6% non-irradiated), based on dual energy X-ray absorptiometry body fat measurements. Nonetheless, no association was observed between cranial radiotherapy and body mass index, waist circumference, waist-to-height ratio or insulin resistance. Adolescent and young adult survivors of childhood acute lymphocytic leukemia showed an increase in body fat and an alteration of fat distribution, which were related to cranial radiotherapy. Fat compartment modifications possibly indicate a disease of adipose tissue, and cranial radiotherapy imports in this process

  6. Docosahexaenoic Acid Sensitizes Leukemia Lymphocytes to Barasertib and Everolimus by ROS-dependent Mechanism Without Affecting the Level of ROS and Viability of Normal Lymphocytes.

    Science.gov (United States)

    Zhelev, Zhivko; Ivanova, Donika; Lazarova, Desislava; Aoki, Ichio; Bakalova, Rumiana; Saga, Tsuneo

    2016-04-01

    The aim of the present study was: (i) to investigate the possibility of sensitizing leukemia lymphocytes to anticancer drugs using docosahexaenoic acid (DHA); (ii) to find combinations with synergistic cytotoxic effect on leukemia lymphocytes, without or with only very low cytotoxicity towards normal lymphocytes; (iii) and to clarify the role of reactive oxygen species (ROS) in the induction of apoptosis and cytotoxicity by such combinations. The study covered 15 anticancer drugs, conventional and new-generation. Well-expressed synergistic cytotoxic effects were observed after treatment of leukemia lymphocytes (Jurkat) with DHA in combination with: barasertib, lonafarnib, everolimus, and palbociclib. We selected two synergistic combinations, DHA with everolimus or barasertib, and investigated their effects on viability of normal lymphocytes, as well as on the production of ROS and induction of apoptosis in both cell lines (leukemia and normal). At the selected concentrations, DHA, everolimus and barasertib (applied separately) were cytotoxic towards leukemia lymphocytes, but not normal lymphocytes. In leukemia cells, the cytotoxicity of combinations was accompanied by strong induction of apoptosis and production of ROS. In normal lymphocytes, drugs alone and in combination with DHA did not affect the level of ROS and did not induce apoptosis. To our knowledge, the present study is the first to report synergistic ROS-dependent cytotoxicity between DHA and new-generation anticancer drugs, such as everolimus and barasertib, that is cancer cell-specific (particularly for acute lymphoblastic leukemia cells Jurkat). These combinations are harmless to normal lymphocytes and do not induce abnormal production of ROS in these cells. The data suggest that DHA could be used as a supplementary component in anticancer chemotherapy, allowing therapeutic doses of everolimus and barasertib to be reduced, minimizing their side-effects. PMID:27069145

  7. Generation of leukemia-reactive cytotoxic T lymphocyte clones from the HLA-identical bone marrow donor of a patient with leukemia

    OpenAIRE

    1992-01-01

    Allogeneic bone marrow transplantation (BMT) has been associated with a graft-vs.-leukemia (GVL) reactivity. Since T cell depletion of the bone marrow graft has decreased the risk of graft-vs.-host disease (GVHD), but has been associated with higher rates of leukemia relapse, GVL reactivity is probably caused by donor-derived T lymphocytes. Previously, we demonstrated that minor histocompatibility (mH) antigen- specific cytotoxic T lymphocyte (CTL) clones, generated from patients after BMT, a...

  8. Oral Manifestations of T-Cell Large Granular Lymphocytic Leukemia: a Case Report

    Directory of Open Access Journals (Sweden)

    Ioanna-Eirini Arvanitidou

    2011-06-01

    Full Text Available Background: T-cell large granular lymphocytic (T-LGL leukemia is a rare, chronic, often indolent lymphoproliferative disorder of mature T cells (CD3+. Severe neutropenia and other cytopenias are common features in patients with T-LGL leukemia and may cause infections, thus representing a major cause of morbidity in this disease. Immunosuppressive therapy with low-dose regimes of methotrexate, cyclophosphamide, corticosteroids or cyclosporine A is the treatment of choice. Amongst the variety of T-LGL leukemia complications, oral manifestations such as ulcers have been rarely reported. The purpose of this paper is to report a case of T-cell large granular lymphocyte leukemia with oral manifestations and to discuss their pathogenesis and management.Methods: In the present case, a 65 year old female with a two-month history of diagnosed T-LGL leukemia presented with oral lesions, including ulcerations on the ventral tongue and soft palate as well as swollen, erythematous and ulcerated gingiva. The patient was under treatment with methotrexate, granulocyte colony-stimulating factor (G-CSF and erythropoietin.Results: Considering patients’ medical history and clinical appearance of the lesions, a clinical diagnosis of a neutropenic ulcer of the tongue was established. The oral lesions resolved after treatment with antibiotics, topical steroids and antiseptics combined with improvement of the hematological condition. The pertinent literature related to T-LGL leukemia ethiopathology, diagnostics and treatment was discussed.Conclusions: Although rare, T-cell large granular lymphocytic leukemia should be included in the list of lymphoproliferative disorders, which may present with oral manifestations as a result of the disease and its treatment complications.

  9. AR-42 in Treating Patients With Advanced or Relapsed Multiple Myeloma, Chronic Lymphocytic Leukemia, or Lymphoma

    Science.gov (United States)

    2016-03-16

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Peripheral T-cell Lymphoma; Post-transplant Lymphoproliferative Disorder; Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Multiple Myeloma; Stage III Adult Burkitt Lymphoma; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Adult Diffuse Mixed Cell Lymphoma; Stage III Adult Diffuse Small Cleaved Cell Lymphoma; Stage III Adult Hodgkin Lymphoma; Stage III Adult Immunoblastic Large Cell Lymphoma; Stage III Adult Lymphoblastic Lymphoma; Stage III Adult T-cell Leukemia/Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Cutaneous T-cell Non-Hodgkin Lymphoma; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage III Marginal Zone Lymphoma; Stage III Multiple Myeloma; Stage III Mycosis Fungoides/Sezary Syndrome; Stage III Small Lymphocytic Lymphoma; Stage IV Adult Burkitt Lymphoma; Stage IV Adult Diffuse Large

  10. Autologous Peripheral Blood Stem Cell Transplant Followed by Donor Bone Marrow Transplant in Treating Patients With High-Risk Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Multiple Myeloma, or Chronic Lymphocytic Leukemia

    Science.gov (United States)

    2016-06-17

    B-Cell Prolymphocytic Leukemia; Plasma Cell Leukemia; Progression of Multiple Myeloma or Plasma Cell Leukemia; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Childhood Hodgkin Lymphoma; Recurrent Childhood Non-Hodgkin Lymphoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Non-Hodgkin Lymphoma; Refractory Plasma Cell Myeloma; Refractory Small Lymphocytic Lymphoma; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia

  11. Idelalisib therapy of indolent B-cell malignancies: chronic lymphocytic leukemia and small lymphocytic or follicular lymphomas

    Directory of Open Access Journals (Sweden)

    Madanat YF

    2016-03-01

    Full Text Available Yazan F Madanat,1 Mitchell R Smith,2 Alexandru Almasan,3 Brian T Hill2 1Department of Internal Medicine, 2Department of Hematology and Medical Oncology, Taussig Cancer Institute, 3Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA Abstract: Chronic lymphocytic leukemia, small lymphocytic lymphoma, and follicular lymphoma are indolent B-cell lymphoproliferative disorders that mainly affect an older population. Although the majority of patients in need of treatment derive significant benefit from conventional chemotherapeutic agents as well as monoclonal antibodies, less toxic and more effective treatments are needed. Novel agents that inhibit the B-cell receptor signaling pathway have shown promising outcomes in these disorders. Idelalisib is a potent selective oral inhibitor of phosphatidylinositol 3-kinase delta and has shown significant clinical activity in B-cell malignancies. In this review, we summarize the clinical trial data using idelalisib as monotherapy or in combination with rituximab for the treatment of relapsed/refractory disease. The adverse effect profile includes autoimmune disorders such as transaminitis, colitis, and pneumonitis. Given the efficacy and manageable toxicity profile of idelalisib, it is being increasingly incorporated into the management of indolent B-cell malignancies. Keywords: idelalisib, PI3Kδ inhibitors, chronic lymphocytic leukemia, follicular lymphoma

  12. Acute myelogenous leukemia (AML) - children

    Science.gov (United States)

    Acute myelogenous leukemia - children; AML; Acute myeloid leukemia - children; Acute granulocytic leukemia - children; Acute myeloblastic leukemia - children; Acute non-lymphocytic leukemia (ANLL) - children

  13. Cellular Immunotherapy Following Chemotherapy in Treating Patients With Recurrent Non-Hodgkin Lymphomas, Chronic Lymphocytic Leukemia or B-Cell Prolymphocytic Leukemia

    Science.gov (United States)

    2016-07-29

    Post-transplant Lymphoproliferative Disorder; B-Cell Prolymphocytic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Burkitt Lymphoma; B-Cell Lymphoma, Unclassifiable, With Features Intermediate Between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma; Recurrent Lymphoplasmacytic Lymphoma

  14. Peripheral T-Cell lymphoma manifested as gingival enlargement in a patient with chronic lymphocytic leukemia

    OpenAIRE

    Buddula, Aravind; Assad, Daniel

    2011-01-01

    Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults and is associated with increased risk of malignancy. T-cell lymphoma associated with CLL has never been reported. The case report presents a unique case of peripheral T-cell lymphoma on the gingiva of a patient with CLL. A 66-year-old man with a history of CLL was referred to the Mayo Clinic, Department of Dental Specialties, for evaluation of swelling in the upper left posterior sextant. An intraoral examination...

  15. p53 mutations in human lymphoid malignancies: association with Burkitt lymphoma and chronic lymphocytic leukemia.

    OpenAIRE

    Gaidano, G; Ballerini, P.; Gong, J. Z.; Inghirami, G.; Neri, A.; Newcomb, E W; Magrath, I. T.; Knowles, D M; Dalla-Favera, R

    1991-01-01

    We have investigated the frequency of p53 mutations in B- and T-cell human lymphoid malignancies, including acute lymphoblastic leukemia, the major subtypes of non-Hodgkin lymphoma, and chronic lymphocytic leukemia. p53 exons 5-9 were studied by using genomic DNA from 197 primary tumors and 27 cell lines by single-strand conformation polymorphism analysis and by direct sequencing of PCR-amplified fragments. Mutations were found associated with (i) Burkitt lymphoma (9/27 biopsies; 17/27 cell l...

  16. Serologic markers of effective tumor immunity against chronic lymphocytic leukemia include non-mutated B cell antigens

    OpenAIRE

    Marina, Ovidiu; Hainz, Ursula; Biernacki, Melinda A.; Zhang, Wandi; Cai, Ann; Duke-Cohan, Jonathan S.; Liu, Fenglong; Brusic, Vladimir; Neuberg, Donna; Kutok, Jeffery L.; Alyea, Edwin P.; Canning, Christine M.; Soiffer, Robert J.; Ritz, Jerome; Wu, Catherine J.

    2010-01-01

    Patients with chronic lymphocytic leukemia (CLL) who relapse after allogeneic transplant may achieve durable remission following donor lymphocytes infusion (DLI), demonstrating the potency of donor-derived immunity in eradicating tumor. We sought to elucidate the antigenic basis of the effective graft-versus-leukemia (GvL) responses associated with DLI for the treatment of CLL by analyzing the specificity of plasma antibody responses developing in two DLI-treated patients who achieved long-te...

  17. A rare case of Acute Lymphocytic Leukemia (ALL presenting with double Philadelphia chromosome: relapse or secondary leukemia?

    Directory of Open Access Journals (Sweden)

    Mireille Guimarães Vaz de Campos

    2003-01-01

    Full Text Available The Philadelphia chromosome is observed in 5% of pediatric acute lymphocytic leukemia (ALL and in 25% to 50% of adult ALL cases, and is associated with poor prognosis. Double Ph in a hyperdiploid karyotype is common in chronic myeloid leukemia (CML, but rarely found in ALL. We report here the case of a girl diagnosed with ALL at 7 years of age. After treatment with the pediatric protocol BFM 83 for ALL, she stayed in continuous complete remission for nine years. At age 19, she was re-admitted with a white blood cell count of 6.8 x 10(9/L with 3% blasts, and a platelet count of 65 x 109/L. Bone marrow aspirate showed 92.6% lymphoid blast cells, and chromosome analysis after G-banding revealed the karyotype 51,XX,+?5,t(9;22(q34.1;q11.2,+16,+20,+21,+der(22t(9;22(q34.1;q11.2 [10]/46,XX[1]. FISH analysis for the BCR/ABL fusion showed 56% of interphase cells with two fusion signals, 30% with one, and 6% with three. Double Ph is rare in relapsed leukemia, and the possibility of secondary leukemia cannot be ruled out.

  18. Romidepsin in Treating Patients With Lymphoma, Chronic Lymphocytic Leukemia, or Solid Tumors With Liver Dysfunction

    Science.gov (United States)

    2016-08-24

    Adult Mixed Glioma; Adult Pineal Gland Astrocytoma; Adult Solid Neoplasm; AIDS Related Immunoblastic Lymphoma; AIDS-Related Burkitt Lymphoma; AIDS-Related Diffuse Large Cell Lymphoma; AIDS-Related Diffuse Mixed Cell Lymphoma; AIDS-Related Diffuse Small Cleaved Cell Lymphoma; AIDS-Related Hodgkin Lymphoma; AIDS-Related Lymphoblastic Lymphoma; AIDS-Related Lymphoma; AIDS-Related Primary Central Nervous System Lymphoma; Glioma; Lymphoma; Recurrent Adult Brain Neoplasm; Recurrent Adult Soft Tissue Sarcoma; Recurrent Bladder Carcinoma; Recurrent Breast Carcinoma; Recurrent Chronic Lymphocytic Leukemia; Recurrent Colorectal Carcinoma; Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma; Recurrent Head and Neck Carcinoma; Recurrent Lung Carcinoma; Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma; Recurrent Melanoma; Recurrent Pancreatic Carcinoma; Recurrent Prostate Carcinoma; Recurrent Renal Cell Carcinoma; Recurrent Thyroid Gland Carcinoma; Refractory Chronic Lymphocytic Leukemia; Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma; Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma

  19. The expression BIRC6 gene in patients with chronic lymphocytic leukemia – a preliminary study

    Directory of Open Access Journals (Sweden)

    Chomik Piotr

    2014-09-01

    Full Text Available The BIRC6 gene encodes the Bruce (Apollon protein. This belongs to the III class of Inhibitors of the Apoptosis Protein (IAP and demonstrates anti-apoptotic activity (binding, inhibiting and degrading the caspases. Moreover, the Bruce protein shows multilevel activities and additional functions. The Bruce protein is involved in the maintenance of cell viability, and it is also suggested that it plays an important role in cell proliferation and diversification. Many researchers have noticed elevated BIRC6 gene expression in cell lines of brain cancer and ovarian carcinoma, leukemia, breast cancer and even in colorectal cancer tissues. Resistance to chemotherapy-inducted apoptosis in cancers characterized by BIRC6 gene over-expression was also reported. The aim of the study was to assess the BIRC6 gene expression in peripheral blood lymphocytes of patients diagnosed with chronic lymphocytic leukemia.

  20. Genetic Counseling for DAPK1 Mutation in a Chronic Lymphocytic Leukemia Family

    OpenAIRE

    Lynch, Henry T.; Ferrara, Kelly; Weisenburger, Dennis; Sanger, Warren; Lynch, Jane F.; Thomé, Stephan

    2008-01-01

    Genetic counseling has become the clinical bedrock of hereditary cancer. Countless advances in molecular genetics contributing to the identification of cancer-causing germline mutations have increased its importance. We report perhaps the world’s first genetic counseling experience involving a family with hereditary chronic lymphocytic leukemia and the cancer-causing mutation in the death-associated protein kinase 1 (DAPK1) gene. This hereditary disorder currently lacks any preventive or cura...

  1. The clinical significance of 8q24/MYC rearrangement in chronic lymphocytic leukemia.

    Science.gov (United States)

    Li, Yan; Hu, Shimin; Wang, Sa A; Li, Shaoying; Huh, Yang O; Tang, Zhenya; Medeiros, L Jeffrey; Tang, Guilin

    2016-05-01

    Chromosome 8q24/MYC rearrangement is associated with Burkitt lymphoma and some aggressive B-cell lymphomas, but is rare in chronic lymphocytic leukemia. We here report a cohort of 20 chronic lymphocytic leukemia patients with 8q24/MYC rearrangement, 3 detected at time of initial diagnosis and 17 acquired after a median interval of 48 months. At the time when 8q24/MYC arrangement was detected, 18 patients had B-symptoms, 17 had lymphadenopathy, and 17 had splenomegaly. Histologically, typical chronic lymphocytic leukemia morphology was seen in six patients, increased prolymphocytes in nine and Richter's transformation in five patients. Eighteen patients had karyotypic information available that showed t(8;v) in a complex karyotype in 12 patients and in a non-complex karyotype in 6 patients. Fluorescence in situ hybridization confirmed MYC rearrangement in 17/17 patients. All patients required therapy after 8q24/MYC rearrangement was detected. At last follow-up, five of six patients with a non-complex karyotype were alive after a median of 74 months (10~143 months) from the detection of 8q24/MYC rearrangement. In contrast, 10 of 12 patients with a complex karyotype died with a median survival of 5.5 months. We conclude that 8q24/MYC rearrangement in chronic lymphocytic leukemia is rare and often acquired during the course of disease. If it is presented in a complex karyotype, it is often associated with Richter's transformation, refractory to therapy and an aggressive clinical course; on the other hand, if it is present in a non-complex karyotype, patients often respond to risk-adapted therapies and achieve remission. PMID:26916070

  2. Executive Function, Coping, and Behavior in Survivors of Childhood Acute Lymphocytic Leukemia*

    OpenAIRE

    Campbell, Laura K.; Scaduto, Mary; Van Slyke, Deborah; Niarhos, Frances; Whitlock, James A.; Compas, Bruce E.

    2008-01-01

    Objective To examine the role of executive function in coping and behavioral outcomes in childhood acute lymphocytic leukemia (ALL) survivors. Methods We examined associations among several domains of executive function (working memory, behavioral inhibition, cognitive flexibility, and self-monitoring), coping, and emotional/behavioral problems in 30 children and adolescents ages 10- to 20-years old who completed treatment for ALL and 30 healthy controls matched on age and sex. Results We fou...

  3. Brown sequard syndrome secondary of soft tissue infection in a patient with acute lymphocyte leukemia

    International Nuclear Information System (INIS)

    A 42-year-old Latin American female with acute lymphocytic leukemia in second relapse developed a small ecthymic lesion around the entrance site of a left subclavian line. This was followed by development of left-sided hemiparesis with contralateral loss of pain and temperature sensation. CT of the neck revealed a diffuse inflammatory process with soft tissue involvement and several bubbles of air in the anterior paraspinal muscles and within the spinal canal in the epidural location. (orig.)

  4. Heightened BTK-dependent cell proliferation in unmutated chronic lymphocytic leukemia confers increased sensitivity to ibrutinib

    OpenAIRE

    Guo, Ailin; Lu, Pin; Galanina, Natalie; Nabhan, Chadi; Smith, Sonali M.; Coleman, Morton; Wang, Y. Lynn

    2015-01-01

    In chronic lymphocytic leukemia (CLL), patients with unmutated immunoglobulin heavy chain variable region gene (UM-CLL) have worse outcomes than mutated CLL (M-CLL) following chemotherapy or chemoimmunotherapy. However, in the era of BCR-targeted therapies, the adverse prognostic impact of unmutated IGHV seems to be diminishing, and there are clinical datasets showing unexpected improved responses in UM-CLL. We investigated the biological differences of BTK activity between these subgroups an...

  5. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

    OpenAIRE

    Tucker DL; Rule SA

    2015-01-01

    David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, ...

  6. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  7. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia

    OpenAIRE

    Marie-Christine R. Shakib; Shreef G. N. Gabrial; Gamal N. Gabrial

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice i...

  8. CRUSTED SCABIES IN A PATIENT WITH ACUTE LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Mamatha

    2015-06-01

    Full Text Available A 17 year s old male patient presented with diffuse, ill defined, hyperpigmented, scaly plaques on the body, for the past 15 days. Lesions were more over the groin and also on both elbows and wrists. Patient is a known case of acute lymphocytic leukaemia, diagnosed a t the age of 13 years and has been on treatment ever since. A KOH ( 10% mount of the scales showed the presence of sarcoptes scabiei and skin biopsy with haematoxylin and eosin showed fragments of mite in the excised skin.

  9. Total-body irradiation with 25-MV photons in advanced non-Hodgkin's lymphoma and chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma were treated with total-body irradiation (TBI). One group was treated after chemotherapy failed, while the other group received TBI initially. TBI was ineffective against CLL after chemotherapy failed. All patients with lymphocytic lymphoma who initially responded to chemotherapy but later relapsed were helped by TBI, as were 88 percent of patients with previously untreated lymphocytic lymphomas

  10. Chronic lymphocytic leukemia presenting with extreme hyperleukocytosis and thrombosis of the common femoral vein.

    Science.gov (United States)

    Cukierman, Tali; Gatt, Moshe E; Libster, Dianna; Goldschmidt, Neta; Matzner, Yaacov

    2002-09-01

    Very few case reports dealing with chronic lymphocytic leukemia (CLL) and hyperleukocytosis have been reported in the medical literature and none with venous thrombosis as a complication. Here, we describe a 73-year-old woman who presented with newly diagnosed CLL, leukostasis, and hyperleukocytosis (2000 x 10(9)/l), affecting the respiratory and nervous system. In addition, she also had deep vein thrombosis (DVT). Although hypercoagulability and thrombosis are well-described phenomena in solid tumors and in myeloproliferative neoplasms, CLL is generally not associated with an acquired coagulopathy. We hypothesize that in our patient the extreme number of circulating lymphocytes resulted in an abnormal accumulation of lymphocytes possibly causing stasis and occlusion of a larger vessel, which resolved after leukopheresis. The patient has since been successfully maintained with chemotherapy. We conclude that leukopheresis should be considered as the therapy of choice in CLL patients presenting with major complications of leukostasis. PMID:12685846

  11. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia.

    Science.gov (United States)

    Del Principe, Maria Ilaria; Dal Bo, Michele; Bittolo, Tamara; Buccisano, Francesco; Rossi, Francesca Maria; Zucchetto, Antonella; Rossi, Davide; Bomben, Riccardo; Maurillo, Luca; Cefalo, Mariagiovanna; De Santis, Giovanna; Venditti, Adriano; Gaidano, Gianluca; Amadori, Sergio; de Fabritiis, Paolo; Gattei, Valter; Del Poeta, Giovanni

    2016-01-01

    In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (Pbax/bcl-2 was correlated with unmutated IGHV (Pbax/bcl-2 (Pbax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. PMID:26565002

  12. Genetically Engineered Lymphocyte Therapy in Treating Patients With B-Cell Leukemia or Lymphoma That is Resistant or Refractory to Chemotherapy

    Science.gov (United States)

    2015-07-31

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  13. The role of idelalisib in the treatment of relapsed and refractory chronic lymphocytic leukemia.

    Science.gov (United States)

    Nair, Kruti Sheth; Cheson, Bruce

    2016-04-01

    Idelalisib is a first in class, delta isoform specific, PI3-kinase inhibitor. Based on its high level of efficacy and acceptable safety profile, this oral drug has been approved by the US Food and Drug Administration as a single agent for the treatment of relapsed or refractory small lymphocytic lymphoma, and follicular non-Hodgkin lymphoma, and in combination with rituximab for patients with chronic lymphocytic leukemia. Adverse effects of particular concern include diarrhea, pneumonitis, and transient elevations of hepatic transaminase levels. Efforts to improve on the activity of this drug have included combinations with standard chemotherapy agents, such as bendamustine, and other targeted therapies, including checkpoint inhibitors. However, other combinations have been associated with life-threatening and fatal toxicities. Thus, the development of such regimens should be conducted carefully in the context of a clinical research study. Idelalisib has a vital role as second-line therapy for chronic lymphocytic leukemia, especially for patients with high-risk disease and multiple comorbidities, and studies are exploring the use of this agent as front-line therapy to improve the outcome of patients with indolent B-cell malignancies. PMID:27054023

  14. Unusual immunophenotype of T-cell large granular lymphocytic leukemia: Report of two cases

    Directory of Open Access Journals (Sweden)

    Nikhil Rabade

    2015-01-01

    Full Text Available Large granular lymphocytes (LGL leukemias are commonly of the T-cell or NK-cell type. T-cell LGL leukemia is typically a disorder of mature CD3, CD8 and T-cell receptor TCR (TCR - T cell receptor-αβ positive cytotoxic T-cells. Rare variants include TCRγδ+ variants and CD4 + TCRαβ+ cases. We report a case of each of these rare variants. An 83-year-old female presented with anemia and lymphocytosis with LGLs on peripheral smear. Six-color multiparametric flowcytometric analysis showed expression of CD3, heterogeneous CD7, dim CD2 and TCRγδ and lacked expression of CD5, TCRαβ, CD56, CD4 and CD8. A final diagnosis of TCRγδ+ T-cell LGL leukemia was made. Differentiation between TCRγδ+ T-cell LGL leukemia and other γδ+ T-cell malignancies is of utmost importance due to the indolent nature of the former as compared to the highly aggressive behavior of the latter. An 85-year-old male diagnosed with liposarcoma was identified to have lymphocytosis during preoperative evaluation. Peripheral smear showed presence of LGLs. Flowcytometric immunophenotyping showed expression of TCRαβ, CD3, CD2, CD5, CD4, dim CD8, CD56 with aberrant loss of CD7 expression. Vβ repertoire analysis by flowcytometry showed 97% cells with Vβ14 clonality. A final diagnosis of TCRαβ+ CD4 + T-cell LGL leukemia was made. CD4 + T-cell large granular lymphocytic leukemias have an indolent, less aggressive course when compared to their CD8 + counterparts and are not necessarily associated with cytopenias. However, their association with secondary neoplasia (29% of the cases warrants a high degree of suspicion in the diagnosis as also noted in the index case. Use of a wide panel of antibodies and newer modalities such as Vβ repertoire analysis helps in accurate subtyping of LGL leukemia.

  15. Graft-versus-leukemia effects associated with detectable Wilms tumor-1–specific T lymphocytes after allogeneic stem-cell transplantation for acute lymphoblastic leukemia

    OpenAIRE

    Rezvani, Katayoun; Yong, Agnes S.M.; Savani, Bipin N.; Mielke, Stephan; Keyvanfar, Keyvan; Gostick, Emma; Price, David A; Douek, Daniel C.; Barrett, A. John

    2007-01-01

    To determine whether the leukemia-associated Wilms tumor antigen (WT1) contributes to a graft-versus-leukemia (GVL) effect after allogeneic stem-cell transplantation (SCT) for acute lymphoblastic leukemia (ALL), we studied CD8+ T-cell responses to WT1 in 10 human lymphocyte antigen (HLA)–A*0201–positive ALL patients during the early phase of immune recovery after SCT (days 30-120). Seven of 10 patients had detectable WT1 expression in their peripheral blood (PB) before SCT by quantitative rev...

  16. Complementary and alternative medicine use in patients with chronic lymphocytic leukemia: an Italian multicentric survey.

    Science.gov (United States)

    D'Arena, Giovanni; Laurenti, Luca; Coscia, Marta; Cortelezzi, Agostino; Chiarenza, Annalisa; Pozzato, Gabriele; Vigliotti, Maria Luigia; Nunziata, Giuseppe; Fragasso, Alberto; Villa, Maria Rosaria; Grossi, Alberto; Selleri, Carmine; Deaglio, Silvia; La Sala, Antonio; Del Poeta, Giovanni; Simeon, Vittorio; Aliberti, Luig; De Martino, Laura; Giudice, Aldo; Musto, Pellegrino; De Feo, Vincenzo

    2014-04-01

    Complementary and alternative medicine (CAM) is common in patients with cancer and its use is steadily increasing over time. We performed a multicenter survey in which the use of CAM in 442 Italian patients with chronic lymphocytic leukemia (CLL), the commonest form of leukemia in Western countries, was assessed. Data were collected by means of a face-to-face standardized questionnaire with several items. Mean age was 69 years; 258 patients (58%) were male and 184 (42%) female. Seventy-three patients (16.5%) were found to be CAM users. The most common CAM therapies were green tea, aloe formulations and high dose vitamins. Predictors of CAM use were female gender, younger age, higher education level, internet availability and newspaper reading. The reasons for CAM popularity among these patients are complex. Given the number of patients combining therapy with CAM and its possible drug interactions, doctor interest as well as patient education about CAM should be improved. PMID:23829282

  17. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

    OpenAIRE

    Del Principe, Maria Ilaria; Bo, Michele Dal; Bittolo, Tamara; Buccisano, Francesco; Rossi, Francesca Maria; Zucchetto, Antonella; Rossi, Davide; Bomben, Riccardo; Maurillo, Luca; Cefalo, Mariagiovanna; De Santis, Giovanna; Venditti, Adriano; Gaidano, Gianluca; Amadori, Sergio; de Fabritiis, Paolo

    2016-01-01

    In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with we...

  18. Improving the treatment outcome of patients with chronic lymphocytic leukemia through targeted antibody therapy.

    Science.gov (United States)

    Stephens, Deborah M; Byrd, John C

    2013-04-01

    Therapy for chronic lymphocytic leukemia (CLL) has evolved dramatically throughout the years. In 1997, rituximab (Rituxan), a CD20 monoclonal antibody (mAb), became the first mAb approved by the Food and Drug Administration for marketing in the treatment of cancer, specifically targeting B-cell malignancies. Over the last 10 years, rituximab or other mAbs including alemtuzumab and ofatumumab have become an integral part of the standard of care for CLL patients as single agents or in combination with chemotherapy or other immunotherapy. This review discusses the currently approved and novel mAbs for the treatment of CLL. PMID:23561475

  19. An Urologic Face of Chronic Lymphocytic Leukemia:Sequential Prostatic and Penis Localization

    Directory of Open Access Journals (Sweden)

    Giovanni D'Arena

    2013-01-01

    Full Text Available We report a patient with chronic lymphocytic leukemia (CLL in whom a leukemic involvement of prostate and penis occurred in the advanced phase of his disease. Obstructive urinary symptoms were indicative of prostatic CLL infiltration, followed by the occurrence of an ulcerative lesion on the glans. Histologic examination confirmed  the  neoplastic B-cell infiltration. Both localizations responded to conventional treatments. A review of the literature confirms that leukemic involvement of the genito-urinary system is   uncommon in CLL patients. However, such an involvement should be considered in CLL patients with urologic symptoms and a long history of the disease.

  20. Mitochondrial DNA alterations of peripheral lymphocytes in acute lymphoblastic leukemia patients undergoing total body irradiation therapy

    OpenAIRE

    2011-01-01

    Background Mitochondrial DNA (mtDNA) alterations, including mtDNA copy number and mtDNA 4977 bp common deletion (CD), are key indicators of irradiation-induced damage. The relationship between total body irradiation (TBI) treatment and mtDNA alterations in vivo, however, has not been postulated yet. The aim of this study is to analyze mtDNA alterations in irradiated human peripheral lymphocytes from acute lymphoblastic leukemia (ALL) patients as well as to take them as predictors for radiatio...

  1. CD52 expression in T-cell large granular lymphocyte leukemia--implications for treatment with alemtuzumab.

    Science.gov (United States)

    Osuji, N; Del Giudice, I; Matutes, E; Morilla, A; Owusu-Ankomah, K; Morilla, R; Dunlop, A; Catovksy, D

    2005-05-01

    Few reports on the successful treatment of T-cell large granular lymphocyte (LGL) leukemia with the humanized anti-CD52 monoclonal antibody alemtuzumab are emerging in the literature. The expression of CD52 by LGLs has not been previously investigated. Using semi-quantitative 2- and 3-color flow cytometry, we documented the expression of CD52 in 100% of abnormal cells in T-cell LGL leukemia (n = 11) and natural killer (NK) cell LGL leukemia (n = 2), and showed no significant difference in CD52 expression between T-cell prolymphocytic leukemia (PLL) and T-cell LGL leukemia. Higher CD52 expression has been noted in responders to alemtuzumab in T-cell PLL and in chronic lymphocytic leukemia (CLL), a B-cell disorder. The strong and consistent expression of CD52 shown here highlights the potential role of alemtuzumab in the treatment of refractory T-cell LGL leukemia and possibly aggressive NK cell leukemia. PMID:16019510

  2. Detection of Hodgkin Transformation in a Case of Chronic Lymphocytic Leukemia by PET/CT

    Directory of Open Access Journals (Sweden)

    Sabire Yılmaz

    2014-06-01

    Full Text Available Richter’s transformation (RT represents the development of high grade lymphoma, most commonly diffuse large B-cell lymphoma, in patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL. CLL/SLL may convert also to Hodgkin’s lymphoma, the so-called Hodgkin’s variant of Richter transformation. Histopathological proof is needed to confirm a definitive diagnosis. Patients with RT generally have a poor prognosis, with prompt recognition optimise clinical management. Whole-body PET scan with 18F-FDG can be used for detection of RT of CLL/SLL. We describe the case of 64-year-old woman with CLL/SLL who developed Hodgkin lymphoma detected with PET/CT.

  3. Improving therapy of chronic lymphocytic leukemia with chimeric antigen receptor T cells.

    Science.gov (United States)

    Fraietta, Joseph A; Schwab, Robert D; Maus, Marcela V

    2016-04-01

    Adoptive cell immunotherapy for the treatment of chronic lymphocytic leukemia (CLL) has heralded a new era of synthetic biology. The infusion of genetically engineered, autologous chimeric antigen receptor (CAR) T cells directed against CD19 expressed by normal and malignant B cells represents a novel approach to cancer therapy. The results of recent clinical trials of CAR T cells in relapsed and refractory CLL have demonstrated long-term disease-free remissions, underscoring the power of harnessing and redirecting the immune system against cancer. This review will briefly summarize T-cell therapies in development for CLL disease. We discuss the role of T-cell function and phenotype, T-cell culture optimization, CAR design, and approaches to potentiate the survival and anti-tumor effects of infused lymphocytes. Future efforts will focus on improving the efficacy of CAR T cells for the treatment of CLL and incorporating adoptive cell immunotherapy into standard medical management of CLL. PMID:27040708

  4. The role of B-cell receptor inhibitors in the treatment of patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Wiestner, Adrian

    2015-12-01

    Chronic lymphocytic leukemia is a malignancy of mature auto-reactive B cells. Genetic and functional studies implicate B-cell receptor signaling as a pivotal pathway in its pathogenesis. Full B-cell receptor activation requires tumor-microenvironment interactions in lymphoid tissues. Spleen tyrosine kinase, Bruton's tyrosine kinase, and the phosphatidylinositol 3-kinase (PI3K) δ isoform are essential for B-cell receptor signal transduction but also mediate the effect of other pathways engaged in chronic lymphocytic leukemia cells in the tissue-microenvironment. Orally bioavailable inhibitors of spleen tyrosine kinase, Bruton's tyrosine kinase, or PI3Kδ, induce high rates of durable responses. Ibrutinib, a covalent inhibitor of Bruton's tyrosine kinase, and idelalisib, a selective inhibitor of PI3Kδ, have obtained regulatory approval in chronic lymphocytic leukemia. Ibrutinib and idelalisib are active in patients with high-risk features, achieving superior disease control in difficult-to-treat patients than prior best therapy, making them the preferred agents for chronic lymphocytic leukemia with TP53 aberrations and for patients resistant to chemoimmunotherapy. In randomized trials, both ibrutinib, versus ofatumumab, and idelalisib in combination with rituximab, versus placebo with rituximab improved survival in relapsed/refractory chronic lymphocytic leukemia. Responses to B-cell receptor inhibitors are mostly partial, and within clinical trials treatment is continued until progression or occurrence of intolerable side effects. Ibrutinib and idelalisib are, overall, well tolerated; notable adverse events include increased bruising and incidence of atrial fibrillation on ibrutinib and colitis, pneumonitis and transaminase elevations on idelalisib. Randomized trials investigate the role of B-cell receptor inhibitors in first-line therapy and the benefit of combinations. This review discusses the biological basis for targeted therapy of chronic lymphocytic

  5. Three newly approved drugs for chronic lymphocytic leukemia (CLL): Incorporating ibrutinib, idelalisib and obinutuzumab into clinical practice

    OpenAIRE

    Sanford, David; Wierda, William G.; Burger, Jan A.; Keating, Michael J.; O’Brien, Susan M.

    2015-01-01

    Three agents have received FDA approval for treatment of chronic lymphocytic leukemia (CLL) within the last year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of BTK and PI3Kδ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in in the relapsed setting and is currently approved for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline...

  6. CONTENTS OF LYMPHOCYTE SUB-POPULATIONS IN THE CHILDREN WITH ACUTE LEUKEMIA AND LYMPHOMAS DEPENDENT ON INFECTIOUS COMPLICATION AND NEUTROPENIA

    Directory of Open Access Journals (Sweden)

    M. V. Peshikova

    2005-01-01

    Full Text Available Abstract. The aim of the present work was to evaluate the contents of some lymphocyte sub-populations in peripheral blood of the children with tumors of hematopoietic and lymphoid tissues, depending on infectious complication of cytostatic therapy and neutropenia. In all children undergoing cytostatic therapy for acute lympho-blastic leukemia and non-B cell non-Hodgkinґs lymphomas, we found significant decrease in the numbers of CD95 lymphocytes, absolute amounts of natural killer cells (CD16, CD56-lymphocytes and activated lymphocytes (СD11b, HLA-DR-cells, irrespective of neutrophile numbers in their blood and infectious complications. However, absolute number of CD25- lymphocytes was significantly decreased in the children with neutropenia. Relative contents of CD16, CD56, СD11b, HLA-DR, CD25-lymphocytes did not significantly differ from those in healthy children, or they were found to be significantly increased.

  7. CONTENTS OF LYMPHOCYTE SUB-POPULATIONS IN THE CHILDREN WITH ACUTE LEUKEMIA AND LYMPHOMAS DEPENDENT ON INFECTIOUS COMPLICATION AND NEUTROPENIA

    Directory of Open Access Journals (Sweden)

    M. V. Peshikova

    2014-07-01

    Full Text Available Abstract. The aim of the present work was to evaluate the contents of some lymphocyte sub-populations in peripheral blood of the children with tumors of hematopoietic and lymphoid tissues, depending on infectious complication of cytostatic therapy and neutropenia. In all children undergoing cytostatic therapy for acute lympho-blastic leukemia and non-B cell non-Hodgkinґs lymphomas, we found significant decrease in the numbers of CD95 lymphocytes, absolute amounts of natural killer cells (CD16, CD56-lymphocytes and activated lymphocytes (СD11b, HLA-DR-cells, irrespective of neutrophile numbers in their blood and infectious complications. However, absolute number of CD25- lymphocytes was significantly decreased in the children with neutropenia. Relative contents of CD16, CD56, СD11b, HLA-DR, CD25-lymphocytes did not significantly differ from those in healthy children, or they were found to be significantly increased.

  8. Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study

    OpenAIRE

    Herman, Sarah E. M.; Niemann, Carsten U.; Farooqui, Mohammed; Jones, Jade; Mustafa, Rashida Z.; Lipsky, Andrew; Saba, Nakhle; Martyr, Sabrina; Soto, Susan; Valdez, Janet; Gyamfi, Jennifer A.; Maric, Irina; Calvo, Katherine R.; Pedersen, Lone B; Geisler, Christian H.

    2014-01-01

    Ibrutinib and other targeted inhibitors of B-cell receptor signaling achieve impressive clinical results for patients with chronic lymphocytic leukemia (CLL). A treatment-induced rise in absolute lymphocyte count (ALC) has emerged as a class effect of kinase inhibitors in CLL and warrants further investigation. We here report correlative studies in 64 patients with CLL treated with ibrutinib. We quantified tumor burden in blood, lymph nodes, spleen, and bone marrow, assessed phenotypic change...

  9. The splicing modulator sudemycin induces a specific antitumor response and cooperates with ibrutinib in chronic lymphocytic leukemia

    OpenAIRE

    Xargay-Torrent, Sçilvia; López Guerra, Mónica; Rosich, Laia; Montraveta, Arnau; Roldán, Jocabed; Rodríguez, Vanina; Villamor Casas, Neus; Aymerich, Marta; Lagisetti, Chandraiah; Webb, Thomas R.; López Otín, Carlos; Campo, Elías; Colomer, Dolors

    2015-01-01

    Mutations or deregulated expression of the components of the spliceosome can influence the splicing pattern of several genes and contribute to the development of tumors. In this context, we report that the spliceosome modulator sudemycin induces selective cytotoxicity in primary chronic lymphocytic leukemia (CLL) cells when compared with healthy lymphocytes and tumor cells from other B-lymphoid malignancies, with a slight bias for CLL cases with mutations in spliceosome-RNA processing machine...

  10. Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond.

    Science.gov (United States)

    Wei, Manman; Wang, Xiang; Song, Zilan; Jiao, Mingkun; Ding, Jian; Meng, Ling-Hua; Zhang, Ao

    2015-07-01

    Chronic lymphocytic leukemia (CLL) remains the most incurable leukemia. Early chemotherapeutic treatments, including alkylating agents, purine nucleoside derivatives, and immunotherapeutic antibodies, only show limited benefits for patients but severe off-target related side effects. Recent advances in understanding of the critical molecular pathways of regulating proliferation and survival of B-CLL cells have spurred a new therapeutical strategy by selectively targeting phosphoinositide 3-kinase delta (PI3Kδ). Idelalisib, a first-in-class PI3Kδ-selective small molecule has received the FDA's fast-track approval in July of 2014 as a new treatment of CLL, indolent B-cell non-Hodgkin's lymphoma, and relapsed small lymphocytic lymphoma. Undoubtedly, the success of idelalisib has provided a solid support in the development of PI3Kδ-specific inhibitors and reformed the concept of treating CLL. However, the number of reported selective inhibitors of PI3Kδ is very limited and very few have advanced into clinical trials. The mechanism of their actions remains elusive. More profound understanding on the modes of action of new PI3Kδ inhibitors will further validate the PI3Kδ-targeting strategy, and help to identify biomarkers capable of stratifying patients who will most likely benefit from the therapy. PMID:25763934

  11. EVALUATION OF SURFACE MARKERS IN CHILDHOOD ACUTE LYMPHOCYTIC LEUKEMIA BEFORE AND AFTER THERAPY

    Directory of Open Access Journals (Sweden)

    A.Massoud

    1980-10-01

    Full Text Available In our study of surface markers of Iranian children affected by acute lymphocytic leukemia, the majority(80 %had non-T, non-B, or null cell leukemia. The null- cell l e ukemia had a better p r ogno s l s as was conf irmed by o t h ers. Twe l v e of our patie nts who had null cell l e ukem i a are a live and well 18 mont hs to 20 mont hs a f t e r initiat i on of the r a py. Three of t he patients who had l e s s than 27' null c e l l s in t he i nitial study died i n a pe r i od o f less than o ne year after d i agnosis. Af t e r therapy while on remission , there was a decrease i n the percentage o f nu l l c e l ls ( i n nul l c e l l l e ukemi a a nd an i ncre ase i n t h e p e r centage of T a nd B lymphocyt e s i n the pe r i phe r a l b lood which approachta o n the a ge and sex-matched norma l control s ubjects .

  12. Surface membrane antigen expression changes induced in vitro by exogenous growth factors in chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Vilpo, J; Hulkkonen, J; Hurme, M; Vilpo, L

    2002-09-01

    The factors determining the growth and survival of cells in B chronic lymphocytic leukemia (CLL) have remained poorly understood. We investigated the effects of optimal mitogen combinations (OMCs) on the expression of 26 surface membrane antigens among 33 CLL patients. The seven OMCs used were selected after pre-testing 14 combinations of (1) S. aureus Cowan I (SAC), (2) interleukin-2 (IL-2), (3) tumor necrosis factor alpha (TNF-alpha) and (4) 12-O-tetradecanoylphorbol 13-acetate (TPA; also known as phorbol 12-myristate 13-acetate or PMA). In flow cytometry we revealed that OMCs induced statistically highly significant upregulation of the expression of CD5, CD11c, CD19, CD22, CD23, CD25, CD38, CD40, CD45, CD45RO, CD95, CD126, CD130 and FMC7, and downregulation of CD20 and CD124 expression. Interestingly, the expression of CD27, CD45RA, CD79b, CD80, CD122 and that of the immunoglobulin gene superfamily members CD21, Ig-kappa, Ig-lambda, Ig-delta and Ig-micro were not significantly affected under similar conditions. The expression of several antigens was co-regulated, suggesting common regulatory pathways. These antigens include CD11c/CD5, CD11c/CD22, CD11c/CD126, CD11c/FMC7 as well as CD27/CD45, CD27/CD45RA and CD27/CD79b. Upregulation of surface antigen expression, induced by OMCs, should be applicable in antibody therapy in vitro and in vivo, and in negative stem cell selection for autotransplantation. Furthermore, the current strategy to enhance cell surface antigen expression may be a versatile tool to raise humoral and cell-mediated host defense against CLL cells. Upregulation of proteins mediating positive growth signals (eg CD25, CD40) and negative signals or apoptosis (eg CD95) may be used to sensitize cells to chemotherapy and programmed cell death. PMID:12200683

  13. Clinical significance of bax/bcl-2 ratio in chronic lymphocytic leukemia

    Science.gov (United States)

    Del Principe, Maria Ilaria; Bo, Michele Dal; Bittolo, Tamara; Buccisano, Francesco; Rossi, Francesca Maria; Zucchetto, Antonella; Rossi, Davide; Bomben, Riccardo; Maurillo, Luca; Cefalo, Mariagiovanna; De Santis, Giovanna; Venditti, Adriano; Gaidano, Gianluca; Amadori, Sergio; de Fabritiis, Paolo; Gattei, Valter; Del Poeta, Giovanni

    2016-01-01

    In chronic lymphocytic leukemia the balance between the pro-apoptotic and anti-apoptotic members of the bcl-2 family is involved in the pathogenesis, chemorefractoriness and clinical outcome. Moreover, the recently proposed anti-bcl-2 molecules, such as ABT-199, have emphasized the potential role of of bcl-2 family proteins in the context of target therapies. We investigated bax/bcl-2 ratio by flow cytometry in 502 patients and identified a cut off of 1.50 to correlate bax/bcl-2 ratio with well-established clinical and biological prognosticators. Bax/bcl-2 was 1.50 or over in 263 patients (52%) with chronic lymphocytic leukemia. Higher bax/bcl-2 was associated with low Rai stage, lymphocyte doubling time over 12 months, beta-2 microglobulin less than 2.2 mg/dL, soluble CD23 less than 70 U/mL and a low risk cytogenetic profile (P<0.0001). On the other hand, lower bax/bcl-2 was correlated with unmutated IGHV (P<0.0001), mutated NOTCH1 (P<0.0001) and mutated TP53 (P=0.00007). Significant shorter progression-free survival and overall survival were observed in patients with lower bax/bcl-2 (P<0.0001). Moreover, within IGHV unmutated (168 patients) and TP53 mutated (37 patients) subgroups, higher bax/bcl-2 identified cases with significant longer PFS (P=0.00002 and P=0.039). In multivariate analysis of progression-free survival and overall survival, bax/bcl-2 was an independent prognostic factor (P=0.0002 and P=0.002). In conclusion, we defined the prognostic power of bax/bcl-2 ratio, as determined by a flow cytometric approach, and highlighted a correlation with chemoresistance and outcome in chronic lymphocytic leukemia. Finally, the recently proposed new therapies employing bcl-2 inhibitors prompted the potential use of bax/bcl-2 ratio to identify patients putatively resistant to these molecules. PMID:26565002

  14. Meningosis prophylaxis with intrathecal /sup 198/Au-colloid and methotrexate in childhood acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    Since 1972, telecobalt irradiation plus intrathecal methotrexate (ITMTX) has been successfully replaced in Jena by intrathecal colloidal radioactive gold (/sup 198/Au) plus ITMTX for meningosis prophylaxis in leukemia. Seventy-three children with acute lymphocytic leukemia (ALL) were given 1.24-4.89 mCi (45.8-181 MBq) of colloidal 198Au IT after successful initiation of remission. During cytostatic therapy, the following relapses occurred: meningosis leucaemica, five patients (6.8%); bone-marrow relapse and the meningosis leucaemica, one patient; and bone-marrow relapse, 20 patients (27.4%). In 18 children, combination chemotherapy was terminated after two and a half or three years of treatment. After that time, one meningeal relapse and six bone-marrow relapses occurred. Within the first 24 hours after application of radioactive gold, headaches, vomiting, and fever occurred in less than 10% of the children. An apathy syndrome, leukecephalopathy, or severe infections, were not observed in a single case. Radioactive gold spreads in the subarachnoid space and is phagocytized by the arachnoidea. The tumoricide effect extends selectively over the space of distribution of the latent meningosis leucaemia. The cerebral parenchyma remains unaffected by radiation. Thus, radioactive gold may be preferable to telecobalt irradiation in preventing central nervous system leukemia

  15. Chronic lymphocytic leukemia-associated chromosomal abnormalities and miRNA deregulation

    Directory of Open Access Journals (Sweden)

    Kiefer Y

    2012-03-01

    Full Text Available Yvonne Kiefer1, Christoph Schulte2, Markus Tiemann2, Joern Bullerdiek11Center for Human Genetics, University of Bremen, Bremen, Germany; 2Hematopathology Hamburg, Hamburg, GermanyAbstract: Chronic lymphocytic leukemia is the most common leukemia in adults. By cytogenetic investigations major subgroups of the disease can be identified that reflect different routes of tumor development. Of these chromosomal deviations, trisomy 12 and deletions of parts of either the long arm of chromosome 13, the long arm of chromosome 11, or the short arm of chromosome 17 are most commonly detected. In some of these aberrations the molecular target has been identified as eg, ataxia telangiectasia mutated (ATM in case of deletions of chromosomal region 11q22~23 and the genes encoding microRNAs miR-15a/16-1 as likely targets of deletions of chromosomal band 13q14.3. Of note, these aberrations do not characterize independent subgroups but often coexist within the metaphases of one tumor. Generally, complex aberrations are associated with a worse prognosis than simple karyotypic alterations. Due to smaller sizes of the missing segment the detection of recurrent deletions is not always possible by means of classical cytogenetics but requires more advanced techniques as in particular fluorescence in situ hybridization (FISH. Nevertheless, at this time it is not recommended to replace classical cytogenetics by FISH because this would miss additional information given by complex or secondary karyotypic alterations. However, the results of cytogenetic analyses allow the stratification of prognostic and predictive groups of the disease. Of these, the group characterized by deletions involving TP53 is clinically most relevant. In the future refined methods as eg, array-based comparative genomic hybridization will supplement the existing techniques to characterize CLL. Keywords: chronic lymphocytic leukemia, chromosomal abnormality, miRNA deregulation

  16. Mitochondrial DNA alterations of peripheral lymphocytes in acute lymphoblastic leukemia patients undergoing total body irradiation therapy

    International Nuclear Information System (INIS)

    Mitochondrial DNA (mtDNA) alterations, including mtDNA copy number and mtDNA 4977 bp common deletion (CD), are key indicators of irradiation-induced damage. The relationship between total body irradiation (TBI) treatment and mtDNA alterations in vivo, however, has not been postulated yet. The aim of this study is to analyze mtDNA alterations in irradiated human peripheral lymphocytes from acute lymphoblastic leukemia (ALL) patients as well as to take them as predictors for radiation toxicity. Peripheral blood lymphocytes were isolated from 26 ALL patients 24 hours after TBI preconditioning (4.5 and 9 Gy, respectively). Extracted DNA was analyzed by real-time PCR method. Average 2.31 times mtDNA and 0.53 fold CD levels were observed after 4.5 Gy exposure compared to their basal levels. 9 Gy TBI produced a greater response of both mtDNA and CD levels than 4.5 Gy. Significant inverse correlation was found between mtDNA content and CD level at 4.5 and 9 Gy (P = 0.037 and 0.048). Moreover, mtDNA content of lymphocytes without irradiation was found to be correlated to age. mtDNA and CD content may be considered as predictive factors to radiation toxicity

  17. Mitochondrial DNA alterations of peripheral lymphocytes in acute lymphoblastic leukemia patients undergoing total body irradiation therapy

    Directory of Open Access Journals (Sweden)

    Ji Fuyun

    2011-10-01

    Full Text Available Abstract Background Mitochondrial DNA (mtDNA alterations, including mtDNA copy number and mtDNA 4977 bp common deletion (CD, are key indicators of irradiation-induced damage. The relationship between total body irradiation (TBI treatment and mtDNA alterations in vivo, however, has not been postulated yet. The aim of this study is to analyze mtDNA alterations in irradiated human peripheral lymphocytes from acute lymphoblastic leukemia (ALL patients as well as to take them as predictors for radiation toxicity. Methods Peripheral blood lymphocytes were isolated from 26 ALL patients 24 hours after TBI preconditioning (4.5 and 9 Gy, respectively. Extracted DNA was analyzed by real-time PCR method. Results Average 2.31 times mtDNA and 0.53 fold CD levels were observed after 4.5 Gy exposure compared to their basal levels. 9 Gy TBI produced a greater response of both mtDNA and CD levels than 4.5 Gy. Significant inverse correlation was found between mtDNA content and CD level at 4.5 and 9 Gy (P = 0.037 and 0.048. Moreover, mtDNA content of lymphocytes without irradiation was found to be correlated to age. Conclusions mtDNA and CD content may be considered as predictive factors to radiation toxicity.

  18. Dicer Gene Expression as a Prognostic Factor in Acute Lymphoblastic Leukemia and Chronic Lymphocytic Leukemia in Fars Province

    Science.gov (United States)

    Farzaneh, Mohamad Reza; Shahryari, Jahanbanoo; Safaei, Akbar; Valibeigi, Behnaz; Davani, Shahrbanou Karimi; Tabibi, Narjes

    2016-01-01

    Alterations in the expression of microRNAs (miRNAs) have been proposed to play a role in the pathogenesis of acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). Dicer is one of the main regulators of miRNA biogenesis, and deregulation of its expression has been indicated as a possible cause of miRNA alterations observed in various cancers. Our aim was to analyze the expression of the Dicer protein and its relationship with ALL and CLL. This cross-sectional study was performed from 2010 to 2012 in Shahid Faghihi Hospital, Shiraz, Iran. In this study, 30 patients with CLL, 21 patients with ALL, 10 child healthy donors, and 19 adult healthy donors were recruited. The patients’ samples were checked via flow cytometry, immunohistochemistry, and immunocytochemistry. The controls’ samples were also examined in the hematology ward. Total RNA was extracted from the bone marrow and peripheral blood samples of the patients and controls. Then, reverse-transcription polymerase chain reaction was used to estimate the level of Dicer miRNA. The outcomes of the expression analysis of Dicer revealed statistically significant differences between the ALL patients/child healthy controls (mean±SD, 0.19±0.28 vs. 0.73±0.12; P<0.001) and the CLL patients/adult healthy controls (mean±SD, 0.24±0.25 vs. 0.41±0.28; P=0.033). This is the first piece of evidence showing that the expression of the Dicer gene greatly decreased in the patients with ALL in comparison to the child controls. The expression of the Dicer gene was also downregulated in the patients with CLL compared to the adult controls. Given the above findings, the expression of Dicer may play an important role in the progression and prognosis of these diseases.

  19. Chronic lymphocytic leukemia and myeloproliferative neoplasms concurrently diagnosed: clinical and biological characteristics.

    Science.gov (United States)

    Todisco, Gabriele; Manshouri, Taghi; Verstovsek, Srdan; Masarova, Lucia; Pierce, Sherry A; Keating, Michael J; Estrov, Zeev

    2016-05-01

    Chronic lymphocytic leukemia (CLL) and myeloproliferative neoplasms (MPN) may occur concomitantly. However, little is known about the pathobiological characteristics and interaction between the neoplastic clones in these rare cases of coinciding malignancies. We retrospectively examined the clinical and biological characteristics of 13 patients with concomitant CLL and MPN--eight primary myelofibrosis (PMF), three essential thrombocytosis (ET), and two polycythemia vera (PV)--who presented to our institution between 1998 and 2014, and tested all patients for MPN-specific aberrations, such as JAK2, MPL and CALR mutations. Along with epidemiological and molecular characterization of this rare condition, we found that JAK2 mutation can be detected 9 years prior to PMF diagnosis, suggesting that PMF clinical phenotype may require several years to develop and CLL/MPN clinical co-occurrence might be sustained by common molecular events. Some features of these patients suggest that pathobiologies of these diseases might be intertwined. PMID:26402369

  20. The influence of pregnancy on the development of autoimmunity in chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Jønsson, Viggo; Bock, Johannes E; Hilden, Jørgen;

    2006-01-01

    To examine whether pregnancy influences the development of autoimmunity in chronic lymphocytic leukemia (CLL), we studied 591 consecutive CLL patients (202 post-menopausal women and 389 men). The mean observation time for all patients was 3.8 years, corresponding to approximately 2200 person...... men. In female CLL patients, the frequency of autoimmunity and the number of pregnancies and the number of partners were strongly correlated. Each of the major autoimmune types approximately doubled in frequency for each additional pregnancy. The impact of pregnancy on expressed autoimmunity increased...... with each additional sexual partner (the odds of autoimmunity increased 11 times with each long-term sexual partner). The average numbers of pregnancies in female CLL patients with and without autoimmunity were 4.92 and 2.24, respectively (P < 0.001). Coombs' positive autoimmune anemia, a gastric ulcer...

  1. No evidence of transmission of chronic lymphocytic leukemia through blood transfusion

    DEFF Research Database (Denmark)

    Hjalgrim, Henrik; Rostgaard, Klaus; Vasan, Senthil K;

    2015-01-01

    occurrence among 7413 recipients of blood from 796 donors diagnosed with CLL after donation cessation, and among 80 431 recipients of blood from 7477 matched CLL-free donors. During follow-up, 12 and 107 cases of CLL occurred among the exposed and unexposed recipients, respectively, yielding a relative risk......Monoclonal B-cell lymphocytosis (MBL) is a precursor of chronic lymphocytic leukemia (CLL). Observations of MBL in blood donors raise concern that transmitted MBL may cause recipient CLL. Using a database with health information on 1.5 million donors and 2.1 million recipients, we compared CLL...... of 0.94 (95% confidence interval, 0.52-1.71). Analyses using the entire database showed no evidence of CLL clustering among recipients of blood from individual donors. In conclusion, when donor MBL was approximated by subsequent donor CLL diagnosis, data from 2 countries' entire computerized...

  2. Evolving Strategies for the Treatment of Chronic Lymphocytic Leukemia in the Upfront Setting.

    Science.gov (United States)

    Bachow, Spencer H; Lamanna, Nicole

    2016-02-01

    Chronic lymphocytic leukemia (CLL) is a disease of marked clinical heterogeneity, and while some patients have a normal life expectancy, others develop rapidly progressive disease shortly after diagnosis. The current standard for upfront treatment of CLL is chemoimmunotherapy for younger fit patients, FCR (fludarabine, cyclophosphamide, and rituximab) being the prototype. For older patients, BR (bendamustine and rituximab) exhibits excellent activity with decreased toxicity. For the frailest patients, CD20 monoclonal antibodies with or without chlorambucil have proven to be efficacious. The novel oral kinase inhibitors ibrutinib and idelalisib are FDA-approved in the relapsed/refractory setting, and ibrutinib is approved upfront for those with del(17p). These drugs have produced long-term durable responses in the relapsed/refractory setting, and studies are underway using these as single agent upfront or in combination with both chemotherapy and monoclonal antibodies. Here, we review standard upfront therapies and new agents and combinations that are on the horizon for CLL. PMID:26951237

  3. Novel agents in the treatment of chronic lymphocytic leukemia: a review about the future.

    Science.gov (United States)

    Desai, Anjali Varma; El-Bakkar, Hassan; Abdul-Hay, Maher

    2015-06-01

    Half of a century ago, physicians managing chronic lymphocytic leukemia (CLL) recognized some of its presenting features such as lymphocytosis, lymphadenopathy, and splenomegaly. Subsequently, an enhanced understanding of the disease mechanisms involved in CLL led to new, more targeted treatments. There is now a plethora of treatments available for CLL. In this review article we discuss in detail several of the novel agents that are being studied or approved for the treatment of CLL including: phosphatidylinositol 3-kinase inhibitors (idelalisib and IPI-145), Bruton tyrosine kinase inhibitors (ibrutinib), B cell lymphoma 2 inhibitors (ABT-263 and ABT-199), new anti-CD20 monoclonal antibodies (obinutuzumab), cyclin-dependent kinase inhibitors (flavopiridol and dinaciclib), immunomodulators (lenalidomide) and chimeric antigen receptor T-cell therapy. PMID:25445466

  4. An unusual case of composite lymphoma involving chronic lymphocytic leukemia follicular lymphoma and Hodgkin disease.

    Science.gov (United States)

    Copur, M Sitki; Ledakis, Peter; Novinski, Daniel; Fu, Kai; Hutchins, Mark; Frankforter, Scot; Mleczko, Kris; Sanger, Warren G; Chan, Wing C

    2004-05-01

    Composite lymphomas constitute the presence of two different types of non-Hodgkin lymphoma or Hodgkin and non-Hodgkin lymphoma at the same anatomic site. We report an unusual case of a 73-year-old woman who initially presented with a composite lymphoma of chronic lymphocytic leukemia (CLL) and follicular lymphoma. After 5 years of follow-up and intermittent treatment, she developed Hodgkin disease with diffuse liver involvement. Biopsy of the liver showed Reed-Sternberg cells with typical morphology and immunophenotype. While fluorescent in situ hybridization (FISH) analyses for t(14;18) were positive in the lymph node tissue with follicular lymphoma, we were unable to show the same in the liver biopsy specimen. Here, we describe the clinical, morphologic, immunophenotypic, and cytogenetic features of this unusual composite lymphoma case involving CLL and follicular lymphoma, with the subsequent development of a Hodgkin lymphoma. PMID:15291370

  5. A critical appraisal of ibrutinib in the treatment of mantle cell lymphoma and chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Tucker DL

    2015-06-01

    Full Text Available David L Tucker, Simon A Rule Department of Haematology, Plymouth Hospitals NHS Trust, Plymouth, UK Abstract: Although chemo-immunotherapy remains at the forefront of first-line treatment for mantle cell lymphoma (MCL and chronic lymphocytic leukemia (CLL, small molecules, such as ibrutinib, are beginning to play a significant role, particularly in patients with multiply relapsed or chemotherapy-refractory disease and where toxicity is an overriding concern. Ibrutinib is a first-in-class, oral inhibitor of Bruton’s tyrosine kinase, which functions by irreversible inhibition of the downstream signaling pathway of the B-cell receptor, which normally promotes cell survival and proliferation. Early clinical trials have demonstrated excellent tolerability and a modest side-effect profile even in elderly and multiply pretreated patient cohorts. Although the majority of disease responses tend to be partial, efficacy data have also been encouraging with more than two-thirds of patients with CLL and MCL demonstrating a durable response, even in the high-risk disease setting. Resistance mechanisms are only partially understood and appear to be multifactorial, including the binding site mutation C481S, and escape through other common cell-signaling pathways. This article appraises the currently available data on safety and efficacy from clinical trials of ibrutinib in the management of MCL and CLL, both as a single agent and in combination with other therapies, and considers how this drug is likely to be used in future clinical practice. Keywords: ibrutinib, mantle cell lymphoma, chronic lymphocytic leukemia, Bruton’s tyrosine kinase, lymphoproliferative disorders

  6. Phase I Dose-Escalation Trial of Clofarabine Followed by Escalating Doses of Fractionated Cyclophosphamide in Children With Relapsed or Refractory Acute Leukemias

    Science.gov (United States)

    2010-09-21

    Myelodysplastic Syndrome; Acute Myeloid Leukemia; Myeloproliferative Disorders; Acute Lymphocytic Leukemia; Acute Promyelocytic Leukemia; Acute Leukemia; Chronic Myelogenous Leukemia; Myelofibrosis; Chronic Myelomonocytic Leukemia; Juvenile Myelomonocytic Leukemia

  7. The development of cerebral CT changes during treatment of acute lymphocytic leukemia in childhood

    International Nuclear Information System (INIS)

    Twenty-three children with acute lymphocytic leukemia (ALL) were examined with cranial CT at least twice with a minimal interval of 10 months. The first CT was performed at the time of diagnosis in 11 children and during therapy in 12; all but two were normal on the first CT examination. These two had slight enlargement of the ventricular system and subarachnoid space at the time of diagnosis. These findings were unchanged on the second CT examinations. Seven patients, all in remission from leukemia of the central nervous system manifested abnormal findings on later CTs. Low density areas in the periventricular white matter were seen in the brains of three, with increasing subcortical calcification in one of these cases. Five children had slight enlargement of the ventricular system and subarachnoid space, especially of the basal and Sylvian cisterns. Later CT examinations in five, plus brain autopsy in two cases, revealed unchanged or progressive conditions. The CT findings have been related to the treatment and some characteristics of the disease. The frequency of CT abnormalities was higher in patients who had received therapeutic irradiation and intraventricular methotrexate treatment. The possible reasons for the CT abnormalities are discussed. (orig.)

  8. B cell receptor pathway in chronic lymphocytic leukemia: specific role of CC-292

    Directory of Open Access Journals (Sweden)

    Arnason JE

    2014-01-01

    Full Text Available Jon E Arnason,1 Jennifer R Brown21Beth Israel Deaconess Medical Center, 2CLL Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USAAbstract: Chronic lymphocytic leukemia (CLL is the most common adult leukemia. The current treatment paradigm involves the use of chemoimmunotherapy, when patients develop an indication for therapy. With this strategy, a majority of patients will obtain a remission, though cure remains elusive. While treatable, the majority of CLL patients will die of complications of their disease. Recent advances in the understanding of the importance of the B cell receptor (BCR pathway in CLL have led to the development of a number of agents targeting this pathway. In this review, we discuss recent developments in the targeting of the BCR pathway, with a focus on CC-292. CC-292 covalently binds to Bruton's tyrosine kinase, a key mediator of BCR signaling, and has demonstrated preclinical and clinical activity in CLL, with acceptable tolerability. Based on the success of CC-292 and other inhibitors of the BCR pathway, these agents are being investigated in combination with standard therapy, with the hope that they will increase the depth and length of response, without significant toxicity.Keywords: Bruton's tyrosine kinase inhibitor, ibrutinib

  9. Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.

    Science.gov (United States)

    Sanford, David S; Wierda, William G; Burger, Jan A; Keating, Michael J; O'Brien, Susan M

    2015-07-01

    Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL. PMID:25817936

  10. VARIATIONS OF THE LEUKOCYTES AND LYMPHOCYTES IN THE CASE OF ACUTE LYMPHOBLASTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Mirela Cozma

    2005-01-01

    Full Text Available The purpose of this study is to approximate the surviving period in patients with acute lymphoblastic leukemia. For this study we took in to consideration 10 patients 0 to 20 years old, coming from rural or urban environments and their evolution has been studied for a period of 60 days from the primary presentation to the hospital. The diagnosis was made after a careful history and physical examination and was completed after a blood count insisting on the number of leukocytes and on the peripheral blood smear. The patients’ evolution was monitored through the hematological parameters of the peripheral blood smear and of the bone marrow. The main Para clinical investigations consisted in the white cells and lymphocytes count from the peripheral blood smear. We counted the absolute and relative number of lymphocytes from the peripheral blood smear of these patients and then we divided them into three groups by criteria of age. We took into consideration at every age group the causes of the primary presentation to the hospital.

  11. Primary cutaneous follicle center lymphoma in the setting of chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    S Konda

    2011-01-01

    Full Text Available Primary cutaneous malignancies arising in association with chronic lymphocytic leukemia (CLL are notable for their atypical clinical and histological presentation. We report a 69-year-old man with a 17-year history of CLL who presented for evaluation of a well-defined red to violaceous nodule with a central depressed scar on the left lower extremity. Microscopic examination of a punch biopsy revealed an infiltrate of predominantly small lymphocytes with scattered large, atypical epithelioid cells. Immunohistochemical stains revealed diffuse positive staining of the lesional cells with CD20+ and bcl-6+ and focal positive staining with bcl-2+ (negative CD10 and CD23, findings which, in conjunction with the histology, were most compatible with a diagnosis of primary cutaneous follicle center lymphoma (PCFCL. A review of the clinical charts revealed several prior biopsies with varied diagnoses. In light of the most recent biopsy findings, all previous biopsies were re-reviewed and interpreted as PCFCL arising in the setting of CLL. Features contributing to the diagnostic conundrum in this case included an atypical clinical and histological presentation, lack of pertinent clinical history and multiple presentations at different institutions.

  12. Novel somatic mutations in large granular lymphocytic leukemia affecting the STAT-pathway and T-cell activation

    International Nuclear Information System (INIS)

    T-cell large granular lymphocytic (T-LGL) leukemia is a clonal disease characterized by the expansion of mature CD3+CD8+ cytotoxic T cells. It is often associated with autoimmune disorders and immune-mediated cytopenias. Our recent findings suggest that up to 40% of T-LGL patients harbor mutations in the STAT3 gene, whereas STAT5 mutations are present in 2% of patients. In order to identify putative disease-causing genetic alterations in the remaining T-LGL patients, we performed exome sequencing from three STAT mutation-negative patients and validated the findings in 113 large granular lymphocytic (LGL) leukemia patients. On average, 11 CD8+ LGL leukemia cell-specific high-confidence nonsynonymous somatic mutations were discovered in each patient. Interestingly, all patients had at least one mutation that affects either directly the STAT3-pathway (such as PTPRT) or T-cell activation (BCL11B, SLIT2 and NRP1). In all three patients, the STAT3 pathway was activated when studied by RNA expression or pSTAT3 analysis. Screening of the remaining 113 LGL leukemia patients did not reveal additional patients with same mutations. These novel mutations are potentially biologically relevant and represent rare genetic triggers for T-LGL leukemia, and are associated with similar disease phenotype as observed in patients with mutations in the STAT3 gene

  13. The Diagnostic Value of Flow Cytometry Imunophenotyping in an Albanian Patient Population with a Preliminary Clinical Diagnosis of Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Valentina Semanaj

    2014-03-01

    Conclusion: Flow cytometry immunophenotyping is a fundamental examination for the final diagnosis of chronic lymphocytic leukemia. The expression of CD38+ in CLL patients stands for a more advanced clinical stage.

  14. Magnetic resonance imaging may simulate progressive multifocal leucoencephalopathy in a patient with chronic lymphocytic leukemia after fludarabine therapy

    Directory of Open Access Journals (Sweden)

    Kalita J

    2008-01-01

    Full Text Available A 60-year-old male with chronic lymphatic leukemia (CLL after 6 months of fludarabine therapy was admitted with status epilepticus and developed left hemiplegia. His magnetic resonance imaging revealed multiple T2 hyperintense lesions in the right frontal and left parieto-occipital lesion, simulating progressive multifocal leucoencephalopathy (PML. Cerebrospinal fluid Polymerase Chain Reaction (PCR for JC virus was negative. We suggest the possible role of fludarabine in producing PML-like lesions in patients with Chronic Lymphocytic Leukemia (CLL.

  15. In vitro generation of cytotoxic lymphocytes against radiation-and radiation leukemia virus-induced tumors. III. Suppression of anti-tumor immunity in vitro by lymphocytes of mice undergoing radiation leukemia virus-induced leukemogenesis

    International Nuclear Information System (INIS)

    Adult C57BL/6 mice exposed to fractionated irradiation or inoculated with the radiation leukemia virus (RadLV), develop high incidence (80 to 100%) of lymphatic leukemias within 3 to 6 months. RadLV-induced lymphomas can elicit cytotoxic responses in vitro in lymphocytes of preimmunized syngeneic mice. As soon as 5 d after RadLV inoculation, and during the entire leukemogenic process, suppressor T cells are detectable in the spleen that are capable of specifically abrogating generation of syngeneic anti-tumor cytotoxic cells in vitro. Mice exposed to fractionated x irradiation do not develop suppressor cells. These findings suggest that although RadLV has been isolated from radiation-induced leukemias, x-ray- and RadLV-induced leukemogenesis do not seem to involve a common viral etilogy, and that induction of suppressor cells during RadLV leukemogenesis may be essential for tumor progression

  16. Phase 1 Study of Terameprocol (EM-1421) in Patients With Leukemia

    Science.gov (United States)

    2016-02-20

    Leukemias; Acute Myeloid Leukemia (AML); Acute Lymphocytic Leukemia (ALL); Adult T Cell Leukemia (ATL); Chronic Myeloid Leukemia (CML-BP); Chronic Lymphocytic Leukemia (CLL); Myelodysplastic Syndrome (MDS); Chronic Myelomonocytic Leukemia (CMML)

  17. DNA repair in lymphocytes from patients with secondary leukemia as measured by strand rejoining and unscheduled DNA synthesis

    DEFF Research Database (Denmark)

    Bohr, V; Køber, L

    1985-01-01

    The ability to repair damage to DNA was compared in 2 groups of patients having undergone treatment for leukemia, one of which developed secondary leukemia (SL), and the other without signs of secondary malignancy (treated controls). Both were related to normal controls. DNA repair was assessed in...... isolated peripheral lymphocytes from the patients by measuring the rejoining of strand breaks following alkylation damage to the lymphocytes or by measuring unscheduled DNA synthesis. Day-to-day variability in the assays was considerable, but findings were that 5 out of 7 SL patients had repair...... deficiencies as measured by their ability to rejoin strand breaks, and 5 out of 7 had increased unscheduled DNA synthesis compared to treated and normal controls. All patients with SL and 4 out of 8 treated controls had inherent strand breaks in their DNA as compared to the normal controls when measured by...

  18. A comparative study of central nervous system irradiation and intensive chemotherapy early in remission of childhood acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    A study was designed to determine whether a one-week course of intensive chemotherapy and 2400 rads craniospinal irradiation prolonged complete remission of acute lymphocytic leukemia (ALL) in children. Of 110 patients entered into the study, 104 (94%) attained complete remission, 94 of whom were available for the 2 randomizations. They were randomly assigned to receive or not receive one week of high-dosage intravenous chemotherapy and, 4 weeks later, were again randomized to receive or not receive 2400 rads cobalt-60 craniospinal irradiation. Patients randomized for no irradiation were to receive identical radiotherapy only if and when central nervous system (CNS) leukemia developed. The one week of intensive chemotherapy had no effect on the duration of remission or on the frequency or site of relapse, but irradiation had marked effect. Complete remission was terminated by CNS leukemia in only 2 of 45 children who received ''prophylactic'' craniospinal irradiation compared to 27 to 49 not irradiated. FIve of the 25 children who were given ''therapeutic'' irradiation for demonstrated CNS leukemia have already had recurrences despite continuous hematologic remission. Under the conditions of this study, the authors conclude that one week of intensive chemotherapy does not prolong remission, that 2400 rads craniospinal irradiation early in remission prevents or delays CNS leukemia and prolongs complete remission, and that once CNS leukemia develops, 2400 rads craniospinal irradiation is not sufficient to eradicate it

  19. Evaluation of 13q14 Status in Patients with Chronic Lymphocytic Leukemia Using Single Nucleotide Polymorphism-Based Techniques

    OpenAIRE

    Hanlon, Katy; Ellard, Sian; Rudin, Claudius E.; Thorne, Susan; Davies, Teresa; Harries, Lorna W.

    2009-01-01

    Deletions of chromosome 13q14 are common in chronic lymphocytic leukemia and other cancers, demonstrating the importance of this region in tumorigenesis. We report the use of two single-nucleotide polymorphism (SNP)-based techniques to determine 13q loss of heterozygosity (LOH) status in 15 patients with CLL: (i) digital SNP (dSNP), where analysis of heterozygous SNPs detects allelic imbalances, and (ii) DNA sequencing, where LOH is identified by comparison of allelic peak heights in normal a...

  20. The microenvironment differentially impairs passive and active immunotherapy in Chronic lymphocytic leukemia - Potential therapeutic synergism of CXCR4 antagonists

    OpenAIRE

    Buchner, Maike; Brantner, Philipp; Prinz, Gabriele; Burger, Meike; Baer, Constance; Dierks, Christine; Pfeifer, Dietmar; Mertelsmann, Roland; Gribben, John G.; Veelken, Hendrik; Zirlik, Katja

    2010-01-01

    Abstract Direct contact with stromal cells protects chronic lymphocytic leukemia (CLL) B cells from chemotherapy-induced apoptosis in vitro. Blockade of CXCR4 signaling antagonizes stroma-mediated interactions and restores CLL chemosensitivity. In vivo, administration of CXCR4 antagonists may also effect efficient mobilization of hematopoetic progenitor cells. Therefore, combinations of CXCR4 blockade with cytoreductive treatment with selective activity on CLL cells may avoid poten...

  1. BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia

    OpenAIRE

    Falchi, Lorenzo; Baron, Jessica M.; Orlikowski, Carrie Anne; Ferrajoli, Alessandra

    2016-01-01

    The B-cell receptor (BCR) signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatmen...

  2. Ibrutinib: A New Frontier in the Treatment of Chronic Lymphocytic Leukemia by Bruton’s Tyrosine Kinase Inhibition

    OpenAIRE

    Dias, Ajoy Lawrence; Jain, Dharamvir

    2013-01-01

    Chronic lymphocytic leukemia (CLL) is characterized by progressive accumulation of nonfunctional mature B cells in blood, bone marrow and lymphoid tissues. In the last decade, our understanding of CLL and consequently our diagnostic and therapeutic approaches have changed dramatically. Conventional fludarabine based chemotherapy has led to improved disease response and longer survival in young patients with CLL. However its application in elderly patients has been restricted by substantial my...

  3. BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    OpenAIRE

    Lorenzo Falchi; Baron, Jessica M.; Carrie Anne Orlikowski; Alessandra Ferrajoli

    2016-01-01

    The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in trea...

  4. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia

    OpenAIRE

    Chavez JC; Sahakian E; Pinilla-Ibarz J

    2013-01-01

    Julio C Chavez, Eva Sahakian, Javier Pinilla-IbarzH Lee Moffitt Cancer and Research Institute, Division of Malignant Hematology, and University of South Florida, Tampa, FL, USAAbstract: Chronic lymphocytic leukemia (CLL) is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as ...

  5. Higher frequencies of chromosomal aberrations in lymphocytes of children with acute lymphoblastic leukemia after in vitro gamma irradiation

    Directory of Open Access Journals (Sweden)

    A Ramyar

    2012-12-01

    Full Text Available Background: Acute lymphoblastic leukemia (ALL is the most common malignancy in childhood, characterized by excess lymphoblasts, and immature white blood cells that are continuously multiplying and overproducing in the bone marrow. The aim of this investigation was to measure the sensitivity of lymphocytes against gamma irradiation in patients with acute lymphoblastic leukemia, and also find out the effect of such irradiations in causing chromosomal abnormalities.Methods: In this investigation performed between April 2010 and July 2011, at the Department of Genetics, Cancer Institute of Iran, we studied the effects of gamma irradiation on the lymphocytes of 20 children with acute lymphoblastic leukemia. The lymphocytes of 30 healthy donors were used to establish as a normal response to gamma irradiation and seven age-matched ataxia telangiectasia patients were recruited as positive control. The chromosomal radiosensitivity was assessed with the G2- and the G0-assay. We compared the mean number of chromosomal abnormalities such as chromosome and chromatid breakages, chromosome and chromatid gaps, and chromatid exchanges in one-hundred metaphases of patients and control groups.Results: The frequency of chromosomal aberrations was statistically higher among patients with acute lymphoblastic leukemia than the normal controls (P<0.01. In total, 65% of the patients were sensitive to gamma irradiation, but the remaining 35% were similar to the normal controls. Patients with ataxia telangiectasia showed the highest sensitivity to gamma irradiation (P=0.001.Conclusion: Our results showed that a high percentage of patients with acute lymphoblastic leukemia were sensitive to irradiation, meaning that maximum care should be taken during their treatment to avoid unnecessary X-rays or radiotherapies.

  6. Immunological effects of donor lymphocyte infusion in patients with chronic myelogenous leukemia relapsing after bone marrow transplantation

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    Castro F.A.

    2004-01-01

    Full Text Available Allogeneic bone marrow transplantation (alloBMT is the only curative therapy for chronic myelogenous leukemia (CML. This success is explained by the delivery of high doses of antineoplastic agents followed by the rescue of marrow function and the induction of graft-versus-leukemia reaction mediated by allogeneic lymphocytes against host tumor cells. This reaction can also be induced by donor lymphocyte infusion (DLI producing remission in most patients with CML who relapse after alloBMT. The immunological mechanisms involved in DLI therapy are poorly understood. We studied five CML patients in the chronic phase, who received DLI after relapsing from an HLA-identical BMT. Using flow cytometry we evaluated cellular activation and apoptosis, NK cytotoxicity, lymphocytes producing cytokines (IL-2, IL-4 and IFN-gamma, and unstimulated (in vivo lymphocyte proliferation. In three CML patients who achieved hematological and/or cytogenetic remission after DLI we observed an increase of the percent of activation markers on T and NK cells (CD3/DR, CD3/CD25 and CD56/DR, of lymphocytes producing IL-2 and IFN-gamma, of NK activity, and of in vivo lymphocyte proliferation. These changes were not observed consistently in two of the five patients who did not achieve complete remission with DLI. The percent of apoptotic markers (Fas, FasL and Bcl-2 on lymphocytes and CD34-positive cells did not change after DLI throughout the different study periods. Taken together, these preliminary results suggest that the therapeutic effect of DLI in the chronic phase of CML is mediated by classic cytotoxic and proliferative events involving T and NK cells but not by the Fas pathway of apoptosis.

  7. The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia

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    Levine, Ross L; Loriaux, Marc; Huntly, Brian J.P.; Loh, Mignon L.; Beran, Miroslav; Stoffregen, Eric; Berger, Roland; Clark, Jennifer J; Willis, Stephanie G; Kim T. Nguyen; Flores, Nikki J.; Estey, Elihu; Gattermann, Norbert; Armstrong, Scott; Look, A. Thomas

    2005-01-01

    Activating mutations in tyrosine kinases have been identified in hematopoietic and nonhematopoietic malignancies. Recently, we and others identified a single recurrent somatic activating mutation (JAK2V617F) in the Janus kinase 2 (JAK2) tyrosine kinase in the myeloproliferative disorders (MPDs) polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. We used direct sequence analysis to determine if the JAK2V617F mutation was present in acute myeloid leukemia (A...

  8. Bovine lymphocytic leukemia: studies of etiology, pathogenesis, and mode of transmission. Progress report No. 19, June 1978-June 1979

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    Sorensen, D.K.

    1979-07-01

    Bovine leukemia is believed to be caused by an oncogenic RNA virus designated bovine leukemia virus (BLV). The presence of BLV particles in lymphocyte cultures from leukemic cattle and cattle with a persistent lymphocytosis has been consistentily demonstrated. Concentrated, cell free, BLV preparations were used to inoculate 12 late stage bovine fetuses (in utero) and two newborn calves. Current studies involve extensive monitoring of these inoculated animals to detect precancerous changes and obtain a detailed description of the events preceding the development of lymphosarcoma. Ongoing monitoring studies will provide a complete record of all changes in the various leukemia associated parameters. We will then be able to detail when, in what sequence, and to what extent each parameter changes in the course of lymphosarcoma development. Fourteen animals were successfully inoculated during the study. Eleven remain alive, and comprise the current monitoring program. All eleven of these animals are definitely infected with BLV, and in nine the infection has substantially progressed with respect to the parameters being monitored. In addition to transmission and monitoring studies, various lymphocyte subpopulations were examined to determine which cell type(s) are involved in the pathogenesis of bovine lymphosarcoma. These studies have conclusively established that B-lymphocytes are the target cells for BLV infection and that they carry the morphologic nuclear abnormality associated with this disease.

  9. MicroRNAs in the pathology of B-Cell Chronic Lymphocytic Leukemia

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    In chronic lymphocytic leukemia (B-CLL), aberrations along the p53 axis lead to decreased overall survival and therapy resistance. Recent studies identified miR-34a as a major downstream target of p53. We monitored the expression of miR-34a during disease development in a murine B-CLL model. miR-34a was upregulated >20-fold during the leukemic but not during the preleukemic phase. In the human system, B-CLL cells also had 4.6-fold higher miR-34a expression as compared to B-cells of healthy controls. In B-CLL cells of patients with p53 aberrations miR-34a expression was consistently low. The broad distribution of miR-34a levels in p53 wild-type individuals prompted us to study the correlation between SNP309 in the intronic promoter of MDM2 and miR-34a expression. B-CLL cells of patients with the SNP309 GG genotype had significantly lower miR-34a expression levels as compared to patients with the TT genotype (P =0.002). Low miR-34a levels were able to predict shorter time to treatment (P = 0.003) and were associated with an abbreviated lymphocyte doubling time. Further, overexpression of miR-34a in primary B-CLL cells induced apoptosis. These findings suggest miR-34a as a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in B-CLL. (author)

  10. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus (RAD001) and alemtuzumab: a Phase I/II study.

    Science.gov (United States)

    Zent, Clive S; Bowen, Deborah A; Conte, Michael J; LaPlant, Betsy R; Call, Timothy G

    2016-07-01

    Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), and especially those with purine analogue refractory disease or TP53 deletion/mutation, had a poor prognosis prior to the introduction of therapy targeting B cell receptor signaling. The mammalian target of rapamycin (mTOR) inhibitor everolimus has biological activity in CLL and can mobilize CLL cells from the lymphoid tissues into the circulation. In this clinical trial we determined the maximum tolerated dose (MTD) of everolimus together with eight weeks of standard dose subcutaneous alemtuzumab (Phase I) and then evaluated the tolerability and efficacy of therapy of relapsed/refractory CLL with the combination of everolimus and alemtuzumab (Phase II). The maximum tolerated dose of oral everolimus was 2.5 mg three times/week. Therapy with everolimus and alemtuzumab was tolerable, but not sufficiently efficacious (33% partial responses, no complete responses) to recommend further development of the regimen. PMID:26699397

  11. Novel Biomarker Proteins in Chronic Lymphocytic Leukemia: Impact on Diagnosis, Prognosis and Treatment

    Science.gov (United States)

    Admoni-Elisha, Lee; Nakdimon, Itay; Shteinfer, Anna; Prezma, Tal; Arif, Tasleem; Arbel, Nir; Melkov, Anna; Zelichov, Ori; Levi, Itai; Shoshan-Barmatz, Varda

    2016-01-01

    In many cancers, cells undergo re-programming of metabolism, cell survival and anti-apoptotic defense strategies, with the proteins mediating this reprogramming representing potential biomarkers. Here, we searched for novel biomarker proteins in chronic lymphocytic leukemia (CLL) that can impact diagnosis, treatment and prognosis by comparing the protein expression profiles of peripheral blood mononuclear cells from CLL patients and healthy donors using specific antibodies, mass spectrometry and binary logistic regression analyses and other bioinformatics tools. Mass spectrometry (LC-HR-MS/MS) analysis identified 1,360 proteins whose expression levels were modified in CLL-derived lymphocytes. Some of these proteins were previously connected to different cancer types, including CLL, while four other highly expressed proteins were not previously reported to be associated with cancer, and here, for the first time, DDX46 and AK3 are linked to CLL. Down-regulation expression of two of these proteins resulted in cell growth inhibition. High DDX46 expression levels were associated with shorter survival of CLL patients and thus can serve as a prognosis marker. The proteins with modified expression include proteins involved in RNA splicing and translation and particularly mitochondrial proteins involved in apoptosis and metabolism. Thus, we focused on several metabolism- and apoptosis-modulating proteins, particularly on the voltage-dependent anion channel 1 (VDAC1), regulating both metabolism and apoptosis. Expression levels of Bcl-2, VDAC1, MAVS, AIF and SMAC/Diablo were markedly increased in CLL-derived lymphocytes. VDAC1 levels were highly correlated with the amount of CLL-cancerous CD19+/CD5+ cells and with the levels of all other apoptosis-modulating proteins tested. Binary logistic regression analysis demonstrated the ability to predict probability of disease with over 90% accuracy. Finally, based on the changes in the levels of several proteins in CLL patients, as

  12. Cardiac tamponade mimicking tuberculous pericarditis as the initial presentation of chronic lymphocytic leukemia in a 58-year-old woman: a case report

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    Nathan Sandeep

    2010-08-01

    Full Text Available Abstract Introduction Chronic lymphocytic leukemia is an indolent disease that often presents with complaints of lymphadenopathy or is detected as an incidental laboratory finding. It is rarely considered in the differential diagnosis of patients presenting with tamponade or a large, bloody pericardial effusion. In patients without known cancer, a large, bloody pericardial effusion raises the possibility of tuberculosis, particularly in patients from endemic areas. However, the signs, symptoms and laboratory findings of pericarditis related to chronic lymphocytic leukemia can mimic tuberculosis. Case Presentation We report the case of a 58-year-old African American-Nigerian woman with a history of travel to Nigeria and a positive tuberculin skin test who presented with cardiac tamponade. She had a mild fever, lymphocytosis and a bloody pericardial effusion, but cultures and stains were negative for acid-fast bacteria. Assessment of blood by flow cytometry and pericardial biopsy by immunohistochemistry revealed CD5 (+ and CD20 (+ lymphocytes in both tissues, demonstrating this to be an unusual manifestation of early stage chronic lymphocytic leukemia. Conclusion Although most malignancies that involve the pericardium clinically manifest elsewhere before presenting with tamponade, this case illustrates the potential for early stage chronic lymphocytic leukemia to present as a large pericardial effusion with tamponade. Moreover, the presentation mimicked tuberculosis. This case also demonstrates that it is possible to treat chronic lymphocytic leukemia-related pericardial tamponade by removal of the fluid without chemotherapy.

  13. Development of fludarabine formulations in the treatment of chronic lymphocytic leukemia

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    Ann Janssens

    2009-10-01

    Full Text Available Ann Janssens, Marc Boogaerts, Gregor VerhoefDepartment of Hematology, University Hospitals Leuven, Campus Gasthuisberg, Leuven, BelgiumAbstract: Fludarabine is an antineoplastic agent used in the treatment of hematological malignancies, particularly chronic lymphocytic leukemia (CLL and indolent B-cell lymphoma. Because of its immunosuppressive effects, fludarabine has been added to reduced intensity conditioning regimens. The oral formulation of fludarabine has become widely available. Pharmacokinetic studies have shown that an oral dose of 40 mg/m2/d would provide systemic drug exposure similar to the standard intravenous (IV dose of 25 mg/m2/d. The oral dose can be taken once daily without any dietary restrictions. Dose adjustments are mandatory in patients with renal impairment to avoid increased toxicity. Several noncomparative trials in previously untreated and treated patients with CLL have shown that treatment with the oral formulation demonstrates similar efficacy compared to historical control groups treated with the IV formulation. The tolerability profile of oral fludarabine seems similar to that of the IV formulation. Myelosuppression and infectious complications are the most frequently reported adverse events. Gastrointestinal toxicity is more frequent with the oral formulation, but is usually of mild or moderate severity. Although oral fludarabine makes treatment more convenient, health care workers must be aware of the compliance behavior of each patient. Keywords: CLL, treatment, oral fludarabine, intravenous fludarabine

  14. Syncytial giant cell hepatitis associated with chronic lymphocytic leukemia: a case report

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    Gupta Eva

    2012-07-01

    Full Text Available Abstract Background Syncytial giant cell hepatitis (GCH is an uncommon and an underreported disease entity. In two previously reported cases of GCH in patients with Chronic Lymphocytic Leukemia (CLL liver failure ensued. Autoimmune and infective causes have been implicated but its etiology remains unclear. Case Presentation A 60-year-old female with CLL presented with acute hepatitis with negative viral and auto-immune serologies and without any prior toxic exposure. Liver biopsy showed typical histological features of GCH. The patient was successfully treated with corticosteroids and intravenous immunoglobulin (IVIG. Her liver enzymes returned to baseline and have remained normal as of the last follow up almost 4 years later. Conclusions Association of GCH with CLL may be under recognized. Clinical suspicion of GCH in CLL patients with serology-negative hepatitis, early liver biopsy and therapeutic intervention may influence outcome. This is the first case report of successful treatment of GCH in CLL patients. Moreover, our case also demonstrates the ability to resume effective CLL therapy post-GCH diagnosis without detriment to the liver.

  15. Treatment of chronic lymphocytic leukemia by total body irradiation alone and combined with chemotherapy

    International Nuclear Information System (INIS)

    Total body irradiation (TBI) offers a new dimension in the treatment of chronic lymphocytic leukemia (CLL), a disease heretofore refractory to effective management. Excellent responses were observed in 50/57 (88%) consecutive patients with active CLL treated since 1964, and complete remissions were achieved in 22/57 (39%). Toxicity was acceptable and was minimized by combining TBI and chemotherapy in attenuated doses of each modality. The responders had a modified natural history of disease as evidenced by prolonged survival, improved quality of life, and even restoration of immunologic competence in some cases. Benefit was particularly evident for patients with a poor prognosis, i.e., those with anemia and/or thrombocytopenia prior to treatment. A median survival of 55 months for the 40 Stage III-IV patients is 2-3 times longer than described for comparable patients in other series. This experience indicates TBI may be the most effective single agent available for the treatment of CLL and warrants consideration in primary therapy

  16. Relationship of blood monocytes with chronic lymphocytic leukemia aggressiveness and outcomes: a multi-institutional study.

    Science.gov (United States)

    Friedman, Daphne R; Sibley, Alexander B; Owzar, Kouros; Chaffee, Kari G; Slager, Susan; Kay, Neil E; Hanson, Curtis A; Ding, Wei; Shanafelt, Tait D; Weinberg, J Brice; Wilcox, Ryan A

    2016-07-01

    Monocyte-derived cells, constituents of the cancer microenvironment, support chronic lymphocytic leukemia (CLL) cell survival in vitro via direct cell-cell interaction and secreted factors. We hypothesized that circulating absolute monocyte count (AMC) reflects the monocyte-derived cells in the microenvironment, and that higher AMC is associated with increased CLL cell survival in vivo and thus inferior CLL patient outcomes. We assessed the extent to which AMC at diagnosis of CLL is correlated with clinical outcomes, and whether this information adds to currently used prognostic markers. We evaluated AMC, clinically used prognostic markers, and time to event data from 1,168 CLL patients followed at the Mayo Clinic, the Duke University Medical Center, and the Durham VA Medical Center. Elevated AMC was significantly associated with inferior clinical outcomes, including time to first therapy (TTT) and overall survival (OS). AMC combined with established clinical and molecular prognostic markers significantly improved risk-stratification of CLL patients for TTT. As an elevated AMC at diagnosis is associated with accelerated disease progression, and monocyte-derived cells in the CLL microenvironment promote CLL cell survival and proliferation, these findings suggest that monocytes and monocyte-derived cells are rational therapeutic targets in CLL. Am. J. Hematol. 91:687-691, 2016. © 2016 Wiley Periodicals, Inc. PMID:27037726

  17. The novel NF-κB inhibitor IMD-0354 induces apoptosis in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Nuclear factor-κB (NF-κB) is an important regulator of cell survival and has been shown to be constitutively active in chronic lymphocytic leukemia (CLL) cells. Recently, a novel NF-κB inhibitor, IMD-0354 (N-(3, 5-bis-trifluoromethyl-phenyl)-5-chloro-2-hydroxy-benzamide), was shown to specifically inhibit the phosphorylation of IκBα by IkB kinases, thus preventing NF-κB release. In this study, we investigated if IMD-0354 can inhibit NF-κB activation and induce apoptosis in CLL cells in vitro. The rate of increase in apoptosis, drug sensitivity and DNA-binding activity of NF-κB were studied using Annexin V stainings, the fluorometric microculture cytotoxicity assay and electrophoretic mobility shift assay, respectively. Finally, the impact of IMD-0354 treatment on the expression of a set of apoptosis-related genes was investigated. The results clearly show that IMD-0354 induced apoptosis (mean 26%, range 8–48%) in CLL cells, independent of immunoglobulin heavy variable (IGHV) gene mutational status, and showed a dose-dependent cytotoxic effect. IMD-0354 treatment also significantly lowered the DNA-binding activity of NF-κB in CLL cells. In addition, we identified differences in expression levels of pro- and antiapoptotic genes following IMD-0354 treatment. In summary, our novel findings show that IMD-0354 can induce apoptosis in CLL cells, and thus merits further investigation as an anticancer agent in vivo

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

    Science.gov (United States)

    Dreger, Peter; Montserrat, Emili

    2015-03-01

    Allogeneic hematopoietic stem cell transplantation (alloHSCT) has been considered as the treatment of choice for patients with high-risk chronic lymphocytic leukemia (CLL) (i.e., refractory to purine analogs, short response (<24 months) to intensive treatments, and/or presence of 17p/TP53 abnormalities). Currently, new and highly effective therapeutic agents targeting BCR-mediated intracellular signal transduction have been incorporated into the CLL treatment armamentarium. These signal transduction inhibitors (STI) will change the algorithms of high-risk CLL (HR-CLL) management. Despite the limited body of evidence, there is sufficient rationale for withholding alloHSCT in patients with 17p-/TP53mut CLL in first remission. In contrast, the perspectives of patients with relapsed 17p-/TP53mut CLL remain uncertain even if responding to STI. The same accounts for patients with HR-CLL progressing under STI. In both scenarios, it is reasonable to consider alloHSCT, ideally after response to alternative STI regimens. PMID:25651976

  19. Sensitivity of chronic lymphocytic leukemia cells to small targeted therapeutic molecules: An in vitro comparative study.

    Science.gov (United States)

    Sylvan, Sandra Eketorp; Skribek, Henriette; Norin, Stefan; Muhari, Orsolya; Österborg, Anders; Szekely, Laszlo

    2016-01-01

    New drugs targeting important cellular signaling pathways are currently being developed for chronic lymphocytic leukemia (CLL). It is therefore of interest to analyze their in vitro killing capacity in manufacturer-independent, comparative experiments. We here report on the sensitivity of CLL cells to a panel of emerging targeted therapeutics using high-throughput screening based on an automated fluorescence digital scanning system. Fresh CLL cells from 42 patients with indolent or progressive CLL were cultured for 72 hours on microtiter plates in a unique primary cell culture medium. Antitumor effects of 31 small therapeutic molecules (and, as controls, 29 cytostatic agents) at equimolar concentration were compared in a fluorescence survival assay. In vitro sensitivity to each drug exhibited considerable interpatient variability. The highest mean direct killing was observed for one survivin inhibitor (YM-155), two bcl-2 inhibitors (ABT-199, ABT-737), and one selective CDK inhibitor (dinaciclib). Their killing capacity was, in contrast to most cytostatic agents, similarly high in refractory versus untreated CLL patients and was significantly higher on cells with the 17p deletion/TP53 mutation than on cells with other cytogenetic abnormalities (p = 0.02). Sensitivity of bone marrow and lymph node cells was highly correlated with that of blood cells. Even though direct killing may not be the only therapeutic effector function in vivo, results from this head-to-head comparison may help to identify drugs of particular interest for intensified clinical development. PMID:26325331

  20. Automatic detection of axillary lymphadenopathy on CT scans of untreated chronic lymphocytic leukemia patients

    Science.gov (United States)

    Liu, Jiamin; Hua, Jeremy; Chellappa, Vivek; Petrick, Nicholas; Sahiner, Berkman; Farooqui, Mohammed; Marti, Gerald; Wiestner, Adrian; Summers, Ronald M.

    2012-03-01

    Patients with chronic lymphocytic leukemia (CLL) have an increased frequency of axillary lymphadenopathy. Pretreatment CT scans can be used to upstage patients at the time of presentation and post-treatment CT scans can reduce the number of complete responses. In the current clinical workflow, the detection and diagnosis of lymph nodes is usually performed manually by examining all slices of CT images, which can be time consuming and highly dependent on the observer's experience. A system for automatic lymph node detection and measurement is desired. We propose a computer aided detection (CAD) system for axillary lymph nodes on CT scans in CLL patients. The lung is first automatically segmented and the patient's body in lung region is extracted to set the search region for lymph nodes. Multi-scale Hessian based blob detection is then applied to detect potential lymph nodes within the search region. Next, the detected potential candidates are segmented by fast level set method. Finally, features are calculated from the segmented candidates and support vector machine (SVM) classification is utilized for false positive reduction. Two blobness features, Frangi's and Li's, are tested and their free-response receiver operating characteristic (FROC) curves are generated to assess system performance. We applied our detection system to 12 patients with 168 axillary lymph nodes measuring greater than 10 mm. All lymph nodes are manually labeled as ground truth. The system achieved sensitivities of 81% and 85% at 2 false positives per patient for Frangi's and Li's blobness, respectively.

  1. GENOMIC PROFILING BY MULTIPLEX LIGATION - DEPENDENT PROBE AMPLIFICATION IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS

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    Georgiana-Emilia Grigore

    2013-11-01

    Full Text Available The clinical management of severe pathological conditions, such as B-cell chronic lymphocytic leukemia (B-CLL, is subject to continuous optimization and re-evaluation. Patients may fully benefit from rapid, standardized laboratory tools designed to facilitate their early stratification according to disease risk, stage and prognosis. Such technologies may also aid the clinician in selecting the therapeutic option with the greatest chances of success. The presence of specific genetic abnormalities are frequently associated with the clinical outcome of oncologic patients in general, and B-CLL patients in particular. In the current study, a group of 58 B-CLL patients were evaluated for the detection of gene copy number alterations (deletions or duplication/ amplifications within 45 distinct genetic targets, by means of a novel molecular methodology, Multiplex Ligation - Dependent Probe Amplification (MLPA. Simple or complex genetic defects were identified in 67% of cases, and the most common aberrations observed were: deletion of the short arm of chromosome 13 in 33% of cases, deletion of the long arm of chromosome 11 in 16% of cases, trisomy 12 in 16% of cases, and deletion of the short arm of chromosome 17 in 7% of cases. The main conclusion of the study presented here points towards MLPA as a potential key step of clinical management protocols in B-CLL, providing that it will be fully standardised for routine diagnosis.

  2. Prognostic signature and clonality pattern of recurrently mutated genes in inactive chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    An increasing numbers of patients are being diagnosed with asymptomatic early-stage chronic lymphocytic leukemia (CLL), with no treatment indication at baseline. We applied a high-throughput deep-targeted analysis, especially designed for covering widely TP53 and ATM genes, in 180 patients with inactive disease at diagnosis, to test the independent prognostic value of CLL somatic recurrent mutations. We found that 40/180 patients harbored at least one acquired variant with ATM (n=17, 9.4%), NOTCH1 (n=14, 7.7%), TP53 (n=14, 7.7%) and SF3B1 (n=10, 5.5%) as most prevalent mutated genes. Harboring one ‘sub-Sanger' TP53 mutation granted an independent 3.5-fold increase of probability of needing treatment. Those patients with a double-hit ATM lesion (mutation+11q deletion) had the shorter median time to first treatment (17 months). We found that a genomic variable: TP53 mutations, most of them under the sensitivity of conventional techniques; a cell phenotypic factor: CD38-positive expression; and a classical marker as β2-microglobulin, remained as the unique independent predictors of outcome. The high-throughput determination of TP53 status, particularly in this set of patients frequently lacking high-risk chromosomal aberrations, emerges as a key step, not only for prediction modeling, but also for exploring mutation-specific therapeutic approaches and minimal residual disease monitoring

  3. Igs Expressed by Chronic Lymphocytic Leukemia B Cells Show Limited Binding-Site Structure Variability

    KAUST Repository

    Marcatili, P.

    2013-05-01

    Ag selection has been suggested to play a role in chronic lymphocytic leukemia (CLL) pathogenesis, but no large-scale analysis has been performed so far on the structure of the Ag-binding sites (ABSs) of leukemic cell Igs. We sequenced both H and L chain V(D)J rearrangements from 366 CLL patients and modeled their three-dimensional structures. The resulting ABS structures were clustered into a small number of discrete sets, each containing ABSs with similar shapes and physicochemical properties. This structural classification correlates well with other known prognostic factors such as Ig mutation status and recurrent (stereotyped) receptors, but it shows a better prognostic value, at least in the case of one structural cluster for which clinical data were available. These findings suggest, for the first time, to our knowledge, on the basis of a structural analysis of the Ab-binding sites, that selection by a finite quota of antigenic structures operates on most CLL cases, whether mutated or unmutated. Copyright © 2013 by The American Association of Immunologists, Inc.

  4. Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia.

    Science.gov (United States)

    Robak, Tadeusz; Blonski, Jerzy Z; Robak, Pawel

    2016-04-01

    The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib, or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future. However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL. PMID:27040707

  5. State-of-the-Art Treatment and Novel Agents in Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Cramer, Paula; Hallek, Michael; Eichhorst, Barbara

    2016-01-01

    Chemoimmunotherapy is the established first-line treatment of patients with chronic lymphocytic leukemia (CLL) who do not display the high-risk genetic features del(17p) and/or TP53 mutation: Physically fit patients without or with only mild comorbidities should receive fludarabine, cyclophosphamide and rituximab, while bendamustine and rituximab can be considered in fit elderly patients of over 65 years and in patients with a higher risk of infections. Patients with relevant coexisting conditions should receive chlorambucil with a CD20 antibody, preferably obinutuzumab. Patients with a del(17p) and/or TP53 mutation respond poorly to conventional chemo(immuno)therapies. However, the recently approved BTK and PI3K inhibitors ibrutinib and idelalisib have the best efficacy ever documented in patients with these high-risk genomic alterations and/or refractory CLL. The choice between ibrutinib and idelalisib should be based on the patients' comorbidities and concomitant medications since both agents have a distinct toxicity profile, although they are generally well tolerated in the majority of patients. For treatment of patients with a late relapse, chemoimmunotherapy instead of kinase inhibitors is still a reasonable approach, but has to be determined for every patient individually. Further targeted drugs and their combinations are currently being evaluated in clinical trials and have the potential to eradicate all residual CLL cells and thus lead to a cure of CLL. PMID:26890007

  6. Pitting new treatments for chronic lymphocytic leukemia against old ones: how do they fare?

    Science.gov (United States)

    Shvidel, Lev; Berrebi, Alain

    2016-03-01

    Significant progress has been made in the treatment of chronic lymphocytic leukemia (CLL) patients during the last two decades. In this review we present a personal case study for discussion on contemporary management in CLL. Presently immunochemotherapy using fludarabine, cyclophosphamide, and rituximab (FCR) is the standard upfront regimen for physically fit patients requiring treatment. Patients older than 65 years can be treated with modified doses of FCR, bendamustine, or chlorambucil combined with anti-CD20 antibody. This treatment can be repeated at relapse when the duration of response is over 2 years. Patients at high risk (with 17p deletion or early relapse) need alternative treatment with novel agents, e.g. ibrutinib or idelalisib. However, the optimal use of the novel agents in terms of duration, combinations, and long-term adverse effects is unknown. In selected eligible patients at high risk, allogeneic transplantation should be considered. Clinical trials in all stages of treatment are encouraged. PMID:26613391

  7. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab.

    Science.gov (United States)

    Laurenti, Luca; Innocenti, Idanna; Autore, Francesco; Sica, Simona; Efremov, Dimitar G

    2016-01-01

    Ofatumumab is one of the three anti-CD20 monoclonal antibodies currently available for the treatment of chronic lymphocytic leukemia (CLL). The US Food and Drug Administration (FDA) approved the use of ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab in 2009, and the European Medicines Agency (EMA) granted approval for the same indication in 2010. Subsequent positive results of ofatumumab in combination with chlorambucil in treatment-naïve patients led the FDA in April 2014 to approve the use of this combination for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate. Later that year, the EMA approved the use of ofatumumab in combination with chlorambucil or bendamustine for the same indication. Ofatumumab has also shown potential as maintenance therapy for patients with relapsed CLL; an application to broaden the label for ofatumumab as maintenance therapy was submitted earlier this year to the EMA and FDA. Finally, ofatumumab has shown promising activity in combination with ibrutinib or idelalisib in relapsed/refractory CLL patients; combinations of ofatumumab with B-cell-receptor pathway inhibitors could represent another potential use of this antibody in the near future. PMID:26855591

  8. The PI3K pathway: clinical inhibition in chronic lymphocytic leukemia.

    Science.gov (United States)

    Brown, Jennifer R

    2016-04-01

    Constitutive or mutational activation of the phosphatidylinositol 3 kinase, or PI3K, has been implicated in many cancers, including chronic lymphocytic leukemia (CLL). The δ isoform of the p110 catalytic subunit of PI3K has its primary physiologic function in B cells and appears to be the predominant mediator of most PI3K signals in CLL cells. Idelalisib is a first-in-class inhibitor of the PI3K delta isoform that shows near complete inhibition of AKT phosphorylation in CLL cells in vitro and in vivo. Idelalisib shows the classic pattern of response to BCR inhibition in CLL, with rapid nodal response and transient increase in lymphocytosis. The phase I study established the recommended dose as 150 mg twice per day. Subsequent registration trials have focused predominantly on antibody combinations, leading to the US Food and Drug Administration (FDA) approval of idelalisib with rituximab for relapsed CLL patients for whom rituximab is appropriate therapy in summer 2014. The median progression-free survival (PFS) of idelalisib-rituximab in this heavily pretreated CLL population with multiple comorbidities and frequent 17p deletion was an impressive 19.4 months. The success of idelalisib has paved the way for the development of other PI3K inhibitors in CLL, including duvelisib and TGR-1202, which are in or moving toward registration trials. PMID:27040704

  9. New developments in the management of chronic lymphocytic leukemia: role of ofatumumab

    Directory of Open Access Journals (Sweden)

    Laurenti L

    2016-01-01

    Full Text Available Luca Laurenti,1 Idanna Innocenti,1 Francesco Autore,1 Simona Sica,1 Dimitar G Efremov2 1Department of Hematology, Catholic University of the Sacred Heart, Rome, 2Molecular Hematology, International Centre for Genetic Engineering and Biotechnology, Monterotondo, Italy Abstract: Ofatumumab is one of the three anti-CD20 monoclonal antibodies currently available for the treatment of chronic lymphocytic leukemia (CLL. The US Food and Drug Administration (FDA approved the use of ofatumumab in patients with CLL refractory to fludarabine and alemtuzumab in 2009, and the European Medicines Agency (EMA granted approval for the same indication in 2010. Subsequent positive results of ofatumumab in combination with chlorambucil in treatment-naïve patients led the FDA in April 2014 to approve the use of this combination for first-line treatment of patients with CLL for whom fludarabine-based therapy is considered inappropriate. Later that year, the EMA approved the use of ofatumumab in combination with chlorambucil or bendamustine for the same indication. Ofatumumab has also shown potential as maintenance therapy for patients with relapsed CLL; an application to broaden the label for ofatumumab as maintenance therapy was submitted earlier this year to the EMA and FDA. Finally, ofatumumab has shown promising activity in combination with ibrutinib or idelalisib in relapsed/refractory CLL patients; combinations of ofatumumab with B-cell-receptor pathway inhibitors could represent another potential use of this antibody in the near future. Keywords: CLL, ofatumumab, monoclonal antibodies, immunotherapy

  10. Differential expression and function of CD27 in chronic lymphocytic leukemia cells expressing ZAP-70.

    Science.gov (United States)

    Lafarge, Sandrine T; Hou, Sen; Pauls, Samantha D; Johnston, James B; Gibson, Spencer B; Marshall, Aaron J

    2015-07-01

    Chronic lymphocytic leukemia is a malignancy driven by abberant B cell signaling and survival. Leukemic B cells accumulate in the peripheral blood and the lymphoid organs where contact with stromal cells and T cells provide critical survival signals. Clinical severity of CLL is associated with several prognostic markers including expression of the kinase ZAP-70. ZAP-70 expression enhances signaling via the B cell antigen receptor and is associated with increased cell adhesion and migration capacity. Here we report that ZAP-70-positive CLL patients display significantly higher expression of the TNF superfamily receptor and memory marker CD27 than do ZAP-70 negative patients. CD27 expression by CLL was acutely elevated upon BCR cross-linking, or upon ectopic expression of ZAP-70. CD27 expression correlated with functional capacity to adhere to stromal cells and antibody blockade of CD27 impaired CLL binding to stroma. These results provide the first evidence for differential expression of CD27 among CLL prognostic groups, suggest a role for ZAP-70 dependent signaling in CD27 induction and implicate CD27 in cell-cell interactions with the lymphoid tissue microenvironment. PMID:26002513

  11. Monoclonal antibodies against ROR1 induce apoptosis of chronic lymphocytic leukemia (CLL) cells.

    Science.gov (United States)

    Daneshmanesh, A H; Hojjat-Farsangi, M; Khan, A S; Jeddi-Tehrani, M; Akhondi, M M; Bayat, A A; Ghods, R; Mahmoudi, A-R; Hadavi, R; Österborg, A; Shokri, F; Rabbani, H; Mellstedt, H

    2012-06-01

    ROR1 is a receptor tyrosine kinase (RTK) recently identified to be overexpressed at the gene and protein levels in chronic lymphocytic leukemia (CLL). Monoclonal antibodies (MAbs) against RTKs have been successfully applied for therapy of solid tumors. We generated five MAbs against the Ig (n = 1), cysteine-rich (CRD) (n = 2) and kringle (KNG) (n = 2) domains, respectively, of the extracellular part of ROR1. All CLL patients (n = 20) expressed ROR1 on the surface of the leukemic cells. A significantly higher frequency of ROR1 expression was found in patients with progressive versus non-progressive disease, and in those with unmutated versus mutated IgVH genes. All five MAbs alone induced apoptosis in the absence of complement or added effector cells (Annexin-V and MTT, as well as cleavage of poly-(ADP ribose)-polymerase, caspase-8 and caspase-9) of CLL cells but not of normal B cells. Most effective were MAbs against CRD and KNG, significantly superior to rituximab (P < 0.005). Cross-linking of anti-ROR1 MAbs using the F(ab')(2) fragments of anti-Fc antibodies significantly augmented apoptosis. Two of the MAbs induced complement-dependent cytotoxicity (CDC) similar to that of rituximab and one anti-ROR1 MAb (KNG) (IgG1) showed killing activity by antibody-dependent cellular cytotoxicity. The identified ROR1 epitopes may provide a basis for generating human ROR1 MAbs for therapy. PMID:22289919

  12. Evaluation of chronic lymphocytic leukemia by BAC-based microarray analysis

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    McDaniel Lisa D

    2011-02-01

    Full Text Available Abstract Background Chronic lymphocytic leukemia (CLL is a highly variable disease with life expectancies ranging from months to decades. Cytogenetic findings play an integral role in defining the prognostic significance and treatment for individual patients. Results We have evaluated 25 clinical cases from a tertiary cancer center that have an established diagnosis of CLL and for which there was prior cytogenetic and/or fluorescence in situ hybridization (FISH data. We performed microarray-based comparative genomic hybridization (aCGH using a bacterial artificial chromosome (BAC-based microarray designed for the detection of known constitutional genetic syndromes. In 15 of the 25 cases, aCGH detected all copy number imbalances identified by prior cytogenetic and/or FISH studies. For the majority of those not detected, the aberrations were present at low levels of mosaicism. Furthermore, for 15 of the 25 cases, additional abnormalities were detected. Four of those cases had deletions that mapped to intervals implicated in inherited predisposition to CLL. For most cases, aCGH was able to detect abnormalities present in as few as 10% of cells. Although changes in ploidy are not easily discernable by aCGH, results for two cases illustrate the detection of additional copy gains and losses present within a mosaic tetraploid cell population. Conclusions Our results illustrate the successful evaluation of CLL using a microarray optimized for the interrogation of inherited disorders and the identification of alterations with possible relevance to CLL susceptibility.

  13. Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia.

    Science.gov (United States)

    Rossi, Davide; Rasi, Silvia; Fabbri, Giulia; Spina, Valeria; Fangazio, Marco; Forconi, Francesco; Marasca, Roberto; Laurenti, Luca; Bruscaggin, Alessio; Cerri, Michaela; Monti, Sara; Cresta, Stefania; Famà, Rosella; De Paoli, Lorenzo; Bulian, Pietro; Gattei, Valter; Guarini, Anna; Deaglio, Silvia; Capello, Daniela; Rabadan, Raul; Pasqualucci, Laura; Dalla-Favera, Riccardo; Foà, Robin; Gaidano, Gianluca

    2012-01-12

    Analysis of the chronic lymphocytic leukemia (CLL) coding genome has recently disclosed that the NOTCH1 proto-oncogene is recurrently mutated at CLL presentation. Here, we assessed the prognostic role of NOTCH1 mutations in CLL. Two series of newly diagnosed CLL were used as training (n = 309) and validation (n = 230) cohorts. NOTCH1 mutations occurred in 11.0% and 11.3% CLL of the training and validation series, respectively. In the training series, NOTCH1 mutations led to a 3.77-fold increase in the hazard of death and to shorter overall survival (OS; P independent predictor of OS after controlling for confounding clinical and biologic variables. The independent prognostic value of NOTCH1 mutations was externally confirmed in the validation series. The poor prognosis conferred by NOTCH1 mutations was attributable, at least in part, to shorter treatment-free survival and higher risk of Richter transformation. Although NOTCH1 mutated patients were devoid of TP53 disruption in more than 90% cases in both training and validation series, the OS predicted by NOTCH1 mutations was similar to that of TP53 mutated/deleted CLL. NOTCH1 mutations are an independent predictor of CLL OS, tend to be mutually exclusive with TP53 abnormalities, and identify cases with a dismal prognosis. PMID:22077063

  14. B lymphocytes from patients with chronic lymphocytic leukemia contain signal transducer and activator of transcription (STAT) 1 and STAT3 constitutively phosphorylated on serine residues.

    Science.gov (United States)

    Frank, D A; Mahajan, S; Ritz, J

    1997-12-15

    To explore the pathogenesis of chronic lymphocytic leukemia (CLL), we examined whether phosphorylation of one or more signal transducer and activator of transcription (STAT) factors was abnormal in cells from CLL patients. No constitutive tyrosine phosphorylation was detected on any STAT in CLL cells. To assess the phosphorylation of serine residues of STAT1 and STAT3 in CLL cells, we raised antibodies that specifically recognize the form of STAT1 phosphorylated on ser-727 and the form of STAT3 phosphorylated on ser-727. We found that in 100% of patients with CLL (n = 32), STAT1 and STAT3 were constitutively phosphorylated on serine. This was in contrast to normal peripheral blood B lymphocytes or CD5+) B cells isolated from tonsils, in which this phosphorylation was absent. Serine phosphorylation of STAT1 and STAT3 was seen occasionally in other leukemias, but it was a universal finding only in CLL. The serine phosphorylation of these STATs was a continuous process, as incubation of CLL cells with the kinase inhibitor H7 led to the dephosphorylation of these serine residues. The STAT serine kinase in CLL cells has not been identified, and appears to be neither mitogen-activated protein kinase nor pp70(s6k). In summary, the constitutive serine phosphorylation of STAT1 and STAT3 is present in all CLL samples tested to date, although the physiologic significance of this modification remains to be determined. PMID:9399961

  15. Surface antigen expression in chronic lymphocytic leukemia: clustering analysis, interrelationships and effects of chromosomal abnormalities.

    Science.gov (United States)

    Hulkkonen, J; Vilpo, L; Hurme, M; Vilpo, J

    2002-02-01

    Chronic lymphocytic leukemia (CLL) is a phenotypically distinguishable form of B-lymphoid leukemias. The regularity of surface membrane antigen expression patterns, their interrelationships as well as the effects of the three frequent chromosomal aberrations, ie 11q deletion, 13q deletion and trisomy 12, were investigated in 35 classic CLL cases by flow cytometry. The two-way cluster analysis of 31 individual antigens revealed three expression patterns: (1) most cells in most cases positive (CD5, CD19, CD20, CD23, CD27, CD40, CD45, CD45RA); (2) most cells in most cases negative (CD10, CD14, CD34, CD122, CD154, mIgG); and (3) a mixed pattern with a variable number of positive cases and a variable percentage of positive cells in individual cases (CD11c, CD21, CD22, CD25, CD38, CD45RO, CD79b, CD80, CD95, CD124, CD126, CD130, FMC7, mIgD, mIgkappa, mIglambda, mIgM). The expressions of several antigens were strongly interdependent, even when antigens belonged to entirely different gene families. Such antigen pairs were: CD11c/CD21; CD19/CD45; CD19/CD79b; CD22/CD45RA; CD23/Igkappa; CD25/mIgM; CD27/CD45; CD45/CD79b; CD45RA/Igkappa. In contrast, the expression of some antigens was mutually exclusive, the best examples being CD45RA/CD45RO, CD38/CD80 and CD45RA/CD80. Deletion of chromosome arm 11q attenuated expression of splicing variant CD45RA, but enhanced CD45RO expression. In contrast, cases of trisomy 12 were associated with enhanced CD45RA and attenuated CD45RO expression. Similarly, trisomy 12 was associated with enhanced CD27 and mIgkappa expression. The variable levels of signaling surface membrane antigens, their interactions and interference by genetic aberrations are likely to affect the clinical progression and drug response of CLL. PMID:11840283

  16. Decrease in cerebral metabolic rate of glucose after high-dose methotrexate in childhood acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    We measured changes in the regional cerebral metabolic rate of glucose (rCMRGlu) using 18F-fluorodeoxyglucose and positron emission tomography for the assessment of neurotoxicity in childhood acute lymphocytic leukemia treated with high-dose methotrexate (HD-MTX) therapy. We studied 8 children with acute lymphocytic leukemia (mean age: 9.6 years) treated with HD-MTX (200 mg/kg or 2,000 mg/M2) therapy. CMRGlu after HD-MTX therapy was most reduced (40%) in the patient who had central nervous system leukemia and was treated with the largest total doses of both intrathecal MTX (IT-MTX) and HD-MTX. CMRGlu in the whole brain after HD-MTX therapy was reduced by an average of 21% (P less than 0.05). The reductions of CMRGlu in 8 patients were correlated with total doses of both IT-MTX (r = 0.717; P less than 0.05) and systemic HD-MTX (r = 0.784; P less than 0.05). CMRGlu of the cerebral cortex, especially the frontal and occipital cortex, was reduced more noticeably than that of the basal ganglia and white matter. We suggest that the measurement of changes in rCMRGlu after HD-MTX therapy is useful for detecting accumulated MTX neurotoxicity

  17. Leucemia de grandes linfócitos granulares Large granular lymphocyte leukemia

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    Bruno Terra

    2010-01-01

    Full Text Available O presente estudo tem como objetivo o estabelecimento de fundamentação teórica atualizada baseada em revisão bibliográfica sobre a leucemia de grandes linfócitos granulares (LGLG, doença onco-hematológica, que, devido à sua relativa raridade, é pouco conhecida e subdiagnosticada. A LGLG é caracterizada pela proliferação clonal de linfócitos T ou NK na medula óssea e/ou no sangue periférico. Dentre as manifestações clínico-laboratoriais, podem ocorrer citopenias (anemia e/ou neutropenia e/ou plaquetopenia, linfocitose (não costuma ser acentuada, linfadenomegalia, hepatoesplenomegalia, alterações imunológicas e sintomas constitucionais (emagrecimento, febre e sudorese. O curso clínico da LGLG é bastante variável, sendo que no subtipo T costuma ser indolente ou oligossintomática, enquanto no subtipo NK a evolução costuma ser desfavorável. O diagnóstico é firmado através de imunofenotipagem por citometria de fluxo e estudo de clonalidade por métodos de biologia molecular. Seu tratamento é bastante diversificado e é definido de acordo com a apresentação clínica da doença.This is a literature review about large granular lymphocyte leukemia (LGLL, a rare and misdiagnosed oncohematological disease, characterized by a clonal expansion of T-cells (T-LGLL or NK-cells (NK-LGLL in the bone marrow and/or peripheral blood. The clinical features of LGLL include cytopenias (anemia, neutropenia and thrombocytopenia, lymphocytosis (usually discrete, lymphadenopathy, hepatomegaly, splenomegaly, immune abnormalities and constitutional symptoms (fever, night sweats and weight loss. The diagnosis is based on the confirmation of the clonality of T-cells or NK-cells (polymerase chain reaction and Southern blot are the two methods most commonly used and typical findings of the immunophenotypic analysis of peripheral blood lymphocytes (flow cytometry analyses for specific surface antigens. In contrast to the chronic and indolent

  18. L-selectin controls trafficking of chronic lymphocytic leukemia cells in lymph node high endothelial venules in vivo.

    Science.gov (United States)

    Lafouresse, Fanny; Bellard, Elisabeth; Laurent, Camille; Moussion, Christine; Fournié, Jean-Jacques; Ysebaert, Loïc; Girard, Jean-Philippe

    2015-09-10

    B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Lymph nodes (LNs) are sites of malignant proliferation and LN enlargement is associated with poor prognosis in the clinics. The LN microenvironment is believed to favor disease progression by promoting CLL cell growth and drug resistance. A better understanding of the mechanisms regulating trafficking of CLL cells to LNs is thus urgently needed. Here, we studied the first step of CLL cell migration to LNs, their interaction with high endothelial venules (HEVs), specialized blood vessels for lymphocyte extravasation in lymphoid organs. We observed that the density of HEV blood vessels was increased in CLL LNs and that CD20(+) CLL cells accumulated within HEV pockets, suggesting intense trafficking. We used intravital imaging to visualize the behavior of human CLL cells within the mouse LN microcirculation, and discovered that CLL cells bind to HEVs in vivo via a multistep adhesion cascade, which involves rolling, sticking, and crawling of the leukemic cells on the endothelium. Functional analyses revealed that the lymphocyte homing receptor L-selectin (CD62L) is the key factor controlling the binding of CLL cells to HEV walls in vivo. Interestingly, L-selectin expression was decreased on CLL cells from patients treated with idelalisib, a phosphoinositide-3-kinase δ inhibitor recently approved for CLL therapy. Interference with L-selectin-mediated trafficking in HEVs could represent a novel strategy to block dissemination of CLL cells to LNs and increase the efficacy of conventional therapy. PMID:26162407

  19. Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation

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    Ochoa-Hernández Alejandra B

    2012-02-01

    Full Text Available Abstract Background WNT7a, a member of the Wnt ligand family implicated in several developmental processes, has also been reported to be dysregulated in some types of tumors; however, its function and implication in oncogenesis is poorly understood. Moreover, the expression of this gene and the role that it plays in the biology of blood cells remains unclear. In addition to determining the expression of the WNT7A gene in blood cells, in leukemia-derived cell lines, and in samples of patients with leukemia, the aim of this study was to seek the effect of this gene in proliferation. Methods We analyzed peripheral blood mononuclear cells, sorted CD3 and CD19 cells, four leukemia-derived cell lines, and blood samples from 14 patients with Acute lymphoblastic leukemia (ALL, and 19 clinically healthy subjects. Reverse transcription followed by quantitative Real-time Polymerase chain reaction (qRT-PCR analysis were performed to determine relative WNT7A expression. Restoration of WNT7a was done employing a lentiviral system and by using a recombinant human protein. Cell proliferation was measured by addition of WST-1 to cell cultures. Results WNT7a is mainly produced by CD3 T-lymphocytes, its expression decreases upon activation, and it is severely reduced in leukemia-derived cell lines, as well as in the blood samples of patients with ALL when compared with healthy controls (p ≤0.001. By restoring WNT7A expression in leukemia-derived cells, we were able to demonstrate that WNT7a inhibits cell growth. A similar effect was observed when a recombinant human WNT7a protein was used. Interestingly, restoration of WNT7A expression in Jurkat cells did not activate the canonical Wnt/β-catenin pathway. Conclusions To our knowledge, this is the first report evidencing quantitatively decreased WNT7A levels in leukemia-derived cells and that WNT7A restoration in T-lymphocytes inhibits cell proliferation. In addition, our results also support the possible

  20. Peripheral T-lymphocytes express WNT7A and its restoration in leukemia-derived lymphoblasts inhibits cell proliferation

    International Nuclear Information System (INIS)

    WNT7a, a member of the Wnt ligand family implicated in several developmental processes, has also been reported to be dysregulated in some types of tumors; however, its function and implication in oncogenesis is poorly understood. Moreover, the expression of this gene and the role that it plays in the biology of blood cells remains unclear. In addition to determining the expression of the WNT7A gene in blood cells, in leukemia-derived cell lines, and in samples of patients with leukemia, the aim of this study was to seek the effect of this gene in proliferation. We analyzed peripheral blood mononuclear cells, sorted CD3 and CD19 cells, four leukemia-derived cell lines, and blood samples from 14 patients with Acute lymphoblastic leukemia (ALL), and 19 clinically healthy subjects. Reverse transcription followed by quantitative Real-time Polymerase chain reaction (qRT-PCR) analysis were performed to determine relative WNT7A expression. Restoration of WNT7a was done employing a lentiviral system and by using a recombinant human protein. Cell proliferation was measured by addition of WST-1 to cell cultures. WNT7a is mainly produced by CD3 T-lymphocytes, its expression decreases upon activation, and it is severely reduced in leukemia-derived cell lines, as well as in the blood samples of patients with ALL when compared with healthy controls (p ≤0.001). By restoring WNT7A expression in leukemia-derived cells, we were able to demonstrate that WNT7a inhibits cell growth. A similar effect was observed when a recombinant human WNT7a protein was used. Interestingly, restoration of WNT7A expression in Jurkat cells did not activate the canonical Wnt/β-catenin pathway. To our knowledge, this is the first report evidencing quantitatively decreased WNT7A levels in leukemia-derived cells and that WNT7A restoration in T-lymphocytes inhibits cell proliferation. In addition, our results also support the possible function of WNT7A as a tumor suppressor gene as well as a therapeutic

  1. B-Cell Chronic Lymphocytic Leukemia with 11q22.3 Rearrangement in Patient with Chronic Myeloid Leukemia Treated with Imatinib.

    Science.gov (United States)

    Lewandowski, Krzysztof; Gniot, Michał; Lewandowska, Maria; Wache, Anna; Ratajczak, Błażej; Czyż, Anna; Jarmuż-Szymczak, Małgorzata; Komarnicki, Mieczysław

    2016-01-01

    The coexistence of two diseases chronic myeloid leukemia (CML) and B-cell chronic lymphocytic leukemia (B-CLL) is a rare phenomenon. Both neoplastic disorders have several common epidemiological denominators (they occur more often in men over 50 years of age) but different origin and long term prognosis. In this paper we described the clinical and pathological findings in patient with CML in major molecular response who developed B-CLL with 11q22.3 rearrangement and Coombs positive hemolytic anemia during the imatinib treatment. Due to the presence of the symptoms of autoimmune hemolytic anemia and optimal CML response to the imatinib treatment, the decision about combined therapy with prednisone and imatinib was made. During the follow-up, the normalization of complete blood count and resolution of peripheral lymphadenopathy were noted. The hematologic response of B-CLL was diagnosed. The repeated FISH analysis of cultured peripheral blood lymphocytes showed 2% of cells carrying 11q22.3 rearrangement. At the same time, molecular monitoring confirmed the deep molecular response of CML. The effectiveness of such combination in the described case raises the question about the best therapeutic option in such situation, especially in patients with good imatinib tolerance and optimal response. PMID:27034682

  2. Biclonal Gammopathy in Chronic Lymphocytic Leukemia: Case Report and Review of the Literature

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    Nafila Al-Riyami

    2015-05-01

    Full Text Available Monoclonal gammopathies are frequently seen in B-cell malignancies. Monoclonal proteins are seen in a significant proportion of patients with chronic lymphocytic leukemia (CLL, which is a clonal disorder of mature B cells. The use of more sensitive laboratory methods has enabled the detection of monoclonal proteins or light chains in the serum and/or urine in the majority of these patients. The presence of some of these monoclonal proteins may explain the different autoimmune phenomena that are associated with this disease. Some reports indicate that the finding of monoclonal proteins has a negative impact on patients’ survival. The presence of two different monoclonal proteins (i.e. biclonal gammopathy is on the other hand rare. Most of the reported cases in the literature are of patients with plasma cell disorders. In this report, we describe a rare occurrence of biclonal gammopathy in a patient with CLL. Serum protein electrophoresis and immunofixation, which were negative at the time of initial diagnosis, showed biclonal immunoglobin A (IgA kappa and IgA lambda during the course of the disease. The patient’s disease showed steady progression, despite multiple treatments. Although this could just be the result of using more sensitive laboratory techniques, biclonal gammopathy in this patient likely reflects the evolution of another clone, which would explain the encountered resistance to therapy. Because of paucity of reports, the impact of biclonal gammopathies in such patients is not known and an effort to collectively report the presentation and outcome of these patients is needed to further understand the pathophysiology and clinical significance of such a finding.

  3. A Novel Natural Product, KL-21, Inhibits Proliferation and Induces Apoptosis in Chronic Lymphocytic Leukemia Cells

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    Aysun Adan Gökbulut

    2015-06-01

    Full Text Available INTRODUCTION: The aims of this study were to examine the cytotoxic and apoptotic effects of KL-21, a novel plant product (produced by Naturin Natural Products, İzmir, Turkey, on 232B4 chronic lymphocytic leukemia (CLL cells and to determine the cytotoxic effects on healthy BEAS-2B human bronchial epithelial cells. METHODS: The cytotoxic effect of KL-21 was determined by MTT cell proliferation assay. Changes in caspase-3 enzyme activity were measured using the caspase-3 colorimetric assay. Changes in mitochondrial membrane potential were determined using the JC-1 dye-based method. Annexin V-FITC/PI double staining was performed to measure the apoptotic cell population. Effects of KL-21 on cell cycle profiles of CLL cells were investigated by flow cytometry. RESULTS: We detected time- and concentration-dependent increases in the cytotoxic effect of KL-21 on 232B4 CLL cells. However, we also showed that, especially at higher concentrations, KL-21 was less cytotoxic towards BEAS-2B healthy cells than towards CLL cells. Annexin-V/PI double staining results showed that the apoptotic cell population increased in 232B4 cells. Increasing concentrations of KL-21 increased caspase-3 enzyme activity and induced loss of mitochondrial membrane potential. KL-21 administration resulted in small increases in the percentage of the cells in the G0/G1 phase while it decreased the S phase cell population up to 1 mg/mL. At the highest concentration, most of the cells accumulated in the G0/G1 phase. DISCUSSION AND CONCLUSION: KL-21 has a growth-inhibitory effect on 232B4 CLL cells. KL-21 causes apoptosis and cell cycle arrest at G0/G1.

  4. Mutation Pattern of Paired Immunoglobulin Heavy and Light Variable Domains in Chronic Lymphocytic Leukemia B Cells

    KAUST Repository

    Ghiotto, Fabio

    2011-01-01

    B-cell chronic lymphocytic leukemia (CLL) patients display leukemic clones bearing either germline or somatically mutated immunoglobulin heavy variable (IGHV ) genes. Most information on CLL immunoglobulins (Igs), such as the definition of stereotyped B-cell receptors (BCRs), was derived from germline unmutated Igs. In particular, detailed studies on the distribution and nature of mutations in paired heavy- and light-chain domains of CLL clones bearing mutated Igs are lacking. To address the somatic hyper-mutation dynamics of CLL Igs, we analyzed the mutation pattern of paired IGHV-diversity-joining (IGHV-D-J ) and immunoglobulin kappa/lambda variable-joining (IGK/LV-J ) rearrangements of 193 leukemic clones that displayed ≥ 2% mutations in at least one of the two immunoglobulin variable (IGV ) genes (IGHV and/or IGK/LV ). The relationship between the mutation frequency in IGHV and IGK/LV complementarity determining regions (CDRs) and framework regions (FRs) was evaluated by correlation analysis. Replacement (R) mutation frequency within IGK/LV chain CDRs correlated significantly with mutation frequency of paired IGHV CDRs in λ but not κ isotype CLL clones. CDRs of IGKV-J rearrangements displayed a lower percentage of R mutations than IGHVs. The frequency/pattern of mutations in kappa CLL Igs differed also from that in κ-expressing normal B cells described in the literature. Instead, the mutation frequency within the FRs of IGHV and either IGKV or IGLV was correlated. Notably, the amount of diversity introduced by replaced amino acids was comparable between IGHVs and IGKVs. The data indicate a different mutation pattern between κ and λ isotype CLL clones and suggest an antigenic selection that, in κ samples, operates against CDR variation.

  5. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy.

    Science.gov (United States)

    Awan, Farrukh T; Jones, Jeffrey A; Maddocks, Kami; Poi, Ming; Grever, Michael R; Johnson, Amy; Byrd, John C; Andritsos, Leslie A

    2016-06-01

    Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104. PMID:27118540

  6. Spontaneous Immunity Against the Receptor Tyrosine Kinase ROR1 in Patients with Chronic Lymphocytic Leukemia.

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    Mohammad Hojjat-Farsangi

    Full Text Available ROR1 is a receptor tyrosine kinase expressed in chronic lymphocytic leukemia (CLL and several other malignancies but absent in most adult normal tissues. ROR1 is considered an onco-fetal antigen. In the present study we analysed spontaneous humoral and cellular immunity against ROR1 in CLL patients.Antibodies against ROR1 were analysed in 23 patients and 20 healthy donors by ELISA and Western blot. Purified serum IgG from patients was tested for cytotoxicity against CLL cells using the MTT viability assay. A cellular immune response against ROR1 derived HLA-A2 restricted 9 aa and 16 aa long peptides were analysed using peptide loaded dendritic cells co-cultured with autologous T cells from CLL patients (n = 9 and healthy donors (n = 6. IFN-γ, IL-5 and IL-17A-secreting T cells were assessed by ELISPOT and a proliferative response using a H3-thymidine incorporation assay.The majority of CLL patients had antibodies against ROR1. Significantly higher titers of anti-ROR1 antibodies were noted in patients with non-progressive as compared to progressive disease. The extracellular membrane-close ROR1 KNG domain seemed to be an immunodominant epitope. Ten patients with high titers of anti-ROR1 binding antibodies were tested for cytotoxicity. Five of those had cytotoxic anti-ROR1 antibodies against CLL cells. ROR1-specific IFN-γ and IL-17A producing T cells could be detected in CLL patients, preferentially in non-progressive as compared to patients with progressive disease (p<0.05.ROR1 seemed to spontaneously induce a humoral as well as a T cell response in CLL patients. The data support the notion that ROR1 might be a specific neo-antigen and may serve as a target for immunotherapy.

  7. Immunoglobulin heavy chain variable region gene repertoire and B-cell receptor stereotypes in Indian patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Rani, Lata; Mathur, Nitin; Gogia, Ajay; Vishnubhatla, Sreenivas; Kumar, Lalit; Sharma, Atul; Dube, Divya; Kaur, Punit; Gupta, Ritu

    2016-10-01

    In chronic lymphocytic leukemia (CLL), the geographical bias in immunoglobulin heavy-chain variable (IGHV) gene usage lead us to analyze IGHV gene usage and B-cell receptor stereotypy in 195 patients from India. IGHV3, IGHV4, and IGHV1 families were the most frequently used. 20.5% sequences had stereotyped BCR and were clustered in 12 pre-defined and 6 novel subsets. Unmutated IGHV was significantly associated with reduced time to first treatment (p cases (p = 0.045) in early stage patients. Regarding subfamily usage, only IGHV1-69 expression was found to have statistically significant poor outcome (p = 0.017). Our results from the analysis of various molecular and clinical features suggest that the expression of specific IGHV gene influences the outcome in early stage CLL, and hence its assessment may be added to the clinical leukemia laboratory armamentarium. PMID:26942309

  8. Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification

    OpenAIRE

    Strati, Paolo; Shanafelt, Tait D.

    2015-01-01

    Monoclonal B lymphocytosis (MBL) is defined as the presence of a clonal B-cell population in the peripheral blood with fewer than 5 × 109/L B-cells and no other signs of a lymphoproliferative disorder. The majority of cases of MBL have the immunophenotype of chronic lymphocytic leukemia (CLL). MBL can be categorized as either low count or high count based on whether the B-cell count is above or below 0.5 × 109/L. Low-count MBL can be detected in ∼5% of adults over the age of 40 years when ass...

  9. Epstein-Barr virus DNA load in chronic lymphocytic leukemia is an independent predictor of clinical course and survival

    OpenAIRE

    Visco, Carlo; Falisi, Erika; Young, Ken H; Pascarella, Michela; Perbellini, Omar; Carli, Giuseppe; Novella, Elisabetta; Rossi, Davide; Giaretta, Ilaria; Cavallini, Chiara; Scupoli, Maria Teresa; De Rossi, Anita; D'Amore, Emanuele Stefano Giovanni; Rassu, Mario; Gaidano, Gianluca

    2015-01-01

    The relation between Epstein-Barr virus (EBV) DNA load and clinical course of patients with chronic lymphocytic leukemia (CLL) is unknown. We assessed EBV DNA load by quantitative PCR at CLL presentation in mononuclear cells (MNC) of 220 prospective patients that were enrolled and followed-up in two major Institutions. In 20 patients EBV DNA load was also assessed on plasma samples. Forty-one age-matched healthy subjects were tested for EBV DNA load on MNC. Findings were validated in an indep...

  10. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

    OpenAIRE

    Lipsky, Andrew H.; Farooqui, Mohammed Z.H.; Tian, Xin; Martyr, Sabrina; Cullinane, Ann M.; Nghiem, Khanh; Sun, Clare; Valdez, Janet; Niemann, Carsten U.; Herman, Sarah E. M.; Saba, Nakhle; Soto, Susan; Marti, Gerald; Uzel, Gulbu; Holland, Steve M.

    2015-01-01

    Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occur...

  11. The effect of food on the pharmacokinetics of oral ibrutinib in healthy participants and patients with chronic lymphocytic leukemia

    OpenAIRE

    de Jong, Jan; Sukbuntherng, Juthamas; Skee, Donna; Murphy, Joe; O’Brien, Susan; Byrd, John C.; James, Danelle; Hellemans, Peter; Loury, David J.; Jiao, Juhui; Chauhan, Vijay; Mannaert, Erik

    2015-01-01

    Purpose To assess ibrutinib pharmacokinetics under fasted and fed conditions, impact of food-intake timing, and the safety and tolerability. Methods Three studies were analyzed. Study 1 was a randomized, open-label, single-dose, four-way crossover study in 44 healthy participants. Study 2 was a randomized, repeat-dose crossover study in 16 patients with previously treated chronic lymphocytic leukemia (CLL). Ibrutinib dose was 420 mg in both studies. Study 3 was an open-label, sequential study...

  12. Molecular Characterization of Chronic Lymphocytic Leukemia Patients with a High Number of Losses in 13q14

    OpenAIRE

    Rodríguez, Ana Eugenia; Hernández, Jose Ángel; Benito, Rocío; Gutiérrez, Norma C.; García, Juan Luis; Hernández-Sánchez, María; Risueño, Alberto; Sarasquete, M. Eugenia; Fermiñán, Encarna; Fisac, Rosa; de Coca, Alfonso García; Martín-Núñez, Guillermo; de las Heras, Natalia; Recio, Isabel; Gutiérrez, Oliver

    2012-01-01

    Background Patients with chronic lymphocytic leukemia and 13q deletion as their only FISH abnormality could have a different outcome depending on the number of cells displaying this aberration. Thus, cases with a high number of 13q- cells (13q-H) had both shorter overall survival and time to first therapy. The goal of the study was to analyze the genetic profile of 13q-H patients. Design and Methods: A total of 102 samples were studied, 32 of which served as a validation cohort and five were ...

  13. Modification of immunocytochemical ZAP-70 assay for potential clinical application in B-cell chronic lymphocytic leukemia

    OpenAIRE

    Jerzy Kawiak; Jacek Roliński; Agnieszka Bojarska-Junak

    2011-01-01

    The ZAP-70 protein is a member of the Syk/ZAP protein tyrosine kinase family, normally expressed in T cells and NK cells but not found in normal, mature B cells. The protein plays a critical role in the initiation of T-cell signaling. Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) that expressed nonmutated immunoglobulin V genes were found to express levels of ZAP-70 protein that were comparable to those detected in T cells of healthy adults. The ZAP-70 protein ...

  14. Trisomy 12 in a Case of Multiple Cutaneous Squamous Cell Carcinoma in Association with Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    XU Zhou-min; CHEN Yan; GAO Wei-ran

    2007-01-01

    Chronic lymphocytic leukaemia (CLL), which shares clinical and morphological overlap with small lymphocytic lyjmphoma (SLL), is a low-grade clonal B-cell lymphoproliferative disorder that accounts for 25% of all cases of leukaemia in Western countries, while it is considered rare in Oriental patients and is thought to constitute only 2% of all leukemias in these patients[1]. CLL is associated with an increased incidence of secondary malignant neoplasms, such as brain tumors, melanomas, and gastrointestinal-tract carcinomas[2]. However, the simulataneous occurrence of CLL and cutaneous squamous cell carcinoma (SCC) is rarely reported. We present here a case of CLL with multiple SCC on the face. Subsequent studies demonstrated the patient to have a trisomy 12 identified in bone marrow specimen.

  15. The ibrutinib B-cell proliferation inhibition is potentiated in vitro by dexamethasone: Application to chronic lymphocytic leukemia.

    Science.gov (United States)

    Manzoni, Delphine; Catallo, Régine; Chebel, Amel; Baseggio, Lucile; Michallet, Anne-Sophie; Roualdes, Olivier; Magaud, Jean-Pierre; Salles, Gilles; Ffrench, Martine

    2016-08-01

    New B-cell receptor-targeted therapies such as ibrutinib, a Bruton tyrosine kinase inhibitor, are now proposed for lymphoid pathologies. The putative benefits of its combination with glucocorticoids were evaluated here. We compared the effects of dexamethasone (DXM), ibrutinib and their in vitro combination on proliferation and metabolic stress markers in stimulated normal B-lymphocytes and in malignant lymphocytes from chronic lymphocytic leukemia (CLL) patients. In both cellular models, cell cycle progression was globally inhibited by DXM and/or ibrutinib. This inhibition was significantly amplified by DXM addition to ibrutinib and was related to a significant decrease in the expression of the cell cycle regulatory proteins CDK4 and cyclin E. Apoptosis increased especially with DXM/ibrutinib combination and was associated with a significant decrease in Mcl-1 expression. Treatment effects on metabolic stress were evaluated by DNA damage recognition after 53BP1 foci labeling. The percentage of cells with more than five 53BP1 foci decreased significantly with ibrutinib in normal and CLL lymphocytes. This decrease was strongly reinforced, in CLL, by DXM addition. Our data indicated that, in vitro, DXM potentiated antiproliferative effects of ibrutinib and decreased DNA damage in lymphoid B-cells. Thus their combination may be proposed for CLL treatment. PMID:27235717

  16. Leukemia.

    Science.gov (United States)

    Juliusson, Gunnar; Hough, Rachael

    2016-01-01

    Leukemias are a group of life threatening malignant disorders of the blood and bone marrow. In the adolescent and young adult (AYA) population, the acute leukemias are most prevalent, with chronic myeloid leukemia being infrequently seen. Factors associated with more aggressive disease biology tend to increase in frequency with increasing age, whilst tolerability of treatment strategies decreases. There are also challenges regarding the effective delivery of therapy specific to the AYA group, consequences on the unique psychosocial needs of this age group, including compliance. This chapter reviews the current status of epidemiology, pathophysiology, treatment strategies and outcomes of AYA leukemia, with a focus on acute lymphoblastic leukemia and acute myeloid leukemia. PMID:27595359

  17. The analysis of clonal diversity and therapy responses using STAT3 mutations as a molecular marker in large granular lymphocytic leukemia

    Science.gov (United States)

    Rajala, Hanna L. M.; Olson, Thomas; Clemente, Michael J.; Lagström, Sonja; Ellonen, Pekka; Lundan, Tuija; Hamm, David E.; Zaman, Syed Arshi Uz; Lopez Marti, Jesus M.; Andersson, Emma I.; Jerez, Andres; Porkka, Kimmo; Maciejewski, Jaroslaw P.; Loughran, Thomas P.; Mustjoki, Satu

    2015-01-01

    T-cell large granular lymphocytic leukemia and chronic lymphoproliferative disorder of natural killer cells are intriguing entities between benign and malignant lymphoproliferation. The molecular pathogenesis has partly been uncovered by the recent discovery of somatic activating STAT3 and STAT5b mutations. Here we show that 43% (75/174) of patients with T-cell large granular lymphocytic leukemia and 18% (7/39) with chronic lymphoproliferative disorder of natural killer cells harbor STAT3 mutations when analyzed by quantitative deep amplicon sequencing. Surprisingly, 17% of the STAT3-mutated patients carried multiple STAT3 mutations, which were located in different lymphocyte clones. The size of the mutated clone correlated well with the degree of clonal expansion of the T-cell repertoire analyzed by T-cell receptor beta chain deep sequencing. The analysis of sequential samples suggested that current immunosuppressive therapy is not able to reduce the level of the mutated clone in most cases, thus warranting the search for novel targeted therapies. Our findings imply that the clonal landscape of large granular lymphocytic leukemia is more complex than considered before, and a substantial number of patients have multiple lymphocyte subclones harboring different STAT3 mutations, thus mimicking the situation in acute leukemia. PMID:25281507

  18. Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  19. Elucidating the CXCL12/CXCR4 signaling network in chronic lymphocytic leukemia through phosphoproteomics analysis.

    Directory of Open Access Journals (Sweden)

    Morgan O'Hayre

    Full Text Available BACKGROUND: Chronic Lymphocytic Leukemia (CLL pathogenesis has been linked to the prolonged survival and/or apoptotic resistance of leukemic B cells in vivo, and is thought to be due to enhanced survival signaling responses to environmental factors that protect CLL cells from spontaneous and chemotherapy-induced death. Although normally associated with cell migration, the chemokine, CXCL12, is one of the factors known to support the survival of CLL cells. Thus, the signaling pathways activated by CXCL12 and its receptor, CXCR4, were investigated as components of these pathways and may represent targets that if inhibited, could render resistant CLL cells more susceptible to chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: To determine the downstream signaling targets that contribute to the survival effects of CXCL12 in CLL, we took a phosphoproteomics approach to identify and compare phosphopeptides in unstimulated and CXCL12-stimulated primary CLL cells. While some of the survival pathways activated by CXCL12 in CLL are known, including Akt and ERK1/2, this approach enabled the identification of additional signaling targets and novel phosphoproteins that could have implications in CLL disease and therapy. In addition to the phosphoproteomics results, we provide evidence from western blot validation that the tumor suppressor, programmed cell death factor 4 (PDCD4, is a previously unidentified phosphorylation target of CXCL12 signaling in all CLL cells probed. Additionally, heat shock protein 27 (HSP27, which mediates anti-apoptotic signaling and has previously been linked to chemotherapeutic resistance, was detected in a subset (approximately 25% of CLL patients cells examined. CONCLUSIONS/SIGNIFICANCE: Since PDCD4 and HSP27 have previously been associated with cancer and regulation of cell growth and apoptosis, these proteins may have novel implications in CLL cell survival and represent potential therapeutic targets. PDCD4 also represents a

  20. E-cadherin gene re-expression in chronic lymphocytic leukemia cells by HDAC inhibitors

    International Nuclear Information System (INIS)

    The tumor suppressor gene E-cadherin gene is frequently silenced in chronic lymphocytic leukemia (CLL) cells and results in wnt-pathway activation. We analyzed the role of histone epigenetic modifications in E-cadherin gene silencing. CLL specimens were treated with histone deacetylase inhibitor (HDACi) MS-275 and analyzed for E-cadherin expression with western blot and RT-PCR analysis. The downstream effects of HDACi treated leukemic cells were studied by analyzing the effect on wnt-pathway signaling. HDACi induced alterations in E-cadherin splicing were investigated by transcript specific real time PCR analysis. Treatment of CLL specimens with histone deacetylase inhibitors (HDACi) treatment resulted in an increase of the E-cadherin RNA transcript (5 to 119 fold increase, n=10) in eight out of ten CLL specimens indicating that this gene is down regulated by histone hypoacetylation in a majority of CLL specimens. The E-cadherin re-expression in CLL specimens was noted by western blot analysis as well. Besides epigenetic silencing another mechanism of E-cadherin inactivation is aberrant exon 11 splicing resulting in an alternatively spliced transcript that lacks exon 11 and is degraded by the non-sense mediated decay (NMD) pathway. Our chromatin immunoprecipitation experiments show that HDACi increased the acetylation of histones H3 and H4 in the E-cadherin promoter region. This also affected the E-cadherin exon 11 splicing pattern as HDACi treated CLL specimens preferentially expressed the correctly spliced transcript and not the exon 11 skipped aberrant transcript. The re-expressed E- cadherin binds to β-catenin with inhibition of the active wnt-beta-catenin pathway in these cells. This resulted in a down regulation of two wnt target genes, LEF and cyclinD1 and the wnt pathway reporter. The E-cadherin gene is epigenetically modified and hypoacetylated in CLL leukemic cells. Treatment of CLL specimens with HDACi MS-275 activates transcription from this silent

  1. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    O'Brien, Susan M; Lamanna, Nicole; Kipps, Thomas J; Flinn, Ian; Zelenetz, Andrew D; Burger, Jan A; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S; Johnson, David M; Miller, Langdon L; Kim, Yeonhee; Dansey, Roger D; Dubowy, Ronald L; Coutre, Steven E

    2015-12-17

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  2. Ibrutinib: an evidence-based review of its potential in the treatment of advanced chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Chavez JC

    2013-05-01

    Full Text Available Julio C Chavez, Eva Sahakian, Javier Pinilla-IbarzH Lee Moffitt Cancer and Research Institute, Division of Malignant Hematology, and University of South Florida, Tampa, FL, USAAbstract: Chronic lymphocytic leukemia (CLL is a heterogeneous disease with a variable course, and remains an incurable disease. Frequent relapses and eventual resistance to fludarabine characterize symptomatic CLL and portends a dismal prognosis for patients. Growing evidence has shown that signaling pathways such as the B cell receptor and NFkB are implicated in the survival and proliferation of the CLL cells which are ultimately associated with persistence of the disease. The Bruton’s tyrosine kinase pathway regulates downstream activation of the B cell receptor and has emerged as an attractive target. Ibrutinib inhibits the Bruton’s tyrosine kinase pathway, and consequently induces apoptosis of B cells. Phase I and II studies have shown impressive response rates with an excellent safety profile in patients with refractory/relapsed CLL and elderly treatment-naïve CLL patients. This paper reviews the preclinical and clinical data for ibrutinib when used in the treatment of CLL. Recent studies showing the benefit of combination therapy using ibrutinib, monoclonal antibodies, and chemoimmunotherapy are also discussed.Keywords: ibrutinib, B-cell receptor, chronic lymphocytic leukemia, Bruton’s tyrosine kinase

  3. Incidence and risk factors of bleeding-related adverse events in patients with chronic lymphocytic leukemia treated with ibrutinib

    DEFF Research Database (Denmark)

    Lipsky, Andrew H; Farooqui, Mohammed Z H; Tian, Xin;

    2015-01-01

    Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator-initiated t......Ibrutinib is associated with bleeding-related adverse events of grade ≤2 in severity, and infrequently with grade ≥3 events. To investigate the mechanisms of bleeding and identify patients at risk, we prospectively assessed platelet function and coagulation factors in our investigator......-initiated trial of single-agent ibrutinib for chronic lymphocytic leukemia. At a median follow-up of 24 months we recorded grade ≤2 bleeding-related adverse events in 55% of 85 patients. No grade ≥3 events occurred. Median time to event was 49 days. The cumulative incidence of an event plateaued by 6 months...... 19 patients on ibrutinib (often transiently). Collagen and adenosine diphosphate induced platelet aggregation was tested using whole blood aggregometry. Compared to normal controls, response to both agonists was decreased in all patients with chronic lymphocytic leukemia, whether on ibrutinib or not...

  4. Forced Expression of Cyclin-Dependent Kinase 6 Confers Resistance of Pro-B Acute Lymphocytic Leukemia to Gleevec Treatment▿ †

    OpenAIRE

    Kuo, Tracy C.; Chavarria-Smith, Joseph E.; Huang, Dan; Schlissel, Mark S.

    2011-01-01

    The gene encoding c-ABL, a nonreceptor protein tyrosine kinase, is involved in a chromosomal translocation resulting in expression of a BCR-Abl fusion protein that causes most chronic myelogenous and some acute lymphocytic leukemias (CML and ALL) in humans. The Abelson murine leukemia virus (A-MuLV) expresses an alternative form of c-Abl, v-Abl, that transforms murine pro-B cells, resulting in acute leukemia and providing an experimental model for human disease. Gleevec (STI571) inhibits the ...

  5. Radiation-induced intracranial osteosarcoma after radiation for acute lymphocytic leukemia associated with Li-Fraumeni syndrome

    International Nuclear Information System (INIS)

    A 28-year-old man presented with osteosarcoma of the occipital bone 16 years after 24 Gy of craniospinal irradiation for acute lymphocytic leukemia. The tumor had both intra- and extra-cranial components. However, the affected skull appeared to be normal on imaging because of permeative infiltration by the tumor. Subtotal resection was achieved and the tumor was verified histologically as an osteosarcoma. The residual tumor soon showed remarkable enlargement and disseminated to the spinal cord. Both of the enlarged and disseminated tumor masses were treated by surgical intervention and chemotherapy. However, the patient deteriorated due to the tumor regrowth and died 11 months after the initial diagnosis. This patient had previously developed a leukemia, a colon cancer, a rectal cancer and a hepatocellular carcinoma. His brother also died of leukemia. The patient had a heterozygous TP53 germ-line mutation of codon 248 in the exon 7. In conclusion, we consider the present tumor to be a rare example of radiation-induced skull osteosarcoma in a member of the cancer-prone family with TP53 germ-line mutation which is associated with Li-Fraumeni syndrome. (author)

  6. Short telomere length is associated with NOTCH1/SF3B1/TP53 aberrations and poor outcome in newly diagnosed chronic lymphocytic leukemia patients

    DEFF Research Database (Denmark)

    Mansouri, Larry; Grabowski, Pawel; Degerman, Sofie; Svenson, Ulrika; Gunnarsson, Rebeqa; Cahill, Nicola; Smedby, Karin Ekström; Geisler, Christian; Juliusson, Gunnar; Roos, Göran; Rosenquist, Richard

    2013-01-01

    Most previous studies on telomere length (TL) in chronic lymphocytic leukemia (CLL) are based on referral cohorts including a high proportion of aggressive cases. Here, the impact of TL was analyzed in a population-based cohort of newly diagnosed CLL (n = 265) and in relation to other prognostic ...

  7. Plasma alemtuzumab levels in patients with chronic lymphocytic leukemia treated with alemtuzumab combined with chemotherapy reflect the efficacy of the treatment - an hypothesis

    DEFF Research Database (Denmark)

    Vojdeman, Fie Juhl; Jurlander, Jesper; Van't Veer, Mars;

    2013-01-01

    ABSTRACT In the HOVON68 trial comparing subcutaneous low-dose alemtuzumab (LD-A) used together with fludarabine (F) and cyclophosphamide (C) with FC alone in high-risk chronic lymphocytic leukemia (CLL), LD-AFC resulted in significantly more clinical and molecular responses than FC, but also in...

  8. Identification and cloning of a prethymic precursor T lymphocyte from a population of common acute lymphoblastic leukemia antigen (CALLA)-positive fetal bone marrow cells

    DEFF Research Database (Denmark)

    Hokland, P; Hokland, M; Daley, J;

    1987-01-01

    of T4 and T8 antigens and at the same time expression of the thymocyte-associated T6 antigens. Thus, given the fact that 10-20% of T cell acute lymphoblastic leukemia (T-ALLs) are CALLA+, we have been able to identify a human prethymic T lymphocyte population that might be the normal counterpart of...

  9. FDA Approves New Drug for Chronic Lymphocytic Leukemia in Patients with a Specific Chromosomal Abnormality

    Science.gov (United States)

    ... diagnosed each year. CLL is characterized by the progressive accumulation of abnormal lymphocytes, a type of white ... orphan drug designation, which provides incentives such as tax credits, user fee waivers and eligibility for exclusivity ...

  10. Monosomy 12 and deletion of 13q34 in a case of chronic lymphocytic leukemia with concomitant lung cancer

    Directory of Open Access Journals (Sweden)

    Antić Darko

    2010-01-01

    Full Text Available Background. We described a patient with chronic lymphocytic leukemia (CLL and lung cancer and unusual chromosomal aberrations. Case report. At the same time with the diagnosis of B-cell CLL, squamocellular lung carcinoma diagnosis was established. Using interphase fluoresecence in situ hybridization technique (FISH we detected monosomy 12 and deletion of 13q34 occured in the same clone. One month after the beginning of examination the patient died unexpectedly during sleep immediately before we applied a specific treatment for CLL or lung carcinoma. Conclusion. Simultaneous occurrence of monosomy 12 and deletion of 13q34 in a patient with B-cell CLL has been described only once before, but as a part of a complex karyotype. The prognostic significance of these abnormalities remains uncertain.

  11. Minimal contribution of severe hypertriglyceridemia in L-asparaginase-associated pancreatitis developed in a child with acute lymphocytic leukemia.

    Science.gov (United States)

    Goto, Yoshinori; Nishimura, Ryosei; Nohara, Atsushi; Mase, Shintaro; Fujiki, Toshihiro; Irabu, Hitoshi; Kuroda, Rie; Araki, Raita; Ikawa, Yasuhiro; Maeba, Hideaki; Yachie, Akihiro

    2016-08-01

    A 10-year-old girl developed L-asparaginase (ASP)-associated pancreatitis during chemotherapy for acute lymphocytic leukemia. Her symptoms showed alleviation with continuous regional arterial infusion of protease inhibitor and systemic somatostatin analog therapy. She had intermittent and marked hypertriglyceridemia, an initial trigger for pancreatitis, probably as a side effect of ASP and steroids. However, we considered the pancreatitis to have developed mainly because of factors other than hypertriglyceridemia as lipoprotein analysis confirmed chylomicron levels to be nearly undetectable. Extremely large chylomicrons contribute directly to the onset of pancreatitis by causing blockage of small vessels. Although it is necessary to examine patients for dyslipidemia developing as a side effect of ASP, therapeutic intervention for hypertriglyceridemia is not considered to prevent the onset of ASP-associated pancreatitis. PMID:27599414

  12. Graft-versus-leukemia effects from donor lymphocyte infusion after nonmyeloablative allogeneic bone marrow transplantation in mice

    Institute of Scientific and Technical Information of China (English)

    DU Bing; LI De-peng; XU Kai-lin; PAN Xiu-ying

    2005-01-01

    Background Nonmyeloablative allogeneic bone marrow transplantation has been used since the 1990s as a new hematological stem cell transplantation strategy for treating hematological diseases. The purpose of this study was to explore the graft-versus-leukemia (GVL) effects of donor lymphocyte infusions (DLIs) after nonmyeloablative allogeneic bone marrow transplantations, while assessing the declines in treatment-associated morbidity, mortality, and graft-versus-host disease (GVHD).Methods A total of 615 (H-2k) mice were injected with L615 tumor cells and received 500 cGy (60Coγ-ray) irradiation three days later, followed by an allogeneic bone marrow transplantation (allo-BMT). The allo-grafts consisted of 3×107 bone marrow cells and 1×107 spleen cells from BALB/C (H-2d) donor mice. Two days after the allo-BMT, the recipient mice were given 200 mg/kg of cyclophosphamide. Subsequently, recipient mice were infused with either donor spleen cells (2×107) on day 14 or 21, or donor spleen cells (5×107) pretreated with hydrocortisone and cyclosporin A (CsA) in vitro on day 14 post-BMT.Results The median survival time of mice that received DLI on day 21 and pretreated DLI on day 14 post-BMT was longer than that of controls and the day 14 DLI group (P<0.01). No evidence of severe GVHD was observed in the day 21 DLI group nor in the day 14 treated DLI group. Mixed chimerism was confirmed in the day 14 DLI group, the day 14 treated DLI group, and the day 21 DLI group on the thirteenth day post-transplantation; full donor chimerism was observed two weeks after DLI.Conclusion Donor lymphocyte infusion after nonmyeloablative bone marrow transplantation may reduce transplantation-associated morbidity and mortality while strengthening graft-versus-leukemia effects.

  13. Expression profile of Eph receptors and ephrin ligands in healthy human B lymphocytes and chronic lymphocytic leukemia B-cells.

    Science.gov (United States)

    Alonso-C, Luis M; Trinidad, Eva M A; de Garcillan, Beatriz; Ballesteros, Monica; Castellanos, Milagros; Cotillo, Ignacio; Muñoz, Juan J; Zapata, Agustin G

    2009-03-01

    Increasing information relates some Eph receptors and their ligands, ephrins (EFN), with the immune system. Herein, we found that normal B-cells from peripheral blood (PB) and lymph nodes (LN) showed a differential expression of certain Eph/EFN members, some of them being modulated upon in vitro stimulation including EFNA1, EFNA4, EphB6 and EphA10. In contrast, PB CLL B-cells showed a more heterogeneous Eph/EFN profile than their normal PB B-cell counterparts, expressing Eph/EFN members frequently found within the LN and activated B-cells, specially EFNA4, EphB6 and EphA10. Two of them, EphB6 and EFNA4 were further related with the clinical course of CLL patients. EphB6 expression correlated with a high content of ZAP-70 mRNA and a poor prognosis. High serum levels of a soluble EFNA4 isoform positively correlated with increasing peripheral blood lymphocyte counts and lymphadenopathy. These findings suggest that Eph/EFN might be relevant in normal B-cell biology and could represent new potential prognostic markers and therapeutic targets for CLL. PMID:18819711

  14. Peptide vaccination induces profound changes in the immune system in patients with B-cell chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Michael Schmitt

    2011-04-01

    Full Text Available Although the immune status of chronic lymphocytic leukemia (CLL patients is mostly characterized by immunosuppression, there is an accumulation of in vivo (graft-versus-leukemia effect and in vitro (spontaneous remissions after infections data that indicates that CLL might be effectively targeted by T-cell based immunotherapy. Recently, we characterized receptor for hyaluronic acid mediated motility (RHAMM as a preferential target for immunotherapy of CLL. We also completed a RHAMM-derived peptide vaccination phase I/II clinical trial in CLL. Here, we present a detailed immunological analysis of six CLL patients vaccinated with HLA-A2 restricted RHAMM-derived epitope R3 (ILSLELMKL. Beside effective induction of R3-specific cytotoxic T-cells, peptide vaccination caused profound changes in different T-cell subsets as well as cytokines. We present longitudinal analyses of Th17, CD8+CD103+, CD8+CD137+ and IL-17 producing CD8+ T cells (CD8+IL- -17+ as well as important cytokines involved in regulation of immune response such as TGF-β, IL-10, IL-2 and TNF throughout the peptide vaccination period. (Folia Histochemica et Cytobiologica 2011, Vol. 49, No. 1, 161–167

  15. Analysis of racial variations in disease characteristics, treatment patterns, and outcomes of patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Nabhan, Chadi; Chaffee, Kari G; Slager, Susan L; Galanina, Natalie; Achenbach, Sara J; Schwager, Susan M; Kay, Neil E; Shanafelt, Tait D

    2016-07-01

    The impact of race on outcomes of patients with chronic lymphocytic leukemia (CLL), the most common leukemia in the west, is not well studied. We aimed to understand racial variations in clinical and disease characteristics, treatment patterns, and outcomes in patients with CLL. We utilized the Mayo Clinic CLL database to perform an analysis of these characteristics and natural history of non-white (NW) compared to white (W) CLL patients. Differences by race in median overall survival (OS) and time-to-first-treatment (TTFT) were investigated. Of the 4215 CLL patients, 4114 (97.6%) were W and 101 (2.4%) were NW. NW patients were younger (median age at diagnosis 59.4 vs. 63.4; P = 0.003) and more likely to have an elevated LDH (28.0% vs. 16.2%; P = 0.02). No differences in prognostic parameters were noted. No major differences were observed in treatment selection. OS and TTFT were similar between both groups. In the largest analysis of NW-CLL patients in North America, and contrary to historical retrospective reports, W and NW patients appear to have comparable outcomes when treated similarly. These findings suggest previously noted outcome differences may be due to disparities in access to care and management rather than differences in disease biology. Am. J. Hematol. 91:677-680, 2016. © 2016 Wiley Periodicals, Inc. PMID:27013143

  16. Intrinsic and extrinsic factors influencing the clinical course of B-cell chronic lymphocytic leukemia: prognostic markers with pathogenetic relevance

    Directory of Open Access Journals (Sweden)

    Gaidano Gianluca

    2009-08-01

    Full Text Available Abstract B-cell chronic lymphocytic leukemia (CLL, the most frequent leukemia in the Western world, is characterized by extremely variable clinical courses with survivals ranging from 1 to more than 15 years. The pathogenetic factors playing a key role in defining the biological features of CLL cells, hence eventually influencing the clinical aggressiveness of the disease, are here divided into "intrinsic factors", mainly genomic alterations of CLL cells, and "extrinsic factors", responsible for direct microenvironmental interactions of CLL cells; the latter group includes interactions of CLL cells occurring via the surface B cell receptor (BCR and dependent to specific molecular features of the BCR itself and/or to the presence of the BCR-associated molecule ZAP-70, or via other non-BCR-dependent interactions, e.g. specific receptor/ligand interactions, such as CD38/CD31 or CD49d/VCAM-1. A putative final model, discussing the pathogenesis and the clinicobiological features of CLL in relationship of these factors, is also provided.

  17. Targeting chronic lymphocytic leukemia cells in the tumor microenviroment: A review of the in vitro and clinical trials to date.

    Science.gov (United States)

    Crassini, Kyle; Mulligan, Stephen P; Best, O Giles

    2015-08-16

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world. Despite significant advances in therapy over the last decade CLL remains incurable. Current front-line therapy often consists of chemoimmunotherapy-based regimens, most commonly the fludarabine, cyclophosphamide plus rituximab combination, but rates of relapse and refractory disease are high among these patients. Several key signaling pathways are now known to mediate the survival and proliferation of CLL cells in vivo, the most notable of which are the pathways mediated by the B-cell receptor (BCR) and cytokine receptors. A better understanding of the pathogenesis of the disease, the underlying biology of the CLL-cell and the roles of the tumour microenvironment has provided the rationale for trials of a range of novel, more targeted therapeutic agents. In particular, clinical trials of ibrutinib and idelalisib, which target the Brutons tyrosine kinase and the delta isoform of phosphoinositol-3 kinase components of the BCR signaling pathway respectively, have shown extremely promising results. Here we review the current literature on the key signaling pathways and interactions of CLL cells that mediate the survival and proliferation of the leukemic cells. For each we describe the results of the recent clinical trials and in vitro studies of novel therapeutic agents. PMID:26301230

  18. The pleiotropic flavonoid quercetin: from its metabolism to the inhibition of protein kinases in chronic lymphocytic leukemia.

    Science.gov (United States)

    Russo, Gian Luigi; Russo, Maria; Spagnuolo, Carmela

    2014-10-01

    Quercetin is a flavonoid, of the subclass flavonols, possessing potential anticancer properties. It has often been defined as a functionally pleiotropic molecule because it can simultaneously target multiple pathways bypassing or ameliorating the onset of drug resistance in malignant cells. In this context, we reviewed the sometimes paradoxical antioxidant properties of quercetin and the functional role of its glucuronide and/or sulfate conjugates to discuss the low bioavailability of the molecule measured in vivo. We recently demonstrated that quercetin is able to sensitize several leukemia cell lines as well as B cells isolated from patients affected by chronic lymphocytic leukemia (CLL) to death ligand agonists (anti-CD95 and rTRAIL). The flavonol also potentiates the effect of canonical and innovative chemotherapeutic drugs (fludarabine and ABT-737) against CLL. The apoptosis-enhancing activity of quercetin in cell lines and B-CLL cells depends upon the modulated expression and activity of Mcl-1, an anti-apoptotic protein belonging to the Bcl-2 family. Herein, we suggest that the pleotropic activity of quercetin in CLL is obtained by the direct inhibition of key protein kinases, which positively regulate Mcl-1 activity and by indirect downregulation of Mcl-1 mRNA and protein levels acting on its mRNA stability and proteasome-mediated degradation. Finally, we highlighted the pros and cons of quercetin supplementation in cancer therapy and in prevention. PMID:25096193

  19. Promoter hypomethylation and expression is conserved in mouse chronic lymphocytic leukemia induced by decreased or inactivated Dnmt3a

    Science.gov (United States)

    Haney, Staci L.; Upchurch, G. Michael; Opavska, Jana; Klinkebiel, David; Hlady, Ryan A.; Suresh, Abhinav; Pirruccello, Samuel J.; Shukla, Vipul; Lu, Runqing; Costinean, Stefan; Rizzino, Angie; Karpf, Adam R.; Joshi, Shantaram; Swanson, Patrick; Opavsky, Rene

    2016-01-01

    SUMMARY DNA methyltransferase 3a (DNMT3A) catalyzes the formation of 5-methyl-cytosine in mammalian genomic DNA and it is frequently mutated in human hematologic malignancies. Bi-allelic loss of Dnmt3a in mice results in leukemia and lymphoma, including chronic lymphocytic leukemia (CLL). Here we investigate whether mono-allelic loss of Dnmt3a is sufficient to induce disease. We show that by 16 months of age, 65% of Dnmt3a+/− mice develop a CLL-like disease and 15% of mice develop non-malignant myeloproliferation. Genome-wide methylation analysis reveals that reduced Dnmt3a levels induce promoter hypomethylation at similar loci in Dnmt3a+/− and Dnmt3aΔ/Δ CLL, suggesting that promoters are particularly sensitive to Dnmt3a levels. Gene-expression analysis identified 26 hypomethylated and over-expressed genes common to both Dnmt3a+/− and Dnmt3aΔ/Δ CLL as putative oncogenic drivers. Our data provide evidence that Dnmt3a is a haplo-insufficient tumor suppressor in CLL and highlights the importance of deregulated molecular events in disease pathogenesis. PMID:27134162

  20. Plumbagin reduces chronic lymphocytic leukemia cell survival by downregulation of Bcl-2 but upregulation of the Bax protein level.

    Science.gov (United States)

    Fu, Chunling; Gong, Yanqing; Shi, Xuanxuan; Sun, Zengtian; Niu, Mingshan; Sang, Wei; Xu, Linyan; Zhu, Feng; Wang, Ying; Xu, Kailin

    2016-09-01

    Chronic lymphocytic leukemia (CLL) is the most common leukemia in Western countries, and mainly originates from an accumulation of abnormal B cells caused by the dysregulation of cell proliferation and apoptosis rates. The aberration of apoptosis-related genes in CLL cells results in defective apoptosis of CLL cells in response to traditional therapeutic medicine. Plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), a natural compound from Plumbago zeylinica, has been shown to exhibit pro-apoptotic activities in tumor cells. In the present study, we report that plumbagin effectively inhibited CLL cell viability with a lower dose compared to fludarabine, and inhibited cell proliferation in a dose-dependent manner. In addition, plumbagin promoted accumulation of MEC-1 cells in the S phase, and blocked cell cycle transition of HG3 cells from G0/G1 to S phase. Molecularly, plumbagin markedly induced CLL cell apoptosis through reduction of Bcl-2, but through an increase in the Bax protein level. These results suggest that plumbagin may be considered as a potential anticancer agent for CLL therapy. PMID:27461100

  1. Pembrolizumab Alone or With Idelalisib or Ibrutinib in Treating Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia or Other Low-Grade B-Cell Non-Hodgkin Lymphomas

    Science.gov (United States)

    2016-04-18

    Recurrent Chronic Lymphocytic Leukemia; Recurrent Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Lymphoplasmacytic Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Nodal Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Recurrent Splenic Marginal Zone Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue; Refractory Follicular Lymphoma; Refractory Lymphoplasmacytic Lymphoma; Refractory Nodal Marginal Zone Lymphoma; Refractory Small Lymphocytic Lymphoma; Refractory Splenic Marginal Zone Lymphoma; Richter Syndrome; Waldenstrom Macroglobulinemia

  2. Concanavalin A receptors on the surface membrane of lymphocytes from patients with acute leukemia.

    Science.gov (United States)

    Ben-Bassat, H; Anor, E; Penchas, S; Shlomai, Z; Prokocimer, M; Or, R; Polliack, A

    1984-01-01

    Peripheral blood mononuclear cells (PBM) isolated from 23 patients with acute lymphoblastic leukemia (ALL) and 24 with acute non-lymphoblastic leukemia (ANLL) were studied for binding and mobility of Concanavalin A (Con A) receptors, using fluorescent Con A (F-Con-A). The cap forming ability of PBM from all patients was 18.7 (+/- 9.3%) and 18.9 (+/- 9.9%) for ANLL patients at the time of diagnosis or during relapse. During clinical complete remission the cap forming ability of the PBM did not change significantly. No correlation was observed between the percentage of blasts present in the peripheral blood at the time of examination and the extent of cap formation, for both types of leukemia. The pattern of F-Con-A binding to PBM in ANLL patients was different compared to that seen in ALL. In ANLL, the fluorescent stain was concentrated in a round body on the cell ("button form") after binding to the membrane, while the rest of the cell showed almost no fluorescence. The present results indicate that PBM cells from patients with acute leukemia are characterized by a high degree of Con-A receptor mobility. PMID:6471903

  3. Cryoglobulinemia in a patient with chronic lymphocytic leukemia - A case report and review of literature of renal involvement in CLL.

    Science.gov (United States)

    Arora, Swaty; Levitan, Daniel; Regmi, Narottam; Sidhu, Gurinder; Gupta, Raavi; Nicastri, Anthony D; Saggi, Subodh J; Braverman, Albert

    2016-09-01

    The incidence of glomerulonephritis, as a manifestation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), has always been considered low. Though renal infiltration is usually detected at post-mortem, it does not often interfere with kidney function [1]. Though immunoglobulin (Ig) levels in most CLL patients are subnormal, small monoclonal Ig peaks are occasionally detected in serum. They were present in a number of reported CLL nephropathy patients, and not all were cryoglobulins; serum and glomerular staining were concordant for Ig type [2,3,4]. Myeloma, which secretes monoclonal light chains, causes nephropathy in 25% of patients. But the little presumably secreted by small plasma cell clones, without myeloma, may also be nephrotoxic. The same is true of the low secretory CLL cells, which may occasionally be associated with cryoglobulins and other nephrotoxic Igs [5]. We report a patient with early stage CLL (Rai stage 0) with cryoglobulins, which led to membranoproliferative glomerulonephritis (MPGN), and death. We located reports of 51 patients with CLL-associated nephrotic syndrome or nephropathy, mostly from MPGN related to local Ig deposits. In those patients screened for cryoglobulins, about half tested positive. Many were early stage cases, where MPGN developed long after CLL presentation, and responded to its treatment. As early diagnosis and treatment CLL-related nephropathy may be curative, we propose a prospective study to determine the incidence of hyperalbuminuria development after presentation. PMID:27519936

  4. Microenvironment interactions and B-cell receptor signaling in Chronic Lymphocytic Leukemia: Implications for disease pathogenesis and treatment.

    Science.gov (United States)

    Ten Hacken, Elisa; Burger, Jan A

    2016-03-01

    Chronic Lymphocytic Leukemia (CLL) is a malignancy of mature B lymphocytes which are highly dependent on interactions with the tissue microenvironment for their survival and proliferation. Critical components of the microenvironment are monocyte-derived nurselike cells (NLCs), mesenchymal stromal cells, T cells and NK cells, which communicate with CLL cells through a complex network of adhesion molecules, chemokine receptors, tumor necrosis factor (TNF) family members, and soluble factors. (Auto-) antigens and/or autonomous mechanisms activate the B-cell receptor (BCR) and its downstream signaling cascade in secondary lymphatic tissues, playing a central pathogenetic role in CLL. Novel small molecule inhibitors, including the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib and the phosphoinositide-3-kinase delta (PI3Kδ) inhibitor idelalisib, target BCR signaling and have become the most successful new therapeutics in this disease. We here review the cellular and molecular characteristics of CLL cells, and discuss the cellular components and key pathways involved in the cross-talk with their microenvironment. We also highlight the relevant novel treatment strategies, focusing on immunomodulatory agents and BCR signaling inhibitors and how these treatments disrupt CLL-microenvironment interactions. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza. PMID:26193078

  5. Highlights in the treatment of chronic lymphocytic leukemia from the 2014 meeting of the American Society of Hematology.

    Science.gov (United States)

    Molica, Stefano

    2015-06-01

    The latest Annual Meeting of the American Society of Hematology, held in San Francisco, included data on novel-targeted agents active in the treatment of chronic lymphocytic leukemia (CLL). MABTENANCE and PROLONG study suggest that either rituximab or ofatumumab improves progression-free survival in CLL. According to final analysis of CLL-10 trial, rituximab and bendamustine may have a role in the upfront treatment of fit elderly patients. Further insight into the use of ibrutinib, a first-in-class covalent Bruton’s tyrosine kinase-inhibitor that is currently approved for patients with relapsed/refractory CLL and with del(17p), was also presented. Idelalisib, a selective inhibitor of PI3K delta, demonstrated its activity with manageable toxicity in previously untreated patients ≥65 years with CLL or small lymphocytic lymphoma. Finally, a series Phase I/II studies of BCL-2 inhibitor (i.e., venetoclax, GDC-0199) used alone or in combination provide promising results in patients with relapsed/refractory CLL. PMID:25804936

  6. The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia.

    Science.gov (United States)

    Hallek, Michael; Kay, Neil E; Osterborg, Anders; Chanan-Khan, Asher A; Mahler, Michelle; Salman, Mariya; Wan, Ying; Sun, Steven; Zhuang, Sen Hong; Howes, Angela

    2015-01-01

    Ibrutinib is an orally administered, covalent inhibitor of Bruton's tyrosine kinase with activity in B-cell malignancies based on Phase I/II studies. We describe the design and rationale for the Phase III HELIOS trial (trial registration: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745) investigating whether ibrutinib added to bendamustine and rituximab (BR) provides benefits over BR alone in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible patients must have relapsed/refractory disease measurable on CT scan and meet ≥ 1 International Workshop on Chronic Lymphocytic Leukemia criterion for requiring treatment; patients with del(17p) are excluded. All patients receive BR (maximum six cycles) as background therapy and are randomized 1:1 to placebo or ibrutinib 420 mg/day. Treatment with ibrutinib or placebo will start concomitantly with BR and continue until disease progression or unacceptable toxicity. The primary end point is progression-free survival. Secondary end points include safety, objective response rate, overall survival, rate of minimal residual disease-negative remissions, and patient-reported outcomes. Tumor response will be assessed using the International Workshop on Chronic Lymphocytic Leukemia guidelines. PMID:24901734

  7. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Shakib, Marie-Christine R; Gabrial, Shreef G N; Gabrial, Gamal N

    2015-06-15

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice is used as a complementary and or/alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil) that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters. Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis. PMID:27275246

  8. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug ‘Chlorambucil’ As A Potential Treatment for Chronic Lymphocytic Leukemia

    Science.gov (United States)

    Shakib, Marie-Christine R.; Gabrial, Shreef G. N.; Gabrial, Gamal N.

    2015-01-01

    Chronic lymphocytic leukemia (CLL) is one of the chronic lymphoproliferative disorders (lymphoid neoplasms). It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL). Beetroot-carrot juice is used as a complementary and or/alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil) that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters. Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis. PMID:27275246

  9. Beetroot-Carrot Juice Intake either Alone or in Combination with Antileukemic Drug 'Chlorambucil' As A Potential Treatment for Chronic Lymphocytic Leukemia

    Directory of Open Access Journals (Sweden)

    Marie-Christine R. Shakib

    2015-06-01

    Full Text Available Chronic lymphocytic leukemia (CLL is one of the chronic lymphoproliferative disorders (lymphoid neoplasms. It is characterized by a progressive accumulation of functionally incompetent lymphocytes. Patients with leukemia often seek unconventional treatments not prescribed by hematologist in order to improve their cancer treatment outcome or to manage symptoms. In the present report, a 76-year-old patient was diagnosed with B-cell chronic lymphocytic leukemia (B-CLL. Beetroot-carrot juice is used as a complementary and or/ alternative therapy used in conjunction with conventional leukemic treatment (chlorambucil that has been a standard first-line chemotherapeutic agent for patients with CLL and known to have serious and undesirable side-effects. After one month and 15 days of administration of beetroot-carrot juice therapy, the patient had improved appetite, a sense of general well-being and increased vigor daily activities. Furthermore, beetroot-carrot juice was used as an adjuvant to chlorambucil resulted in a substantial reduction in leukocytes and lymphocytes count in peripheral blood and improvement in the relevant biochemical parameters.  Beetroot-carrot juice can be used as an effective treatment for CLL alone or in combination with chlorambucil when taken orally with regular diet on daily basis.

  10. Detection of chromosomal changes in chronic lymphocytic leukemia using classical cytogenetic methods and FISH: application of rich mitogen mixtures for lymphocyte cultures.

    Science.gov (United States)

    Koczkodaj, Dorota; Popek, Sylwia; Zmorzyński, Szymon; Wąsik-Szczepanek, Ewa; Filip, Agata A

    2016-04-01

    One of the research methods of prognostic value in chronic lymphocytic leukemia (CLL) is cytogenetic analysis. This method requires the presence of appropriate B-cell mitogens in cultures in order to obtain a high mitotic index. The aim of our research was to determine the most effective methods of in vitro B-cell stimulation to maximize the number of metaphases from peripheral blood cells of patients with CLL for classical cytogenetic examination, and then to correlate the results with those obtained using fluorescence in situ hybridization (FISH). The study group involved 50 consecutive patients with CLL. Cell cultures were maintained with the basic composition of culture medium and addition of respective stimulators. We used the following stimulators: Pokeweed Mitogen (PWM), 12-O-tetradecanoylphorbol 13-acetate (TPA), ionophore, lipopolysaccharide (LPS), and CpG-oligonucleotide DSP30. We received the highest mitotic index when using the mixture of PWM+TPA+I+DSP30. With classical cytogenetic tests using banding techniques, numerical and structural aberrations of chromosomes were detected in 46 patients, and no change was found in only four patients. Test results clearly confirmed the legitimacy of using cell cultures enriched with the mixture of cell stimulators and combining classical cytogenetic techniques with the FISH technique in later patient diagnosing. PMID:26956786

  11. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine

    Directory of Open Access Journals (Sweden)

    Mandrik O

    2015-08-01

    Full Text Available Olena Mandrik,1 Isaac Corro Ramos,2 Saskia Knies,1,3 Maiwenn Al,1,2 Johan L Severens1,2 1Institute of Health Policy and Management, Erasmus University Rotterdam, Rotterdam, the Netherlands; 2Institute of Medical Technology Assessment (iMTA, Erasmus University Rotterdam, Rotterdam, the Netherlands; 3National Health Care Institute, Diemen, the Netherlands Abstract: The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients' survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER

  12. Occupation and leukemia in Nordic countries

    DEFF Research Database (Denmark)

    Talibov, Madar; Kautiainen, Susanna; Martinsen, Jan Ivar;

    2012-01-01

    We studied occupational variation of the risk of acute myeloid leukemia, chronic lymphocytic leukemia, and other leukemia in Nordic countries.......We studied occupational variation of the risk of acute myeloid leukemia, chronic lymphocytic leukemia, and other leukemia in Nordic countries....

  13. Automated classification of patients with chronic lymphocytic leukemia and immunocytoma from flow cytometric three-color immunophenotypes.

    Science.gov (United States)

    Valet, G K; Höffkes, H G

    1997-12-15

    The goal of this study was the discrimination between chronic lymphocytic leukemia (B-CLL), clinically more aggressive lymphoplasmocytoid immunocytoma (LP-IC) and other low-grade non-Hodgkin's lymphomas (NHL) of the B-cell type by automated analysis of flow cytometric immunophenotypes CD45/14/20, CD4/8/3, kappa/CD19/5, lambda/CD19/5 and CD10/23/19 from peripheral blood and bone marrow aspirate leukocytes using the multiparameter classification program CLASSIF1. The immunophenotype list mode files were exhaustively evaluated by combined lymphocyte, monocyte, and granulocyte (LMG) analysis. The results were introduced into databases and automatically classified in a standardized way. The resulting triple matrix classifiers are laboratory and instrument independent, error tolerant, and robust in the classification of unknown test samples. Practically 100% correct individual patient classification was achievable, and most manually unclassifiable patients were unambiguously classified. It is of interest that the single lambda/CD19/5 antibody triplet provided practically the same information as the full set of the five antibody triplets. This demonstrates that standardized classification can be used to optimize immunophenotype panels. On-line classification of test samples is accessible on the Internet: http://www.biochem.mpg.de/valet/leukaem1.html Immunophenotype panels are usually devised for the detection of the frequency of abnormal cell populations. As shown by computer classification, most the highly discriminant information is, however, not contained in percentage frequency values of cell populations, but rather in total antibody binding, antibody binding ratios, and relative antibody surface density parameters of various lymphocyte, monocyte, and granulocyte cell populations. PMID:9440819

  14. Leukemias

    Directory of Open Access Journals (Sweden)

    Riccardo Masetti

    2011-01-01

    Full Text Available Acute leukemia is the most common type of childhood and adolescence cancer, characterized by clonal proliferation of variably differentiated myeloid or lymphoid precursors. Recent insights into the molecular pathogenesis of leukemia have shown that epigenetic modifications, such as deacetylation of histones and DNA methylation, play crucial roles in leukemogenesis, by transcriptional silencing of critical genes. Histone deacetylases (HDACs are potential targets in the treatment of leukaemia, and, as a consequence, inhibitors of HDACs (HDIs are being studied for therapeutic purposes. HDIs promote or enhance several different anticancer mechanisms, such as apoptosis, cell cycle arrest, and cellular differentiation and, therefore, are in evidence as promising treatment for children and adolescents with acute leukemia, in monotherapy or in association with other anticancer drugs. Here we review the main preclinical and clinical studies regarding the use of HDIs in treating childhood and adolescence leukemia.

  15. Testicular relapse of acute lymphocytic leukemia: Usefulness of color and power Doppler sonography

    International Nuclear Information System (INIS)

    To evaluate the usefulness of color and power Doppler sonography in detecting testicular relapse of leukemia. Both gray- scale and color (power) Doppler ultrasound (US) were performed in seven patients. Two additional patients examined by gray-scale US only were included. The patients were 4-14 years old (mean age, 9 years). Ten tests were confirmed to have leukemic relapse, eight by pathology and two by clinical evidence. Gray-scale US showed variable findings: heterogeneous hypoechogenicity (5) and homogeneous isoechogenicity (5). In all seven patients (8 tests) who underwent both color and power Doppler US, diffuse and marked hypervascularity was demonstrated. One case showed enlarged epididymis with heterogeneous echogenicity, which was the same character as the involved testis. Color and power Doppler US are useful methods in the identification of the testicular relapse of leukemia by demonstrating diffuse, marked hypervascularity in the proper clinical settings.

  16. Expression of MDM2 in an acute lymphocytic leukemia mice model induced by γ-radiation

    International Nuclear Information System (INIS)

    Objective: To investigate the role of the MDM2 in the process of carcinogenesis induced by γ-rays and its molecular mechanisms. Methods: Animal model of radiation-induced leukemia was established by γ-irradiation. According to the histological and morphological results, mice tissues were divided into three groups: cancerization group, incancerization group and control group. Expression of MDM2 protein and mRNA in thymus/bone marrow was detected with Western blot and in situ hybridization (ISH), respectively. The authors also examined the protein phosphorylation level of MDM2 protein by immunoprecipitation (IP). PCR-SSCP was performed to detect gene mutation. Results: A mice leukemia model was successfully established as verified by pathological findings and confirmed by transplantation test in nude mice. The protein expression in thymus/bone marrow in irradiation groups was significantly higher than that in controls (P2 was found to be hyper-phosphorylated in the cancerization group as compared with other groups. No gene mutation was detected by SSCP/silver-staining assay in the tumor samples. Conclusion: MDM2 may be involved in the development and progression of leukemia induced by γ-irradiation. The over-expression but not gene mutation may be responsible for malignant transformation induced by radiation. Phosphorylation is at least partly attributed to activation of MDM2

  17. Low-Dose Total Body Irradiation and Donor Peripheral Blood Stem Cell Transplant Followed by Donor Lymphocyte Infusion in Treating Patients With Non-Hodgkin Lymphoma, Chronic Lymphocytic Leukemia, or Multiple Myeloma

    Science.gov (United States)

    2015-10-30

    Adult Nasal Type Extranodal NK/T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Angioimmunoblastic T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Nodal Marginal Zone B-cell Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; Testicular Lymphoma; Waldenström Macroglobulinemia

  18. Subacute herpes simplex virus type 1 encephalitis as an initial presentation of chronic lymphocytic leukemia and multiple sclerosis: a case report

    Directory of Open Access Journals (Sweden)

    Corman Lourdes C

    2011-02-01

    Full Text Available Abstract Introduction Herpes simplex virus type 1 encephalitis presents acutely in patients who are immunocompetent. We report what we believe to be the first published case of a subacute course of herpes simplex virus type 1 encephalitis in a patient with asymptomatic chronic lymphocytic leukemia who subsequently developed multiple sclerosis. Case presentation A 49-year-old Caucasian woman with a history of fever blisters presented to the emergency department with a history of left temporal headache for four weeks, and numbness of the left face and leg for two weeks. A complete blood count revealed white blood cell count of 11,820 cells/mL, with an absolute lymphocyte count of 7304 cells/mL. The cerebrospinal fluid contained 6 white blood cells/μL, 63 red blood cells/μL, 54 mg glucose/dL, and 49 mg total protein/dL. Magnetic resonance imaging of the brain revealed meningoencephalitis and bilateral ventriculitis. Cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 was positive, and the patient's symptoms resolved after ten days of treatment with parenteral aciclovir. Incidental findings on peripheral blood smear and flow cytometry testing confirmed chronic lymphocytic leukemia. One month later, she developed bilateral numbness of the hands and feet; a repeat cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 at this time was negative. A repeat magnetic resonance imaging scan showed an expansion of the peri-ventricular lesions, and the cerebrospinal fluid contained elevated oligoclonal bands and myelin basic protein. A brain biopsy revealed gliosis consistent with multiple sclerosis, and the patient responded to treatment with high-dose parenteral steroids. Conclusion Herpes simplex virus type 1 encephalitis is a rare presentation of chronic lymphocytic leukemia. Our patient had an atypical, subacute course, presumably due to immunosuppression from chronic lymphocytic leukemia. This unusual

  19. Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation.

    OpenAIRE

    Yeomans, Alison; Thirdborough, Stephen M.; Valle-Argos, Beatriz; Linley, Adam; Krysov, Sergey; Hidalgo, Marina Sanchez; Leonard, Elodie; Ishfaq, Muhammad; Wagner, Simon D.; Willis, Anne E.; Steele, Andrew; Stevenson, Freda; Forconi, Francesco; Coldwell, Mark J; Packham, Graham

    2015-01-01

    Antigenic stimulation via the B-cell receptor (BCR) is a major driver of the proliferation and survival of chronic lymphocytic leukemia (CLL) cells. However, the precise mechanisms by which BCR stimulation leads to accumulation of malignant cells remain incompletely understood. Here, we investigated the ability of BCR stimulation to increase messenger RNA (mRNA) translation, which can promote carcinogenesis by effects on both global mRNA translation and upregulated expression of specific onco...

  20. Southwest Oncology Group Study S0530: A Phase 2 Trial of Clofarabine and Cytarabine for Relapsed or Refractory Acute Lymphocytic Leukemia

    OpenAIRE

    Advani, Anjali S; Gundacker, Holly M.; Sala-Torra, Olga; Radich, Jerald P.; Lai, Raymond; Slovak, Marilyn L.; Lancet, Jeffrey E.; Coutre, Steve E.; Stuart, Robert K.; Mims, Martha P.; Stiff, Patrick J.; Appelbaum, Frederick R.

    2010-01-01

    Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non-overlapping toxicities making this combination a potentially promising treatment for acute lymphocytic leukemia (ALL). Study goals were to: (1) evaluate the complete remission (CR) rate with Clo/Cy in patients with relapsed/refractory ALL; and (2) assess expression of connective tissue growth factor (CTGF) and nucleoside transporters in leukemic blasts. Associated with poo...

  1. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo

    OpenAIRE

    Ponader, Sabine; Chen, Shih-Shih; Buggy, Joseph J.; Balakrishnan, Kumudha; Gandhi, Varsha; William G Wierda; Michael J Keating; O'Brien, Susan; Chiorazzi, Nicholas; Burger, Jan A.

    2012-01-01

    B-cell receptor (BCR) signaling is a critical pathway in the pathogenesis of several B-cell malignancies, including chronic lymphocytic leukemia (CLL), and can be targeted by inhibitors of BCR-associated kinases, such as Bruton tyrosine kinase (Btk). PCI-32765, a selective, irreversible Btk inhibitor, is a novel, molecularly targeted agent for patients with B-cell malignancies, and is particularly active in patients with CLL. In this study, we analyzed the mechanism of action of PCI-32765 in ...

  2. Deficiency of complement factor MBL in a patient required cardiac surgery after an acute myocardial infarction with underlining chronic lymphocytic leukemia

    OpenAIRE

    Lai, Lawrence T.; Lee, Daniel C.; Ko, Wilson; Shevde, Ketan; Zhang, Ming

    2008-01-01

    Increasing evidence suggests that Mannan-binding lectin (MBL), the initial factor of the lectin pathway of complement, plays a role in cardiovascular diseases, i.e. inversely associated with risk of myocardial infarction (MI). In the present case, a patient with MBL deficiency underwent coronary artery bypass grafting (CABG) after an acute MI with underlining chronic lymphocytic leukemia (CLL). Post-operatively, the patient had a cerebral vascular accident and eventually expired. Analysis of ...

  3. Defining Molecular Phenotypes of Mesenchymal and hematopoietic Stem Cells derived from Peripheral blood of Acute Lymphocytic Leukemia patients for regenerative stem cell therapy

    OpenAIRE

    Pravin D. Potdar; Rambhadur P Subedi

    2011-01-01

    Acute Lymphocytic Leukemia (ALL) is a clonal myeloid disorder affecting all age groups, characterized by accumulation of immature blast cells in bone marrow and in peripheral blood. Autologous Bone Marrow Transplantation is a present treatment for cure of ALL patients, which is very expensive, invasive process and may have possibility of transplantation of malignant stem cells to patients. In the present study, we hypothesized to isolate large number of normal Mesenchymal & Hematopoietic stem...

  4. A Proline/Arginine-Rich End Leucine-Rich Repeat Protein (PRELP) Variant Is Uniquely Expressed in Chronic Lymphocytic Leukemia Cells

    OpenAIRE

    Eva Mikaelsson; Anders Österborg; Mahmood Jeddi-Tehrani; Parviz Kokhaei; Mahyar Ostadkarampour; Reza Hadavi; Mehran Gholamin; Mehdi Akhondi; Fazel Shokri; Hodjattallah Rabbani; Håkan Mellstedt

    2013-01-01

    Proline/arginine-rich end leucine-rich repeat protein (PRELP) belongs to the small leucine-rich proteoglycan (SLRP) family, normally expressed in extracellular matrix of collagen-rich tissues. We have previously reported on another SLRP, fibromodulin (FMOD) in patients with chronic lymphocytic leukemia (CLL). PRELP is structurally similar to FMOD with adjacent localization on chromosome 1 (1q32.1). As cluster-upregulation of genes may occur in malignancies, the aim of our study was to analyze...

  5. A Systemic Capillary Leak Syndrome (Clarkson Syndrome) in a Patient with Chronic Lymphocytic Leukemia: A Case Report in an Out-of-Hospital Setting

    OpenAIRE

    Manon Durand Bechu; Antoine Rouget; Christian Recher; Elie Azoulay; Vincent Bounes

    2016-01-01

    Systemic Capillary Leak Syndrome (SCLS) is a rare disease with poor prognosis, characterized by the occurrence of mucocutaneous and visceral edema with hypotension, hemoconcentration, and unexpected hypoalbuminemia. The disease can be idiopathic (Clarkson syndrome) or secondary to other diseases and treatments. We describe this syndrome in a prehospitalized, 63-year-old patient with chronic lymphocytic leukemia and an idiopathic form of SCLS manifesting as hypovolemic shock. Initial care is h...

  6. Kinetics of indium-111-labeled leukemic cells in patients with acute non-lymphocytic leukemia

    International Nuclear Information System (INIS)

    The kinetics of autologous leukemic cells labeled with In-111 oxine were studied in 5 patients with acute myeloblastic leukemia (AML) and one patient with acute premyelocytic leukemia (APL), and kinetics of OKM1 monoclonal antibody-treated leukemic cells were studied in one patient with acute monoblastic leukemia (AMoL). Recoveries of 33.7 +- 23.3%(range, 22.0 to 48.1%) were achieved at 10min after injection of In-111 oxine labeled leukemic cells in AML and APL patients. However, in a patient with AMoL recovery of 12.3% was only achieved at 10min after injection of OKM1-treated leukemic cells. Clearance of the activity from blood was rapid up to one in all patients. The clearance curve of the activity in 5 AML patients showed a hump or a plateau from one to 5hr after injection of labeled leukemic cells. In APL patient and AMoL patient, however, this hump or plateau was not noted. In AML and APL patients the activity over the spleen was higher than that of over the liver at from 30min to 3hr after and showed a plateau or gradual rising thereafter. In a patient with AMoL, the hepatic activity was higher than the splenic activity at 30min after, but thereafter the latter became higher than the former. Liver activity curves showed transient fall at 3hr after and then gradual uprising in all patients. In a patient with APL, high activity was noted over the kidneys. This rose to a maximum after 3hr and then decreased rapidly. Since In-111 oxine stays firmly attached to the cells in spite of the possibility of radiation damage in a long-term survey, it seems an ideal label for studying leukemic cell kinetics

  7. Targeting inhibitor of apoptosis proteins by Smac mimetic elicits cell death in poor prognostic subgroups of chronic lymphocytic leukemia.

    Science.gov (United States)

    Opel, Daniela; Schnaiter, Andrea; Dodier, Dagmar; Jovanovic, Marjana; Gerhardinger, Andreas; Idler, Irina; Mertens, Daniel; Bullinger, Lars; Stilgenbauer, Stephan; Fulda, Simone

    2015-12-15

    Inhibitor of apoptosis (IAP) proteins are highly expressed in chronic lymphocytic leukemia (CLL) cells and contribute to evasion of cell death and poor therapeutic response. Here, we report that Smac mimetic BV6 dose-dependently induces cell death in 28 of 51 (54%) investigated CLL samples, while B-cells from healthy donors are largely unaffected. Importantly, BV6 is significantly more effective in prognostic unfavorable cases with, e.g., non-mutated VH status and TP53 mutation than samples with unknown or favorable prognosis. The majority of cases with 17p deletion (10/12) and Fludarabine refractory cases respond to BV6, indicating that BV6 acts independently of p53. BV6 also triggers cell death under survival conditions mimicking the microenvironment, e.g., by adding CD40 ligand or conditioned medium. Gene expression profiling identifies cell death, NF-κB and redox signaling among the top pathways regulated by BV6 not only in CLL but also in core-binding factor (CBF) acute myeloid leukemia (AML). Consistently, BV6 stimulates production of reactive oxygen species (ROS), which are contributing to BV6-induced cell death, since antioxidants reduce cell death. While BV6 causes degradation of cellular inhibitor of apoptosis (cIAP)1 and cIAP2 and nuclear factor-kappaB (NF-κB) pathway activation in primary CLL samples, BV6 induces cell death independently of caspase activity, receptor-interacting protein (RIP)1 activity or tumor necrosis factor (TNF)α, as zVAD.fmk, necrostatin-1 or TNFα-blocking antibody Enbrel fail to inhibit cell death. Together, these novel insights into BV6-regulated cell death in CLL have important implications for developing new therapeutic strategies to overcome cell death resistance especially in poor prognostic CLL subgroups. PMID:26096065

  8. A study of cranial computed tomography scan in acute lymphocytic leukemia and non-Hodgkin lymphoma in children

    International Nuclear Information System (INIS)

    A serial follow-up of cranial computed tomography (CT) scan was performed in total of 55 children with acute lymphocytic leukemia and non-Hodgkin lymphoma in order to elucidate the early and late influences of the chemoradiotherapy to the cerebrum. Scoring system was applied in evaluation of the cerebral surface changes, namely atropy, counting 0 to 2 points for the widening of extracerebral space, surface sulici, Sylvian fissure, and rounding of the gyri respectively. Lateral vetricular measurement was also performed at the level of basal ganglia, calculating the anterior horn width/maximum cerebral width (C/B), and bicaudate width/maximum cerebral width (D/B). All the patients except for 3 in the remission (CR) group, and for 1 in the relapsed group (REL) had been treated with cranial irradiation and intrathecal methotrexate as a prophylaxis of central nervous system leukemia. Analysis of CR patients showed mild to moderate degree of cerebral atropy early at the preprophylactic stage, with mean surface score of 3, C/B of 26.5 %, and D/B of 12.7 %. The main factor for this change may well be corticosteroid used at the time of initial remission induction. Serial follow-up of CT revealed that these changes improved even after the cranial irradiation phase in most cases. In the period from 12 to 36 months after diagnosis, 28 % of CR patient showed atrophic changes, and 13.3 % from 36 to 60 months, and 16.6 % from 60 months or later. No remarkable alterations were observed after the first 12 months in individual cases, indicating that the major changes in CT findings in these patient occur in quite early phase of the therapy, and persist with various degree of improvements during the long course of chemotherapy. In the relapsed group of patients, the atrophic changes of the cranial CT progressed as they repeated the relapse, either of marrow or CNS, including 5 cases of leukoencephalopathy. (author)

  9. VARIATIONS OF THE LEUKOCYTES AND LYMPHOCYTES IN THE CASE OF ACUTE LYMPHOBLASTIC LEUKEMIA

    OpenAIRE

    Mirela Cozma; Marioara Nicoleta Filimon

    2005-01-01

    The purpose of this study is to approximate the surviving period in patients with acute lymphoblastic leukemia. For this study we took in to consideration 10 patients 0 to 20 years old, coming from rural or urban environments and their evolution has been studied for a period of 60 days from the primary presentation to the hospital. The diagnosis was made after a careful history and physical examination and was completed after a blood count insisting on the number of leukocytes and on the peri...

  10. Computed tomographic diagnosis of methotrexate leukoencephalopathy, developed in children with acute lymphocytic leukemia

    International Nuclear Information System (INIS)

    The difference of Hounsfield units between the white and gray matter are highly reliable indexes for the numerical analysis of infant cranial CT. These indexes were evaluated in 239 healthy children at ages ranging from 1 to 15 years. CT findings of white matter changes due to methotrexate were evaluated numerically in 80 children with acute lymphatic leukemia. This analysis resulted in detection of transient, or preclinical, slight pathological changes in the white matter. This method was also considered to give objectivity to evaluation of the changes in CT. (Ueda, J.)

  11. Using the geometric mean fluorescence intensity index method to measure ZAP-70 expression in patients with chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Wu YJ

    2016-02-01

    Full Text Available Yu-Jie Wu, Hui Wang, Jian-Hua Liang, Yi Miao, Lu Liu, Hai-Rong Qiu, Chun Qiao, Rong Wang, Jian-Yong Li Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, People’s Republic of China Abstract: Expression of ζ-chain-associated protein kinase 70 kDa (ZAP-70 in chronic lymphocytic leukemia (CLL is associated with more aggressive disease and can help differentiate CLL from cases expressing mutated or unmutated immunoglobulin heavy chain variable region (IgHV genes. However, standardizing ZAP-70 expression by flow cytometric analysis has proved unsatisfactory. The key point is that ZAP-70 is weakly expressed with a continuous expression pattern rather than a clear discrimination between positive and negative CLL cells, which means that the resulting judgment is subjective. Thus, in this study, we aimed at assessing the reliability and repeatability of ZAP-70 expression using the geometric mean fluorescence intensity (geo MFI index method based on flow cytometry with 256-channel resolution in a series of 402 CLL patients and to compare ZAP-70 with other biological and clinical prognosticators. According to IgHV mutational status, we were able to confirm that the optimal cut-off point for the geo MFI index was 3.5 in the test set. In multivariate analyses that included the major clinical and biological prognostic markers for CLL, the prognostic impact of ZAP-70 expression appeared to have stronger discriminatory power when the geo MFI index method was applied. In addition, we found that ZAP-70-positive patients according to the geo MFI index method had shorter time to first treatment or overall survival (P=0.0002, P=0.0491. This is the first report showing that ZAP-70 expression can be evaluated by a new approach, the geo MFI index, which could be a useful prognostic method as it is more reliable, less subjective, and therefore better associated with improvement of CLL prognostication

  12. Idelalisib given front-line for treatment of chronic lymphocytic leukemia causes frequent immune-mediated hepatotoxicity.

    Science.gov (United States)

    Lampson, Benjamin L; Kasar, Siddha N; Matos, Tiago R; Morgan, Elizabeth A; Rassenti, Laura; Davids, Matthew S; Fisher, David C; Freedman, Arnold S; Jacobson, Caron A; Armand, Philippe; Abramson, Jeremy S; Arnason, Jon E; Kipps, Thomas J; Fein, Joshua; Fernandes, Stacey; Hanna, John; Ritz, Jerome; Kim, Haesook T; Brown, Jennifer R

    2016-07-14

    Idelalisib is a small-molecule inhibitor of PI3Kδ with demonstrated efficacy for the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as front-line therapy, we enrolled 24 subjects in a phase 2 study consisting of 2 months of idelalisib monotherapy followed by 6 months of combination therapy with idelalisib and the anti-CD20 antibody ofatumumab. After a median follow-up period of 14.7 months, hepatotoxicity was found to be a frequent and often severe adverse event. A total of 19 subjects (79%) experienced either grade ≥1 ALT or AST elevation during the study, and 13 subjects (54%) experienced grade ≥3 transaminitis. The median time to development of transaminitis was 28 days, occurring before ofatumumab introduction. Younger age and mutated immunoglobulin heavy chain status were significant risk factors for the development of hepatotoxicity. Multiple lines of evidence suggest that this hepatotoxicity was immune mediated. A lymphocytic infiltrate was seen on liver biopsy specimens taken from 2 subjects with transaminitis, and levels of the proinflammatory cytokines CCL-3 and CCL-4 were higher in subjects experiencing hepatotoxicity. All cases of transaminitis resolved either by holding the drug, initiating immunosuppressants, or both, and rates of recurrent toxicity were lower in patients taking steroids when idelalisib was reinitiated. A decrease in peripheral blood regulatory T cells was seen in patients experiencing toxicity on therapy, which is consistent with an immune-mediated mechanism. These results suggest that caution should be taken as drugs within this class are developed for CLL, particularly in younger patients who have not received prior disease-specific therapy. This study was registered at www.clinicaltrials.gov as #NCT02135133. PMID:27247136

  13. A combination of an anti-SLAMF6 antibody and ibrutinib efficiently abrogates expansion of chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Yigit, Burcu; Halibozek, Peter J; Chen, Shih-Shih; O'Keeffe, Michael S; Arnason, Jon; Avigan, David; Gattei, Valter; Bhan, Atul; Cen, Osman; Longnecker, Richard; Chiorazzi, Nicholas; Wang, Ninghai; Engel, Pablo; Terhorst, Cox

    2016-05-01

    The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220+CD5+ Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo, we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors. PMID:27029059

  14. MicroRNAs in chronic lymphocytic leukemia: miRacle or miRage for prognosis and targeted therapies?

    Science.gov (United States)

    Van Roosbroeck, Katrien; Calin, George A

    2016-04-01

    Chronic lymphocytic leukemia (CLL) is a heterogeneous disease and has a highly variable clinical course with survival ranging from a couple of months to several decades. MicroRNAs (miRNAs), small non-coding RNAs that regulate transcription and translation of genes, have been found to be involved in CLL initiation, progression, and resistance to therapy. In addition, they can be used as prognostic biomarkers and as targets for novel therapies. In this review, we describe the association between miRNAs and the cytogenetic aberrations commonly found in CLL, as well as with other prognostic factors. We describe the presence of miRNAs as extracellular entities in the plasma and serum of CLL patients and discuss their role in resistance to therapy. Finally, we will explore the potential of targeted miRNA therapy for the treatment of CLL, with a special emphasis on MRX34, the first miRNA mimic that is currently being evaluated for clinical use. PMID:27040698

  15. Chromosome abnormalities induced by anticancer drugs and radiation in cultured lymphocytes of children with acute leukemia in complete remission

    International Nuclear Information System (INIS)

    In an attempt to evaluate possible secondary carcinogenic and genetic effects of intensive chemotherapy and radiotherapy, the types and frequencies of chromosome abnormalities were investigated in cultured lymphocytes from 15 children with acute leukemia who had achieved therapeutically a complete remission. The controls were 14 healthy adults (group A). Of the 15 leukemic children, 12 had received only chemotherapy (group B), while the remaining 3 had received both chemotherapy and radiotherapy of central nervous system (group C). In addition, 2 brain tumor patients who had received cranial radiotherapy were studied (group D). A significantly higher incidence of chromosome abnormalities was observed in group B, C and D, as than in group A. The incidence of aberration was highest in group C, which was ascribed to the increased number of hypodiploid cells with chromosome-type structural rearrangements, probably due to the radiotherapy. In contrast, the chromosome aberrations shown in group B were mostly of chromatid type, though chromosome-type aberrations were also noted in some cases of this group. Comparing the aberration rates of groups C and D, it was suggested that cranial irradiation is less hazardous than spino-cranial irradiation. (J.P.N.)

  16. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

    Science.gov (United States)

    Wendtner, Clemens-Martin; Hillmen, Peter; Mahadevan, Daruka; Bühler, Andreas; Uharek, Lutz; Coutré, Steven; Frankfurt, Olga; Bloor, Adrian; Bosch, Francesc; Furman, Richard R; Kimby, Eva; Gribben, John G; Gobbi, Marco; Dreisbach, Luke; Hurd, David D; Sekeres, Mikkael A; Ferrajoli, Alessandra; Shah, Sheetal; Zhang, Jennie; Moutouh-de Parseval, Laure; Hallek, Michael; Heerema, Nyla A; Stilgenbauer, Stephan; Chanan-Khan, Asher A

    2012-03-01

    Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL. PMID:21879809

  17. Ionizing radiation exposures in treatments of solid neoplasms are not associated with subsequent increased risks of chronic lymphocytic leukemia.

    Science.gov (United States)

    Radivoyevitch, Tomas; Sachs, Rainer K; Gale, Robert Peter; Smith, Mitchell R; Hill, Brian T

    2016-04-01

    Exposure to ionizing radiation is not thought to cause chronic lymphocytic leukemia (CLL). Challenging this notion are recent data suggesting CLL incidence may be increased by radiation exposure from the atomic bombs (after many decades), uranium mining and nuclear power facility accidents. To assess the effects of therapeutic ionizing radiation for the treatment of solid neoplasms we studied CLL risks in data from the Surveillance, Epidemiology, and End Results (SEER) Program. Specifically, we compared the risks of developing CLL in persons with a 1(st) non-hematologic cancer treated with or without ionizing radiation. We controlled for early detection effects on CLL risk induced by surveillance after 1(st) cancer diagnoses by forming all-time cumulative CLL relative risks (RR). We estimate such CLL RR to be 1.20 (95% confidence interval, 1.17, 1.23) for persons whose 1(st) cancer was not treated with ionizing radiation and 1.00 (0.96, 1.05) for persons whose 1(st) cancer was treated with ionizing radiations. These results imply that diagnosis of a solid neoplasm is associated with an increased risk of developing CLL only in persons whose 1(st) cancer was not treated with radiation therapy. PMID:26922774

  18. TP53 mutations are early events in chronic lymphocytic leukemia disease progression and precede evolution to complex karyotypes.

    Science.gov (United States)

    Lazarian, Gregory; Tausch, Eugen; Eclache, Virginie; Sebaa, Amel; Bianchi, Vincent; Letestu, Remi; Collon, Jean-Francois; Lefebvre, Valerie; Gardano, Laura; Varin-Blank, Nadine; Soussi, Thierry; Stilgenbauer, Stephen; Cymbalista, Florence; Baran-Marszak, Fanny

    2016-10-15

    TP53 abnormalities lead to resistance to purine analogues and are found in over 40% of patients with refractory chronic lymphocytic leukemia (CLL). At diagnosis, no more than 5% of patients carry the 17p deletion, most cases harbour mutations within the other TP53 allele. The incidence of a TP53 mutation as the only alteration is approximately 5%, but this depends on the sensitivity of the technique. Recently, having a complex karyotype has been considered a strong adverse prognostic factor. However, there are no longitudinal studies simultaneously examining the presence of the 17p deletion, TP53 mutations and karyotype abnormalities. We conducted a retrospective longitudinal study of 31 relapsed/refractory CLL patients. Two to six blood samples per patient were analyzed, with a median follow-up of 8 years. In this report, we assessed the sequence of events of TP53 clonal evolution and correlated the presence of TP53 abnormalities to genetic instability during progression and treatment. Next-generation sequencing allowed the early detection of TP53 mutated clones and was able to be performed on a routine basis, demonstrating an excellent correlation between the Illumina and Ion Torrent technologies. We concluded that TP53 mutations are early events and precede clonal evolution to complex karyotypes. We strongly recommend the early and iterated detection of TP53 mutations in progressive cases. PMID:27270786

  19. Autologous Stem Cell Transplantation for Chronic Lymphocytic Leukemia - Still a Valid Treatment Option, or is the Game Over?

    Science.gov (United States)

    McClanahan, Fabienne; Dreger, Peter

    2012-01-01

    Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been established as the current standard of care for young and fit patients with chronic lymphocytic leukemia (CLL). In the early nineties of the last century, long before the advent of fludarabine or antibody-based strategies, there was realistic hope that myeloablative therapy followed by autologous stem cell transplantation (autoSCT) might be an effective and potentially curative front-line treatment option for suitable patients with CLL. Since then, several prospective trials have disenthralled this hope: although autoSCT can prolong event and progression-free survival if used as part of early front-line treatment, it does not improve overall survival, while it is associated with an increased risk of late adverse events such as secondary malignancies. In addition, autoSCT lacks the potential to overcome the negative impact of biomarkers that confer resistance to chemotherapy or early relapse. The role of autoSCT has also been explored in the context of FCR, and it was demonstrated that its effect is inferior to the currently established optimal treatment regimen. In view of ongoing attempts to improve on FCR, promising clinical activity of new substances even in relapsed/ refractory CLL patients, exciting novel cell therapy approaches and advantages in the understanding of the disease and detection of Minimal Residual Disease (MRD), autoSCT has lost its place as a standard treatment option for CLL. PMID:23205259

  20. AUTOLOGOUS STEM CELL TRANSPLANTATION FOR CHRONIC LYMPHOCYTIC LEUKEMIA STILL A VALID TREATMENT OPTION, OR IS THE GAME OVER ?

    Directory of Open Access Journals (Sweden)

    Fabienne McClanahan

    2012-01-01

    Full Text Available

    Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR has been established as the current standard of care for young and fit patients with chronic lymphocytic leukemia (CLL. In the early nineties of the last century, long before the advent of fludarabine or antibody-based strategies, there was realistic hope that myeloablative therapy followed by autologous stem cell transplantation (autoSCT might be an effective and potentially curative front-line treatment option for suitable patients with CLL. Since then, several prospective trials have disenthralled this hope: although autoSCT can prolong event and progression-free survival if used as part of early front-line treatment, it does not improve overall survival, while it is associated with an increased risk of late adverse events such as secondary malignancies. In addition, autoSCT lacks the potential to overcome the negative impact of biomarkers that confer resistance to chemotherapy or early relapse. The role of autoSCT has also been explored in the context of FCR, and it was demonstrated that its effect is inferior to the currently established optimal treatment regimen. In view of ongoing attempts to improve on FCR, promising clinical activity of new substances even in relapsed/ refractory CLL patients, exciting novel cell therapy approaches and advantages in the understanding of the disease and detection of Minimal Residual Disease (MRD, autoSCT has lost its place as a standard treatment option for CLL.

  1. Bovine lymphocytic leukemia: studies of etiology, pathogenesis and mode of transmission. Progress report, November 1, 1979-October 31, 1980

    Energy Technology Data Exchange (ETDEWEB)

    Sorensen, D.K.

    1980-06-01

    The primary project objectives are to elucidate the cause(s) and early pathogenesis of the adult form of lymphosarcoma in cattle. This goal is to be accomplished through experimental transmission of the disease. For these studies large quantities of bovine leukemia virus (BLV) were propagated in short-term, mitogen stimulated, lymphocyte cultures. Cultures containing abundant BLV particles were pooled (33 liters total) and further processed by continuous flow, density gradient, ultracentrifugation. This higly concentrated, cell free, BLV preparation was then used as inoculum for 12 late stage bovine fetuses (inoculated in utero) and two newborn calves. Extensive monitoring studies have been carrid out on these inoculated animals to detect precancerous changes and to obtain a detailed description of the events preceding the development of lymphosarcoma. These extensive records on lymphosarcoma associated blood parameters have established that all of the inoculated animals became persistently BLV infected. However, after more than five years of incubation, no cases of lymphosarcoma developed. Consequently, during the past seven months, five of these well characterized animals have been subjected to frequent BLV re-exposure in order to study BLV-host interactions in previously infected adults and to potentially accelerate tumor formation in these animals.

  2. Absolute lymphocyte count at the end of induction therapy is a prognostic factor in childhood acute lymphoblastic leukemia.

    Science.gov (United States)

    Hirase, Satoshi; Hasegawa, Daiichiro; Takahashi, Hironobu; Moriwaki, Kensuke; Saito, Atsuro; Kozaki, Aiko; Ishida, Toshiaki; Yanai, Tomoko; Kawasaki, Keiichiro; Yamamoto, Nobuyuki; Kubokawa, Ikuko; Mori, Takeshi; Hayakawa, Akira; Nishimura, Noriyuki; Nishio, Hisahide; Iijima, Kazumoto; Kosaka, Yoshiyuki

    2015-11-01

    Recent studies have reported that the absolute lymphocyte count (ALC) during induction therapy is predictive of treatment outcome in de novo acute lymphoblastic leukemia (ALL); however, the significance of ALC on outcomes remains controversial. In the present study, we assessed the significance of ALC at day 29 (ALC-29), the end of induction therapy, on outcomes in our Japanese cohort. The outcomes of 141 patients aged ≤18 years with newly diagnosed ALL who were enrolled on the JACLS ALL-02 at our hospitals were analyzed in terms of ALC-29. Patients with ALC-29 ≥750/μL (n = 81) had a superior 5-year EFS (95.2 ± 2.7 vs 84.3 ± 4.8 %, P = 0.016) and OS (100 vs 87.0 ± 4.7 %, P = 0.0062). A multivariate analysis identified ALC-29 ≥750/μL as a significant predictor of improved EFS and OS after controlling for confounding factors. A multiple linear regression model revealed a significant inverse relationship between the percentage of blasts in bone marrow on day 15 and ALC-29 (P = 0.005). These results indicate that ALC is a simple prognostic factor in childhood ALL, and, thus, has the potential to refine current risk algorithms. PMID:26440971

  3. Minimal residual disease detection with tumor-specific CD160 correlates with event-free survival in chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    In chronic lymphocytic leukemia (CLL), the detection of minimal residual disease (MRD) correlates with outcome in the trial setting. However, MRD assessment does not guide routine clinical management and its assessment remains complex. We incorporated detection of the B cell, tumor-specific antigen CD160 to develop a single-tube, flow cytometry assay (CD160FCA) for CLL MRD to a threshold of 10−4 to 10−5. One hundred and eighty-seven patients treated for CLL were enrolled. Utilizing the CD160FCA methodology, there was a high level of comparison between blood and bone marrow (R=0.87, P<0.001). In a validation cohort, CD160FCA and the international standardised approach of the European Research Initiative on CLL group demonstrated high concordance (R=0.91, P<0.01). Patients in complete remission (CR) and CD160FCA negative had longer event-free survival (EFS) (63 vs 16 months, P<0.01) and prolonged time to next treatment (60 vs 15 months, P<0.001) vs MRD positive patients; with a median time to MRD positivity of 36 months. In multivariate analysis, CD160FCA MRD detection was independently predictive of EFS in patients in CR and even predicted EFS in the good-risk cytogenetic subgroup. CD160FCA offers a simple assay for MRD detection in CLL and gives prognostic information across different CLL risk groups

  4. Integrating oncogeriatric tools into the management of chronic lymphocytic leukemia: current state of the art and challenges for the future.

    Science.gov (United States)

    Merli, Francesco; Mammi, Caterina; Ilariucci, Fiorella

    2015-07-01

    Although the achievement of deep and long lasting remissions is a realistic goal of therapy in the fit patient with chronic lymphocytic leukemia (CLL), this disease typically affects elderly patients who also show one or more concomitant pathological conditions or functional limitations that have an additive effects on the reduction of patient's life expectancy and represent major limitations in the adoption of standard therapies. In these unfit but typical patients with CLL, the goals of treatment may vary from achieving good remissions without severe toxicity to simple palliation. Differently from the past when the definition of patient medical status was mainly based on age and was left to the subjective assessment of the physician, today there are several tools to define in a standardized, reproducible, and multidimensional way the initial patient assessment and to plan treatment goals in an objective way. In this review, an overview of the current approaches to the definition of the medical fitness of the patient is provided along with some practical suggestions to integrate these tools in the clinical approach to elderly patients with CLL. PMID:25986721

  5. Lyn sustains oncogenic signaling in chronic lymphocytic leukemia by strengthening SET-mediated inhibition of PP2A.

    Science.gov (United States)

    Zonta, Francesca; Pagano, Mario Angelo; Trentin, Livio; Tibaldi, Elena; Frezzato, Federica; Trimarco, Valentina; Facco, Monica; Zagotto, Giuseppe; Pavan, Valeria; Ribaudo, Giovanni; Bordin, Luciana; Semenzato, Gianpietro; Brunati, Anna Maria

    2015-06-11

    Aberrant protein kinase activities, and the consequent dramatic increase of Ser/Thr and -Tyr phosphorylation, promote the deregulation of the survival pathways in chronic lymphocytic leukemia (CLL), which is crucial to the pathogenesis and progression of the disease. In this study, we show that the tumor suppressor protein phosphatase 2A (PP2A), one of the major Ser/Thr phosphatases, is in an inhibited form because of the synergistic contribution of 2 events, the interaction with its physiologic inhibitor SET and the phosphorylation of Y307 of the catalytic subunit of PP2A. The latter event is mediated by Lyn, a Src family kinase previously found to be overexpressed, delocalized, and constitutively active in CLL cells. This Lyn/PP2A axis accounts for the persistent high level of phosphorylation of the phosphatase's targets and represents a key connection linking phosphotyrosine- and phosphoserine/threonine-mediated oncogenic signals. The data herein presented show that the disruption of the SET/PP2A complex by a novel FTY720-analog (MP07-66) devoid of immunosuppressive effects leads to the reactivation of PP2A, which in turn triggers apoptosis of CLL cells. When used in combination with SFK inhibitors, the action of MP07-66 is synergistically amplified, providing a new option in the therapeutic strategy for CLL patients. PMID:25931585

  6. Combination of Targeted Drugs to Control Chronic Lymphocytic Leukemia: Harnessing the Power of New Monoclonal Antibodies in Combination With Ibrutinib.

    Science.gov (United States)

    Cramer, Paula; Langerbeins, Petra; Hallek, Michael

    2016-01-01

    The landscape of treatment for chronic lymphocytic leukemia is rapidly changing at present. Considerable improvement has been achieved with the introduction of the anti-CD20 antibodies, and chemoimmunotherapy has now become an established standard for patients without the high-risk features del(17p)/TP53 mutation. Also, the outcome of patients with these adverse genetic aberrations was dramatically improved with the introduction of the kinase inhibitors ibrutinib and idelalisib. Different combinations of these and additional novel agents are currently evaluated in clinical trials. The combination of the Bruton tyrosine kinase inhibitor ibrutinib with an anti-CD20 antibody is an attractive option, because both drugs act synergistically: ibrutinib redistributes the CLL cells from their homing organs to the peripheral blood, and obinutuzumab eliminates the leukemic cells in the blood with particular efficiency. Adding the Bcl-2 antagonist venetoclax could further intensify the treatment of CLL. This combination might hold the potential to achieve a deep remission with an eradication of residual CLL cells and thus lead to long-term remissions of CLL. PMID:26841018

  7. BCR Signaling Inhibitors: an Overview of Toxicities Associated with Ibrutinib and Idelalisib in Patients with Chronic Lymphocytic Leukemia.

    Science.gov (United States)

    Falchi, Lorenzo; Baron, Jessica M; Orlikowski, Carrie Anne; Ferrajoli, Alessandra

    2016-01-01

    The B-cell receptor (BCR) signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment of chronic lymphocytic leukemia (CLL) and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology and clinical experience with the use of BCR signaling inhibitors for the treatment of patients with CLL. We next focus on both the most common and the most clinically significant toxicities associated with these drugs. PMID:26977270

  8. BCR SIGNALING INHIBITORS: AN OVERVIEW OF TOXICITIES ASSOCIATED WITH IBRUTINIB AND IDELALISIB IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA

    Directory of Open Access Journals (Sweden)

    Lorenzo Falchi

    2016-02-01

    Full Text Available The B-cell receptor signaling inhibitors ibrutinib and idelalisib are revolutionizing the treatment landscape of chronic lymphocytic leukemia (CLL and other B-cell malignancies. These oral agents, both alone and in combination with other drugs, have shown remarkable clinical activity in relapsed or refractory CLL across all risk groups, and have been approved by the Food and Drug Administration for this indication. Preliminary data suggest that an even greater benefit can be expected in treatment-naïve CLL patients. Both ibrutinib and idelalisib are well tolerated by most patients, including older, frailer individuals. Toxicities are usually mild and self-resolving. Clinicians must, however, be aware of a number of peculiar adverse events, the effects of which can be severe enough to limit the clinical use of these agents. In this review, we survey the salient aspects of the pharmacology of these agents, as well as clinical experience regarding their use for the treatment of patients with CLL. Our foci will be both the most common and the most clinically significant toxicities associated with these drugs.

  9. Association of interleukin-6 and interleukin-8 with poor prognosis in elderly patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Yoon, Ju-Yoon; Lafarge, Sandrine; Dawe, Dave; Lakhi, Sunjay; Kumar, Rajat; Morales, Carmen; Marshall, Aaron; Gibson, Spencer B; Johnston, James B

    2012-09-01

    In population studies, the relative survival in chronic lymphocytic leukemia (CLL) decreases with age. In this study, we demonstrated in a cohort of 189 patients from a CLL clinic that overall survival was lower in the sub-cohort of patients aged ≥ 70 years, but causes of death were similar for all age groups, being progressive CLL, secondary malignancies and infections. As normal individuals age, the plasma levels of inflammatory cytokines, such as interleukin-6 (IL-6) and IL-8, can increase. In our patients with CLL, IL-6, IL-8 and tumor necrosis factor-α (TNF-α) levels increased with age to a greater degree than in normal individuals, and the levels correlated closely with plasma β(2)-microglobulin and with one another. In addition, in patients ≥ 70 years, IL-6 was found to be a better prognostic marker than immunoglobulin variable heavy chain gene (IgV(H)) status. In vitro studies demonstrated that IL-6 and IL-8 could enhance the binding of CLL cells to stromal cells, suggesting that their clinical activity may be mediated through their effects on the microenvironment. Thus, plasma IL-6 is an important prognostic marker for the elderly with CLL, and this study highlights that the utility of prognostic markers may depend on patient age. PMID:22475215

  10. Epstein-Barr virus DNA load in chronic lymphocytic leukemia is an independent predictor of clinical course and survival.

    Science.gov (United States)

    Visco, Carlo; Falisi, Erika; Young, Ken H; Pascarella, Michela; Perbellini, Omar; Carli, Giuseppe; Novella, Elisabetta; Rossi, Davide; Giaretta, Ilaria; Cavallini, Chiara; Scupoli, Maria Teresa; De Rossi, Anita; D'Amore, Emanuele Stefano Giovanni; Rassu, Mario; Gaidano, Gianluca; Pizzolo, Giovanni; Ambrosetti, Achille; Rodeghiero, Francesco

    2015-07-30

    The relation between Epstein-Barr virus (EBV) DNA load and clinical course of patients with chronic lymphocytic leukemia (CLL) is unknown. We assessed EBV DNA load by quantitative PCR at CLL presentation in mononuclear cells (MNC) of 220 prospective patients that were enrolled and followed-up in two major Institutions. In 20 patients EBV DNA load was also assessed on plasma samples. Forty-one age-matched healthy subjects were tested for EBV DNA load on MNC. Findings were validated in an independent retrospective cohort of 112 patients with CLL. EBV DNA load was detectable in 59%, and high (≥2000 copies/µg DNA) in 19% of patients, but it was negative in plasma samples. EBV DNA load was significantly higher in CLL patients than in healthy subjects (P variables, except for 11q deletion (P = .004), CD38 expression (P = .003), and NOTCH1 mutations (P = .05). High EBV load led to a 3.14-fold increase in the hazard ratio of death and to a shorter overall survival (OS; P = .001). Poor OS was attributable, at least in part, to shorter time-to-first-treatment (P = .0008), with no higher risk of Richter's transformation or second cancer. Multivariate analysis selected high levels of EBV load as independent predictor of OS after controlling for confounding clinical and biological variables. EBV DNA load at presentation is an independent predictor of OS in patients with CLL. PMID:26087198

  11. Modification of immunocytochemical ZAP-70 assay for potential clinical application in B-cell chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Jerzy Kawiak

    2011-08-01

    Full Text Available The ZAP-70 protein is a member of the Syk/ZAP protein tyrosine kinase family, normally expressed in T cells and NK cells but not found in normal, mature B cells. The protein plays a critical role in the initiation of T-cell signaling. Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL that expressed nonmutated immunoglobulin V genes were found to express levels of ZAP-70 protein that were comparable to those detected in T cells of healthy adults. The ZAP-70 protein expression can be evaluated by flow cytometry and may be used as a prognostic marker in B-CLL patients. We modified the method of immunocytochemical assessment of ZAP-70 expression. The traditional two-step method with monoclonal anti-ZAP-70 antibody in the first step followed by FITC-conjugated goat anti-mouse IgG was changed for one-step method with monoclonal anti-ZAP-70 antibody labeled by Zenon Alexa Fluor 488. The method is simple and fast. The major advantage of Zenon labeling technique is its compatibility with simultaneous staining of surface antigens. The cells may be earlier immunostained for CD3, CD19 and/or CD5 to compare of the ZAP-70 kinase expression in B and T cells.

  12. Modification of immunocytochemical ZAP-70 assay for potential clinical application in B-cell chronic lymphocytic leukemia.

    Science.gov (United States)

    Bojarska-Junak, Agnieszka; Roliński, Jacek; Kawiak, Jerzy

    2005-01-01

    The ZAP-70 protein is a member of the Syk/ZAP protein tyrosine kinase family, normally expressed in T cells and NK cells but not found in normal, mature B cells. The protein plays a critical role in the initiation of T-cell signaling. Leukemic cells from patients with B-cell chronic lymphocytic leukemia (B-CLL) that expressed nonmutated immunoglobulin V genes were found to express levels of ZAP-70 protein that were comparable to those detected in T cells of healthy adults. The ZAP-70 protein expression can be evaluated by flow cytometry and may be used as a prognostic marker in B-CLL patients. We modified the method of immunocytochemical assessment of ZAP-70 expression. The traditional two-step method with monoclonal anti-ZAP-70 antibody in the first step followed by FITC-conjugated goat anti-mouse IgG was changed for one-step method with monoclonal anti-ZAP-70 antibody labeled by Zenon Alexa Fluor 488. The method is simple and fast. The major advantage of Zenon labeling technique is its compatibility with simultaneous staining of surface antigens. The cells may be earlier immunostained for CD3, CD19 and/or CD5 to compare of the ZAP-70 kinase expression in B and T cells. PMID:15871558

  13. Chaetoglobosin A preferentially induces apoptosis in chronic lymphocytic leukemia cells by targeting the cytoskeleton

    DEFF Research Database (Denmark)

    Knudsen, Peter Boldsen; Hanna, B.; Ohl, S.;

    2013-01-01

    family that showed preferential induction of apoptosis in CLL cells, even under culture conditions that mimic lymphoid tissues. In vitro testing of 89 CLL cases revealed effective targeting of CLL cells by Chaetoglobosin A, independent of bad prognosis characteristics, like 17p deletion or TP53 mutation...... novel drugs that target CLL cells also in protective microenvironments, we performed a fungal extract screen using cocultures of primary CLL cells with bone marrow-derived stromal cells. A metabolite produced by Penicillium aquamarinium was identified as Chaetoglobosin A, a member of the cytochalasan...... treatment with PI3K and BTK inhibitors, suggesting this compound as a novel potential drug for CLL.Leukemia accepted article preview online, 27 November 2013. doi:10.1038/leu.2013.360....

  14. Biological and clinical meaning of myeloid antigen expression in the acute lymphocytic leukemia in children

    International Nuclear Information System (INIS)

    In 238 children presenting with acute lymphoid leukemia (ALL) authors studied the possible association between the myeloid antigens expression with determined biologic and clinic features at disease onset. The cellular immunophenotyping was performed by ultraimmunocytochemical method. From the total of diagnosed ALLs, the 21,8% were LLA-Mi+. There was a lymphadenopathies predominance (71,2%), splenomegaly (65,4%) and hepatomegaly (57,7%) in patients with LLA-Mi+ and very significant differences (p =0,003, p = 0,0068, and p = 0,000, respectively. There was also alight predominance of mediastinum adenopathies, CNS infiltration and hemorrahagic manifestations in patients with LLA-Mi+, no statistically significant. Results showed that in our patients the myeloid antigen expression on the lymphoid blasts influenced on appearance of determined presentation of morphologic and clinical features in children

  15. Adult Leukemias

    OpenAIRE

    Moore, Lyall K.

    1984-01-01

    Over the past several years, advances have been made in the classification, diagnosis and therapy of the adult leukemias. The overall prognosis and quality of life have improved greatly, especially for patients with acute nonlymphoblastic leukemias. Some of the advances are described in this article. The importance of the clinical, laboratory and diagnostic tests for acute, chronic granulocytic and chronic lymphocytic leukemia are stressed. The therapy and prognosis for patients with the vari...

  16. Biochemical and immunologic heterogeneity of Ia glycoproteins isolated from a chronic lymphocytic leukemia

    International Nuclear Information System (INIS)

    Ia glycoproteins have been isolated from human chronic lymphocytic leukemic cells (CLL) by Lens culinaris chromatography and by filtration on ACA-34 Ultrogel. Ia antigenic activity, measured by inhibition of the cellular radioimmunoassay, was separated by gel filtration into 2 fractions, peak I and II. Monoclonal antibodies, produced against peak II glycoproteins, appear to recognize different antigenic determinants of Ia molecules. Monoclonal antibody 18a4 reacted with Ia molecules of peaks I and II, whereas monoclonal antibodies 18c2 and 18d5 reacted almost exclusively with peak II molecules both in the cellular radioimmunoassay and by immunoprecipitation. In addition to antigenic differences, minor variations in the apparent m.w. of the Ia polypeptide chains were observed between peaks I and II. These results indicate the existence of antigenically distinct subsets of Ia molecules that are separated by gel filtration

  17. Cytomegalovirus infection does not impact on survival or time to first treatment in patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Parry, Helen Marie; Damery, Sarah; Hudson, Christopher; Maurer, Matthew J; Cerhan, James R; Pachnio, Annette; Begum, Jusnara; Slager, Susan L; Fegan, Christopher; Man, Stephen; Pepper, Christopher; Shanafelt, Tait D; Pratt, Guy; Moss, Paul A H

    2016-08-01

    Human cytomegalovirus (HCMV) is a widely prevalent herpes virus which establishes a state of chronic infection. The establishment of CMV-specific immunity controls viral reactivation and leads to the accumulation of very large numbers of virus-specific T cells which come to dominate the immune repertoire. There is concern that this may reduce the immune response to heterologous infections and HCMV infection has been associated with reduced survival in elderly people. Patients with chronic lymphocytic leukemia (B-CLL) suffer from a state of immune suppression but have a paradoxical increase in the magnitude of the CMV-specific T cell and humoral immune response. As such, there is now considerable interest in how CMV infection impacts on the clinical outcome of patients with B-CLL. Utilizing a large prospective cohort of patients with B-CLL (n = 347) we evaluated the relationship between HCMV seropositivity and patient outcome. HCMV seropositive patients had significantly worse overall survival than HCMV negative patients in univariate analysis (HR = 2.28, 95% CI: 1.34-3.88; P = 0.002). However, CMV seropositive patients were 4 years older than seronegative donors and this survival difference was lost in multivariate modeling adjusted for age and other validated prognostic markers (P = 0.34). No significant difference was found in multivariate modeling between HCMV positive and negative patients in relation to the time to first treatment (HR = 1.12, 95% CI: 0.68-1.84; P = 0.65). These findings in a second independent cohort of 236 B-CLL patients were validated. In conclusion no evidence that HCMV impacts on the clinical outcome of patients with B-CLL was found. Am. J. Hematol. 91:776-781, 2016. © 2016 Wiley Periodicals, Inc. PMID:27124884

  18. Efficacy of phosphatidylinositol-3 kinase inhibitors with diverse isoform selectivity profiles for inhibiting the survival of chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Göckeritz, Elisa; Kerwien, Susan; Baumann, Michael; Wigger, Marion; Vondey, Verena; Neumann, Lars; Landwehr, Thomas; Wendtner, Clemens M; Klein, Christian; Liu, Ningshu; Hallek, Michael; Frenzel, Lukas P; Krause, Günter

    2015-11-01

    Pharmacological inhibition of phosphatiylinositide-3-kinase (PI3K)-mediated signaling holds great promise for treating chronic lymphocytic leukemia (CLL). Therefore we assessed three structurally related PI3K inhibitors targeting the PI3K-δ isoform for their ability to inhibit the survival of freshly isolated CLL cells. The purely PI3K-δ-selective inhibitor idelalisib was compared to copanlisib (BAY 80-6946) and duvelisib (IPI-145), with isoform target profiles that additionally include PI3K-α or PI3K-γ, respectively. The concentrations leading to half-maximal reduction of the survival of CLL cells were more than ten-fold lower for copanlisib than for idelalisib and duvelisib. At concentrations reflecting the biological availability of the different inhibitors, high levels of apoptotic response among CLL samples were attained more consistently with copanlisib than with idelalisib. Copanlisib selectively reduced the survival of CLL cells compared to T cells and to B cells from healthy donors. In addition copanlisib and duvelisib impaired the migration of CLL cells towards CXCL12 to a greater extent than equimolar idelalisib. Similarly copanlisib and duvelisib reduced the survival of CLL cells in co-cultures with the bone marrow stroma cell line HS-5 more strongly than idelalisib. Survival inhibition by copanlisib and idelalisib was enhanced by the monoclonal CD20 antibodies rituximab and obinutuzumab (GA101), while antibody-dependent cellular cytotoxicity mediated by alemtuzumab and peripheral blood mononuclear cells was not substantially impaired by both PI3K inhibitors for the CLL-derived JVM-3 cell line as target cells. Taken together, targeting the α- and δ- p110 isoforms with copanlisib may be a useful strategy for the treatment of CLL and warrants further clinical investigation. PMID:25912635

  19. Hedgehog/GLI and PI3K signaling in the initiation and maintenance of chronic lymphocytic leukemia.

    Science.gov (United States)

    Kern, D; Regl, G; Hofbauer, S W; Altenhofer, P; Achatz, G; Dlugosz, A; Schnidar, H; Greil, R; Hartmann, T N; Aberger, F

    2015-10-16

    The initiation and maintenance of a malignant phenotype requires complex and synergistic interactions of multiple oncogenic signals. The Hedgehog (HH)/GLI pathway has been implicated in a variety of cancer entities and targeted pathway inhibition is of therapeutic relevance. Signal cross-talk with other cancer pathways including PI3K/AKT modulates HH/GLI signal strength and its oncogenicity. In this study, we addressed the role of HH/GLI and its putative interaction with the PI3K/AKT cascade in the initiation and maintenance of chronic lymphocytic leukemia (CLL). Using transgenic mouse models, we show that B-cell-specific constitutive activation of HH/GLI signaling either at the level of the HH effector and drug target Smoothened or at the level of the GLI transcription factors does not suffice to initiate a CLL-like phenotype characterized by the accumulation of CD5(+) B cells in the lymphatic system and peripheral blood. Furthermore, Hh/Gli activation in Pten-deficient B cells with activated Pi3K/Akt signaling failed to enhance the expansion of leukemic CD5(+) B cells, suggesting that genetic or epigenetic alterations leading to aberrant HH/GLI signaling in B cells do not suffice to elicit a CLL-like phenotype in mice. By contrast, we identify a critical role of GLI and PI3K signaling for the survival of human primary CLL cells. We show that combined targeting of GLI and PI3K/AKT/mTOR signaling can have a synergistic therapeutic effect in cells from a subgroup of CLL patients, thereby providing a basis for the evaluation of future combination therapies targeting HH/GLI and PI3K signaling in this common hematopoietic malignancy. PMID:25639866

  20. Pharmacokinetics of dasatinib for Philadelphia-positive acute lymphocytic leukemia with acquired T315I mutation

    Directory of Open Access Journals (Sweden)

    Takahashi Naoto

    2012-05-01

    Full Text Available Abstract Background The BCR-ABL T315I kinase domain mutation is insensitive to dasatinib therapy for Philadelphia-positive acute lymphoid leukemia (Ph + ALL patients. Resistant T315I clone may be present prior to initiating dasatinib, which could expand under selective pressures during treatment. However, it is also possible that Ph + ALL patients newly acquire the T315I mutation during dasatinib therapy. Despite the potent inhibition of BCR-ABL kinase by dasatinib, little is known about the relationship between dasatinib pharmacokinetics and the emergence of kinase domain mutations in vivo. Methods To determine whether plasma dasatinib pharmacokinetics influences the emergence of BCR-ABL mutations, we measured plasma dasatinib levels in 11 Ph + ALL patients undergoing dasatinib monotherapy. Results Bone marrow relapse occurred in 5 of the 11 Ph + ALL patients (45%. Importantly, a T315I mutation was detected in 4 of the 5 relapsed patients, despite the absence of BCR-ABL mutations in any patient at baseline. The median plasma concentration at 2 hours (C2h, the median plasma maximum concentration (Cmax, and the median area under the observed plasma concentration-time curve from 0 to 4 hours (AUC0-4 were all significantly lower in patients with T315I than those without the mutation (C2h, 22.3 ng/mL vs. 111.6 ng/mL, P = 0.0242; Cmax, 43.8 ng/mL vs. 112.4 ng/mL, P = 0.0242; AUC0-4, 108.3 ng·h/mL vs. 268.3 ng·h/mL, P = 0.0061, respectively. Conclusions These data indicate that the emergence of the T315I mutation among Ph + ALL patients treated with dasatinib is, in part, dependent on plasma dasatinib pharmacokinetics. Notably, these data also suggest that newly acquired BCR-ABL mutations may be inhibited by an increased exposure of dasatinib.

  1. Defining Molecular Phenotypes of Mesenchymal and hematopoietic Stem Cells derived from Peripheral blood of Acute Lymphocytic Leukemia patients for regenerative stem cell therapy

    Science.gov (United States)

    Potdar, PD; Subedi, RP

    2011-01-01

    Acute Lymphocytic Leukemia (ALL) is a clonal myeloid disorder affecting all age groups, characterized by accumulation of immature blast cells in bone marrow and in peripheral blood. Autologous Bone Marrow Transplantation is a present treatment for cure of ALL patients, which is very expensive, invasive process and may have possibility of transplantation of malignant stem cells to patients. In the present study, we hypothesized to isolate large number of normal Mesenchymal & Hematopoietic stem cells from peripheral blood of ALL patients, which will be further characterized for their normal phenotypes by using specific molecular stem cell markers. This is the first study, which defines the existing phenotypes of isolated MSCs and HSCs from peripheral blood of ALL patients. We have established three cell lines in which two were Mesenchymal stem cells designated as MSCALL and MSCnsALL and one was suspension cell line designated as HSCALL. The HSCALL cell line was developed from the lymphocyte like cells secreted by MSCALL cells. Our study also showed that MSCALL from peripheral blood of ALL patient secreted hematopoietic stem cells in vitro culture. We have characterized all three-cell lines by 14 specific stem cell molecular markers. It was found that both MSC cell lines expressed CD105, CD13, and CD73 with mixed expression of CD34 and CD45 at early passage whereas, HSCALL cell line expressed prominent feature of hematopoietic stem cells such as CD34 and CD45 with mild expression of CD105 and CD13. All three-cell lines expressed LIF, OCT4, NANOG, SOX2, IL6, and DAPK. These cells mildly expressed COX2 and did not express BCR-ABL. Overall it was shown that isolated MSCs and HSCs can be use as a model system to study the mechanism of leukemia at stem cell level and their use in stem cell regeneration therapy for Acute Lymphocytic Leukemia. PMID:24693170

  2. Defining Molecular Phenotypes of Mesenchymal and hematopoietic Stem Cells derived from Peripheral blood of Acute Lymphocytic Leukemia patients for regenerative stem cell therapy

    Directory of Open Access Journals (Sweden)

    Pravin D. Potdar

    2011-01-01

    Full Text Available Acute Lymphocytic Leukemia (ALL is a clonal myeloid disorder affecting all age groups, characterized by accumulation of immature blast cells in bone marrow and in peripheral blood. Autologous Bone Marrow Transplantation is a present treatment for cure of ALL patients, which is very expensive, invasive process and may have possibility of transplantation of malignant stem cells to patients. In the present study, we hypothesized to isolate large number of normal Mesenchymal & Hematopoietic stem cells from peripheral blood of ALL patients, which will be further characterized for their normal phenotypes by using specific molecular stem cell markers. This is the first study, which defines the existing phenotypes of isolated MSCs and HSCs from peripheral blood of ALL patients. We have established three cell lines in which two were Mesenchymal stem cells designated as MSCALL and MSCnsALL and one was suspension cell line designated as HSCALL. The HSCALL cell line was developed from the lymphocyte like cells secreted by MSCALL cells. Our study also showed that MSCALL from peripheral blood of ALL patient secreted hematopoietic stem cells in vitro culture. We have characterized all three-cell lines by 14 specific stem cell molecular markers. It was found that both MSC cell lines expressed CD105, CD13, and CD73 with mixed expression of CD34 and CD45 at early passage whereas, HSCALL cell line expressed prominent feature of hematopoietic stem cells such as CD34 and CD45 with mild expression of CD105 and CD13. All three-cell lines expressed LIF, OCT4, NANOG, SOX2, IL6, and DAPK. These cells mildly expressed COX2 and did not express BCR-ABL. Overall it was shown that isolated MSCs and HSCs can be use as a model system to study the mechanism of leukemia at stem cell level and their use in stem cell regeneration therapy for Acute Lymphocytic Leukemia.

  3. S-phase induction by interleukin-6 followed by chemotherapy in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma

    DEFF Research Database (Denmark)

    Brown, P D; Diamant, Marcus; Jensen, P O;

    1999-01-01

    Interleukin-6 (IL-6) has in vitro demonstrated growth regulatory effects on tumor cells from patients with chronic lymphocytic leukemia (CLL) and lymphoma. The proliferation rate of these cells is usually very low and this is thought to be one of the reasons for the lack of a curative potential of...... cytostatic chemotherapy in CLL and low grade NHL. Recombinant human (rh) IL-6 might increase the in vivo proliferation rate leading to a higher sensitivity for chemotherapy. We tested this hypothesis by administering rhIL-6 to 9 CLL patients and 3 NHL patients in doses of 2.5 micrograms/kg, 5 micrograms...

  4. T-cell independent, B-cell receptor-mediated induction of telomerase activity differs among IGHV mutation-based subgroups of chronic lymphocytic leukemia patients

    OpenAIRE

    Damle, Rajendra N.; Temburni, Sonal; Banapour, Taraneh; Paul, Santanu; Mongini, Patricia K. A.; Allen, Steven L.; Kolitz, Jonathan E.; Rai, Kanti R; Chiorazzi, Nicholas

    2012-01-01

    Although B-cell chronic lymphocytic leukemia (B-CLL) clones with unmutated IGHV genes (U-CLL) exhibit greater telomerase activity than those with mutated IGHV genes (M-CLL), the extent to which B-cell receptor (BCR) triggering contributes to telomerase up-regulation is not known. Therefore, we studied the effect of BCR stimulation on modulating telomerase activity. The multivalent BCR ligand, dextran conjugated anti-μ mAb HB57 (HB57-dex), increased telomerase activity and promoted cell surviv...

  5. Crucial role of timing of donor lymphocyte infusion in generating dissociated graft-versus-host and graft-versus-leukemia responses in mice receiving allogeneic bone marrow transplants

    OpenAIRE

    Billiau, An; Fevery, Sabine; Rutgeerts, Omer; Landuyt, Willy; Waer, Mark

    2002-01-01

    A murine model of minor histocompatibility antigen-mismatched bone marrow transplantation (BMT) was used to study the role of timing of donor lymphocyte infusion (DLI) in eliciting graft-versus-host (GVH) and graft-versus-leukemia (GVL) reactivity. We gave DLI at weeks 3 and 12 after BMT and related its ability to induce a GVL effect with (1) evolution of T cell chimeric status and (2) the extent to which DLI could elicit lymphohematopoietic GVH (LHGVH) reactivity. All mice remained free of G...

  6. A Systemic Capillary Leak Syndrome (Clarkson Syndrome in a Patient with Chronic Lymphocytic Leukemia: A Case Report in an Out-of-Hospital Setting

    Directory of Open Access Journals (Sweden)

    Manon Durand Bechu

    2016-01-01

    Full Text Available Systemic Capillary Leak Syndrome (SCLS is a rare disease with poor prognosis, characterized by the occurrence of mucocutaneous and visceral edema with hypotension, hemoconcentration, and unexpected hypoalbuminemia. The disease can be idiopathic (Clarkson syndrome or secondary to other diseases and treatments. We describe this syndrome in a prehospitalized, 63-year-old patient with chronic lymphocytic leukemia and an idiopathic form of SCLS manifesting as hypovolemic shock. Initial care is hospitalization in intensive care. In addition to etiological treatment if fluid replacement is necessary, treatment must be closely monitored for secondary overload complications. Catecholamine rather than arrhythmogenic support may be associated.

  7. A Systemic Capillary Leak Syndrome (Clarkson Syndrome) in a Patient with Chronic Lymphocytic Leukemia: A Case Report in an Out-of-Hospital Setting

    Science.gov (United States)

    Durand Bechu, Manon; Rouget, Antoine; Recher, Christian; Azoulay, Elie; Bounes, Vincent

    2016-01-01

    Systemic Capillary Leak Syndrome (SCLS) is a rare disease with poor prognosis, characterized by the occurrence of mucocutaneous and visceral edema with hypotension, hemoconcentration, and unexpected hypoalbuminemia. The disease can be idiopathic (Clarkson syndrome) or secondary to other diseases and treatments. We describe this syndrome in a prehospitalized, 63-year-old patient with chronic lymphocytic leukemia and an idiopathic form of SCLS manifesting as hypovolemic shock. Initial care is hospitalization in intensive care. In addition to etiological treatment if fluid replacement is necessary, treatment must be closely monitored for secondary overload complications. Catecholamine rather than arrhythmogenic support may be associated. PMID:27069700

  8. Therapeutic Autologous Lymphocytes and Aldesleukin in Treating Patients With High-Risk or Recurrent Myeloid Leukemia After Undergoing Donor Stem Cell Transplant

    Science.gov (United States)

    2011-07-12

    Accelerated Phase Chronic Myelogenous Leukemia; Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Childhood Myelodysplastic Syndromes; Recurrent Adult Acute Myeloid Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia

  9. Epidemiologia da leucemia linfocítica crônica e leucemia linfocítica crônica familiar Epidemiology of chronic lymphocytic leukemia and familial chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Mihoko Yamamoto

    2005-12-01

    Full Text Available A leucemia linfocítica crônica (LLC é uma doença linfoproliferativa crônica (DLPC que apresenta características epidemiológicas peculiares; acomete indivíduos com idade mais avançada (não ocorre em crianças e é rara abaixo dos 30 anos e a sua incidência varia conforme a origem étnica dos pacientes. É a leucemia mais freqüente nos países ocidentais enquanto muito rara nos orientais. A sua etiologia não está ainda esclarecida, não se conhecendo fatores ambientais que mostrem forte associação com o surgimento da doença. Não tem relação com radiação ionizante (sobreviventes da bomba atômica não apresentaram aumento na incidência da LLC, assim como não foi demonstrada associação com agentes tóxicos ou virais específicos. A LLC familiar é assim denominada quando, pelo menos, dois membros de uma família apresentam LLC e o diagnóstico nestes pacientes costuma ocorrer em idade mais precoce. A ocorrência é maior em parentes de primeiro grau (irmãos, filhos, podendo, porém, afetar parentes mais distantes. Os familiares de pacientes com LLC apresentam maior freqüência de outras DLPC (risco relativo 30x maior e de proliferação monoclonal de linfócitos B (13%-18% e parece que o HLADR1.11 está implicado na LLC familiar, pelo menos em algumas populações.Chronic lymphocytic leukemia (CLL is a chronic lympho-proliferative desorder (CLPD with peculiar epidemiologic characteristics. It is a disease of the elderly, which is very rare in under 30-year-old individuals and absent among children. Its incidence largely varies according to the ethnical origin: CLL is the most common leukemia in Western countries while it is rarely seen in Eastern countries. The etiology of CLL is still unknown. Environmental factors such as exposure to ionizing radiation (atomic bomb survivors did not show an increased incidence of CLL or toxic or viral agents are not associated to the occurrence of CLL. Familiar CLL is characterized when

  10. Expression of Functional Sphingosine-1 Phosphate Receptor-1 Is Reduced by B Cell Receptor Signaling and Increased by Inhibition of PI3 Kinase δ but Not SYK or BTK in Chronic Lymphocytic Leukemia Cells

    OpenAIRE

    Till, Kathleen J.; Andrew R Pettitt; Slupsky, Joseph R.

    2015-01-01

    BCR signaling pathway inhibitors such as ibrutinib, idelalisib, and fostamatinib (respective inhibitors of Bruton’s tyrosine kinase, PI3Kδ, and spleen tyrosine kinase) represent a significant therapeutic advance in B cell malignancies, including chronic lymphocytic leukemia (CLL). These drugs are distinctive in increasing blood lymphocytes while simultaneously shrinking enlarged lymph nodes, suggesting anatomical redistribution of CLL cells from lymph nodes into the blood. However, the mechan...

  11. Surface antigen expression and correlation with variable heavy-chain gene mutation status in chronic lymphocytic leukemia.

    Science.gov (United States)

    Vilpo, Juhani; Tobin, Gerard; Hulkkonen, Janne; Hurme, Mikko; Thunberg, Ulf; Sundström, Christer; Vilpo, Leena; Rosenquist, Richard

    2003-01-01

    Recent studies have demonstrated that B-cell chronic lymphocytic leukemia (CLL) consists of two clinical entities with either somatically hypermutated (M-CLL) or unmutated (UM-CLL) immunoglobulin variable heavy-chain (VH) regions. In view of the fact that the cellular biology of these two subsets of disease is currently unexplored, we performed an extensive analysis of the surface antigen expression and correlated this with the VH gene mutation status in a cohort of 32 CLL patients. Using polymerase chain reaction amplification and nucleotide sequencing, the VH genes were shown to be mutated in 10 cases (31%) and unmutated in 22 (69%). The expression of 27 surface membrane antigens in peripheral blood leukemic cells was analyzed by flow cytometry, measuring both the percentage of positive cells as well as the geometric mean fluorescence intensity (GMF). Most of the surface membrane antigens (CD5, CD11c, CD19, CD20, CD21, CD22, CD23, CD25, CD40, CD45, VD79b, CD80, CD95, CD122, CD124, CD126, CD130, CD154, IgM, and IgD) showed a similar expression pattern in both UM-CLL and M-CLL patients. The similarity of M-CLL and UM-CLL, as demonstrated here for the first time with many protein markers, indicates a considerably homogeneous phenotype in both subsets. Furthermore, CD27 was strongly expressed in all cases, which may suggest a memory cell phenotype for both M-CLL and UM-CLL. More positive cells in the UM-CLL group were observed regarding CD38, but CD38 was not a good predictor of VH gene mutation status. Seventy percent of the M-CLL cases, but only 36% of UM-CLL cases, were Ig-lambda+. The most striking differential expression, however, was observed in the two slicing variants of the common leukocyte antigen CD45, namely CD45RO and CD45RA. CD45RO expression was significantly associated with M-CLL, whereas the GMF intensity of CD45RA tended to be associated with UM-CLL. The role of these CD45 splicing variants in the pathogenesis of CLL deserves further investigation

  12. Evaluation of ZAP-70 expression by flow cytometry in chronic lymphocytic leukemia: A multicentric international harmonization process.

    Science.gov (United States)

    Letestu, Remi; Rawstron, Andy; Ghia, Paolo; Villamor, Neus; Boeckx, Nancy; Leuven, Nancy Boeckx; Boettcher, Sebastian; Buhl, Anne Mette; Duerig, Jan; Ibbotson, Rachel; Kroeber, Alexander; Langerak, Anton; Le Garff-Tavernier, Magali; Mockridge, Ian; Morilla, Alison; Padmore, Ruth; Rassenti, Laura; Ritgen, Matthias; Shehata, Medhat; Smolewski, Piotr; Staib, Peter; Ticchioni, Michel; Walker, Clare; Ajchenbaum-Cymbalista, Florence

    2006-07-15

    The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous with some patients requiring early therapy whereas others will not be treated for years. The evaluation of an individual CLL patient's prognosis remains a problematic issue. The presence or absence of somatic mutations in the IgVH genes is currently the gold-standard prognostic factor, but this technique is labor intensive and costly. Genomic studies uncovered that 70 kDa zeta-associated protein (ZAP-70) expression was associated with unmutated IgVH genes and ZAP-70 protein expression was proposed as a surrogate for somatic mutational status. Among the available techniques for ZAP-70 detection, flow cytometry is most preferable as it allows the simultaneous quantification of ZAP-70 protein expression levels in CLL cells and residual normal lymphocyte subsets. However, several factors introduce variability in the results reported from different laboratories; these factors include the anti-ZAP-70 antibody clone and conjugate, the staining procedure, the gating strategy, and the method of reporting the results. The need for standardization of the approach led to the organization of an international working group focused on harmonizing all aspects of the technique. During this workshop, a technical consensus was reached on the methods for cell permeabilization and immunophenotyping procedures. An assay was then designed that allowed comparison of two clones of anti-ZAP-70 antibody and the identification of the expression of this molecule in B, T, and NK cells identified in a four multicolor analysis. This procedure was applied to three stabilized blood samples, provided by the UK NEQAS group to all participating members of this study, in order to minimize variability caused by sample storage and shipment. Analysis was performed in 20 laboratories providing interpretable data from 14 centers. Various gating strategies were used and the ZAP-70 levels were expressed as percentage

  13. Chronic lymphocytic leukemia cells diversify and differentiate in vivo via a nonclassical Th1-dependent, Bcl-6–deficient process

    Science.gov (United States)

    Patten, Piers E.M.; Ferrer, Gerardo; Chen, Shih-Shih; Simone, Rita; Marsilio, Sonia; Yan, Xiao-Jie; Gitto, Zachary; Yuan, Chaohui; Kolitz, Jonathan E.; Barrientos, Jacqueline; Allen, Steven L.; Rai, Kanti R.; MacCarthy, Thomas; Chu, Charles C.; Chiorazzi, Nicholas

    2016-01-01

    Xenografting primary tumor cells allows modeling of the heterogeneous natures of malignant diseases and the influences of the tissue microenvironment. Here, we demonstrate that xenografting primary chronic lymphocytic leukemia (CLL) B lymphocytes with activated autologous T cells into alymphoid mice results in considerable CLL B cell division and sizable T cell expansion. Nevertheless, most/all CD5+CD19+ cells are eventually lost, due in part to differentiation into antibody-secreting plasmablasts/plasma cells. CLL B cell differentiation is associated with isotype class switching and development of new IGHV-D-J mutations and occurs via an activation-induced deaminase-dependent pathway that upregulates IRF4 and Blimp-1 without appreciable levels of the expected Bcl-6. These processes were induced in IGHV-unmutated and IGHV-mutated clones by Th1-polarized T-bet+ T cells, not classical T follicular helper (Tfh) cells. Thus, the block in B cell maturation, defects in T cell action, and absence of antigen-receptor diversification, which are often cardinal characteristics of CLL, are not inherent but imposed by external signals and the microenvironment. Although these activities are not dominant features in human CLL, each occurs in tissue proliferation centers where the mechanisms responsible for clonal evolution operate. Thus, in this setting, CLL B cell diversification and differentiation develop by a nonclassical germinal center–like reaction that might reflect the cell of origin of this leukemia.

  14. A case repot of Merkel cell carcinoma on chronic lymphocytic leukemia: differential diagnosis of coexisting lymphadenopathy and indications for early aggressive treatment

    International Nuclear Information System (INIS)

    Chronic lymphocytic leukemia (CLL) is a monoclonal disorder, characterized by a progressive proliferation of functionally incompetent B lymphocytes. There is increased evidence of association between CLL and skin cancers, including the uncommon Merkel cell carcinoma (MCC). A case report of an 84-year old male, who presented with an aggressively recurrent form of MCC on the lower lip, on the background of an 8-year history of untreated CLL. During the recurrences of MCC, coexisting regional lymphadenopathy, posed a problem in the differential diagnosis and treatment of lymph node involvement. Histopathology and immunoistochemistry showed that submandibular lymphadenopathy coexisting with the second recurrence of MCC, was due to B-cell small lymphocytic lymphoma. The subsequent and more aggressive recurrence of the skin tumor had involved the superficial and deep cervical lymph nodes. Surgical excision followed by involved field radiation therapy has been proven effective for both malignancies. MCC has a high incidence of regional lymphadenopathy at presentation (12–45%) and even when it arises on the background of chronic leucemia, lymphadenopathy at presentation should be managed agressively with elective lymph node dissection. We overview the postulated correlation between Merkel tumor and CCL, the differential diagnosis of regional lymphadenopathy during the recurrences of the skin tumor and the strategies of treatment

  15. Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

    DEFF Research Database (Denmark)

    Coiffier, B.; Lepretre, S.; Pedersen, L.M.;

    2008-01-01

    Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusio...

  16. Cranial computer assisted tomography and electroencephalography in children with acute lymphocytic leukemia : a longitudinal study : Computertomografie van de schedel en electroencephalografisch onderzoek bij kinderen met een acute lymfatische leukemie. Een longitudinale studie

    NARCIS (Netherlands)

    K. Hählen (Karel)

    1990-01-01

    textabstractThis longitudinal study was initiated in order to examine the nature and sequence of structural and functional cerebral abnormalities in children with acute lymphocytic leukemia (ALL). For this purpose computer assisted tomography scans of the brain ( CT scans ) and electroencephalograms

  17. Prognostic Significance of Lymphoid Enhancer-Binding Factor-1 Expression in Egyptian Adult B-Acute Lymphocytic Leukemia Patients

    OpenAIRE

    Aly, Rabab M.; Ansaf B. Yousef

    2015-01-01

    Objective: Lymphoid enhancer-binding factor-1 (LEF-1) is a key transcription factor of wingless-type (Wnt) signaling in various tumors and it is associated with a number of malignant diseases such as leukemia. We explored the expression profile of LEF-1 in acute lymphoblastic leukemia (ALL) and determined its specific prognostic significance in this disease. Materials and Methods: We studied LEF-1 expression in 56 newly diagnosed B-acute ALL adult patients using real-time quantitative polymer...

  18. Total Marrow and Lymphoid Irradiation and Chemotherapy Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Lymphocytic or Myelogenous Leukemia

    Science.gov (United States)

    2016-04-07

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia

  19. Molecular characterization of resistant chronic lymphocytic leukemia (CLL): function of a new phosphorylated form of Ku70

    International Nuclear Information System (INIS)

    We have identified a new form of phospho-S27-S33-Ku70 constitutively over expressed in a subset of chronic lymphocytic leukemia (CLL) B cells resistant to apoptosis induced by DNA double strand breaks (DSB). Ku70 is one of the essential proteins involved in the maintenance of genomic stability through its role in DNA double strand break repair (non-homologous end-joining, NHEJ) and in telomeric protection. Laboratory previously established that resistant CLL cells disclose an up-regulated NHEJ DNA repair and an impaired structure of telomeres. The goal of this thesis was to characterize the biological function(s) of this new form of Ku70. For this purpose we have constructed specific EBV-based vectors (siRNA / cDNA) enabling a simultaneous inhibition of endogenous Ku70 and an expression of different forms (mutated, wild, phospho-mimetic at ser27-33) of Ku70 resistant to siRNA. Thus, we showed: i) a strict co-localisation of phospho-Ku70 with γ-H2AX foci; ii) that DSB induces the phosphorylation of Ku70 within minutes after genotoxic stress in heterodimer complex Ku70/Ku80. This phosphorylation necessitates both the physical interaction and the activity of pS2056-DNA-PKcs and/or ATM, linking phospho-Ku70 to NHEJ-mediated DNA DSB repair; iii) cells expressing mutated A27-A33-Ku70 exhibit a delayed G2/M cell cycle arrest, slower kinetic of DNA repair, lower level of genotoxic stress-induced chromosomal aberrations, and a higher cellular impedance correlated with translocation of transcriptional factor β-catenin from cytoplasmic membrane to the nucleus. Together, these data unveil an involvement of phospho-Ku70 in fast and inaccurate DNA repair; new paradigm for NHEJ regulation and to the control of resistance and maintenance of malignant cells.In parallel, we have initiated experimental approaches to explore other potential roles of phospho-Ku70. Especially, we were interested to determine whether it could play a role in an initiation of cell senescence induced by

  20. Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib - findings from an investigator initiated phase 2 study

    DEFF Research Database (Denmark)

    Niemann, Carsten U; Herman, Sarah E M; Maric, Irina;

    2016-01-01

    PURPOSE: Chronic lymphocytic leukemia (CLL) cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. Ibrutinib, a Bruton's tyrosine kinase inhibitor, disrupts BCR signaling and leads to the egress of...... tumor cells from the microenvironment. While the on-target effects on CLL cells are well defined, the impact on the microenvironment is less well studied. We therefore sought to characterize the in vivo effects of ibrutinib on the tumor microenvironment. EXPERIMENTAL DESIGN: Patients received single...... agent ibrutinib on an investigator-initiated phase 2 trial. Serial blood and tissue samples were collected pre-treatment and during treatment. Changes in cytokine levels, cellular subsets and microenvironmental interactions were assessed. RESULTS: Serum levels of key chemokines and inflammatory...

  1. Evaluation of some Mannich bases derived from substituted acetophenones against P-388 lymphocytic leukemia and on respiration in isolated rat liver mitochondria.

    Science.gov (United States)

    Dimmock, J R; Shyam, K; Hamon, N W; Logan, B M; Raghavan, S K; Harwood, D J; Smith, P J

    1983-08-01

    Series of 3-dimethylamino-1-aryl-1-propanone hydrobromides (IV) and 3-dimethylamino-2-dimethylaminomethyl-1-aryl-1-propanone dihydrobromides (V) were synthesized. Evaluation of these derivatives against P-388 lymphocytic leukemia growth revealed that two compounds show promise as antineoplastic agents. Compounds of the V series were unstable in phosphate buffer (in contrast to series IV), and when the same nuclear substituent was present in both series of compounds, V was approximately 100 times more active than IV in both the stimulation and inhibition of respiration of mitochondria isolated from rat liver cells. Representatives from both series showed that respiration in mitochondria was affected by changing the pH of the aqueous buffer from 7.4 to 6.9 or 6.4 and by reducing the temperature from 37 degrees to 20 degrees. The compounds showed reactivity toward a biomimetic thiol. PMID:6620142

  2. Evaluation of geriatric assessment in patients with chronic lymphocytic leukemia: Results of the CLL9 trial of the German CLL study group.

    Science.gov (United States)

    Goede, Valentin; Bahlo, Jasmin; Chataline, Viktoria; Eichhorst, Barbara; Dürig, Jan; Stilgenbauer, Stephan; Kolb, Gerald; Honecker, Friedemann; Wedding, Ulrich; Hallek, Michael

    2016-04-01

    Multidimensional geriatric assessment (GA) has been demonstrated to predict outcomes in older patients with cancer. This study evaluated GA in a cohort of older patients with chronic lymphocytic leukemia (CLL). Seventy-five of 97 subjects with CLL who were enrolled in a clinical trial of the German CLL Study Group underwent GA prior to the start of study treatment (low-dose chemotherapy with fludarabine). GA included cumulative illness rating scale (CIRS), timed-up-and-go (TUG) test, dementia detection (DEMTECT) test and instrumental activities of daily living (IADL) index. There was little correlation between CIRS, TUG, DEMTECT or IADL results and treatment toxicity, feasibility or efficacy in this study. CIRS and IADL had no statistically significant impact on overall prognosis. However, under-performance in TUG or DEMTECT test was strongly associated with poor survival. The latter findings provide a rationale to further investigate geriatric assessment in CLL and in the context with other CLL treatments. PMID:26377031

  3. Phase II study of palliative low-dose local radiotherapy in disseminated indolent non-Hodgkin's lymphoma and chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Jóhannsson, Jakob; Specht, Lena; Mejer, Johannes;

    2002-01-01

    PURPOSE: Indolent non-Hodgkin's lymphoma (INHL) and chronic lymphocytic leukemia (CLL) are highly sensitive to radiotherapy (RT). Previous retrospective studies have shown high response rates after local palliative RT of 4 Gy in 2 fractions, which prompted this prospective Phase II trial of the...... estimated at 22 months. None of the patients had significant side effects from the treatment. CONCLUSION: Low-dose RT (4 Gy in 2 fractions) is a highly effective palliative treatment of localized lymphoma masses in patients with disseminated INHL and CLL. The treatment has minimal side effects....... palliation from localized lymphoma masses. The patients were treated to a total of 31 different sites. Seventeen patients had previously been treated with chemotherapy. The median observation time after the start of RT was 8 months (range 3-26). RESULTS: All patients and all irradiated sites were assessable...

  4. S-phase induction by interleukin-6 followed by chemotherapy in patients with chronic lymphocytic leukemia and non-Hodgkin's lymphoma

    DEFF Research Database (Denmark)

    Brown, P D; Diamant, Marcus; Jensen, P O;

    1999-01-01

    cytostatic chemotherapy in CLL and low grade NHL. Recombinant human (rh) IL-6 might increase the in vivo proliferation rate leading to a higher sensitivity for chemotherapy. We tested this hypothesis by administering rhIL-6 to 9 CLL patients and 3 NHL patients in doses of 2.5 micrograms/kg, 5 micrograms......Interleukin-6 (IL-6) has in vitro demonstrated growth regulatory effects on tumor cells from patients with chronic lymphocytic leukemia (CLL) and lymphoma. The proliferation rate of these cells is usually very low and this is thought to be one of the reasons for the lack of a curative potential of...... had progressive disease and the remaining patients demonstrated no change. Two patients, who received 10 micrograms/kg/day rhIL-6, demonstrated a significant increase in LI, one of these was first observed in the second treatment cycle. A significant decrease was seen in two patients receiving 2...

  5. Screening for copy-number alterations and loss of heterozygosity in chronic lymphocytic leukemia--a comparative study of four differently designed, high resolution microarray platforms

    DEFF Research Database (Denmark)

    Gunnarsson, R.; Staaf, J.; Jansson, M.;

    2008-01-01

    Screening for gene copy-number alterations (CNAs) has improved by applying genome-wide microarrays, where SNP arrays also allow analysis of loss of heterozygozity (LOH). We here analyzed 10 chronic lymphocytic leukemia (CLL) samples using four different high-resolution platforms: BAC arrays (32K...... of 32 additional regions present in 2-3 platforms illustrated a discrepancy in detection of small CNAs, which often involved reported copy-number variations. LOH analysis using dChip revealed concordance of mainly large regions, but showed numerous, small nonoverlapping regions and LOH escaping...... detection. Evaluation of baseline variation and copy-number ratio response showed the best performance for the Agilent platform and confirmed the robustness of BAC arrays. Accordingly, these platforms demonstrated a higher degree of platform-specific CNAs. The SNP arrays displayed higher technical variation...

  6. Fruit Extract from Pyropolyporus fomentarius (L. ex Fr.) Teng Induces Mitochondria-Dependent Apoptosis in Leukemia Cells but Enhances Immunomodulatory Activities of Splenic Lymphocytes.

    Science.gov (United States)

    Li, Yixiang; Zhou, Yuetao; Wang, Xiaobing; Wang, Pan; Xiao, Yaping; Cheng, Xiaoxia; Zhang, Yanhua; Liu, Yilin; Liu, Quanhong

    2016-01-01

    Pyropolyporus fomentarius (L. ex Fr.) Teng is a unique woody mushroom due to its medicinal value with numerous pharmacological activities. This study presented the potential antitumor and immunomodulatory properties of ethanol extract of P. fomentarius. The results showed that P. fomentarius extract inhibited the viability of murine leukemia L1210 cells in a dose-dependent manner with IC50 value of 69.35 μg/ml. Flow cytometry analysis demonstrated that the extract induced apoptosis in L1210 cells. Additionally, the decline of mitochondrial membrane potential was observed as well as the changes of caspase-3, caspase-9, Bcl-2, and Bax, suggesting that proapoptosis effect of the extract involved mitochondria-related pathway. Simultaneously, the P. fomentarius extract significantly enhanced the proliferation and activation of splenic lymphocytes in a dose-dependent manner. This P. fomentarius extract has potential applications as a natural antitumor agent with immunomodulatory activity. PMID:27115601

  7. Single-institution long-term outcomes for patients receiving nonmyeloablative conditioning hematopoeitic cell transplantation for chronic lymphocytic leukemia and follicular lymphoma

    DEFF Research Database (Denmark)

    Mortensen, Bo K; Petersen, Søren; Kornblit, Brian; Andersen, Per Kragh; Braendstrup, Peter; Andersen, Niels S; Sengeløv, Henrik; Vindeløv, Lars

    2012-01-01

    Non-myeloablative conditioning hematopoietic cell transplantation (NMC-HCT) has improved the treatment of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). In a cohort of 85 patients (45 with CLL and 40 with FL), we observed 5-yr overall survival (OS) and progression-free survival...... (PFS) of 53% and 38% in the CLL group and 81% and 76% in the FL group. In the both the CLL group and the FL group, a strong trend toward better OS and PFS was observed among patients in complete remission (CR) at HCT. Within the FL group, sixteen patients had at one or more time points in their disease...... history had transformed FL. In contrast to the poor survival found in patients with transformed FL in previous studies, the 5-yr OS was almost identical in patients with transformed and non-transformed FL, 83% and 78%, respectively. In conclusion, our study supports that NMC-HCT is a safe and efficacious...

  8. Therapeutic potential of new B cell-targeted agents in the treatment of elderly and unfit patients with chronic lymphocytic leukemia.

    Science.gov (United States)

    Rai, Kanti R

    2015-01-01

    Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is primarily a disease of the elderly, with most patients ≥65 years of age and having at least one major comorbidity. Aggressive chemoimmunotherapy regimens recommended to achieve remission and improve survival in young, fit patients are often poorly tolerated in elderly and/or less physiologically fit ("unfit") patients, necessitating alternative treatment options. Although patient age, fitness, and comorbidities are key considerations in the selection of a treatment regimen, historically, clinical trials have been limited to young, fit patients by virtue of the ethical concerns associated with potential end organ toxic effects that could worsen comorbidities. However, the availability of new therapies promises a shift to a research paradigm that encompasses the identification of optimal treatments for elderly and unfit patients. Anti-CD20 monoclonal antibody therapy, which overall has improved response rates and survival in patients with CLL, has only recently been evaluated elderly and unfit patients. B cell-targeted agents such as the Bruton's tyrosine kinase inhibitor ibrutinib and the phosphatidylinositol 3-kinase inhibitor idelalisib are the first of a new generation of oral agents for CLL. Available clinical data suggest that these therapies have the potential to address the unmet need in elderly and unfit patients with CLL and result in clinical remission, and not merely symptom palliation and improved quality of life, which, by themselves, are also a reasonable goal. PMID:26170206

  9. E2A-Pbx1, the t(1;19) translocation protein of human pre-B-cell acute lymphocytic leukemia, causes acute myeloid leukemia in mice

    OpenAIRE

    Kamps, M P; Baltimore, D

    1993-01-01

    One-quarter of pediatric pre-B-cell leukemias contain the t(1;19) chromosomal translocation, which fuses 5' exons encoding the transactivation domain of the E2A transcription factor gene to 3' exons ecoding the putative DNA-binding region of the unusual homeobox gene, PBX1. To test the leukemic potential of this fused gene, a cDNA encoding its major protein product, p85E2A-Pbx1, was incorporated into a retrovirus construct and introduced into normal mouse marrow progenitors by infection. The ...

  10. HLA-G is a component of the chronic lymphocytic leukemia escape repertoire to generate immune suppression: impact of the HLA-G 14 base pair (rs66554220) polymorphism

    Science.gov (United States)

    Rizzo, Roberta; Audrito, Valentina; Vacca, Paola; Rossi, Davide; Brusa, Davide; Stignani, Marina; Bortolotti, Daria; D’Arena, Giovanni; Coscia, Marta; Laurenti, Luca; Forconi, Francesco; Gaidano, Gianluca; Mingari, Maria Cristina; Moretta, Lorenzo; Malavasi, Fabio; Deaglio, Silvia

    2014-01-01

    This work investigates the possibility that HLA-G, a molecule modulating innate and adaptive immunity, is part of an immune escape strategy of chronic lymphocytic leukemia cells. A 14 base pair insertion/deletion polymorphism (rs66554220) in the 3′-untranslated region of HLA-G influences mRNA stability and protein expression. The analysis of a cohort of patients with chronic lymphocytic leukemia confirmed that del/del individuals are characterized by higher levels of surface and soluble HLA-G than subjects with the other two genotypes. In line with its role in immunomodulation, the percentage of regulatory T lymphocytes is higher in del/del patients than in patients with the other genotypes and correlates with the amounts of surface or soluble HLA-G. Furthermore, addition of sHLA-G-rich plasma from patients with chronic lymphocytic leukemia induces natural killer cell apoptosis and impairs natural killer cell lysis, with effects proportional to the amount of soluble HLA-G added. Lastly, the presence of an HLA-G 14 base pair polymorphism is of prognostic value, with del/del patients showing reduced overall survival, as compared to those with other genotypes. These results suggest that: (i) the HLA-G 14 base pair polymorphism influences the levels of surface and soluble HLA-G expression, and (ii) the over-expression of HLA-G molecules contributes to creating tolerogenic conditions. PMID:24362551

  11. Proliferative index and expression of CD38, Zap-70, and CD25 in different lymphoid compartments of chronic lymphocytic leukemia patients

    Directory of Open Access Journals (Sweden)

    Olga Khoudoleeva

    2011-01-01

    Full Text Available Olga Khoudoleeva1 Eugeny Gretsov1 Natasha Barteneva2,3 Ivan Vorobjev11Hematology Scientific Center, Russian Academy of Medical Sciences, Moscow, Russia; 2Immune Disease Institute and Program in Cellular and Molecular Biology, Children Hospital of Boston, Boston, MA, USA; 3Department of Pathology, Harvard Medical School, Boston, MA, USAAbstract: Recent studies of chronic lymphocytic leukemia (CLL show that malignant B cells proliferate at a rate similar to normal B lymphocytes. This is in apparent contradiction to the very low proliferation rate found in blood specimens from CLL patients. To address this problem, we studied the expression of Ki-67, CD38, CD25, and Zap-70 in different compartments of CLL patients. Using triple-color flow cytometry, we examined the expression of CD38, CD25, Zap-70, and Ki-67 antigens in the peripheral blood, bone marrow, spleen, and lymph nodes biopsies of patients with CLL, splenic marginal zone lymphoma (SMZL, and nonmalignant diseases. In parallel probes of lymph node/spleen biopsies and blood taken from one and the same patient, Ki-67 expression was 17 times higher. Among the whole cohort, we also found significantly higher Ki-67 expression in biopsies from lymph nodes and spleen (4.95% ± 0.55%, compared with bone marrow (1.88% ± 0.32% and peripheral blood (0.45% ± 0.03%, P < 0.01. In CLL patients, there are statistically significant correlations between the expression of CD38 and Ki-67 in bone marrow (P ≤ 0.01, Zap-70 and Ki-67 in blood (P ≤ 0.01, and Zap-70 and CD38 in blood (P ≤ 0.01. Patients with SMZL also showed a significant correlation between Ki-67 and CD38 expression (P ≤ 0.01 and between Ki-67 and Zap-70 expression (P ≤ 0.01. We show for the first time that proliferation of B lymphocytes in CLL patients is associated primarily with lymph nodes/spleen. Malignant cells in the blood represent only a subpopulation of nonproliferating and less-activated B cells in this disease

  12. Graft-versus-leukemia effects of Wilms' tumor 1 protein-specific cytotoxic T lymphocytes in patients with chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation

    Institute of Scientific and Technical Information of China (English)

    WANG Zhi-dong; LI Dan; HUANG Xiao-jun

    2010-01-01

    Background The role of Wilms' tumor 1 protein (WT1)-specific cytotoxic T cells (CTL) in eradicating chronic myeloid leukemia (CML) cells is to be established. The aim of this study was to determine whether WT1 contributed to the graft-versus-leukemia effects (GVLE) for CML following allogeneic hematopoietic stem cell transplantation (HSCT). Methods High-resolution human leukocyte antigen (HLA) class I genotyping was performed by sequence-specific polymerase chain reaction (PCR). Fifteen HLA-A~*2402 patients with CML who underwent allogeneic HSCT were enrolled in this study. We monitored the frequency of WT1-specific CTL by pentamer assay and the molecular minimal residual disease by real-time quantitative PCR.Results A CD8~+ T-cell response to WT1 was observed in 14 of 15 patients after HSCT. The median frequencies of WT1-CTL were 0.54%, 0.62%, 0.81% and 1.28% (%CD8) on days 30, 60, 90 and 180, respectively. The median frequency of WT1-CTL (1.38%) in patients with molecular remission (MoR) was significantly higher than that in those without MoR (0.38%) on day 30, while no significant differences between them were detected on days 60, 90 and 180. The increase of WT1-CTL was associated with a decrease in bcr-abl expression and MoR; and the decrease of WT1-CTL was associated with an increase in bcr-abl expression, suggesting a WT1 -driven GVL effect. WT1-CTL had a predominant effector-memory phenotype (CD45RO~+CD27~-CD57~+).Conclusions The emergence of WT1-CTL with an effector-memory phenotype is associated with GVLE in CML patients after HSCT. This will pave the way for the WT1 vaccines to enhance GVLE after HSCT in CML.

  13. The Hsp90 inhibitor SNX-7081 is synergistic with fludarabine nucleoside via DNA damage and repair mechanisms in human, p53-negative chronic lymphocytic leukemia.

    Science.gov (United States)

    Kaufman, Kimberley L; Jenkins, Yiping; Alomari, Munther; Mirzaei, Mehdi; Best, O Giles; Pascovici, Dana; Mactier, Swetlana; Mulligan, Stephen P; Haynes, Paul A; Christopherson, Richard I

    2015-12-01

    Clinical trials of heat shock protein 90 (Hsp90) inhibitors have been limited by high toxicity. We previously showed that the Hsp90 inhibitor, SNX-7081, synergizes with and restores sensitivity to fludarabine nucleoside (2-FaraA) in human chronic lymphocytic leukemia (CLL) cells with lesions in the p53 pathway (Best OG, et al., Leukemia Lymphoma 53:1367-75, 2012). Here, we used label-free quantitative shotgun proteomics and comprehensive bioinformatic analysis to determine the mechanism of this synergy. We propose that 2-FaraA-induced DNA damage is compounded by SNX-7081-mediated inhibition of DNA repair, resulting in enhanced induction of apoptosis. DNA damage responses are impaired in part due to reductions in checkpoint regulators BRCA1 and cyclin D1, and cell death is triggered following reductions of MYC and nucleolin and an accumulation of apoptosis-inducing NFkB2 p100 subunit. Loss of nucleolin can activate Fas-mediated apoptosis, leading to the increase of pro-apoptotic proteins (BID, fas-associated factor-2) and subsequent apoptosis of p53-negative, 2-FaraA refractory CLL cells. A significant induction of DNA damage, indicated by increases in DNA damage marker γH2AX, was observed following the dual drug treatment of additional cell lines, indicating that a similar mechanism may operate in other p53-mutated human B-lymphoid cancers. These results provide valuable insight into the synergistic mechanism between SNX-7081 and 2-FaraA that may provide an alternative treatment for CLL patients with p53 mutations, for whom therapeutic options are currently limited. Moreover, this drug combination reduces the effective dose of the Hsp90 inhibitor and may therefore alleviate any toxicity encountered. PMID:26556860

  14. T-cell independent, B-cell receptor-mediated induction of telomerase activity differs among IGHV mutation-based subgroups of chronic lymphocytic leukemia patients.

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    Damle, Rajendra N; Temburni, Sonal; Banapour, Taraneh; Paul, Santanu; Mongini, Patricia K A; Allen, Steven L; Kolitz, Jonathan E; Rai, Kanti R; Chiorazzi, Nicholas

    2012-09-20

    Although B-cell chronic lymphocytic leukemia (B-CLL) clones with unmutated IGHV genes (U-CLL) exhibit greater telomerase activity than those with mutated IGHV genes (M-CLL), the extent to which B-cell receptor (BCR) triggering contributes to telomerase up-regulation is not known. Therefore, we studied the effect of BCR stimulation on modulating telomerase activity. The multivalent BCR ligand, dextran conjugated anti-μ mAb HB57 (HB57-dex), increased telomerase activity and promoted cell survival and proliferation preferentially in U-CLL cases, whereas the PI3K/Akt inhibitor LY294002 blocked HB57-dex induced telomerase activation. Although both U-CLL and M-CLL clones exhibited similar membrane proximal signaling responses to HB57-dex, telomerase activity and cell proliferation, when inducible in M-CLL, differed. B-CLL cells stimulated using bivalent F(ab')(2) -goat anti-μ antibody (goat anti-μ) exhibited higher membrane proximal response in U-CLL than M-CLL cells, whereas telomerase activity, cell survival, and proliferation were induced to lower levels than those induced by HB57-dex. In normal B lymphocytes, HB57-dex induced less protein phosphorylation but more cell proliferation and survival than goat anti-μ. Although both anti-BCR stimuli induced comparable telomerase activity, normal CD5(+) B cells preferentially exhibited higher hTERT positivity than their CD5(-) counterparts. These findings provide an understanding of how BCR-mediated signals impact telomerase modulation in IGHV mutation-based subgroups of B-CLL and normal B cells. PMID:22875913

  15. Pentostatin and Lymphocyte Infusion in Preventing Graft Rejection in Patients Who Have Undergone Donor Stem Cell Transplant

    Science.gov (United States)

    2016-02-29

    Acute Lymphoblastic Leukemia; Acute Myeloid Leukemia; Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Graft Versus Host Disease; Hodgkin Lymphoma; Myelodysplastic/Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Plasma Cell Myeloma; Waldenstrom Macroglobulinemia

  16. Different frequencies and effects of ABCB1 T3435C polymorphism on clinical and laboratory features of B cell chronic lymphocytic leukemia in Kurdish patients.

    Science.gov (United States)

    Maroofi, Farzad; Amini, Sabrieh; Roshani, Daem; Ghaderi, Bayazid; Abdi, Mohammad

    2015-04-01

    Finding the effects of gene polymorphism on cancer pathogenesis is very desirable. The ATP-binding cassette is involved in drug metabolism, and the polymorphism of this gene may be an important risk factor in B cell chronic lymphocytic leukemia (B-CLL) or progression and/or response to chemotherapy agents. For the first time, the present study was aimed to evaluate the probable effects of ABCB1 T3435C polymorphism on clinical and laboratory features of Kurdish patients with B-CLL. This descriptive analytical case-control study was performed on 50 B-CLL patients and 100 healthy subjects. Serum levels of beta-2-microglobulin (B2M) and lactate dehydrogenase (LDH) and blood WBC, RBC, Plt and ESR were measured. The T3435C polymorphism of the ABCB1 gene was determined by PCR-RFLP. Concentration of serum and blood markers was significantly higher in the malignant group than in the benign subjects. The CC genotype had the highest frequency (66%) in the patient groups. There are no significant differences between the genotypes and type of treatment. Our results demonstrate the high frequency of C allele of ABCB1 T3435C in B-CLL patients with Kurdish ethnicity. We also show that this polymorphism has a significant risk factor in B-CLL. However, the effect of this polymorphism on clinical and laboratory characteristics of B-CLL patients was not significant. PMID:25586345

  17. Synergistic Activity of Deguelin and Fludarabine in Cells from Chronic Lymphocytic Leukemia Patients and in the New Zealand Black Murine Model

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    Rebolleda, Nerea; Losada-Fernandez, Ignacio; Perez-Chacon, Gema; Castejon, Raquel; Rosado, Silvia; Morado, Marta; Vallejo-Cremades, Maria Teresa; Martinez, Andrea; Vargas-Nuñez, Juan A.

    2016-01-01

    B-cell chronic lymphocytic leukemia (CLL) remains an incurable disease, and despite the improvement achieved by therapeutic regimes developed over the last years still a subset of patients face a rather poor prognosis and will eventually relapse and become refractory to therapy. The natural rotenoid deguelin has been shown to induce apoptosis in several cancer cells and cell lines, including primary human CLL cells, and to act as a chemopreventive agent in animal models of induced carcinogenesis. In this work, we show that deguelin induces apoptosis in vitro in primary human CLL cells and in CLL-like cells from the New Zealand Black (NZB) mouse strain. In both of them, deguelin dowregulates AKT, NFκB and several downstream antiapoptotic proteins (XIAP, cIAP, BCL2, BCL-XL and survivin), activating the mitochondrial pathway of apoptosis. Moreover, deguelin inhibits stromal cell-mediated c-Myc upregulation and resistance to fludarabine, increasing fludarabine induced DNA damage. We further show that deguelin has activity in vivo against NZB CLL-like cells in an experimental model of CLL in young NZB mice transplanted with spleen cells from aged NZB mice with lymphoproliferation. Moreover, the combination of deguelin and fludarabine in this model prolonged the survival of transplanted mice at doses of both compounds that were ineffective when administered individually. These results suggest deguelin could have potential for the treatment of human CLL. PMID:27101369

  18. Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey.

    Science.gov (United States)

    Baer Ii, William H; Maini, Archana; Jacobs, Ira

    2014-01-01

    Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia. PMID:24810947

  19. Indolent lymphomas in the pediatric population: follicular lymphoma, IRF4/MUM1+ lymphoma, nodal marginal zone lymphoma and chronic lymphocytic leukemia.

    Science.gov (United States)

    Quintanilla-Martinez, Leticia; Sander, Birgitta; Chan, John K C; Xerri, Luc; Ott, German; Campo, Elias; Swerdlow, Steven H

    2016-02-01

    Indolent lymphomas in the pediatric population were discussed during the 2014 European Association for Haematopathology/Society of Hematopathology workshop in Istanbul, Turkey. This session was focused on pediatric-type follicular lymphoma (FL), and its differential diagnosis with the newly recognized entity of IRF4/MUM1+ lymphomas mainly involving Waldeyer's ring. The differential diagnosis between t(14;18) negative FL grade 1/2 and pediatric-type FL in adults was highlighted. The overlapping pathological and clinical features between FL and nodal marginal zone lymphoma (NMZL) in children and young adults were recognized and morphologic and immunophenotypical criteria helpful for the differential diagnosis were presented. Both pediatric-type FL and NMZL are indolent processes that should be distinguished from atypical lymphoid hyperplasia of the tonsils and lymph nodes. The demonstration of a B cell monoclonal population by molecular studies is strongly recommended for the diagnosis. Recognition of these indolent variants to avoid overtreatment was emphasized. Whereas most indolent lymphomas in the pediatric population show characteristic clinical, pathologic, and genetic features that differ from the adult counterpart, other rare indolent lymphoid tumors such as chronic lymphocytic leukemia (CLL) have similar characteristics. In this report, novel findings, areas of special interest, and diagnostic challenges emerging from the cases submitted to the workshop will be discussed. PMID:26416032

  20. Association between gene and miRNA expression profiles and stereotyped subset #4 B-cell receptor in chronic lymphocytic leukemia.

    Science.gov (United States)

    Maura, Francesco; Cutrona, Giovanna; Mosca, Laura; Matis, Serena; Lionetti, Marta; Fabris, Sonia; Agnelli, Luca; Colombo, Monica; Massucco, Carlotta; Ferracin, Manuela; Zagatti, Barbara; Reverberi, Daniele; Gentile, Massimo; Recchia, Anna Grazia; Bossio, Sabrina; Rossi, Davide; Gaidano, Gianluca; Molica, Stefano; Cortelezzi, Agostino; Di Raimondo, Francesco; Negrini, Massimo; Tassone, Pierfrancesco; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2015-01-01

    In this study we investigated specific biological and clinical features associated with chronic lymphocytic leukemia (CLL) patients carrying stereotyped BCR subset #4 (IGHV4-34) among a prospective cohort of 462 CLL/MBL patients in early stage (Binet A). All subset #4 patients (n = 16) were characterized by the IGHV mutated gene configuration, and absence of unfavorable cytogenetic lesions, NOTCH1 or SF3B1 mutations. Gene and miRNA expression profiling evidenced that the leukemic cells of subset #4 cases showed significant downregulation of WDFY4, MF2A and upregulation of PDGFA, FGFR1 and TFEC gene transcripts, as well as the upregulation of miR-497 and miR-29c. The transfection of miR-497 mimic in primary leukemic CLL cells induced a downregulation of BCL2, a known validated target of this miRNA. Our data identify biological characteristics associated with subset #4 patients, providing further evidence for the putative role of BCR in shaping the features of the tumor cells in CLL. PMID:25860243

  1. Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin’s Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey

    Directory of Open Access Journals (Sweden)

    William H. Baer II

    2014-05-01

    Full Text Available Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin’s lymphoma (NHL and chronic lymphocytic leukemia (CLL. Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia.

  2. CD137 is induced by the CD40 signal on chronic lymphocytic leukemia B cells and transduces the survival signal via NF-κB activation.

    Directory of Open Access Journals (Sweden)

    Yukana Nakaima

    Full Text Available CD137 is a member of the tumor necrosis factor receptor family that is expressed on activated T cells. This molecule provides a co-stimulatory signal that enhances the survival, and differentiation of cells, and has a crucial role in the development of CD8 cytotoxic T cells and anti-tumor immunity. Here we report that CD137 expression is also induced on normal or malignant human B cells by CD40 ligation by its ligand CD154. This CD137 induction was more prominent in chronic lymphocytic leukemia (CLL cells than in other types of B cells. CD137 stimulation on B cells by its ligand induced the nuclear translocation of p52 (a non-canonical NF-κB factor. In agreement with this finding, expression of the survival factor BCL-XL was upregulated. Consequently, the CD137 signal augmented the survival of CD154-stimulated CLL B cells in vitro. This unexpected induction of CD137 on B cells by CD40 signal may influence the clinical course of CLL.

  3. Current strategies for the diagnosis and management of chronic lymphocytic leukemia (CLL, with a focus on poor-risk CLL: A review

    Directory of Open Access Journals (Sweden)

    Fabienne Mc Clanahan

    2011-06-01

    Full Text Available Despite substantial advancement in the understanding and treatment of chronic lymphocytic leukemia (CLL, a standard curative approach does not exist. The choice of treatment is generally based on the existence of biological and genetic factors associated with the prediction of prognosis, individual response to therapy, and duration of remission. About 20% of patients that require treatment have an aggressive disease course and die within a few years, despite early initiation of intensive therapy (poor-risk CLL. Poor-risk CLL can be predicted by the presence of genomic markers, and the quality and duration of response to purine-analogue-based treatment. Within this patient subgroup alternative treatment approaches such as alemtuzumab or new substances such as flavopiridol or IMiDs® should be considered. To date, the only treatment bearing curative potential is allogeneic stem cell transplantation; in contrast to conventional immunochemotherapy, it can provide long-term disease control, even in patients with del 17p or other unfavorable biological and clinical risk factors. The aim of this review was to outline the current strategies for the diagnosis and management of CLL, with a focus on high-risk CLL.

  4. Evaluation of chronic lymphocytic leukemia by oligonucleotide-based microarray analysis uncovers novel aberrations not detected by FISH or cytogenetic analysis

    Directory of Open Access Journals (Sweden)

    Kolquist Kathryn A

    2011-11-01

    Full Text Available Abstract Background Cytogenetic evaluation is a key component of the diagnosis and prognosis of chronic lymphocytic leukemia (CLL. We performed oligonucleotide-based comparative genomic hybridization microarray analysis on 34 samples with CLL and known abnormal karyotypes previously determined by cytogenetics and/or fluorescence in situ hybridization (FISH. Results Using a custom designed microarray that targets >1800 genes involved in hematologic disease and other malignancies, we identified additional cryptic aberrations and novel findings in 59% of cases. These included gains and losses of genes associated with cell cycle regulation, apoptosis and susceptibility loci on 3p21.31, 5q35.2q35.3, 10q23.31q23.33, 11q22.3, and 22q11.23. Conclusions Our results show that microarray analysis will detect known aberrations, including microscopic and cryptic alterations. In addition, novel genomic changes will be uncovered that may become important prognostic predictors or treatment targets for CLL in the future.

  5. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children

    International Nuclear Information System (INIS)

    We compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other sanctuary areas. Patients were then treated with a standard maintenance regimen. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation (P less than 0.01). The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group (8 of 120) (P . 0.01). Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate (P . 0.03); there was no difference in the rate of hematologic relapse. In both risk strata the frequency of testicular relapse was significantly lower in the methotrexate group (1 patient) than the radiation group (10 patients) (P . 0.01). Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation

  6. Comparison of intermediate-dose methotrexate with cranial irradiation for the post-induction treatment of acute lymphocytic leukemia in children

    International Nuclear Information System (INIS)

    The authors compared two regimens with respect to their ability to prolong disease-free survival in 506 children and adolescents with acute lymphocytic leukemia. All responders to induction therapy were randomized to treatment with 2400 rad of cranial irradiation plus intrathecal methotrexate or to treatment with intermediate-dose methotrexate plus intrathecal methotrexate, as prophylaxis for involvement of the central nervous system and other sanctuary areas. Complete responders were stratified into either standard-risk or increased-risk groups on the basis of age and white-cell count at presentation. Among patients with standard risk, hematologic relapses occurred in 9 of 117 given methotrexate and 24 of 120 given irradiation. The rate of central-nervous-system relapse was higher in the methotrexate group (23 of 117) than in the irradiation group. Among patients with increased risk, radiation offered greater protection to the central nervous system than methotrexate; there was no difference in the rate of hematologic relapse. Methotrexate offered better protection against systemic relapse in standard-risk patients and better protection against testicular relapse overall, but it offered less protection against relapses in the central nervous system than cranial irradiation

  7. Intractable diffuse alopecia caused by multifactorial side-effects in treatment of acute lymphocytic leukemia: connection to iatrogenic failure of estrogen secretion.

    Science.gov (United States)

    Nomiyama, Tomoko; Arakawa, Akiko; Hattori, Sayoko; Konishi, Keisuke; Takenaka, Hideya; Katoh, Norito

    2013-01-01

    Treatment of infantile acute lymphocytic leukemia (ALL) may cause failure to thrive and hypogonadism due to hypopituitarism induced by chemotherapy and whole-brain radiotherapy. We report the case of a 22-year-old girl with a genetic predisposition to pattern hair loss who developed inveterate diffuse alopecia. The patient had onset of ALL at 8 years old and underwent bone marrow transplantation (BMT). Diffuse alopecia gradually advanced over her whole body. Her vellus scalp hair gradually came out, and hair loss progressed again at 8 years, after BMT. She later developed iatrogenic failure of secretion of estrogen and was treated with estrogen substitution therapy for 14 months from the age of 20. There was a small increase in the volume of hair during therapy, but alopecia returned to the former level after the therapy was suspended. Histopathologic examinations of the scalp performed during estrogen substitution therapy and 2 years after suspension of the therapy showed a 60% decrease in the number of hair follicles and prominent development of vellus hair. We conclude that estrogen influenced hair growth in the context of a genetic predisposition for pattern hair loss in this case. PMID:22211668

  8. Retrotransposon insertion in the T-cell acute lymphocytic leukemia 1 (Tal1 gene is associated with severe renal disease and patchy alopecia in Hairpatches (Hpt mice.

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    Vishnu Hosur

    Full Text Available "Hairpatches" (Hpt is a naturally occurring, autosomal semi-dominant mouse mutation. Hpt/Hpt homozygotes die in utero, while Hpt/+ heterozygotes exhibit progressive renal failure accompanied by patchy alopecia. This mutation is a model for the rare human disorder "glomerulonephritis with sparse hair and telangiectases" (OMIM 137940. Fine mapping localized the Hpt locus to a 6.7 Mb region of Chromosome 4 containing 62 known genes. Quantitative real time PCR revealed differential expression for only one gene in the interval, T-cell acute lymphocytic leukemia 1 (Tal1, which was highly upregulated in the kidney and skin of Hpt/+ mice. Southern blot analysis of Hpt mutant DNA indicated a new EcoRI site in the Tal1 gene. High throughput sequencing identified an endogenous retroviral class II intracisternal A particle insertion in Tal1 intron 4. Our data suggests that the IAP insertion in Tal1 underlies the histopathological changes in the kidney by three weeks of age, and that glomerulosclerosis is a consequence of an initial developmental defect, progressing in severity over time. The Hairpatches mouse model allows an investigation into the effects of Tal1, a transcription factor characterized by complex regulation patterns, and its effects on renal disease.

  9. Intrathecal donor lymphocyte infusion for isolated leukemia relapse in the central nervous system following allogeneic stem cell transplantation: a case report and literature review.

    Science.gov (United States)

    Yanagisawa, Ryu; Nakazawa, Yozo; Sakashita, Kazuo; Saito, Shoji; Tanaka, Miyuki; Shiohara, Masaaki; Shimodaira, Shigetaka; Koike, Kenichi

    2016-01-01

    An 8-year-old boy with a bone marrow relapse of T cell acute lymphoblastic leukemia underwent stem-cell transplantation from a human leukocyte antigen (HLA)-haploidentical mother. Five months later, he relapsed with central nervous system (CNS) involvement. Systemic chemotherapy and repeated intrathecal chemotherapy induced consciousness disturbances and frequent arrhythmia, prompting us to discontinue the chemotherapy. He had already received an 18-Gy prophylactic cranial irradiation, an 8-Gy total body irradiation, and a 15-Gy local irradiation for pituitary gland involvement. We therefore performed five intrathecal donor lymphocyte infusions (IDLIs) in escalating doses from 1 × 10(4) up to 1 × 10(6) cells/kg. All IDLIs were safe without infusion reactions or graft-versus-host disease. After the second and later IDLIs, donor mononuclear cells were continuously detected in cerebrospinal fluid; however, he did not achieve donor-dominant chimerism. Based on our case and four cases reported in the literature, the efficacy of IDLI therapy is limited for CNS relapse of hematological malignancies. However, we suggest that IDLI remains a feasible and safe option, as no GVHD or other adverse effects occurred, even in the HLA-haploidentical setting. We will make further efforts to increase the efficacy. PMID:26586462

  10. CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia.

    Science.gov (United States)

    Montraveta, Arnau; Lee-Vergés, Eriong; Roldán, Jocabed; Jiménez, Laura; Cabezas, Sandra; Clot, Guillem; Pinyol, Magda; Xargay-Torrent, Sílvia; Rosich, Laia; Arimany-Nardí, Cristina; Aymerich, Marta; Villamor, Neus; López-Guillermo, Armando; Pérez-Galán, Patricia; Roué, Gaël; Pastor-Anglada, Marçal; Campo, Elías; López-Guerra, Mónica; Colomer, Dolors

    2016-02-01

    Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases. PMID:26701728

  11. Tris (dibenzylideneacetone) dipalladium: a small-molecule palladium complex is effective in inducing apoptosis in chronic lymphocytic leukemia B-cells.

    Science.gov (United States)

    Kay, Neil E; Sassoon, Traci; Secreto, Charla; Sinha, Sutapa; Shanafelt, Tait D; Ghosh, Asish K; Arbiser, Jack L

    2016-10-01

    Here we tested impact of Tris (dibenzylideneacetone) dipalladium (Tris-DBA) on chronic lymphocytic leukemia (CLL) B-cell survival. Indeed, treatment of CLL B-cells with Tris-DBA induced apoptosis in a dose-dependent manner irrespective of IgVH mutational status. Further analyses suggest that Tris-DBA-induced apoptosis involves reduced expression of the anti-apoptotic proteins Bcl-xL, and XIAP with an upregulation of the pro-apoptotic protein BIM in CLL B-cells. Our findings also indicate that Tris-DBA targets the ribosomal protein (rp)-S6, an essential component of the Akt/mTOR signaling axis in CLL B-cells. Of interest, CLL bone marrow stromal cells were unable to protect the leukemic B cells from Tris-DBA-induced apoptosis in an in vitro co-culture system. Finally, co-administration of Tris-DBA and the purine nucleoside analog fludarabine (F-ara-A) augmented CLL B-cell apoptosis levels in vitro showing synergistic effects. In total, Tris-DBA is effective at inducing apoptosis in CLL B-cells even in the presence of stromal cells likely by targeting directly the signal mediator, rpS6. PMID:27189785

  12. Latent central nervous disorders observed in the acute lymphocytic leukemia children after treatment. Comparison between the evaluation of electroencephalogram and MRI

    International Nuclear Information System (INIS)

    For 8 children with acute lymphocytic leukemia (ALL) which finished the treatment, the existence of the latent central nervous disorders was examined and was compared of MRI and brain wave. In the MRI, the T2-weighted image showed the large number of nodule abnormal high signal lesions in the cerebral white matter in 2 of 8 patients, and one of these patients was accompanied by the slight cerebrum atrophy. There was the diffuse high signal tendency of periventricular white matter and the slight expansion of ventriculus cerebri in one patient. In the brain wave, there was the abnormality of the basic pattern in 3 of 8 patients, and there was the slowing tendency in 2. There was no case which showed the paroxysm extraordinary wave. The patient who showed the abnormality by the MRI was all accompanied by the brain wave abnormality. The frequency of the latent central nervous disorders incidence in ALL treatment was high (3/8 on the brain wave, 5/8 on the MRI). The brain wave was supersensitively able to detect the failure than the MRI, if the finding of the basic pattern is evaluated in detail. (A.N.)

  13. Veltuzumab, an anti-CD20 mAb for the treatment of non-Hodgkin's lymphoma, chronic lymphocytic leukemia and immune thrombocytopenic purpura.

    Science.gov (United States)

    Milani, Cannon; Castillo, Jorge

    2009-04-01

    Veltuzumab is a humanized, second-generation anti-CD20 mAb currently under development by Immunomedics Inc for the potential treatment of B-cell non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Licensee Nycomed is developing veltuzumab for the potential treatment of rheumatoid arthritis and immune thrombocytopenic purpura (ITP). Veltuzumab contains 90 to 95% human antibody sequences with identical antigen framework regions to epratuzumab (a humanized anti-CD22 mAb) and similar antigen-binding determinants to rituximab (chimeric, anti-CD20 mAb and the first-line treatment of aggressive and indolent NHL). In vitro studies have demonstrated that veltuzumab has enhanced binding avidities and a stronger effect on complement-dependent cytotoxicity compared with rituximab in selected cell lines. In dose-finding phase I/II clinical trials in patients with low-grade NHL, intravenous veltuzumab demonstrated a substantial rate of complete responses in concurrence with shorter and more tolerable infusions compared with rituximab. Currently there has been no evidence of an immune response to repeated administrations, and no serious adverse events related to veltuzumab treatment in patients with NHL. Veltuzumab is undergoing clinical trials using a low-dose subcutaneous formulation in patients with NHL, CLL and ITP. Prospective, randomized clinical trials are needed to clarify the role veltuzumab will play in a market where the therapy of B-cell lymphoproliferative disorders is dominated by rituximab. PMID:19330725

  14. A proline/arginine-rich end leucine-rich repeat protein (PRELP) variant is uniquely expressed in chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Mikaelsson, Eva; Österborg, Anders; Jeddi-Tehrani, Mahmood; Kokhaei, Parviz; Ostadkarampour, Mahyar; Hadavi, Reza; Gholamin, Mehran; Akhondi, Mehdi; Shokri, Fazel; Rabbani, Hodjattallah; Mellstedt, Håkan

    2013-01-01

    Proline/arginine-rich end leucine-rich repeat protein (PRELP) belongs to the small leucine-rich proteoglycan (SLRP) family, normally expressed in extracellular matrix of collagen-rich tissues. We have previously reported on another SLRP, fibromodulin (FMOD) in patients with chronic lymphocytic leukemia (CLL). PRELP is structurally similar to FMOD with adjacent localization on chromosome 1 (1q32.1). As cluster-upregulation of genes may occur in malignancies, the aim of our study was to analyze PRELP expression in CLL. PRELP was expressed (RT-PCR) in all CLL patients (30/30), as well as in some patients with mantle cell lymphoma (3/5), but not in healthy donor leukocytes (0/20) or tumor samples from other hematological malignancies (0/35). PRELP was also detected in CLL cell-lines (4/4) but not in cell-lines from other hematological tumors (0/9). PRELP protein was detected in all CLL samples but not in normal leukocytes. Deglycosylation experiments revealed a CLL-unique 38 kDa core protein, with an intact signal peptide. This 38 kDa protein was, in contrast to the normal 55 kDa size, not detected in serum which, in combination with the uncleaved signal peptide, suggests cellular retention. The unique expression of a 38 kDa PRELP in CLL cells may suggest involvement in the pathobiology of CLL and merits further studies. PMID:23826326

  15. A proline/arginine-rich end leucine-rich repeat protein (PRELP variant is uniquely expressed in chronic lymphocytic leukemia cells.

    Directory of Open Access Journals (Sweden)

    Eva Mikaelsson

    Full Text Available Proline/arginine-rich end leucine-rich repeat protein (PRELP belongs to the small leucine-rich proteoglycan (SLRP family, normally expressed in extracellular matrix of collagen-rich tissues. We have previously reported on another SLRP, fibromodulin (FMOD in patients with chronic lymphocytic leukemia (CLL. PRELP is structurally similar to FMOD with adjacent localization on chromosome 1 (1q32.1. As cluster-upregulation of genes may occur in malignancies, the aim of our study was to analyze PRELP expression in CLL. PRELP was expressed (RT-PCR in all CLL patients (30/30, as well as in some patients with mantle cell lymphoma (3/5, but not in healthy donor leukocytes (0/20 or tumor samples from other hematological malignancies (0/35. PRELP was also detected in CLL cell-lines (4/4 but not in cell-lines from other hematological tumors (0/9. PRELP protein was detected in all CLL samples but not in normal leukocytes. Deglycosylation experiments revealed a CLL-unique 38 kDa core protein, with an intact signal peptide. This 38 kDa protein was, in contrast to the normal 55 kDa size, not detected in serum which, in combination with the uncleaved signal peptide, suggests cellular retention. The unique expression of a 38 kDa PRELP in CLL cells may suggest involvement in the pathobiology of CLL and merits further studies.

  16. Cross-talk between chronic lymphocytic leukemia (CLL) tumor B cells and mesenchymal stromal cells (MSCs): implications for neoplastic cell survival.

    Science.gov (United States)

    Trimarco, Valentina; Ave, Elisa; Facco, Monica; Chiodin, Giorgia; Frezzato, Federica; Martini, Veronica; Gattazzo, Cristina; Lessi, Federica; Giorgi, Carlo Alberto; Visentin, Andrea; Castelli, Monica; Severin, Filippo; Zambello, Renato; Piazza, Francesco; Semenzato, Gianpietro; Trentin, Livio

    2015-12-01

    Leukemic cells from Chronic Lymphocytic Leukemia (CLL) patients interact with stromal cells of the surrounding microenvironment. Mesenchymal Stromal Cells (MSCs) represent the main population in CLL marrow stroma, which may play a key role for disease support and progression. In this study we evaluated whether MSCs influence in vitro CLL cell survival. MSCs were isolated from the bone marrow of 46 CLL patients and were characterized by flow cytometry analysis. Following co-culture of MSCs and leukemic B cells, we demonstrated that MSCs were able to improve leukemic B cell viability, this latter being differently dependent from the signals coming from MSCs. In addition, we found that the co-culture of MSCs with leukemic B cells induced an increased production of IL-8, CCL4, CCL11, and CXCL10 chemokines.As far as drug resistance is concerned, MSCs counteract the cytotoxic effect of Fludarabine/Cyclophosphamide administration in vivo, whereas they do not protect CLL cells from the apoptosis induced by the kinase inhibitors Bafetinib and Ibrutinib. The evidence that leukemic clones are conditioned by environmental stimuli suggest new putative targets for therapy in CLL patients. PMID:26517523

  17. CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia

    Science.gov (United States)

    Roldán, Jocabed; Jiménez, Laura; Cabezas, Sandra; Clot, Guillem; Pinyol, Magda; Xargay-Torrent, Sílvia; Rosich, Laia; Arimany-Nardí, Cristina; Aymerich, Marta; Villamor, Neus; López-Guillermo, Armando; Pérez-Galán, Patricia; Roué, Gaël; Pastor-Anglada, Marçal; Campo, Elías; López-Guerra, Mónica; Colomer, Dolors

    2016-01-01

    Clinical responses to bendamustine in chronic lymphocytic leukemia (CLL) are highly heterogeneous and no specific markers to predict sensitivity to this drug have been reported. In order to identify biomarkers of response, we analyzed the in vitro activity of bendamustine and the gene expression profile in primary CLL cells. We observed that mRNA expression of CD69 (CD69) and ITGAM (CD11b) constitute the most powerful predictor of response to bendamustine. When we interrogated the predictive value of the corresponding cell surface proteins, the expression of the activation marker CD69 was the most reliable predictor of sensitivity to bendamustine. Importantly, a multivariate analysis revealed that the predictive value of CD69 expression was independent from other clinico-biological CLL features. We also showed that when CLL cells were co-cultured with distinct subtypes of stromal cells, an upregulation of CD69 was accompanied by a reduced sensitivity to bendamustine. In agreement with this, tumor cells derived from lymphoid tumor niches harbored higher CD69 expression and were less sensitive to bendamustine than their peripheral blood counterparts. Furthermore, pretreatment of CD69 high CLL cases with the B-cell receptor (BCR) pathway inhibitors ibrutinib and idelalisib decreased CD69 levels and enhanced bendamustine cytotoxic effect. Collectively, our findings indicate that CD69 could be a predictor of bendamustine response in CLL patients and the combination of clinically-tested BCR signaling inhibitors with bendamustine may represent a promising strategy for bendamustine low responsive CLL cases. PMID:26701728

  18. Normalization of lymphocyte count after high ablative dose of I-131 in a patient with chronic lymphoid leukemia and secondary papillary carcinoma of the thyroid: case report

    International Nuclear Information System (INIS)

    The authors report the case of a 70-year-old male patient with chronic lymphoid leukemia who presented subsequently a papillary carcinoma of the thyroid with metastases to regional lymph nodes. The patient was treated with surgical thyroidectomy with regional and cervical lymph node excision and radioiodine therapy (I-131). The protocolar control scintigraphy 4 days after the radioactive dose showed I-131 uptake in both axillae and even in the inguinal regions. PET/CT showed faint FDG-F-18 uptake in one lymph node of the left axilla. An ultrasound guided fine needle biopsy of this lymph node identified by I-131 SPECT/CT and FDG-F-18 PET/CT revealed lymphoma cells and was negative for thyroid tissue and thyroglobulin content. The sequential blood counts done routinely after radiation treatment showed a marked fall until return to normal values of leucocytes and lymphocytes (absolute and relative), which were still normal in the last control 19 months after the radioiodine administration. Chest computed tomography showed a decrease in size of axillary and paraaortic lymph nodes. By immunohistochemistry, cells of the lymphoid B lineage decreased from 52% before radioiodine therapy to 5% after the procedure. The authors speculate about a possible sodium iodide symporter expression by the cells of this lymphoma, similar to some other non-thyroid tumors, such as breast cancer cells. (author)

  19. In vitro and in vivo evaluation of direct rhenium-188-labeled anti-CD52 monoclonal antibody alemtuzumab for radioimmunotherapy of B-cell chronic lymphocytic leukemia

    Energy Technology Data Exchange (ETDEWEB)

    Decker, Mario de [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent (Belgium); Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, Groningen (Netherlands)], E-mail: mario.dedecker@health.wa.gov.au; Bacher, Klaus; Thierens, Hubert [Department of Medical Physics and Radiation Protection, Ghent University, Ghent (Belgium); Slegers, Guido [Department of Medical Imaging of Domestic Animals, Ghent University, Ghent (Belgium); Dierckx, Rudi A. [Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen, Groningen (Netherlands); Vos, Filip de [Department of Radiopharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ghent (Belgium)

    2008-07-15

    Alemtuzumab (Campath, Berlex) is a humanized IgG1 rat monoclonal antibody directed against the cell surface CD52 antigen, found on lymphocytes and monocytes. It is being developed for the treatment of chronic lymphocytic leukemia (CLL), autoimmune disease and for the prevention of transplant rejection. This study focused on synthesis, quality control, in vitro evaluation and biodistrubution of {sup 188}Re-labeled alemtuzumab for radioimmunotherapy of B-cell CLL. {sup 188}Re-alemtuzumab was synthesized using a direct radiolabeling method. Reduction of the intramolecular disulfide bonds of the antibody was performed with tris-(carboxyethyl)-phosphine (Pierce), using a 1:60 molar excess. Reaction took place at room temperature for 20 min. A PD-10 desalting column was used to purify the reduced antibody from excess phospine. Complexation and transchelation of {sup 188}ReO{sub 4}{sup -} was achieved using sodium gluconate as weak chelator and SnCl{sub 2} as reducing agent. Quality control was done using instant thin-layer chromatography. Binding assays were performed on a CD52-positive cell line (HuT-78). Female NMRI mice were injected intravenously with 20 {mu}g radiolabeled alemtuzumab and killed at preset time intervals for biodistribution studies. Tissues were dissected, weighed and counted for determination of radioactivity. Data were expressed as percentage injected activity per gram of tissue (% IA/g tissue) or as percentage injected activity (% IA). {sup 188}Re-alemtuzumab was prepared achieving high radiochemical yields. Labeling efficiency of more than 95% can be obtained using optimal reaction conditions. {sup 188}Re-alemtuzumab showed good in vitro stability, remaining intact at 24 h after radiolabeling. In mice, {sup 188}Re-alemtuzumab showed high uptake in the blood (25.10{+-}1.36% IA at 1 h p.i.), followed by a biexponential clearance (t{sub 1/2{alpha}}=4.790 h and t{sub 1/2{beta}}=55.45 h). Increased uptake was observed in kidneys and heart (9

  20. Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.

    Science.gov (United States)

    Johnson, Nichola; De Ieso, Paolo; Migliorini, Gabriele; Orr, Nick; Broderick, Peter; Catovsky, Daniel; Matakidou, Athena; Eisen, Timothy; Goldsmith, Christy; Dudbridge, Frank; Peto, Julian; Dos-Santos-Silva, Isabel; Ashworth, Alan; Ross, Gillian; Houlston, Richard S; Fletcher, Olivia

    2016-03-15

    CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers. Cancer Res; 76(6); 1485-93. ©2016 AACR. PMID:26964624

  1. Relevance of stereotyped B-cell receptors in the context of the molecular, cytogenetic and clinical features of chronic lymphocytic leukemia.

    Directory of Open Access Journals (Sweden)

    Francesco Maura

    Full Text Available Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV genes and heavy-chain complementarity determining region-3 (HCDR3, are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL. We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT of patients with early stage disease (Binet A. Stereotyped HCDR3 sequences were found in 357 cases (31.7%, 231 of which (64.7% were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17(p13. Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.

  2. Hypothalamic-pituitary function of children with acute lymphocytic leukemia after three forms of central nervous system prophylaxis. A retrospective study.

    Science.gov (United States)

    Voorhess, M L; Brecher, M L; Glicksman, A S; Jones, B; Harris, M; Krischer, J; Boyett, J; Forman, E; Freeman, A I

    1986-04-01

    The hypothalamic-pituitary function of 93 children, who had received central nervous system (CNS) prophylaxis as part of their therapy for acute lymphocytic leukemia (ALL), and who remained in continuous complete remission, was evaluated retrospectively. Treatment regimens included--Group I: 31 subjects, intrathecal methotrexate (IT MTX); Group II: 31 subjects, IT MTX plus 2400 rad cranial irradiation; and Group III: 31 subjects, IT MTX and intravenous intermediate-dose methotrexate. Serum thyroid-stimulating hormone (TSH) and T4 levels were normal. All participants had normal adrenocorticotropic hormone (ACTH) secretion as assessed by plasma cortisol responses to insulin hypoglycemia. Urinary follicle-stimulating hormone (FSH) and luteinizing hormone (LH) excretion of pubertal and postpubertal patients (N = 37) was appropriate, except for one subject from Group I who had an abnormally high output of gonadotropins, and one from Group II who had abnormally low levels. Growth hormone (GH) responses were subnormal after sequential arginine-insulin stimulation as follows--Group 1: 3 of 31 patients; Group II: 6 of 25 patients; and Group III: 2 of 29 patients. Nevertheless, all children had normal linear growth. It was concluded that the three forms of CNS prophylaxis evaluated had no long-term adverse effect on TSH and ACTH secretion. FSH-LH production appears to be normal, but final judgment must await follow-up studies because 60% of the patients were prepuberteral or still receiving chemotherapy. Eleven patients had subnormal GH responses after pharmacologic stimulation of the pituitary, but long-term linear growth was unaffected. PMID:3753892

  3. Multidimensional single-cell analysis of BCR signaling reveals proximal activation defect as a hallmark of chronic lymphocytic leukemia B cells.

    Directory of Open Access Journals (Sweden)

    M Lia Palomba

    Full Text Available PURPOSE: Chronic Lymphocytic Leukemia (CLL is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation. EXPERIMENTAL DESIGN: We developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR. Results from multidimensional modeling were validated using an independent test cohort of 38 patients. RESULTS: We identified a dynamic and variable imbalance between proximal (pSYK, pBTK and distal (pPLCγ2, pBLNK, ppERK phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCγ2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness. CONCLUSION: Single-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to-cell. Disruption of the pSYK/pPLCγ2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets.

  4. Downregulation of IL-17-producing T cells is associated with regulatory T cell expansion and disease progression in chronic lymphocytic leukemia.

    Science.gov (United States)

    Jadidi-Niaragh, Farhad; Ghalamfarsa, Ghasem; Memarian, Ali; Asgarian-Omran, Hossein; Razavi, Seyed Mohsen; Sarrafnejad, Abdolfattah; Shokri, Fazel

    2013-04-01

    Little is known about the immunobiology of interleukin-17 (IL-17)-producing T cells and regulatory T cells (Treg) in chronic lymphocytic leukemia (CLL). In this study, the frequencies of Th17, Tc17, and CD39(+) Treg cells were enumerated in peripheral T cells isolated from 40 CLL patients and 15 normal subjects by flow cytometry. Our results showed a lower frequency of Th17 and Tc17 cells in progressive (0.99 ± 0.12 % of total CD3(+)CD4(+) cells; 0.44 ± 0.09 % of total CD8(+) cells) compared to indolent patients (1.57 ± 0.24 %, p = 0.042; 0.82 ± 0.2 %, p = 0.09) and normal subjects (1.78 ± 0.2 %, p = 0.003; 0.71 ± 0.09 %, p = 0.04). Decrease in IL-17-producing T cells was associated with CD39(+) Treg cells expansion. Variation of IL-17-producing cells and Treg cells in indolent and progressive patients was neither associated to the expression levels of Th1- and Th2-specific transcription factors T-bet and GATA-3 nor to the frequencies of IFN-γ and IL-4-producing CD4(+) T cells in a selected number of samples. Additionally, suppressive potential of CD4(+) Treg was similar in CLL patients and normal subjects. Our data indicate that progression of CLL is associated with downregulation of IL-17-producing T cells and expansion of Treg cells, implying contribution of these subsets of T cells in the progression of CLL. PMID:23269607

  5. Laboratory diagnosis of chronic myelomonocytic leukemia and progression to acute leukemia in association with chronic lymphocytic leukemia: morphological features and immunophenotypic profile Diagnóstico laboratorial de leucemia mielomonocítica crônica agudizada em associação com leucemia linfocítica crônica: aspectos morfológicos e imunofenotípicos

    Directory of Open Access Journals (Sweden)

    Iris Mattos Santos

    2012-01-01

    Full Text Available Chronic myelomonocytic leukemia is a clonal stem cell disorder that is characterized mainly by absolute peripheral monocytosis. This disease can present myeloproliferative and myelodysplastic characteristics. According to the classification established by the World Health Organization, chronic myelomonocytic leukemia is inserted in a group of myeloproliferative/myelodysplastic disorders; its diagnosis requires the presence of persistent monocytosis and dysplasia involving one or more myeloid cell lineages. Furthermore, there should be an absence of the Philadelphia chromosome and the BCR/ABL fusion gene and less than 20% blasts in the blood or bone marrow. Phenotypically, the cells in chronic myelomonocytic leukemia can present myelomonocytic antigens, such as CD33 and CD13, overexpressions of CD56 and CD2 and variable expressions of HLA-DR, CD36, CD14, CD15, CD68 and CD64. The increase in the CD34 expression may be associated with a transformation into acute leukemia. Cytogenetic alterations are frequent in chronic myelomonocytic leukemia, and molecular mutations such as NRAS have been identified. The present article reports on a case of chronic myelomonocytic leukemia, diagnosed by morphologic and phenotypical findings that, despite having been suggestive of acute monocytic leukemia, were differentiated through a detailed analysis of cell morphology. Furthermore, typical cells of chronic lymphocytic leukemia were found, making this a rare finding.A Leucemia Mielomonocítica Crônica (LMMC é uma desordem clonal de células-tronco hematopoiéticas caracterizada principalmente por monocitose absoluta no sangue periférico. Esta doença pode apresentar características de síndromes mielodisplásicas e de doenças mieloproliferativas. De acordo com a classificação estabelecida pela OMS, a LMMC está inserida no grupo de neoplasias mieloproliferativas/mielodisplásicas e seu diagnóstico requer a presença de monocitose persistente no sangue

  6. Detection of t(12;14)(p13;q32) in a patient with IGH-CCND1 negative mantle cell lymphoma resembling ultra-high risk chronic lymphocytic leukemia

    OpenAIRE

    Miao, Yi; Wang, Rong; Fan, Lei; Qiu, Hairong; Wu, Yujie; Chen, Yaoyu; Xu, Wei; Li, Jianyong

    2015-01-01

    t(12;14)(p13;q32) is a rare recurrent chromosomal translocation, which has only been identified in a small subgroup of mantle cell lymphoma (MCL) without typical t(11;14)(q13;q32). This rearrangement causes aberrant over-expression of cyclin D2 (CCND2), which disrupts the normal cell cycle. Here we report a subtle case of MCL with t(12;14)(p13;q32) that was initially misdiagnosed as ultra-high risk chronic lymphocytic leukemia (CLL). A 60-year-old male patient presented with obvious leukocyto...

  7. [National guidelines for the management of patients with chronic lymphocytic leukemia. Sociedad Espan˜ola de Hematologı´a y Hemoterapia and Grupo Espan˜ol de Leucemia Linfocı´tica Cro´ nica].

    Science.gov (United States)

    García Marco, José A; Giraldo Castellano, Pilar; López Jiménez, Javier; Ríos Herranz, Eduardo; Sastre Moral, José Luis; Terol Casterá, M José; Bosch Albareda, Francesc

    2013-08-17

    Chronic lymphocytic leukemia is the most common chronic lymphoproliferative disorder in Spain. The clinical management of this entity varies widely. Currently, in Spain, there are no national consensus guidelines, such as those published in other countries, to guide the diagnosis and treatment of this malignancy and the use of prognostic scores. This article reviews the current scientific literature and addresses issues on the diagnosis of chronic lymphocytic leukemia, the spread of the disease, the presence of comorbidities, the classification of prognostic scores, the common treatment regimens stratified by risk factors, and the management of complications associated with both the disease and its treatment, as well as the various controversies related to this entity. This document was drafted with the collaboration of national experts and aims to establish practical guidelines with their corresponding levels of evidence and grades of recommendation to guide the diagnosis, treatment and follow-up of patients with chronic lymphocytic leukemia. PMID:23830547

  8. Lymphocyte migration studies in man

    International Nuclear Information System (INIS)

    In this paper the author outlines what is known of the migration and recirculation of the lymphocyte in man and animals. He then attempts to demonstrate how a better grasp of these phenomena may contribute to an understanding of the pathophysiology of human diseases such as chronic lymphocytic leukemia, non-Hodgkin's lymphomas, Hodgkin's, and other diseases

  9. Immunosuppression for 6-8 weeks after modified donor lymphocyte infusion reduced acute graft-versus-host disease without influencing graft-versus-leukemia effect in haploidentical transplant

    Institute of Scientific and Technical Information of China (English)

    Yan Chenhua; Xu Lanping; Liu Daihong; Chen Huan; Wang Yu; Liu Kaiyan; Huang Xiaojun

    2014-01-01

    Background In haploidentical hematopoietic stem cell transplantation (HSCT),the duration of graft-versus-host disease (GVHD) prophylaxis after modified donor lymphocyte infusion (DLI) was the only risk factor of DLI-associated grades 3-4 acute GVHD.However,the successful application of modified DLI depended not only on the reduction of severe GVHD,but also on the preservation of graft-versus-leukemia (GVL) effect.Therefore,this study was performed to compare the impact of prophylaxis for 6-8 weeks and prophylaxis for <6 weeks on GVL effect after modified DLI in haploidentical HSCT.Methods A total of 103 consecutive patients developing hematological relapse or minimal residual disease (MRD)-positive status after haploidentical HSCT and receiving modified DLI were investigated retrospectively.Fifty-two patients received prophylaxis for 6-8 weeks after modified DLI; the remaining 51 patients received prophylaxis for <6 weeks.Results First,compared with prophylaxis for <6 weeks,prophylaxis for 6-8 weeks reduced incidence of relapse in total patients (26.6% vs.69.0%,P <0.001).Besides,prophylaxis for 6-8 weeks also reduced incidence of relapse in 54 patients developing hematological relapse post-transplant (P=0.018) and in 49 patients developing MRD-positive status post-transplant (P <0.001).Second,prophylaxis for 6-8 weeks reduced incidence of acute GVHD (P <0.05),reduced the therapeutic application of immunosuppressive agents (P=0.019),but increased the incidence of chronic GVHD (P<0.05).Third,prophylaxis for 6-8 weeks improved overall survival and disease-free survival in total patients,as well as in patients developing hematological relapse post-transplant and in patients developing MRD-positive status post-transplant (P <0.05).Conclusions In haploidentical HSCT,prophylaxis for 6-8 weeks after modified DLI does not reduce GVL effect,but reduces the incidence of DLI-associated acute GVHD compared with prophylaxis for <6 weeks.This strategy will

  10. Indicações para início de tratamento na leucemia linfóide crônica Chronic lymphocytic leukemia: when to start treatment

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    Carlos S. Chiattone

    2005-12-01

    Full Text Available Apesar do grande avanço no conhecimento da sua biologia, a leucemia linfóide crônica (LLC-B permanece incurável. Historicamente, o objetivo do tratamento da LLC-B tem sido o de aliviar os sintomas relacionados com a doença e prolongar a sobrevida. Quimioterapia para todos os pacientes em estádio inicial da doença não ocasiona aumento da sobrevida, determinando apenas toxicidade desnecessária. A decisão de tratar o paciente é orientada pelo estádio clínico, pela presença de sintomas e pelos sinais de atividade da doença. Com os tratamentos convencionais atualmente disponíveis; só há evidência de vantagem no tratamento imediato, logo após o diagnóstico, para pacientes com estádio avançado (Rai III e IV ou Binet B e C. Pacientes em estádios iniciais (Rai 0-II ou Binet A geralmente não devem receber tratamento imediato, sendo apenas observados periodicamente. Nos estádios iniciais, o tratamento é indicado apenas se houver presença de sintomas relacionados com a doença (sintomas B, redução do performance status, ou sintomas ou complicações de organomegalia ou sinais de alta atividade da LLC-B (tempo de duplicação de linfócitos menos que seis meses ou rápido crescimento de linfonodos.In spite of the great advances made in understanding its biology, chronic lymphocytic leukemia (CLL-B is still incurable. Historically, the objective of the treatment of CLL-B has been to alleviate the disease-related symptoms and to prolong the survival. Chemotherapy for all patients in the initial stages of the disease does not obtain an increase in the survival, but rather, only causes an unnecessary toxicity. The decision to treat the patient is oriented by the clinical conditions, by the presence of symptoms and by the signs of activity of the disease. With the conventional treatments currently available, there is only evidence of an advantage in immediate treatment, directly following the diagnosis, for patients in an advanced

  11. Cancer Statistics: Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... population data for older age groups are available. Statistics at a Glance Show More At a Glance ... their lifetime, based on 2010-2012 data. Survival Statistics Show More How Many People Survive 5 Years ...

  12. MEAD方案治疗难治复发性成年人急性淋巴细胞白血病%Clinical study on MEAD regimens for relapsed or refractory adult patients with acute lymphocyte leukemia

    Institute of Scientific and Technical Information of China (English)

    赵万红; 杨云; 张王刚; 曹星梅; 陈银霞; 何爱丽; 黄芳; 刘捷; 马肖容; 王剑利

    2010-01-01

    Objective To study the clinic effect and safety of MEAD chemotherapy regimen for adult patients with relapsed or refractory acute lymphocyte leukemia. Methods Between July 2006 and July 2009,twenty-two adult patients with relapsed or refractory acute lymphocyte leukemia received MEAD regimen (mitoxantrone 6 mg/d dl-3 iv drip,cytarabine 100 mg/d dl-5 iv drip,etoposide 100 mg/d dl-5 iv drip,dexmethasone 10 mg/d dl-8 iv drip). Results The complete remission (CR) rate of adult patients with relapsed or refractory acute lymphocyte leukemia was 31.8 %,the partial remission(PR) rate was 22.7 % and the overall response (OR) rate 54.5 %. The cumulitive CR rate was 50.0 %,and the PR rate 40.9 % after two times MEAD chemotherapy regimen. The main adverse effect was different level of myelosuppression,and other toxicity of vital organ was mild. Conclusion MEAD regimen is effective and can be tolerated for adult patients with relapsed or refractory acute lymphocyte leukemia,and its side effect is mild.%目的 观察MEAD化疗方案治疗难治复发性成年人急性淋巴细胞白血病(ALL)的疗效和安全性.方法 对2006年6月至2009年6月收治的22例成年人难治复发性ALL患者,采用MEAD方案化疗,米托蒽醌6 mg/d静脉滴注,第1天至第3天;阿糖胞苷100 mg/d静脉滴注,第1天至第5天;依托泊苷100mg/d静脉滴注,第1天至第5天;地塞米松10mg/d静脉滴注,第1天至第8天.结果 成年人难治复发性ALL完全缓解率31.8%.部分缓解率22.7%,总有效率54.5%;两次MEAD方案化疗后,累积完全缓解率为50.0%,部分缓解率40.9%.主要不良反应为不同程度的骨髓抑制,重要脏器毒性反应轻微.结论 MEAD化疗方案对难治复发性成年人ALL有较好的疗效.患者不良反应轻微.

  13. Outcome of advanced chronic lymphocytic leukemia following different first-line and relapse therapies: a meta-analysis of five prospective trials by the German CLL Study Group (GCLLSG)

    Science.gov (United States)

    Cramer, Paula; Isfort, Susanne; Bahlo, Jasmin; Stilgenbauer, Stephan; Döhner, Hartmut; Bergmann, Manuela; Stauch, Martina; Kneba, Michael; Lange, Elisabeth; Langerbeins, Petra; Pflug, Natali; Kovacs, Gabor; Goede, Valentin; Fink, Anna-Maria; Elter, Thomas; Fischer, Kirsten; Wendtner, Clemens-Martin; Hallek, Michael; Eichhorst, Barbara

    2015-01-01

    To evaluate the effect of first-line and subsequent therapies, the outcome of 1,558 patients with chronic lymphocytic leukemia from five prospective phase II/III trials conducted between 1999 and 2010 was analyzed. The 3-year overall survival rate was higher after first-line treatment with chemoimmunotherapies such as fludarabine/cyclophosphamide/rituximab (87.9%) or bendamustine/rituximab (90.7%) compared to chemotherapies without an antibody (fludarabine/cyclophosphamide: 84.6%; fludarabine: 77.5%; chlorambucil: 77.4%). Furthermore, the median overall survival was longer in patients receiving at least one antibody-containing regimen in any treatment line (94.4 months) compared to the survival in patients who never received an antibody (84.3 months, P24 months after first-line therapy repeated the first-line regimen. Among 315 patients requiring treatment ≤24 months after first-line therapy, cyclophosphamide/doxorubicin/vincristine/prednisone with or without rituximab as well as alemtuzumab were the most commonly used therapies. In these early relapsing patients, the median overall survival was shorter following therapies containing an anthracycline and/or three or more cytotoxic agents (e.g. cyclophosphamide/doxorubicin/vincristine/prednisone or fludarabine/cyclophosphamide/mitoxantrone, 30.0 months) compared to single agent chemotherapy (e.g. fludarabine; 39.6 months) and standard chemoimmunotherapy (e.g. fludarabine/cyclophosphamide/rituximab: 61.6 months). In conclusion, the analysis confirms the superior efficacy of chemoimmunotherapies in patients with chronic lymphocytic leukemia. Moreover, the use of aggressive chemo(immuno)therapy combinations in patients with an early relapse does not offer any benefit when compared to less intensive therapies. Trial identifier: NCT00281918, ISRCTN75653261, ISRCTN36294212, NCT00274989 and NCT00147901. PMID:26315931

  14. Research progress on treatment and novel agents of chronic lymphocytic leukemia%慢性淋巴细胞白血病的治疗及新药研究进展

    Institute of Scientific and Technical Information of China (English)

    许新宁; 杨威

    2015-01-01

    Chronic lymphocytic leukemia ( CLL) is a common leukemia of adult.Researchers have made great progress on the treatment of CLL.At present,immunochemotherapy is still the standard first-line treatment of CLL.Obinutuzumab and ofatumumab as immunotherapies,ibrutinib and idelalisib as targeted drugs,could significantly im-prove the prognosis of CLL patients,especially for the elderly and frail patients.In addition,T-cell therapy for relapsed CLL also made a breakthrough.This article summarizes the progress of treatment and novel agents of CLL according to the clinical trial's data.%慢性淋巴细胞白血病( CLL)是成人常见白血病的一种,近年来其治疗有了很大进展. 目前,免疫化学治疗依旧是CLL患者的标准一线治疗方案. 免疫治疗药物Obinutuzumab及奥法木单抗、靶向药物依鲁替尼及Idelalisib等4种新药显著改善了CLL患者(特别是老年及虚弱CLL患者)的预后. 此外,T细胞疗法治疗复发CLL也取得了突破性进展. 本文结合临床试验数据概述了CLL的治疗及新药的研究进展.

  15. Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia

    DEFF Research Database (Denmark)

    Robak, Tadeusz; Dmoszynska, Anna; Solal-Céligny, Philippe;

    2010-01-01

    Rituximab, a monoclonal antibody that targets the CD20 cell surface antigen, has clinical activity in patients with non-Hodgkin's lymphoma and other B-lymphocyte disorders when administered alone or in combination with chemotherapy. Promising results have previously been reported in nonrandomized...

  16. Parameters of disease progression in long-term experimental feline retrovirus (feline immunodeficiency virus and feline leukemia virus) infections: hematology, clinical chemistry, and lymphocyte subsets.

    OpenAIRE

    Hofmann-Lehmann, R.; Holznagel, E; Ossent, P.; Lutz, H.

    1997-01-01

    After several years of latency, feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV) cause fatal disease in the cat. The aim of this study was to determine laboratory parameters characteristic of disease progression which would allow a better description of the asymptomatic phase and a better understanding of the pathogenesis of the two infections. Therefore, experimentally infected cats (FIV and/or FeLV positive) and control animals were observed over a period of 6.5 years un...

  17. Increased leukemia risk in Chernobyl cleanup workers

    Science.gov (United States)

    A new study found a significantly elevated risk for chronic lymphocytic leukemia among workers who were engaged in recovery and clean-up activities following the Chernobyl power plant accident in 1986.

  18. RPPA-based protein profiling reveals eIF4G overexpression and 4E-BP1 serine 65 phosphorylation as molecular events that correspond with a pro-survival phenotype in chronic lymphocytic leukemia.

    Science.gov (United States)

    Shull, Austin Y; Noonepalle, Satish K; Awan, Farrukh T; Liu, Jimei; Pei, Lirong; Bollag, Roni J; Salman, Huda; Ding, Zhiyong; Shi, Huidong

    2015-06-10

    Chronic lymphocytic leukemia (CLL), the most common adult leukemia, remains incurable despite advancements in treatment regimens over the past decade. Several expression profile studies have been pursued to better understand CLL pathogenesis. However, these large-scale studies only provide information at the transcriptional level. To better comprehend the differential protein changes that take place in CLL, we performed a reverse-phase protein array (RPPA) analysis using 167 different antibodies on B-cell lysates from 18 CLL patients and 6 normal donors. From our analysis, we discovered an enrichment of protein alterations involved with mRNA translation, specifically upregulation of the translation initiator eIF4G and phosphorylation of the cap-dependent translation inhibitor 4E-BP1 at serine 65. Interestingly, 4E-BP1 phosphorylation occurred independently of AKT phosphorylation, suggesting a disconnect between PI3K/AKT pathway activation and 4E-BP1 phosphorylation. Based on these results, we treated primary CLL samples with NVP-BEZ235, a PI3K/mTOR dual inhibitor, and compared its apoptotic-inducing potential against the BTK inhibitor Ibrutinib and the PI3Kδ inhibitor Idelalisib. We demonstrated that treatment with NVP-BEZ235 caused greater apoptosis, greater apoptotic cleavage of eIF4G, and greater dephosphorylation of 4E-BP1 in primary CLL cells. Taken together, these results highlight the potential dependence of eIF4G overexpression and 4E-BP1 phosphorylation in CLL survival. PMID:25999352

  19. Idarubicin-intensified BUCY2 conditioning regimen improved survival in high-risk acute myeloid, but not lymphocytic leukemia patients undergoing allogeneic hematopoietic stem cell transplantation: A retrospective comparative study.

    Science.gov (United States)

    Fang, Jun; Zhang, Ran; Wang, Huafang; Hong, Mei; Wu, Qiuling; Nie, Dimin; You, Yong; Zhong, Zhaodong; Li, Weiming; Hu, Yu; Xia, Linghui

    2016-07-01

    The intensity of conditioning regimen is highly correlated with outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We have previously reported that idarubicin (IDA) intensified BUCY2 regimen could reduce relapse and improve survival for high-risk hematological malignancies undergoing allo-HSCT. However, there is no published study comparing the efficacy of IDA-BUCY2 regimen for high-risk acute myeloid leukemia (AML) versus acute lymphocytic leukemia (ALL). We further retrospectively compared therapeutic outcomes of intensified conditioning regimen on 140 high-risk AML and ALL patients in the data analyses. IDA 15mg/m(2)/d was administered by continuous infusion from day -11 to -9, followed by intravenous injection of busulfan (BU) (3.2mg/kg/d) from day -6 to -4, and intravenous injection of cyclophosphamide (CY) (1.8g/m(2)/d) from day -3 to -2 in IDA-BUCY2 regimen. For high-risk AML, cumulative probabilities of 3-year relapse rates in IDA-BUCY2 and traditional BUCY2 regimens were 16.9%, 43.3% (P=0.016). Cumulative probabilities of 3-year overall survival (OS) and disease-free survival (DFS) were 69.2% vs 44.0% (P=0.024), and 66.9% vs 38.2% (P=0.01). However, two regimens showed no significant differences for high-risk ALL. Multivariate analysis also indicated that IDA intensified BUCY2 conditioning was the favorable variable to reduce relapse and elevate survival for high-risk AML patients. In conclusion, IDA-BUCY2 regimen reduces relapse and improves survival for high-risk AML undergoing allo-HSCT, but not presenting uniform therapeutic effects for high-risk ALL. PMID:27131062

  20. Osseous pseudo-myelomatose compromise, in leukemia chronic lymphoid

    International Nuclear Information System (INIS)

    It was described a case of chronic lymphocytic leukemia in a 75 year old man, with pseudomyelomatosis osteolytic lesions in the skull, excluding other potential causes of osteolytic lesions in the clinical context of malignant lymphoproliferative neoplasm. The real frequency of osseous compromise in chronic lymphocytic leukemia is 10%. Lesions are defined as generalized osteoporosis and osteolysis with lacunar aspect, similar to myeloma lesions. Because histopathology in lymphoproliferative neoplasms may be similar, it might be difficult to diagnose chronic lymphocytic leukemia certainly, if the clinical manifestations are not considered. Differential diagnosis with other lymphoproliferative neoplasm is based basically in absolute lymphocytosis greater than 10 X 109/L, with lymphocytes with mature appearance

  1. PEG10 Activation by Co-Stimulation of CXCR5 and CCR7 Essentially Contributes to Resistance to Apoptosis in CD19+CD34+ B Cells from Patients with B Cell Lineage Acute and Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    ChunsongHu; JeiXiong; LinjeiZhang; BaojunHuang; QiupingZhang; QunLi; MingzhenYang; YaouWu; QunWu; QianShen; QingpingGao; KejianZhang; ZhiminSun; JunyanLin; YouxinJin

    2004-01-01

    We investigated CD19+CD34+ and CD19+CD34 B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-α-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevatedlevel of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-α-mediated apoptosis. We suggested that normal lymphocytes, especially naive B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis. Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration, resistance to apoptosis, and inappropriate proliferation. Cellular & Molecular Immunology.

  2. PEG10 Activation by Co-Stimulation of CXCR5 and CCR7 Essentially Contributes to Resistance to Apoptosis in CD19+CD34+ B Cells from Patients with B Cell Lineage Acute and Chronic Lymphocytic Leukemia

    Institute of Scientific and Technical Information of China (English)

    Chunsong Hu; Qian Shen; Qingping Gao; Kejian Zhang; Zhimin Sun; Junyan Liu; Youxin Jin; Jinquan Tan; Jei Xiong; Linjei zhang; Baojun Huang; Qiuping Zhang; Qun Li; Mingzhen Yang; Yaou Wu; Qun Wu

    2004-01-01

    We investigated CD19+CD34+ and CD19+CD34- B cells from cord blood (CB) and typical patients with B cell lineage acute and chronic lymphocytic leukemia (B-ALL and B-CLL) in terms of expression and functions of CXCR5/CXCL13 and CCR7/CCL19. CXCR5 and CCR7 were selectively frequent expressed on B-ALL, B-CLL and CB CD19+CD34+ B cells, but not on CD19+CD34- B cells. Instead of induction of impressive chemotactic responsiveness, CXCL13 and CCL19 together induced significant resistance to TNF-α-mediated apoptosis in B-ALL and B-CLL but not CB CD19+CD34+ B cells. B-ALL and B-CLL CD19+CD34+ B cells expressed elevated level of Paternally Expressed Gene 10 (PEG10), and CXCL13 and CCL19 together significantly up-regulated PEG10 expression in the cells. We found that CXCL13 and CCL19 together by means of activation of CXCR5 and CCR7 up-regulated PEG10 expression and function, subsequent stabilized caspase-3 and caspase-8 in B-ALL and B-CLL CD19+CD34+ B cells, and rescued the cells from TNF-α-mediated apoptosis. We suggested that normal lymphocytes, especially na(I)ve B and T cells, utilized CXCR5/CXCL13 and CCR7/CCL19 for migration, homing, maturation, and cell homeostasis as well as secondary lymphoid tissues organogenesis.Meanwhile certain malignant cells took advantages of CXCR5/CXCL13 and CCR7/CCL19 for infiltration,resistance to apoptosis, and inappropriate proliferation.

  3. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

    Science.gov (United States)

    Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

    2014-07-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  4. CT60 single-nucleotide polymorphism as a surrogate marker for donor lymphocyte infusion outcome after allogeneic cell transplantation for acute leukemia.

    Science.gov (United States)

    Metaxas, Y; Bertz, H; Spyridonidis, A; Spyroupoulou-Vlachou, M; Porzelius, C; Finke, J

    2012-03-01

    The benefit of survival at the expense of new GVHD after DLI for acute leukemia following human allogeneic hematopoietic cell transplantation (allo-HCT) remains a matter of controversy. The detection of biological markers predicting this outcome would be an enormous breakthrough. The purpose of this study was the analysis of CT60 single-nucleotide polymorphism (SNP) of the CTLA-4 T-regulatory gene as a surrogate marker for DLI outcome in this difficult setting. Using Pyrosequencing, we genotyped the alleles of the CT60 SNP of 79 DLI donors and correlated them with the post-DLI outcome of their matching recipients. The presence of a donor 'AA' or 'AG' CT60 genotype vs a 'GG' genotype was an independent factor for remaining in complete chimerism/remission post-DLI (odds ratio (OR) 2.61 vs 0.42, respectively, P=0.05). Further, in cases with evident post-DLI allo-reactivity the importance of an 'AA' or 'AG' vs a 'GG' genotype gained significance for ongoing complete chimerism (OR 4.35 vs 0.32, P=0.03). Neither alterations in cumulative DLI dose nor any other clinical parameter significantly weakened the importance of CT60 SNP. Our results provide evidence for the necessity of genotyping CT60 SNP prior to DLI administration in patients with acute leukemia. PMID:21552305

  5. Engineering CD19-specific T lymphocytes with interleukin-15 and a suicide gene to enhance their anti-lymphoma/leukemia effects and safety

    OpenAIRE

    Hoyos, Valentina; Savoldo, Barbara; Quintarelli, Concetta; Mahendravada, Aruna; Zhang, Ming; Vera, Juan; Heslop, Helen E.; Rooney, Cliona M; Brenner, Malcolm K; Dotti, Gianpietro

    2010-01-01

    T lymphocytes expressing a chimeric antigen receptor (CAR) targeting the CD19 antigen (CAR.19) may be of value for the therapy of B-cell malignancies. Because the in vivo survival, expansion and anti-lymphoma activity of CAR.19+ T cells remain suboptimal even when the CAR contains a CD28 costimulatory endodomain, we generated a novel construct that also incorporates the interleukin-15 (IL15) gene and an inducible caspase-9-based suicide gene (iC9/CAR.19/IL15). We found that compared to CAR.19...

  6. CAR-pNK Cell Immunotherapy in CD7 Positive Leukemia and Lymphoma

    Science.gov (United States)

    2016-07-11

    Acute Myeloid Leukemia; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; T-cell Prolymphocytic Leukemia; T-cell Large Granular Lymphocytic Leukemia; Peripheral T-cell Lymphoma, NOS; Angioimmunoblastic T-cell Lymphoma; Extranodal NK/T-cell Lymphoma, Nasal Type; Enteropathy-type Intestinal T-cell Lymphoma; Hepatosplenic T-cell Lymphoma

  7. Deregulation of the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) gene in a B-cell chronic lymphocytic leukemia with a t(12;14)(q23;q32).

    Science.gov (United States)

    Schmidt, Helmut H; Dyomin, Vadim G; Palanisamy, Nallasivam; Itoyama, Takahiro; Nanjangud, Gouri; Pirc-Danoewinata, Hendrati; Haas, Oskar A; Chaganti, R S K

    2004-09-01

    The t(12;14)(q23;q32) breakpoints in a case of B-cell chronic lymphocytic leukemia (B-CLL) were mapped by fluorescence in situ hybridization (FISH) and Southern blot analysis and cloned using an IGH switch-gamma probe. The translocation affected a productively rearranged IGH allele and the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) locus at 12q23, with a reciprocal break in intron 2 of the CHST11 gene. CHST11 belongs to the HNK1 family of Golgi-associated sulfotransferases, a group of glycosaminoglycan-modifying enzymes, and is expressed mainly in the hematopoietic lineage. Northern Blot analysis of tumor RNA using CHST11-specific probes showed expression of two CHST11 forms of abnormal size. 5'- and 3'-Rapid Amplification of cDNA Ends (RACE) revealed IGH/CHST11 as well as CHST11/IGH fusion RNAs expressed from the der(14) and der(12) chromosomes. Both fusion species contained open reading frames making possible the translation of two truncated forms of CHST11 protein. The biological consequence of t(12;14)(q23;q32) in this case presumably is a disturbance of the cellular distribution of CHST11 leading to deregulation of a chondroitin-sulfate-dependent pathway specific to the hematopoietic lineage. PMID:15273723

  8. Role for elevated H-2 antigen expression in resistance to neoplasia caused by radiation-induced leukemia virus. Enhancement of effective tumor surveillance by killer lymphocytes

    International Nuclear Information System (INIS)

    Resistance to neoplasia caused by radiation-induced leukemia virus (RadLV) is mediated by gene(s) in the H-2D region of the major histocompatibility complex. The previous observation that rapid increases in cellular synthesis and cell-surface expression of H-2 antigens are detectable immediately after virus inoculation has suggested that altered expression of H-2 antigens may play a significant role in the mechanism(s) of host defense to virus infection. This concept is supported by the following observations. First, cell-mediated immunity against RadLV transformed or infected cells can be detected with ease when H-2-positive target cells are used in the cell-mediated lympholysis (CML) assay. Second, resistant mice develop greater numbers of effectors when infected with RadLV than do susceptible mice. Third, injection of normal (uninfected) thymocytes into syngeneic recipients of resistant or susceptible H-2 type does not stimulate a CML response. However, injection of RadLV infected thymocytes from resistant mice produces a vigorous CMI response, and such thymocytes elicit the strongest response at a time when both H-2 and viral antigen expression is elevated. By contrast, injection of infected thymocytes from susceptible mice, which express viral antigens, but low levels of H-2 antigens, does not stimulate a CML reaction. These findings may explain the easier induction of leukemia found by many investigators when virus is inoculated into neonatal mice and the preferential thymus tropism of some oncogenic type-C RNA virus. Cells expressing very low levels of H-2, such as thymocytes, may serve as permissive targets for virus infection because they lack an important component (H-2 antigens) of the dual or altered recognition signal required to trigger a defensive host immune response

  9. Genetically Engineered Lymphocyte Therapy in Treating Patients With Lymphoma That is Resistant or Refractory to Chemotherapy

    Science.gov (United States)

    2015-09-27

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Prolymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  10. Induction of endothelial cell proliferation and von Willebrand factor expression and secretion by leukemic plasma of patients with chronic lymphocytic leukemia before and after inhibition of NF-κB.

    Science.gov (United States)

    Shahidi, Minoo; Mohsen Razavi, Seyed; Hayat, Parisa

    2016-09-01

    Although certain evidence has indicated a role for angiogenesis in the pathophysiology of hematopoietic malignancies, its role in chronic lymphocytic leukemia (CLL) prognosis is yet to be defined. To our knowledge, the effects of CLL plasma on cell culture have not been addressed. Therefore, we investigated the effects of CLL plasma on cell cycle regulation and von Willebrand factor (vWF) secretion, and expression in human umbilical vein endothelial cell cultures (HUVECs). Since nuclear factor-kappa B (NF-κB) transcription factor has been a therapeutic target for treatment of cancer, we inhibited NF-κB using small interfering RNA to clarify if there is a role for this factor in probable effects. The cells were treated with the plasma of patients with CLL. Subsequently, cell cycle phase distribution, vWF secretion, expression, and storage were detected using ELISA, flow cytometry, and immunohistochemical staining. In addition, NF-κB was inhibited using small interfering RNA. Plasma treatment promoted cell cycle progression by decreasing the cell number in G1 phase, while increasing the cell number in S phase and G2M phase. A significant increase of vWF expression, secretion, and storage was found, associated with the vWF levels of patients' plasma. We found that induction of cell cycle promotion, but not vWF expression and secretion, was partially suppressed by this inhibition. We found that endothelial cell cycle and vWF expression and secretion affected by CLL plasma and NF-κB play a role in the former. These findings would be useful for understanding the prognostic importance of plasma angiogenic factor levels in CLL. PMID:27472040

  11. Chronic myelogenous leukemia (CML)

    Science.gov (United States)

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

  12. Childhood Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. It is the most common type of childhood cancer. ... blood cells help your body fight infection. In leukemia, the bone marrow produces abnormal white blood cells. ...

  13. Genetically Engineered Lymphocytes, Cyclophosphamide, and Aldesleukin in Treating Patients With Relapsed or Refractory Mantle Cell Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma

    Science.gov (United States)

    2014-08-04

    B-cell Chronic Lymphocytic Leukemia; Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  14. Arsenic Trioxide in Treating Patients With Relapsed or Refractory Lymphoma or Leukemia

    Science.gov (United States)

    2013-01-31

    Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue; Nodal Marginal Zone B-cell Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Small Lymphocytic Lymphoma; Refractory Chronic Lymphocytic Leukemia; Splenic Marginal Zone Lymphoma; Waldenström Macroglobulinemia

  15. Leukemia cutis

    Directory of Open Access Journals (Sweden)

    Varuna Mallya

    2015-01-01

    Full Text Available Patients with leukemia may show involvement of the skin. This skin involvement can be due to infiltration of skin by leukemic cells or it may be a part of nonspecific cutaneous manifestations. Leukemia cutis is the infiltration of neoplastic leucocytes or their precursors into the skin resulting in extensive clinical manifestations. Described mostly in acute myeloid leukemia and acute myelocytic monocytic leukemia, it is rare in chronic myeloid leukemia and is seen mostly during the blast crises. Its presence signals poor prognosis.

  16. Congenital Leukemia

    OpenAIRE

    Raj, Aishwarya; Talukdar, Sewali; Das, Smita; Gogoi, Pabitra Kumar; Das, Damodar; Bhattacharya, Jina

    2013-01-01

    Congenital leukemia is a rare but a well-documented disease in which leukemic process is detected at birth or very shortly thereafter (Philip McCoy and Roy Overton, Commun Clin Cytom 22:85–88, 1995). These leukemias represent approximately 0.8 % of all childhood leukemias. We present a case of congenital acute myeloid leukemia manifesting from the very first day of birth. Diagnosis of acute myeloid leukemia was suspected by the presence of blasts in the peripheral blood smear and was confirme...

  17. Anemia hemolítica auto-imune e outras manifestações imunes da leucemia linfocítica crônica Autoimmune hemolytic anemia and other autoimmune diseases related to chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    José O. Bordin

    2005-12-01

    Full Text Available A leucemia linfocítica crônica (LLC é freqüentemente associada a manifestações auto-imunes principalmente relacionadas às células do sistema hematopoético causando anemia hemolítica auto-imune (AHAI, púrpura trombocitopênica imune (PTI, aplasia pura de série vermelha (APSV, e neutropenia imune. A LLC é diagnosticada em até 15% dos pacientes com AHAI, e em cerca de 50% dos pacientes com AHAI secundária a doença maligna. A PTI ocorre em 2%, e a APSV em 1% dos pacientes com LLC. Prednisona é o tratamento inicial de escolha para a citopenia imune associada à LLC. Para cerca de 60% dos pacientes que apresentam recidiva da manifestação auto-imune tem sido utilizada esplenectomia, imunoglobulina endovenosa, ou ciclosporina. Embora as evidências sobre fisiopatologia sejam limitadas, os mecanismos fisiopatológicos da auto-imunidade na LLC estão relacionados à atividade dos linfócitos B leucêmicos que atuam como células apresentadoras de antígeno aberrantes, e são eficientes em processar e apresentar proteínas da membrana de hemácias e de plaquetas às células TH auto-reativas. Linfócitos TH específicos para certos auto-antígenos podem escapar de mecanismos de controle de auto-tolerância, e, se ativados, podem causar doença auto-imune. O diagnóstico de AHAI contra-indica o uso de fludarabina em pacientes com LLC, pois esse análogo da purina tem sido associado ao desenvolvimento de AHAI grave e fatal, com risco consideravelmente mais alto para pacientes mais imunossuprimidos devido a vários tratamentos anteriores.Chronic lymphocytic leukemia (CLL is frequently associated with autoimmune diseases directed against hematopoietic cells, including autoimmune hemolytic anemia (AIHA, immune thrombocytopenic purpura (ITP, pure red cell aplasia (PRCA, and immune neutropenia. CLL represents the diagnosis in up to 15% of the patients with AIHA, and in 50% of the patients with AIHA secondary to malignancy. ITP occurs in 2% and

  18. Prolonged T1 relaxation of the hemopoietic bone marrow in patients with chronic leukemia

    DEFF Research Database (Denmark)

    Jensen, K E; Sørensen, P G; Thomsen, C;

    1990-01-01

    Eleven patients with chronic leukemia (7 with chronic lymphocytic leukemia and 4 with chronic myeloid leukemia) were evaluated with magnetic resonance (MR) imaging and T1 relaxation time measurements by use of a 1.5 tesla whole body MR scanner. Bone marrow biopsies were obtained from the posterior...

  19. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

    Science.gov (United States)

    ... the relapsed/refractory setting include: • Alemtuzumab (Campath) • Fludarabine (Fludara) • Bendamustine (Treanda) • Ofatumumab (Arzerra) • Chlorambucil (Leukeran) • Rituximab (Rituxan) Some common combination treatment regimens used in ...

  20. Differentiation between tuberculosis and leukemia in abdominal and pelvic lymph nodes: evaluation with contrast-enhanced multidetector computed tomography

    Directory of Open Access Journals (Sweden)

    Ge Zhang

    2015-03-01

    Full Text Available PURPOSE: To compare the characteristics of tubercular vs. leukemic involvement of abdominopelvic lymph nodes using multidetector computed tomography (CT. MATERIALS AND METHODS: We retrospectively reviewed multidetector computed tomography features including lymph node size, shape, enhancement patterns, and anatomical distribution, in 106 consecutive patients with newly diagnosed, untreated tuberculosis (55 patients; 52% or leukemia (51 patients; 48%. In patients with leukemia, 32 (62.7% had chronic lymphocytic leukemia, and 19 (37.3% had acute leukemias; of these, 10 (19.6% had acute myeloid leukemia, and 9 (17.6% had acute lymphocytic leukemia. RESULTS: The lower para-aortic (30.9% for tuberculosis, 63.2% for acute leukemias and 87.5% for chronic lymphocytic leukemia and inguinal (9.1% for tuberculosis, 57.9% for acute leukemias and 53.1% for chronic lymphocytic leukemia lymph nodes were involved more frequently in the three types of leukemia than in tuberculosis (both with p <0.017. Tuberculosis showed peripheral enhancement, frequently with a multilocular appearance, in 43 (78.2% patients, whereas patients with leukemia (78.9% for acute myeloid leukemia and acute lymphocytic leukemia, 87.5% for chronic lymphocytic leukemia demonstrated predominantly homogeneous enhancement (both with p <0.017. For the diagnosis of tuberculosis, the analysis showed that a peripheral enhancement pattern had a sensitivity of 78.2%, a specificity of 100%, and an accuracy of 88.7%. For the diagnosis of leukemia, the analysis showed that a homogeneous enhancement pattern was associated with a sensitivity of 84.3%, a specificity of 94.5%, and an accuracy of 89.6%. CONCLUSION: Our findings indicate that the anatomical distribution and enhancement patterns of lymphadenopathy seen on multidetector computed tomography are useful for differentiating between untreated tuberculosis and leukemia of the abdominopelvic lymph nodes.

  1. Acute childhood leukemia: Nursing care

    International Nuclear Information System (INIS)

    Modern therapy for childhood acute leukemia has provided a dramatically improved prognosis over that of just 30 years ago. In the early 1960's survival rates for acute lymphocytic leukemia (ALL) and acute myelogenous leukemia (AML) were 4% and 3%, respectively. By the 1980's survival rates had risen to 72% for all and 25% to 40% for AML. Today, a diagnosis of all carries an 80% survival rate and as high as a 90% survival rate for some low-risk subtypes. Such high cure rates depend on intense and complex, multimodal therapeutic protocols. Therefore, nursing care of the child with acute leukemia must meet the demands of complicated medical therapies and balance those with the needs of a sick child and their concerned family. An understanding of disease process and principles of medical management guide appropriate and effective nursing interventions. Leukemia is a malignant disorder of the blood and blood- forming organs (bone marrow, lymph nodes and spleen). Most believe that acute leukemia results from a malignant transformation of a single early haematopoietic stem cell that is capable of indefinite self-renewal. These immature cells of blasts do not respond to normal physiologic stimuli for differentiation and gradually become the predominant cell in the bone marrow

  2. How Is Chronic Lymphocytic Leukemia Diagnosed?

    Science.gov (United States)

    ... this protein generally indicate a more advanced CLL. Bone marrow tests Blood tests are often enough to diagnose ... is called an incisional biopsy . Lumbar puncture (or spinal tap) This procedure is used to take samples ...

  3. How Is Acute Lymphocytic Leukemia Diagnosed?

    Science.gov (United States)

    ... at a sample of bone marrow cells. Blood chemistry and coagulation tests: Blood chemistry tests measure the amounts of certain chemicals in ... and strong magnets instead of x-rays. The energy from the radio waves is absorbed by the ...

  4. Leukemia -- Chronic T-Cell Lymphocytic

    Science.gov (United States)

    ... of an Overview? If you would like additional introductory information, explore these related items. Please note these ... research. The next section in this guide is Statistics and it helps explain how many people are ...

  5. Supportive Care for Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... affect the immune system, like corticosteroids, IVIG, and rituximab (Rituxan). Removing the spleen is also an option. If you develop AIHA while taking fludarabine (Fludara), the drug may be the cause, and so ...

  6. Stromal control of chronic lymphocytic leukemia cells

    OpenAIRE

    Seke Etet, Paul Faustin

    2013-01-01

    Paul Faustin Seke Etet,1 Armel Herve Nwabo Kamdje,2 Jeremie Mbo Amvene,2 Yousef Aldebasi,3 Mohammed Farahna,1 Lorella Vecchio41Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 2Department of Medicine, University of Ngaoundere, Ngaoundere, Cameroon; 3Department of Optometry, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia; 4Laboratory of Cytometry, Institute of Molecular Genetics, CNR, University...

  7. General Information about Chronic Lymphocytic Leukemia

    Science.gov (United States)

    ... of the lymph system . Having relatives who are Russian Jews or Eastern European Jews. Signs and symptoms ... based on an independent review of the medical literature. They are not policy statements of the NCI ...

  8. Radiotherapy for leukemia in children, (1)

    International Nuclear Information System (INIS)

    Following the development of effective chemotherapy for producing remissions of acute lymphocytic leukemia (ALL), a new phenomenon has emerged in this disease--central nervous system (CNS) leukemia. CNS leukemia has become an increasingly frequent obstacle to prolongation of initial complete remission. Prophylactic irradiation of the CNS concomitant with intrathecal administration of methotrexate (IT-MTX) has proved to be effective in the reduction of CNS involvement. The purpose of this paper is to describe the results of irradiation for prevention of CNS leukemia and to discuss their implications. The patients consisted of 32 children with acute leukemia, admitted to MAIZURU National Hospital from 1966 to 1980; 22 patients of them had ALL, the others ANLL (acute non-lymphocytic leukemia). Preventive CNS therapy was started in 1974, (group A), but there was no prevention before 1974 (group B). 1. In group B, six patients was treated by therapeutic cranial irradiation, but all cases resulted in death. 2. In group A, seven patients was treated by prophylactic cranial irradiation combined with IT-MTX, and all of them have been alive without CNS relapse for 2 to 4 2/3 years after therapy. 3. In group A, none of 7 patients (0 %) relapsed CNS leukemia initially as compared to 7 (50 %) of 14 in group B, thus preventive efficacy was clear. 4. There were no severe complications attributable to the radiotherapy, with or without IT-MTX. (author)

  9. FR901228 in Treating Children With Refractory or Recurrent Solid Tumors or Leukemia

    Science.gov (United States)

    2013-01-15

    Blastic Phase Chronic Myelogenous Leukemia; Childhood Central Nervous System Germ Cell Tumor; Childhood Choroid Plexus Tumor; Childhood Chronic Myelogenous Leukemia; Childhood Craniopharyngioma; Childhood Grade I Meningioma; Childhood Grade II Meningioma; Childhood Grade III Meningioma; Childhood High-grade Cerebral Astrocytoma; Childhood Infratentorial Ependymoma; Childhood Low-grade Cerebral Astrocytoma; Childhood Spinal Cord Neoplasm; Childhood Supratentorial Ependymoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Brain Stem Glioma; Recurrent Childhood Cerebellar Astrocytoma; Recurrent Childhood Cerebral Astrocytoma; Recurrent Childhood Ependymoma; Recurrent Childhood Medulloblastoma; Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumor; Recurrent Childhood Visual Pathway and Hypothalamic Glioma; Refractory Chronic Lymphocytic Leukemia; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

  10. Atypical Chronic Myelogenous Leukemia

    Science.gov (United States)

    ... myeloproliferative neoplasms, leukemia , and other conditions . Chronic Myelomonocytic Leukemia Key Points Chronic myelomonocytic leukemia is a disease ... chance of recovery) and treatment options. Chronic myelomonocytic leukemia is a disease in which too many myelocytes ...

  11. Juvenile Myelomonocytic Leukemia

    Science.gov (United States)

    ... myeloproliferative neoplasms, leukemia , and other conditions . Chronic Myelomonocytic Leukemia Key Points Chronic myelomonocytic leukemia is a disease ... chance of recovery) and treatment options. Chronic myelomonocytic leukemia is a disease in which too many myelocytes ...

  12. Childhood Leukemia

    Science.gov (United States)

    ... cells. It is the most common type of childhood cancer. Your blood cells form in your bone ... in the bones or joints Risk factors for childhood leukemia include having a brother or sister with ...

  13. Leukemia cutis

    Directory of Open Access Journals (Sweden)

    Angoori G Rao

    2012-01-01

    Full Text Available Leukemia cutis is the infiltration of neoplastic leukocytes or their precursors into the epidermis, the dermis, or the subcutis, resulting in clinically identifiable cutaneous lesions. Leukemia cutis may follow, precede or occur concomitantly with the diagnosis of systemic leukemia. A 50-year-old woman presented with asymptomatic multiple cutaneous nodules all over the body of 4 months duration. Cutaneous examination showed multiple hyperpigmented nodules and plaques involving face, trunk, and extremities. Peripheral smear showed abnormally elevated leucocyte count (TLC-70,000 with abnormal cells: myeloblasts 40%, promyelocytes 8% and myelocytes 39%. Auer rods were present in few myeloblasts. Bone marrow aspiration showed increased cellularity, erythroid hyperplasia with megaloblastic change, increased myeloblasts with maturation arrest. Immunohistochemistry showed strongly positive myeloperoxidase infiltrating cells and negative for CD20 and CD3 consistent with the diagnosis of AML-M 2 with leukemia cutis. This case is reported for its rarity.

  14. Studies of lymphocyte growth and differentiation. Progress report, September 1, 1975--July 31, 1976

    Energy Technology Data Exchange (ETDEWEB)

    Rubin, A.D.

    1976-01-01

    Studies were continued on ribonuclear protein synthesis and the assembly of ribosomes in resting and stimulated lymphocytes. We demonstrated the interdependency of protein synthesis and RNA synthesis in the formation and processing of nascent ribonuclear protein particles. We further explored lymphocyte nuclei in a cell-free system. By isolating lymphocyte chromatin we showed a direct effect of PHA on the ability of this nuclear structure to incorporate radioactivity into acid precipitable RNA. We returned to our previous studies on the delayed response of chronic lymphocytic leukemia (CLL) lymphocytes to PHA. We traced this alternate response identifying it as a characteristic of the CLL cell. The evidence questioned the generally accepted conclusion that CLL represents a B cell malignancy. We went on further to describe delayed reacting lymphocytes in the circulation of patients with nodular lymphoma and acute lymphoblastic leukemia (ALL). The ALL, unlike the lymphoma and CLL cells, showed a normal magnitude of response, even though it was delayed. We described the technique which might be employed as a diagnostic test for detecting abnormal lymphocytes in patients with lymphocytic lymphoma and leukemia and could help distinguish these diseases from benign lymphoid hyperplasia and other forms of non-lymphocytic leukemia.

  15. [Linear and adhesive phenotype of tumor lymphocytes and clinical course of chronic leucosis].

    Science.gov (United States)

    Golenkov, A K; Baryshnikov, A Iu; Mitina, T A; Novikov, V V

    2005-01-01

    Determination of chronic lymphatic leukemia immunological phenotype, performed by the authors, was based upon the study of quantitative expression of membrane differentiation antigens on peripheral blood lymphocytes. The research included study of co-expression of adhesion molecules, belonging to the following families: beta 2 integrins (CD 11 beta, CD 18), immunoglobulins (CD 50), and CD 38 on tumor blood B-lymphocytes of various CD-types and T-lymphocytes in chronic leucosis. The authors developed a functional model of trans-endothelial migration of peripheral blood lymphocytes in chronic chronic lymphatic leukemia, taking into account their membrane adhesive characteristics and serum level of CD 50. The researchers determined clinical importance of the expression of linear and adhesive antigens on peripheral blood lymphocytes, and soluble HLA-1 (sHLA-1) serum levels in patients with chronic lymphatic leukemia. PMID:15960204

  16. 急性非淋巴细胞白血病化疗后血型变异2例%Two cases of the blood type variation after chemotherapy in patients with acute non-lymphocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    陆娟; 陈世兰

    2013-01-01

    Two patients after admission were diagnosed with acute myelocytic leukemia-M2a.After chemotherapy,the bone marrow of the two patients was in spontaneous remission.During the later treatment of chemotherapy,the patients' blood type changed.One patient's blood type was from O Rh(+) to B Rh(+),the other patient's blood type was from A Rh(+) to A Rh(-).Blood types of the two patients were both mutated.Then,they were transfused with the blood of the same types after variation,and no adverse reaction occurred.The reason why the blood type variation of the two patients with leukemia occurred after chemotherapy was the changes in cell membrane antigen caused by the effect of chemotherapy drugs.

  17. Cancers other than leukemia

    International Nuclear Information System (INIS)

    Cancers which are unlikely to appear among atomic bomb survirors in excess of natural incidence include skin cancer and bone cancer, as these appear to require for their initiation doses that are incompatible with life if administered on a whole body basis. Although chronic lymphocytic leukemia continues to provide an important exception, and for many sites of cancer there is not yet evidence that radiation has increased incidence above normal levels, the data on A-bomb survivors are otherwise consistent with the hypothesis that the carcinogenic effect of ionizing radiation is general, involving all tissues. Studies of cancer among A-bomb survivors are notably limited with respect to the influence of variables other than dose, age, sex, and time. It seems highly desirable that other risk factors be studied in conjunction with radiation dose and demographic variables in an effort to detect interactions that might provide clues as to the etiology of cancer and as to the mechanisms by which ionizing radiation produces cancer. Provisional estimates suggest that the absolute risk of cancer, in terms of excess cases per 106 person-year rads (T65 dose) are about 1.6 for leukemia, 1.2 for thyroid, 2.1 for breast and 2.0 for lung, when estimation is based on age-ATB groups that have demonstrated these effects. (JPN)

  18. Expression of CD123 in lymphocytic leukemia and its significance for monitoring minimal residual diseases%CD123在淋巴细胞白血病细胞中的表达及在微量残留病监测中的作用

    Institute of Scientific and Technical Information of China (English)

    王跃飞; 陈葆国; 罗文达; 郑瑞; 李伯利

    2010-01-01

    目的 探讨CD123在淋巴细胞白血病中的表达特点及意义.方法 应用多参数流式细胞术检测139例淋巴细胞白血病患者CD123的表达.以10名正常人骨髓淋巴细胞作对照.对105例急性B淋巴细胞白血病(B-ALL)患者行细胞遗传学分析.对97例B-ALL患者进行白血病微量残留病(MRD)分析.结果 ①10名正常人骨髓中B淋巴干/祖细胞、成熟B淋巴细胞及T淋巴细胞均不表达CD123.139例淋巴细胞白血病患者中,5例T-ALL和23例慢性B淋巴细胞白血病(B-CLL)患者CD123均阴性.111例B-ALL患者中106例CD123阳性(阳性率95.49%),其中包括12例早期前B-ALL、57例普通B-ALL、37例前B-ALL;5例成熟B-ALL患者CD123阴性.②在B-ALL患者中,CD123表达水平与p-Akt表达水平呈正相关,超二倍体患者组CD123表达水平高于非超二倍体患者组.③MRD阳性与阴性组患者比较,12个月内复发率分别为63.04%和21.56%,差异有统计学意义(P<0.01).MRD阴性组无病生存率[(48.23±1.82)%]高于MRD阳性组[(36.06±2.62)%].CD123在复发B-ALL患者中表达稳定性高.结论 CD123在B-ALL患者中普遍中度至强度表达,复发时表达稳定性高,是MRD分析较好的标志之一.%Objective To investigate the expression of CD 123 and its significance in lymphocytic leukemia.Methods CD123 expression in 139 lymphocytic leukemia patients and in lymphocytes from 10 normal bone marrows( BM) was analyzed by multi-parameter flow cytometry.Cytogenetic and minimal residual disease (MRD) analysis were performed in acute B-lymphocytic leukemia (B-ALL) patients.Results CD123 expression was absent in B lymphoid lineage stem-progenitor cells, mature B and T lymphocytes from 10 normal BM.Among 139 lymphocytic leukemia patients, CD123 was negative in 5 T-ALL and 23 B-CLL patients.However, among 111 B-ALL patients, CD123 was expressed in 106 (12 pro B-ALL, 57 common B-ALL and 37 Pre B-ALL) (95.49% ) but not in 5 mature B-ALL patients.There was a positive correlation

  19. 非经典性NF-κB活性在慢性B淋巴细胞白血病中的作用%Function of alternative NF-κB activity in B-cell chronic lymphocytic leukemia cells

    Institute of Scientific and Technical Information of China (English)

    徐晶晶; 周鹏; 国风

    2014-01-01

    Objective To investigate the function of alternative NF-κB activity in B-cell chronic lymphocytic leukemia cells (B-CLL).Methods The mRNA expression of individual NF-κB subunits in CD5+CD19+ cells (CLL B-cells) from bone marrow (BM) of 56 patients with B-CLL was analyzed by quantitative RT-PCR.An ELISA-based NF-κB family transcription factor activity assay was performed to quantify the κB DNA-binding activity in nuclear extracts from CLL B-cells.Cell death of CLL-B cells was determined by PI staining,RelA and RelB expression at protein level of CLL B-cells by Western blot analyses.Results The expression levels of RelA,p50,RelB and p52 mRNA in CLL B-cells were all higher than that of normal B cells with statistical significance (P<0.05).RelA was activated in almost all the patients detected while RelB activity was induced in part of samples.The average RelA activity in CLL B-cells was increased compared to that in normal B cells while the average RelB activity was similar to that of normal B cells.When cultured in vitro for 24,48 and 72 hours,the frequencies of cell death of CLL B-cells from RelA+/RelB-group were (35.54±4.43)%,(50.92±8.44)%,and (49.24±8.16)%,respectively;that of the RelA+/RelB+ group were (20.65±2.37)%,(18.17± 1.36)%,and (26.55±4.08)%,respectively.When the cells from RelA+/RelB-group were co-cultured with bone marrow stromal cells (hBMSCs),the frequencies of cell death of CLL B-cells were decreased compared to that of the cells cultured alone,while the frequencies of cell death of RelA+/RelB-CLL B-cells were higher than that of CLL B-cells from RelA+/ RelB+ group when co-cultured with hBMSCs.RelA and RelB expression in CLL-B cells from the RelA+/RelB-group was induced after co-cultured with hBMSCs for 48h.RelB was reduced in the cytoplasm and increased in the nucleus in CLL-B cells from the RelA+/RelB+ group.Conclusion The alternative NF-κB was indeed activated and presented heterogenous in CLL B-cells from BM.Activation of

  20. Human T cell leukemia virus type 1 infection drives spontaneous proliferation of natural killer cells

    OpenAIRE

    Norris, Philip J; Hirschkorn, Dale F.; DeVita, Deborah A.; Lee, Tzong-Hae; Murphy, Eedward L

    2010-01-01

    Most human T cell leukemia virus type 1 (HTLV-1) infected subjects remain asymptomatic throughout their lives, with a few individuals developing HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP) or adult T cell leukemia. Lymphocytes from about half of HTLV-1 infected subjects spontaneously proliferate in vitro, and how this phenomenon relates to symptomatic disease outcome and viral burden is poorly understood. Spontaneous proliferation was measured in lymphocyte subsets, an...

  1. Methylation of Gene CHFR Promoter in Acute Leukemia Cells

    Institute of Scientific and Technical Information of China (English)

    GONG Hui; LIU Wengli; ZHOU Jianfeng; XU Huizhen

    2005-01-01

    Summary: In order to explore whether gene CHFR was inactivated by methylation in leukemia cells, the expression of CHFR was examined before and after treatment with demethylation agent in Molt-4, Jurkat and U937 leukemia cell lines by means of RT-PCR. The methylation of promoter in Molt-4, Jurkat and U937 cells as well as 41 acute leukemia patients was analyzed by MS-PCR. The results showed that methylation of CHFR promoter was inactivated and could be reversed by treatment with a demethylating agent in Molt-4, Jurkat and U937. CHFR promoter methylation was detected in 39 % of acute leukemia patients. There was no difference in incidence of CHFR promoter methylation between acute myelocytic leukemia and acute lymphocytic leukemia. In conclusion, CHFR is frequently inactivated in acute leukemia and is a good candidate for the leukemia supper gene. By affecting mitotic checkpoint function, CHFR inactivation likely plays a key role in tumorigenesis in acute leukemia. Moreover, the methylation of gene CHFR appears to be a good index with which to predict the sensitivity of acute leukemia to microtubule inhibitors.

  2. Understanding Leukemia

    Science.gov (United States)

    ... a second cancer, including melanoma, sarcoma, colorectal cancer, lung cancer, basal cell cancer, squamous cell skin cancer or myeloma. {{ See your primary care doctor to keep up with other healthcare needs. Understanding Leukemia I page 21 {{ Talk with family and friends about how ...

  3. The role of induciable transcription factors and microenvironment in leukemia

    OpenAIRE

    Qattan, Malak

    2014-01-01

    Although the survival rates of 80% in acute lymphocytic leukemia (ALL) is a remarkable achievement, the 20% of affected children are facing the risk of death and toxicity of the treatment is significant. The drugs used in ALL are anthracyclines and steroids. Glucocorticoids exert their therapeutic effects in leukemia by inducing apoptosis through intracellular glucocorticoid receptor (GR). Anthracyclines have the ability to inhibit the DNA topoisomerase II causing DNA double strands breaks an...

  4. Allogeneic cellular immunotherapy for chronic B-cell leukemia

    OpenAIRE

    Hoogendoorn, Mels

    2007-01-01

    Allogeneic stem cell transplantation (SCT) following reduced-intensity conditioning (RIC) as treatment modality has curative potential in patients suffering from chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL), illustrating susceptibility of these leukemic cells for the graft-versus-leukemia (GvL) effect. However, effectiveness of this therapy is limited due to low immunogenicity of leukemic cells and the lack of specificity resulting in concurrent development of graft-versus...

  5. Estimation of bovine leukemia virus (BLV) proviral load harbored by lymphocyte subpopulations in BLV-infected cattle at the subclinical stage of enzootic bovine leucosis using BLV-CoCoMo-qPCR

    OpenAIRE

    Panei, Carlos Javier; Takeshima, Shin-nosuke; Omori, Takashi; NUNOYA, Tetsuo; Davis, William C.; Ishizaki, Hiroshi; Matoba, Kazuhiro; Aida, Yoko

    2013-01-01

    Background Bovine leukemia virus (BLV) is associated with enzootic bovine leukosis (EBL), which is the most common neoplastic disease of cattle. BLV infection may remain clinically silent at the aleukemic (AL) stage, cause persistent lymphocytosis (PL), or, more rarely, B cell lymphoma. BLV has been identified in B cells, CD2+ T cells, CD3+ T cells, CD4+ T cells, CD8+ T cells, γ/δ T cells, monocytes, and granulocytes in infected cattle that do not have tumors, although the most consistently i...

  6. The dynamics of DNA double-strand breaks and apoptosis in peripheral blood human lymphocytes

    International Nuclear Information System (INIS)

    Two-phase nature of the DNA double-strand breaks (DSBs) formation and apoptosis under the influence of ionizing radiation in normal and chronic lymphocytic leukemia lymphocytes was observed. The highest level of DSBs was in first minutes after irradiation, and then their repair was seen. The dynamics of DSBs and apoptosis were similar in both types of lymphocytes and the correlation of the processes was revealed. (authors)

  7. Successful treatment with interferon of chicken pox in children with acute leukemia.

    OpenAIRE

    Kim, Byung Soo

    1984-01-01

    Childhood leukemia, especially acute lymphocytic leukemia, can now be completely cured by a multimodality approach in one out of every two patients. Since prolonged maintenance therapy with anti-cancer agents for three years is required for complete cure, a significant problem during this course of treatment is death due to secondary infection. Those with childhood leukemia receiving anti-cancer chemotherapy who became secondarily injected with chicken pox can now be treated successfully with...

  8. In vitro radiosensitivity of human leukemia cell lines

    International Nuclear Information System (INIS)

    The in vitro radiobiologic survival values (n, D0) of four tumor lines derived from human hematopoietic tumors were studied. These cell lines were HL50 (n . 1.3, D0 . 117 rad[1.17 Gy]), promyelocytic leukemia; K562 (n . 1.4, D0 . 165 rad[1.65 Gy]), erythroleukemia; 45 (n . 1.1, D0 . 147 rad[1.47 Gy]), acute lymphocyte leukemia; and 176 (n . 4.0, D0 . 76 rad[0.76 Gy]), acute monomyelogenous leukemia. More cell lines must be examined before the exact relationship between in vitro radiosensitivity and clinical radiocurability is firmly established

  9. An increased risk of non-Hodgkin lymphoma and chronic lymphocytic leukemia in US patients with Merkel cell carcinoma versus Australian patients: A clinical clue to a different mechanism of pathogenesis?

    Science.gov (United States)

    Bloom, Romi; Amber, Kyle T; Nouri, Keyvan

    2016-08-01

    The US and Queensland populations both demonstrate an increased risk of secondary malignancies following the diagnosis of Merkel cell carcinoma (MCC). A recent Queensland study failed to demonstrate a significantly increased risk of developing non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukaemia (CLL) in these patients. In contrast, using the US Surveillance, Epidemiology, and End Results database, we demonstrate there is an increased risk in CLL and NHL following the diagnosis of MCC in the USA. We hypothesise that this difference may be a result of a differing pathogenesis. PMID:25801041

  10. 慢性淋巴细胞白血病治疗进展:第57届美国血液学会年会报道%Treatment progress of chronic lymphocytic leukemia: reports from the 57th American Society of Hematology annual meeting

    Institute of Scientific and Technical Information of China (English)

    李悦; 徐卫; 李建勇

    2016-01-01

    Chronic lymphocytic leukemia (CLL) is a chronic B-cell lymphoproliferative clonal disease with a highly heterogeneous clinical course. In recent years, with the emerging of immunochemotherapy, bcl-2 inhibitor, B-cell receptor signal transduction kinase inhibitors and the chimeric antigen receptor-T cell (CAR-T), more and more improvements were made in CLL therapy and remission. This report addressed the progress of CLL therapy in the 57th American Society of Hematology annual meeting.%慢性淋巴细胞白血病(CLL)是一种高度异质性的慢性B淋巴细胞克隆增殖性疾病.近年来,随着化学免疫、bcl-2抑制剂、BCR信号通路抑制剂、PD-1抑制剂和嵌合抗原受体的T细胞(CAR-T)等新型药物及治疗方法不断涌现,CLL的治疗效果和缓解程度不断提高.文章就2015年第57届美国血液学会(ASH)年会CLL的治疗进展进行报道.

  11. Normalization of lymphocyte count after high ablative dose of I-131 in a patient with chronic lymphoid leukemia and secondary papillary carcinoma of the thyroid: case report; Normalizacao da contagem de linfocitos apos dose ablativa de I-131 em um paciente com leucemia linfoide cronica e carcinoma papilifero da tireoide: relato de caso

    Energy Technology Data Exchange (ETDEWEB)

    Thom, Anneliese Rosmarie Gertrud Fischer; Hamerschlak, Nelson; Osawa, Akemi; Santos, Fabio Pires de Souza; Pasqualin, Denise da Cunha; Wagner, Jairo; Yamaga, Lilian Yuri Itaya; Cunha, Marcelo Livorsi da; Campos Neto, Guilherme de Carvalho; Funari, Marcelo Buarque de Gusmao, E-mail: afthom@einstein.br [Hospital Israelita Albert Einstein, Sao Paulo, SP (Brazil); Teles, Veronica Goes [Sociedade Brasileira de Diabetes, Sao Paulo, SP (Brazil)

    2014-07-01

    The authors report the case of a 70-year-old male patient with chronic lymphoid leukemia who presented subsequently a papillary carcinoma of the thyroid with metastases to regional lymph nodes. The patient was treated with surgical thyroidectomy with regional and cervical lymph node excision and radioiodine therapy (I-131). The protocolar control scintigraphy 4 days after the radioactive dose showed I-131 uptake in both axillae and even in the inguinal regions. PET/CT showed faint FDG-F-18 uptake in one lymph node of the left axilla. An ultrasound guided fine needle biopsy of this lymph node identified by I-131 SPECT/CT and FDG-F-18 PET/CT revealed lymphoma cells and was negative for thyroid tissue and thyroglobulin content. The sequential blood counts done routinely after radiation treatment showed a marked fall until return to normal values of leucocytes and lymphocytes (absolute and relative), which were still normal in the last control 19 months after the radioiodine administration. Chest computed tomography showed a decrease in size of axillary and paraaortic lymph nodes. By immunohistochemistry, cells of the lymphoid B lineage decreased from 52% before radioiodine therapy to 5% after the procedure. The authors speculate about a possible sodium iodide symporter expression by the cells of this lymphoma, similar to some other non-thyroid tumors, such as breast cancer cells. (author)

  12. Marijuana Smoking in Patients With Leukemia.

    Science.gov (United States)

    Khwaja, Sara; Yacoub, Abraham; Cheema, Asima; Rihana, Nancy; Russo, Robin; Velez, Ana Paula; Nanjappa, Sowmya; Sandin, Ramon L; Bohra, Chandrashekar; Gajanan, Ganesh; Greene, John N

    2016-07-01

    Worldwide, marijuana (cannabis) is a widely used drug. The incidence of marijuana smoking is increasing and is second only to tobacco as the most widely smoked substance in the general population. It is also the second most commonly used recreational drug after alcohol. Some adverse effects of marijuana smoking have been documented; however, the number of studies on the pulmonary effects of marijuana in individuals with leukemia is limited. In our case series, we report on 2 men with acute myeloid leukemia with miliary nodular lung patterns on computed tomography of the chest due to heavy marijuana use. We also report on 2 patients with acute lymphocytic leukemia who had a history of smoking marijuana and then developed lung opacities consistent with mold infection. PMID:27556668

  13. Evolución de la leucemia linfática crónica: Valor predictivo del inmunofenotipo, el CD23 soluble y la morfología Evolution of chronic lymphocytic leukemia: Predictive value of immunophenotype, sCD23 and morphology

    Directory of Open Access Journals (Sweden)

    Marcela A. Sarmiento

    2002-08-01

    Full Text Available En la leucemia linfática crónica (LLC se reconocen factores pronósticos útiles como la duplicación linfocitaria, el estadio clínico y el patrón de infiltración medular. Otros, como el porcentaje de células CD38+ están en estudio y requieren confirmación. El objetivo del presente estudio fue evaluar si existe asociación entre morfología, inmunofenotipo linfocitario, CD23 soluble (SL y sobrevida libre de eventos (SLE. Se evaluaron prospectivamente 36 pacientes sin tratamiento. Se determinaron: morfología típica, mixta y LLC-PL; inmunofenotipo linfocitario (score de Matutes; niveles plasmáticos de CD23 SL; estadio clínico, duplicación linfocitaria; b2microglobulina y alteraciones citogenéticas. Se consideró evento: progresión de enfermedad (necesidad de tratamiento, evolución a estadios avanzados, desarrollo de organomegalia voluminosa y muerte por enfermedad. Mediana de seguimiento: 24 meses. Resultados: estadio 0: 11/36, SLE 80%; I: 10/36 SLE 90%; II: 13/36; III y IV: 2/36. SLE > II 37%. p= 0.023. Duplicación linfocitaria: 12m 24/31. SLE 28% vs 80% p 350 UI/ml 17/32. SLE 92% vs 53% p=0.005. Inmunofenotipo: Score 5: 15/36, Score 4: 19/36, SLE 64%. Score 3: 2/36. p=0.516. Morfología típica 17/35, mixta 17/35. SLE 81% vs 57%, p=0.099. LLC-PL 1/35. El CD 23 SL resultó adecuado para predecir SLE, particularmente útil en estadios iniciales sin otros marcadores de actividad. La morfología y el fenotipo linfocitario, dos variables accesibles, no fueron útiles para el propósito del estudio.Some prognostic factors are useful in chronic lymphocytic leukemia (CLL: lymphocyte doubling time, clinical stage and bone marrow pattern infiltration, while others, such as the percentage of CD38+ cells, are under study and require confirmation. The objective of this study was to evaluate whether there is an association between morphology, lymphocyte immunophenotype, soluble CD23 (sCD23 and progression free survival (PFS. A total of 36 non

  14. The incidence of leukemia, lymphoma, and multiple myeloma among atomic bomb survivors: 1950 – 2001

    Science.gov (United States)

    Hsu, Wan-Ling; Preston, Dale L.; Soda, Midori; Sugiyama, Hiromi; Funamoto, Sachiyo; Kodama, Kazunori; Kimura, Akiro; Kamada, Nanao; Dohy, Hiroo; Tomonaga, Masao; Iwanaga, Masako; Miyazaki, Yasushi; Cullings, Harry M.; Suyama, Akihiko; Ozasa, Kotaro; Shore, Roy E.; Mabuchi, Kiyohiko

    2013-01-01

    A marked increase in leukemia risks was the first and most striking late effect of radiation exposure seen among the Hiroshima and Nagasaki atomic bomb survivors. This paper presents analyses of radiation effects on leukemia, lymphoma, and multiple myeloma incidence in the Life Span Study cohort of atomic bomb survivors updated 14 years since the last comprehensive report on these malignancies. These analyses make use of tumor- and leukemia-registry-based incidence data on 113,011 cohort members with 3.6 million person-years of follow-up from late 1950 through the end of 2001. In addition to a detailed analysis of the excess risk for all leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia (neither of which appear to be radiation-related), we present results for the major hematopoietic malignancy types: acute lymphoblastic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, adult T-cell leukemia, Hodgkin and non-Hodgkin lymphoma, and multiple myeloma. Poisson regression methods were used to characterize the shape of the radiation dose response relationship and, to the extent the data allowed, to investigate variation in the excess risks with sex, attained age, exposure age, and time since exposure. In contrast to the previous report that focused on describing excess absolute rates, we considered both excess absolute rate (EAR) and excess relative risk (ERR) models and found that ERR models can often provide equivalent and sometimes more parsimonious descriptions of the excess risk than EAR models. The leukemia results indicated that there was a non-linear dose response for leukemias other than chronic lymphocytic leukemia or adult T-cell leukemia, which varied markedly with time and age at exposure, with much of the evidence for this non-linearity arising from the acute myeloid leukemia risks. Although the leukemia excess risks generally declined with attained age or time since exposure, there was evidence

  15. Leukemia revisited

    International Nuclear Information System (INIS)

    Selected features of the historical development of our knowledge of leukemia are discussed. The use of different methodologies for study of the nature of leukemic cell proliferation are analyzed. The differences between older cell kinetic data using tritiated thymidine and autoradiography and the newer cell culture methods are more apparent than real. It is suggested that tritiated thymidine and extracorporeal irradiation of the blood may be useful for therapeutic agents that have not been given an adequate trial. Radiation leukemogenesis presents an opportunity for study of the nature of leukemogenesis that has not been exploited adequately

  16. Leukemia revisited

    Energy Technology Data Exchange (ETDEWEB)

    Cronkite, E P

    1980-01-01

    Selected features of the historical development of our knowledge of leukemia are discussed. The use of different methodologies for study of the nature of leukemic cell proliferation are analyzed. The differences between older cell kinetic data using tritiated thymidine and autoradiography and the newer cell culture methods are more apparent than real. It is suggested that tritiated thymidine and extracorporeal irradiation of the blood may be useful for therapeutic agents that have not been given an adequate trial. Radiation leukemogenesis presents an opportunity for study of the nature of leukemogenesis that has not been exploited adequately.

  17. Resistance to BN myelogenous leukemia in rat radiation chimeras

    International Nuclear Information System (INIS)

    Lewis → LBNFl rat radiation chimeras showed marked resistance to transplanted BN myelogenous leukemia when compared to naive LBNFl, LBNFl → LBNFl, or BN → LBNFl. This occurred in the absence of overt graft versus host disease or of anti-BN response in mixed lymphocyte culture. Bone marrow specific antigens may serve as the target of the resistance mechanism. (author)

  18. Somnolence syndrome after cranial radiation in children with lymphatic leukemia

    International Nuclear Information System (INIS)

    Thirty-five children with acute lymphocytic leukemia were reviewed to study the incidence of somnolence syndrome. Fourteen evaluable patients received 1,800 rad (12x150 rad) and twenty-one similar evaluable patients received 2,400 rad (16x150 rad). For both groups the same chemotherapy schedule including intratecal methotrexate was admnistered. (M.A.C.)

  19. Disseminated Gastric MALT Lymphoma with Monoclonal Gammopathy, t(11;18(q21;q21, and Subsequent Development of T-Large Granular Lymphocytic Leukemia: A Case Report and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Riad Akoum

    2015-01-01

    Full Text Available Background. Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT is a well-characterized entity that may share clinical and morphological findings with other low-grade non-Hodgkin’s lymphomas. Dissemination of MALT-type lymphoma to bone marrow and peripheral blood simultaneously with the presence of T-large granular cell leukemia (T-LGL has rarely been reported. Case Presentation. This is the case of a 42-year-old male who presented with a gastric MALT-type lymphoma, disseminated to the bone marrow and the peripheral blood with high serum IgM levels and t(11;18(q21;q21. The morphological, immunophenotypical and, immunohistochemical studies of the successive bone marrow and peripheral blood samples had revealed the coexistence of two distinct lymphoma cell populations: a B-cell, marginal zone type population expressing CD19, CD20, CD22, CD79b, IgM, and kappa light chain, and a T-large granular cell population, developed after treatment with rituximab expressing CD3, CD8, CD5, CD7, and CD45. Conclusion. Based on the analysis of this unusual case we performed an extensive review of the literature to elucidate the relationship between T-LGL and B-cell lymphomas and to emphasize the importance of paraprotein analysis at diagnosis of gastric MALT lymphoma.

  20. Mechanistic Study of the Phytocompound, 2- β -D-Glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne in Human T-Cell Acute Lymphocytic Leukemia Cells by Using Combined Differential Proteomics and Bioinformatics Approaches

    Science.gov (United States)

    Shiau, Jeng-Yuan; Yin, Shu-Yi; Chang, Shu-Lin; Hsu, Yi-Jou; Chen, Kai-Wei; Kuo, Tien-Fen; Feng, Ching-Shan; Yang, Ning-Sun; Shyur, Lie-Fen; Yang, Wen-Chin; Wen, Tuan-Nan

    2015-01-01

    Bidens pilosa, a medicinal herb worldwide, is rich in bioactive polyynes. In this study, by using high resolution 2-dimensional gel electrophoresis coupled with mass spectrometry analysis, as many as 2000 protein spots could be detected and those whose expression was specifically up- or downregulated in Jurkat T cells responsive to the treatment with 2-β-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne (GHTT) can be identified. GHTT treatment can upregulate thirteen proteins involved in signal transduction, detoxification, metabolism, energy pathways, and channel transport in Jurkat cells. Nine proteins, that is, thioredoxin-like proteins, BH3 interacting domain death agonist (BID protein involving apoptosis), methylcrotonoyl-CoA carboxylase beta chain, and NADH-ubiquinone oxidoreductase, were downregulated in GHTT-treated Jurkat cells. Further, bioinformatics tool, Ingenuity software, was used to predict signaling pathways based on the data obtained from the differential proteomics approach. Two matched pathways, relevant to mitochondrial dysfunction and apoptosis, in Jurkat cells were inferred from the proteomics data. Biochemical analysis further verified both pathways involving GHTT in Jurkat cells. These findings do not merely prove the feasibility of combining proteomics and bioinformatics methods to identify cellular proteins as key players in response to the phytocompound in Jurkat cells but also establish the pathways of the proteins as the potential therapeutic targets of leukemia. PMID:26557148

  1. Mechanistic Study of the Phytocompound, 2-β-D-Glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne in Human T-Cell Acute Lymphocytic Leukemia Cells by Using Combined Differential Proteomics and Bioinformatics Approaches

    Directory of Open Access Journals (Sweden)

    Jeng-Yuan Shiau

    2015-01-01

    Full Text Available Bidens pilosa, a medicinal herb worldwide, is rich in bioactive polyynes. In this study, by using high resolution 2-dimensional gel electrophoresis coupled with mass spectrometry analysis, as many as 2000 protein spots could be detected and those whose expression was specifically up- or downregulated in Jurkat T cells responsive to the treatment with 2-β-D-glucopyranosyloxy-1-hydroxytrideca-5,7,9,11-tetrayne (GHTT can be identified. GHTT treatment can upregulate thirteen proteins involved in signal transduction, detoxification, metabolism, energy pathways, and channel transport in Jurkat cells. Nine proteins, that is, thioredoxin-like proteins, BH3 interacting domain death agonist (BID protein involving apoptosis, methylcrotonoyl-CoA carboxylase beta chain, and NADH-ubiquinone oxidoreductase, were downregulated in GHTT-treated Jurkat cells. Further, bioinformatics tool, Ingenuity software, was used to predict signaling pathways based on the data obtained from the differential proteomics approach. Two matched pathways, relevant to mitochondrial dysfunction and apoptosis, in Jurkat cells were inferred from the proteomics data. Biochemical analysis further verified both pathways involving GHTT in Jurkat cells. These findings do not merely prove the feasibility of combining proteomics and bioinformatics methods to identify cellular proteins as key players in response to the phytocompound in Jurkat cells but also establish the pathways of the proteins as the potential therapeutic targets of leukemia.

  2. Competitive Transfer of αCD19-TCRz-CD28 and αCD19-TCRz-CD137 CAR-T Cells for B-cell Leukemia/Lymphoma

    Science.gov (United States)

    2016-04-25

    Hematopoietic/Lymphoid Cancer; Adult Acute Lymphoblastic Leukemia in Remission; B-cell Adult Acute Lymphoblastic Leukemia; B-cell Chronic Lymphocytic Leukemia; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Refractory Chronic Lymphocytic Leukemia; Stage III Adult Diffuse Large Cell Lymphoma; Stage III Chronic Lymphocytic Leukemia; Stage III Grade 1 Follicular Lymphoma; Stage III Grade 2 Follicular Lymphoma; Stage III Grade 3 Follicular Lymphoma; Stage III Mantle Cell Lymphoma; Stage IV Adult Diffuse Large Cell Lymphoma; Stage IV Chronic Lymphocytic Leukemia; Stage IV Grade 1 Follicular Lymphoma; Stage IV Grade 2 Follicular Lymphoma; Stage IV Grade 3 Follicular Lymphoma; Stage IV Mantle Cell Lymphoma

  3. Neutropenia in rheumatoid arthritis and large granular lymphocyte leucosis

    Directory of Open Access Journals (Sweden)

    V A Doronin

    2003-01-01

    Full Text Available Objective. Pts with chronic clonal proliferation of large granular lymphocytes (LGL leukemia often have neutropenia, splenomegaly, and rheumatoid arthritis (RA, thereby resembling the manifestations observed in pts with Felty’s syndrome. The present study sought to indicate that pts with these disorders represent two distinct subsets. We compare clinical, hematological, immunophenotiping and immunogenetic features in Felty’s syndrome pts with and without the LGL leukemia. Material and methods 10 pts with T-LGL leukemia were studied. Surface phenotype was estimated using monoclonal antibodies CD8-PE and CD3-FITC/CD16-PE (two-color (Caltag, USA by the flow cytometric analysis (Partec, Daco. Analysis of TCR gene rearrangement was performed by using PCR-LIS SSCP (low ionic strength single strand conformational polymorphism. Comparison with Felty s syndrome and RA pts based on the review of literature. Results. LGL leukemia is a distinct clinicopathologic entity often associated with RA. LGL leukemia pts with RA showed the same immunogenetis associations seen in RA/Felty’s syndrome, while LGL leukemia pts without arthritis did not. Conclusion. Hematologic, immunophenotyping and molecular genetic analysis are very important and highly representative tools in differential diagnosis of neutropenia in RA, and propose that Felty’s syndrome and LGL leukemia represent different variants of broader syndrome comprising RA, neutropenia, LGL expansions, and splenomegaly.

  4. Rearrangement of the breakpoint cluster region in Philadelphia chromosome positive acute leukemia.

    OpenAIRE

    Takahashi, Isao; Sekito,Noriko; Takeuchi, Makoto; Osada, Ken; Matsuzaki,Toshiro; Fukuda, Shunichi; Lai,Minyu; Uchida, Kozaburo; Kimura,Ikuro; Miyamoto,Kanji; Kitajima,Koichi; Sanada, Hiroshi

    1988-01-01

    The rearrangement of breakpoint cluster region (ber) was examined in leukemic cells obtained from 3 patients initially diagnosed as having Ph+ acute leukemia, 2 with acute lymphocytic leukemia (ALL) and one with acute mixed leukemia. DNA was digested with Bgl II and BamH I. The ber rearrangement was present in the case of acute mixed leukemia (Case 1), but was absent in the 2 cases of ALL (Cases 2 and 3). These results suggest that Case 1 represented a type of blast crisis of chronic myelocyt...

  5. What Is Chronic Myeloid Leukemia?

    Science.gov (United States)

    ... leukemia? Next Topic Normal bone marrow and blood What is chronic myeloid leukemia? Cancer starts when cells ... their treatment is the same as for adults. What is leukemia? Leukemia is a cancer that starts ...

  6. Kelainan Hemostasis pada Leukemia

    Directory of Open Access Journals (Sweden)

    Zelly Dia Rofinda

    2012-09-01

    Full Text Available AbstrakLatar belakang: Leukemia adalah penyakit keganasan pada jaringan hematopoietik yang ditandai denganpenggantian elemen sumsum tulang normal oleh sel darah abnormal atau sel leukemik. Salah satu manifestasi klinisdari leukemia adalah perdarahan yang disebabkan oleh berbagai kelainan hemostasis.Kelainan hemostasis yang dapat terjadi pada leukemia berupa trombositopenia, disfungsi trombosit,koagulasi intravaskuler diseminata, defek protein koagulasi, fibrinolisis primer dan trombosis. Patogenesis danpatofosiologi kelainan hemostasis pada leukemia tersebut terjadi dengan berbagai mekanisme.Kata kunci: leukemia, kelainan hemostasisAbstractBackground: AbstractLeukemia is a malignancy of hematopoietic tissue which is characterized bysubstituted of bone marrow element with abnormal blood cell or leukemic cell. One of clinical manifestation ofleukemia is bleeding that is caused by several hemostasis disorders.Hemostasis disorders in leukemia such asthrombocytopenia, platelet dysfunction, disseminated intravascular coagulation, coagulation protein defect, primaryfibrinolysis and thrombosis. Pathogenesis and pathophysiology of thus hemostasis disorders in leukemia occur withdifferent mechanism.Keywords: leukemia, hemostasis disorder

  7. Functional impairment of Tax-specific but not cytomegalovirus-specific CD8+ T lymphocytes in a minor population of asymptomatic human T-cell leukemia virus type 1-carriers

    Directory of Open Access Journals (Sweden)

    Takamori Ayako

    2011-12-01

    Full Text Available Abstract Background Human T-cell leukemia virus type 1 (HTLV-1 causes adult T-cell leukemia (ATL and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP in a small percentage of infected individuals. ATL is often associated with general immune suppression and an impaired HTLV-1-specific T-cell response, an important host defense system. We previously found that a small fraction of asymptomatic HTLV-1-carriers (AC already showed impaired T-cell responses against the major target antigen, Tax. However, it is unclear whether the impaired HTLV-1 Tax-specific T-cell response in these individuals is an HTLV-1-specific phenomenon, or merely reflects general immune suppression. In this study, in order to characterize the impaired HTLV-1-specific T-cell response, we investigated the function of Tax-specific CD8+ T-cells in various clinical status of HTLV-1 infection. Results By using tetramers consisting of HLA-A*0201, -A*2402, or -A*1101, and corresponding Tax epitope peptides, we detected Tax-specific CD8+ T-cells in the peripheral blood from 87.0% of ACs (n = 20/23 and 100% of HAM/TSP patients (n = 18/18 tested. We also detected Tax-specific CD8+ T-cells in 38.1% of chronic type ATL (cATL patients (n = 8/21, although its frequencies in peripheral blood CD8+ T cells were significantly lower than those of ACs or HAM/TSP patients. Tax-specific CD8+ T-cells detected in HAM/TSP patients proliferated well in culture and produced IFN-γ when stimulated with Tax peptides. However, such functions were severely impaired in the Tax-specific CD8+ T-cells detected in cATL patients. In ACs, the responses of Tax-specific CD8+ T-cells were retained in most cases. However, we found one AC sample whose Tax-specific CD8+ T-cells hardly produced IFN-γ, and failed to proliferate and express activation (CD69 and degranulation (CD107a markers in response to Tax peptide. Importantly, the same AC sample contained cytomegalovirus (CMV pp65-specific CD8+ T

  8. Analysis of the T-cell receptor repertoire of human T-cell leukemia virus type 1 (HTLV-1) Tax-specific CD8+ cytotoxic T lymphocytes from patients with HTLV-1-associated disease: evidence for oligoclonal expansion.

    Science.gov (United States)

    Utz, U; Banks, D; Jacobson, S; Biddison, W E

    1996-02-01

    Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic, progressive neurological disease characterized by marked degeneration of the spinal cord and the presence of antibodies against HTLV-1. Patients with HAM/TSP, but not asymptomatic carriers, show very high precursor frequencies of HTLV-1-specific CD8+ T cells in peripheral blood and cerebrospinal fluid, suggestive of a role of these T cells in the pathogenesis of the disease. In HLA-A2+ HAM/TSP patients, HTLV-1-specific T cells were demonstrated to be directed predominantly against one HTLV-1 epitope, namely, Tax11-19. In the present study, we analyzed HLA-A2-restricted HTLV-1 Tax11-19-specific cytotoxic T cells from three patients with HAM/TSP. An analysis of the T-cell receptor (TCR) repertoire of these cells revealed an absence of restricted variable (V) region usage. Different combinations of TCR V alpha and V beta genes were utilized between, but also within, the individual patients for the recognition of Tax11-19. Sequence analysis of the TCR showed evidence for an oligoclonal expansion of few founder T cells in each patient. Apparent structural motifs were identified for the CDR3 regions of the TCR beta chains. One T-cell clone could be detected within the same patient over a period of 3 years. We suggest that these in vivo clonally expanded T cells might play a role in the pathogenesis of HAM/TSP and provide information on HTLV-1-specific TCR which may elucidate the nature of the T cells that infiltrate the central nervous system in HAM/TSP patients. PMID:8551623

  9. Quantification of B cells and T lymphocyte subsets in bovine leukemia virus infected dairy cowsQuantificação da população de linfócitos B e das subpopulações de linfócitos T em bovinos infectados pelo vírus da leucose enzoótica bovina

    Directory of Open Access Journals (Sweden)

    Claúdia Regina Stricagnolo

    2012-08-01

    Full Text Available O objetivo do presente trabalho foi avaliar a frequência e número absoluto de linfócitos B e das subpopulações de linfócitos T em bovinos infectados pelo vírus da leucemia bovina (BLV com distintos perfis leucocitários conhecidos como não leucêmicos (AL e com linfocitose persistente (LP. Deste modo, 15 animais foram selecionados e divididos uniformemente em três grupos (negativo, AL e LP. A infecção pelo vírus da BLV foi detectada por imunodifusão em ágar gel e por ensaio imunoenzimático. A quantificação das populações de linfócitos B e T foi determinada por citometria de fluxo utilizando anticorpos monoclonais. Os resultados do presente estudo apontaram para aumento da população de linfócitos B, e também das células CD5+ e CD11b+, que geralmente são alvo da infecção pelo vírus da BLV, nos animais com LP. Consequentemente pode-se observar redução da porcentagem de linfócitos T, T CD4+ no sangue periférico, e de linfócitos T, T CD4+ e T CD8+ nas células mononucleares do sangue periférico isoladas por gradiente de centrifugação. No entanto, nenhuma alteração no número absoluto de linfócitos T, T CD4+ e T CD8+ no sangue periférico foi encontrada nos animais manifestando LP. Entretanto, encontrou-se correlação alta e significativa entre o número absoluto de linfócitos T e T CD8+ e o número absoluto de linfócitos B no sangue periférico nos animais manifestando LP, não encontrando a mesma correlação com os linfócitos T CD4+. Além disso, não foram observadas correlações significativas entre o número absoluto de linfócitos T, T CD4+ e T CD8+ e o número absoluto de linfócitos B no sangue periférico nos animais AL e negativos.The aim of the present trial was to determine the frequencies and absolute number of B and T lymphocytes subpopulations in bovine leukemia virus (BLV-infected dairy cows with distinct lymphocyte profile known as non-leukemic (AL and persistent lymphocytosis (PL. Thus

  10. Addition of Rice Bran Arabinoxylan to Curcumin Therapy May Be of Benefit to Patients With Early-Stage B-Cell Lymphoid Malignancies (Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Stage 0/1 Chronic Lymphocytic Leukemia): A Preliminary Clinical Study.

    Science.gov (United States)

    Golombick, Terry; Diamond, Terrence H; Manoharan, Arumugam; Ramakrishna, Rajeev

    2016-06-01

    Hypothesis Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies. PMID:27154182

  11. Obatoclax Mesylate, Vincristine Sulfate, Doxorubicin Hydrochloride, and Dexrazoxane Hydrochloride in Treating Young Patients With Relapsed or Refractory Solid Tumors, Lymphoma, or Leukemia

    Science.gov (United States)

    2014-04-30

    Acute Leukemias of Ambiguous Lineage; Acute Undifferentiated Leukemia; Angioimmunoblastic T-cell Lymphoma; Blastic Phase Chronic Myelogenous Leukemia; Childhood Burkitt Lymphoma; Childhood Chronic Myelogenous Leukemia; Childhood Diffuse Large Cell Lymphoma; Childhood Immunoblastic Large Cell Lymphoma; Childhood Nasal Type Extranodal NK/T-cell Lymphoma; Cutaneous B-cell Non-Hodgkin Lymphoma; Hepatosplenic T-cell Lymphoma; Intraocular Lymphoma; Noncutaneous Extranodal Lymphoma; Peripheral T-cell Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Childhood Anaplastic Large Cell Lymphoma; Recurrent Childhood Grade III Lymphomatoid Granulomatosis; Recurrent Childhood Large Cell Lymphoma; Recurrent Childhood Lymphoblastic Lymphoma; Recurrent Childhood Small Noncleaved Cell Lymphoma; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Relapsing Chronic Myelogenous Leukemia; Small Intestine Lymphoma; Unspecified Childhood Solid Tumor, Protocol Specific

  12. Leukemia & Lymphoma Society

    Science.gov (United States)

    ... with the Baltimore chapter of The Leukemia & Lymphoma Society. She does office work regularly, participates in events ... I hereby authorize and permit The Leukemia & Lymphoma Society or its authorized agent, without compensation therefore, permission ...

  13. Chronic Myeloid Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. ...

  14. Drugs Approved for Leukemia

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Leukemia This page lists cancer drugs approved by the ... not listed here. Drugs Approved for Acute Lymphoblastic Leukemia (ALL) Abitrexate (Methotrexate) Arranon (Nelarabine) Asparaginase Erwinia chrysanthemi ...

  15. Acute Myeloid Leukemia

    Science.gov (United States)

    Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, however, the bone marrow produces abnormal white blood ...

  16. Alterations of Lymphoid Enhancer Factor-1 Isoform Expression in Solid Tumors and Acute Leukemias

    Institute of Scientific and Technical Information of China (English)

    Wenbing WANG; Carsten M(U)LLER-TIDOW; Ping JI; Bj(o)rn STEFFEN; Ralf METZGER; Paul M. SCHNEIDER; Hartmut HALFTER; Mark SCHRADER; Wolfgang E. BERDEL; Hubert SERVE

    2005-01-01

    Two major transcripts of lymphoid enhancer factor-1 (LEF-1) have been described. The long isoform with β-catenin binding domain functions as a transcriptional enhancer factor. The short isoform derives from an intronic promoter and exhibits dominant negative activity. Recently, alterations of LEF- 1isoforms distribution have been described in colon cancer. In the current study we employed a quantitative real-time reverse transcription PCR method (TaqMan) to analyze expression of LEF-1 isoforms in a large cohort of human tumor (n=304) and tumor-free control samples (n=56). The highest expression level of LEF-1 was found in carcinoma samples whereas brain cancer samples expressed little. Expression of LEF1 was different in distinct cancer types. For example, the mRNA level of LEF-1 was lower in testicular tumor samples compared with tumor-free control samples. Besides epithelial cancers, significant LEF-1expression was also found in hematopoietic cells. In hematological malignancies, overall LEF-1 level was higher in lymphocytic leukemias compared with myeloid leukemias and normal hematopoiesis. However,acute myeloid leukemia and acute lymphocytic leukemia showed a significantly increased fraction of the oncogenic LEF-1 compared with chronic lymphocytic leukemia and chronic myeloid leukemia. Taken together,these data suggest that LEF-1 is abundantly expressed in human tumors and the ratio of the oncogenic and the dominant negative short isoform altered not only in carcinomas but also in leukemia.

  17. Lymphocyte Functions in Microgravity

    Science.gov (United States)

    Pellis, Neal R.; Risin, Diane; Sundaresan, A.; Cooper, D.; Dawson, David L. (Technical Monitor)

    1999-01-01

    To understand the mechanism of immunity impairment in space it is important to analyze the direct effects of space-related conditions on different lymphocytes functions. Since 1992, we are investigating the effect of modeled and true microgravity (MG) on numerous lymphocyte functions. We had shown that modeled (MMG) and true microgravity inhibit lymphocyte locomotion through type I collagen. Modeled microgravity also suppresses polyclonal and antigen-specific lymphocyte activation. Polyclonal activation of lymphocytes prior to exposure to MMG abrogates the MG-induced inhibition of lymphocyte locomotion. The relationship between activation deficits and the loss of locomotion in MG was investigated using PKC activation by phorbol ester (PMA) and calcium ionophore (ionomycin). Direct activation of PKC by PMA substantially restored the MMG-inhibited lymphocyte locomotion and PHA-induced lymphocyte activation lonomycin by itself did not restore either locomotion or activation of the lymphocytes, indicating that these changes are not related to the impairment in the calcium flux in MMG. Treatment of lymphocytes with PMA before exposure to MMG prevented the loss of locomotion. It was observed that DNA synthesis is not necessary for restoration of locomotion since mitomicin C treated and untreated cells recovered their locomotion to the same level after PKC activation. Our recent data indicate that microgravity may selectively effect the expression of novel Ca2+ independent isoforms of PKC, in particularly PKC sigma and delta. This provides a new insight in understanding of the mechanisms of MG-sensitive cellular functions.

  18. Late effect of atomic bomb radiation on myeloid disorders: leukemia and myelodysplastic syndromes.

    Science.gov (United States)

    Tsushima, Hideki; Iwanaga, Masako; Miyazaki, Yasushi

    2012-03-01

    Leukemia was the first malignancy linked to radiation exposure in atomic bomb survivors. Clear evidence of the dose-dependent excess risk of three major types of leukemia (acute lymphocytic leukemia, acute myeloid leukemia [AML], and chronic myeloid leukemia) was found, especially in people exposed at young ages. Such leukemia risks were at their highest in the late 1950s, and declined gradually thereafter over the past 50 years. Findings from recent risk analyses, however, suggest the persistence of AML risk even after 1990, and evidence of increased risk of myelodysplastic syndromes (MDS) due to atomic bomb radiation has recently been shown. High-risk MDS and forms involving complex chromosomal aberrations were found to be much more frequent in people exposed to higher radiation doses. These lines of epidemiological evidence suggest that the risk of radiation-induced hematological malignancies has persisted for six decades since the initial exposure. PMID:22370711

  19. High-Dose Busulfan and High-Dose Cyclophosphamide Followed By Donor Bone Marrow Transplant in Treating Patients With Leukemia, Myelodysplastic Syndrome, Multiple Myeloma, or Recurrent Hodgkin or Non-Hodgkin Lymphoma

    Science.gov (United States)

    2010-08-05

    Adult Acute Myeloid Leukemia; Recurrent Adult Burkitt Lymphoma; Recurrent Adult Diffuse Large Cell Lymphoma; Recurrent Adult Diffuse Mixed Cell Lymphoma; Recurrent Adult Diffuse Small Cleaved Cell Lymphoma; Recurrent Adult Grade III Lymphomatoid Granulomatosis; Recurrent Adult Hodgkin Lymphoma; Recurrent Adult Immunoblastic Large Cell Lymphoma; Recurrent Adult Lymphoblastic Lymphoma; Recurrent Adult Non-Hodgkin Lymphoma; Recurrent Adult T-cell Leukemia/Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Cutaneous T-cell Non-Hodgkin Lymphoma; Recurrent Grade 1 Follicular Lymphoma; Recurrent Grade 2 Follicular Lymphoma; Recurrent Grade 3 Follicular Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Small Lymphocytic Lymphoma; Refractory Multiple Myeloma; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Testicular Lymphoma; Waldenstrom Macroglobulinemia

  20. Intracranial CT abnormality associated with childhood leukemia

    International Nuclear Information System (INIS)

    We showed three abnormal CT findings of childhood leukemia. Case 1: A 3-year-old boy was found to have acute lymphocytic leukemia in January, 1980. Following prophylactic skull irradiation totaling 2,300 rad and 30 mg of intrathecal methotrexate, he was treated with oral and intravenous methotrexate (10-15 mg once weekly, totaling 2,035 mg). CT taken 2 years and 3 months after the onset showed fine, high-density spots in the left frontal, temporal, and bilateral parietal subcortical regions, without any contrast enhancement. The high-density spots were diagnosed as parenchymal calcification induced by the irradiation and methotrexate therapy. Case 2: A 5-year-old boy complaining of anemia and fever was diagnosed as having acute myelocytic leukemia and was treated with VAMP and DCVP. In March, 1982, he complained of severe headache, nausea, and vomiting 4.5 years after his onset. There were no neurological deficits nor any nuchal stiffness. A lumbar puncture showed increasing pressure of CSF over 250 mm H2O and a pleocytosis of the myeloblasts. CT showed an enhanced high-density mass in the pineal region and hydrocephalus. He improved and showed a normal CT after treatment with skull irradiation of 2,400 rad and four intraventricular injections of 15 mg methotrexate, 30 mg cytosine arabinoside, and 15 mg hydrocortisone via Ommaya's reservoir. Case 3: A 14-year-old boy who had suffered from acute lymphocytic leukemia, associated with meningeal infiltration, for 2 years and 10 months, complained of headache, disturbance of consciousness, and focal convulsion of the left upper limb in December, 1982. CT demonstrated multiple, round, high-density areas in the cerebral hemispheres. Those high-density areas were diagnosed as intracerebral leukemic masses and/or hemorrhages. After 1400 rad of skull irradiation and steroid therapy, the patient rallied shortly, but then expired. An autopsy was refused. (J.P.N.)

  1. 急性淋巴细胞白血病患儿MTHFR基因多态性与大剂量甲氨蝶呤毒副反应的关系%Relationship between the methylenetetrahydrofolate reductase gene polymorphism and adverse reactions of high-dose methotrexate in children with acute lymphocytic leukemia

    Institute of Scientific and Technical Information of China (English)

    郑苗苗; 岳丽杰; 陈小文; 文飞球; 李长钢; 杨春兰; 谢偲; 丁慧

    2013-01-01

    Objective To study the association between methylenetetrahydrofolate reductase ( MTHFR) gene polymorphisms and toxicities after high-dose methotrexate (HD-MTX) infusion in children with acute lymphocytic leukemia (ALL). Methods MTHFR variants in 52 children with ALL were determined by reverse transcriptase-polymerase chain reaction-denaturing gradient gel electrophoresis and sequencing. Toxicities of children who received HD-MTX chemotherapy were evaluated according to the National Cancer Institute-Common Toxicity Criteria ( NCI-CTC ). Results The children carrying MTHFR 1298AC had a higher risk of developing thrombocytopenia compared with the carriers of the 1298 AA genotype (OR = 13. 7, 95% CI = 1. 18 - 159. 36, P = 0. 036). There was no significant difference in HD-MTX chemotherapy-related adverse effects between the patients with different MTHFR C677T or G1793A genotypes. Conclusions MTHFR A1298C polymorohism may associate with the toxicity of HD-MTX chemotherapy in children with ALL.%目的 探讨亚甲基四氢叶酸还原酶(MTHFR)基因单核苷酸多态性对急性淋巴细胞白血病(ALL)患儿使用大剂量甲氨蝶呤(HD-MTX)化疗后毒副反应的影响.方法 应用RT-PCR-变性梯度凝胶电泳结合DNA测序技术,对52例ALL患儿MTHFR C677T、A1298C和G1793A基因型进行检测.按照国立癌症研究所常规毒性判定标准(NCI-CTC)对患儿HD-MTX化疗后的不良反应统一评价.结果 MTHFR 1298AC基因型患儿发生血小板减少的风险较AA型提高了13.7倍(OR =13.7,95%CI=1.18~159.36,P=0.036).MTHFR C677T和G1793A各基因型发生各类HD-MTX化疗不良反应的差异无统计学意义(P>0.05).结论 MTHFR A1298C多态性可能与ALL患儿HD-MTX化疗后的毒副反应相关.

  2. Mixed phenotype acute leukemia

    Institute of Scientific and Technical Information of China (English)

    Ye Zixing; Wang Shujie

    2014-01-01

    Objective To highlight the current understanding of mixed phenotype acute leukemia (MPAL).Data sources We collected the relevant articles in PubMed (from 1985 to present),using the terms "mixed phenotype acute leukemia","hybrid acute leukemia","biphenotypic acute leukemia",and "mixed lineage leukemia".We also collected the relevant studies in WanFang Data base (from 2000 to present),using the terms "mixed phenotype acute leukemia" and "hybrid acute leukemia".Study selection We included all relevant studies concerning mixed phenotype acute leukemia in English and Chinese version,with no limitation of research design.The duplicated articles are excluded.Results MPAL is a rare subgroup of acute leukemia which expresses the myeloid and lymphoid markers simultaneously.The clinical manifestations of MPAL are similar to other acute leukemias.The World Health Organization classification and the European Group for Immunological classification of Leukaemias 1998 cdteria are most widely used.MPAL does not have a standard therapy regimen.Its treatment depends mostly on the patient's unique immunophenotypic and cytogenetic features,and also the experience of individual physician.The lack of effective treatment contributes to an undesirable prognosis.Conclusion Our understanding about MPAL is still limited.The diagnostic criteria have not been unified.The treatment of MPAL remains to be investigated.The prognostic factor is largely unclear yet.A better diagnostic cdteria and targeted therapeutics will improve the therapy effect and a subsequently better prognosis.

  3. Fludarabine Phosphate, Low-Dose Total-Body Irradiation, and Donor Stem Cell Transplant Followed by Cyclosporine, Mycophenolate Mofetil, Donor Lymphocyte Infusion in Treating Patients With Hematopoietic Cancer

    Science.gov (United States)

    2016-08-01

    ; Recurrent Mantle Cell Lymphoma; Recurrent Marginal Zone Lymphoma; Recurrent Mycosis Fungoides/Sezary Syndrome; Recurrent Renal Cell Cancer; Recurrent Small Lymphocytic Lymphoma; Recurrent/Refractory Childhood Hodgkin Lymphoma; Refractory Chronic Lymphocytic Leukemia; Refractory Hairy Cell Leukemia; Refractory Multiple Myeloma; Small Intestine Lymphoma; Splenic Marginal Zone Lymphoma; Stage II Multiple Myeloma; Stage III Multiple Myeloma; T-cell Large Granular Lymphocyte Leukemia; Testicular Lymphoma; Waldenström Macroglobulinemia

  4. Molecular biomarkers for the study of childhood leukemia

    International Nuclear Information System (INIS)

    Various specific chromosome rearrangements, including t(8;21), t(15;17), and inv(16), are found in acute myeloid leukemia (AML) and in childhood acute lymphocytic leukemia (ALL), t(12;21) and t(1;19) are common. We sequenced the translocation breakpoints of 56 patients with childhood ALL or AML harboring t(12;21), t(8;21), t(15;17), inv(16), and t(1;19), and demonstrated, with the notable exception of t(1;19), that these rearrangements are commonly detected in the neonatal blood spots (Guthrie cards) of the cases. These findings show that most childhood leukemias begin before birth and that maternal and perinatal exposures such as chemical and infectious agents are likely to be critical. Indeed, we have reported that exposure to indoor pesticides during pregnancy and the first year of life raises leukemia risk, but that later exposures do not. We have also examined aberrant gene methylation in different cytogenetic subgroups and have found striking differences between them, suggesting that epigenetic events are also important in the development of some forms of childhood leukemia. Further, at least two studies now show that the inactivating NAD(P)H:quinone acceptor oxidoreductase (NQO1) C609T polymorphism is positively associated with leukemias arising in the first 1-2 years of life and polymorphisms in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene have been associated with adult and childhood ALL. Thus, low folate intake and compounds that are detoxified by NQO1 may be important in elevating leukemia risk in children. Finally, we are exploring the use of proteomics to subclassify leukemia, because cytogenetic analysis is costly and time-consuming. Several proteins have been identified that may serve as useful biomarkers for rapidly identifying different forms of childhood leukemia

  5. Analysis of low Z elements in serum of patients with leukemias by SRTXRF

    International Nuclear Information System (INIS)

    Leukemia is a disease that occurs all over the world. Leukemia is a type of cancer. All cancers begin in cells, which make up blood and other tissues. Normally, cells grow and divide to form new cells as the body needs them. When cells grow old, they die, and new cells take their place. Sometimes this orderly process goes wrong. New cells form when the body does not need them, and old cells do not die when they should. Leukemia is a kind of cancer that begins in blood cells. There are four common types of leukemia: Chronic Myelogenous Leukemia (CML), Acute Myelogenous Leukemia (AML), Chronic Lymphocytic Leukemia (CLL) and Acute Lymphocytic Leukemia (ALL). In this work, low Z elements were determined in serum of patients with four groups of leukemia (CML, AML, CLL and ALL) and control group (CG) or healthy subjects using Total Reflection X-Ray Fluorescence induced by Synchrotron Radiation (SRTXRF). We studied thirty patients - male gender and feminine gender - with ages ranging from 18 to 60 years, suffering from CML, AML, CLL, ALL and thirty healthy volunteers aged 18 to 60 years. All the serum samples were collected from people who live in the urban area of Rio de Janeiro City/Brazil. All of them were submitted to medical history. This study was performed with the approval of the ethics committee. It was possible to determine the elemental concentrations of the following six elements: Na, P, S, Cl, K and Ca. By using t-test it could be seen significant differences (α = 0.05) between groups of healthy subjects and four groups of leukemia. The t- test showed real differences among the elemental concentrations. Thus, our findings indicate that the elements can be directly related to the biochemical processes in leukemias. The significant differences found between the groups may be indicators of these diseases. This could help biomedical field with regard to early diagnosis and improved medical treatment. (author)

  6. Diagnosis and treatment of acute and chronic leukemia

    International Nuclear Information System (INIS)

    The Cancergram covers both acute and chronic leukemia in all of its forms (acute lymphocytic, acute monocytic, acute or sub-acute granulocytic, chronic granulocytic, chronic lymphocytic, chronic monocytic, plasma cell, stem cell, and hairy cell). Other neoplastic conditions of the reticuloendothelial system, lymphatic system, spleen, multiple myeloma, macroglobulinemia and other monoclonal gammopathies are excluded, and will be coveted by other Cancergrams now under development. This Cancergram includes abstracts concerning all clinical aspects of the disease, such as diagnosis and staging, supportive care, evaluation, and therapy. Animal models, tissue culture experiments, carcinogenesis and other pre-clinical studies are generally excluded, except for those considered to have direct clinical relevance

  7. Leukemia in the proximity of a German boiling-water nuclear reactor: evidence of population exposure by chromosome studies and environmental radioactivity.

    OpenAIRE

    Schmitz-Feuerhake, I; Dannheim, B; Heimers, A; Oberheitmann, B.; Schröder, H; Ziggel, H

    1997-01-01

    Exceptional elevation of children's leukemia appearing 5 years after the 1983 startup of the Krümmel nuclear power plant, accompanied by a significant increase of adult leukemia cases, led to investigations of radiation exposures of the population living near the plant. The rate of dicentric chromosomes in peripheral lymphocytes of seven parents of children with leukemia and in 14 other inhabitants near the plant was significantly elevated and indicated ongoing exposures over the years of its...

  8. Molecular diagnosis of lymphoblastic leukemia

    OpenAIRE

    Kalal Iravathy Goud; Seetha Dayakar; Prasad, S. V. S. S.; Koteshwar N Rao; Amina Shaik; S Vanjakshi

    2013-01-01

    The mixed lineage leukemia (MLL) gene at chromosome band 11q23 is commonly involved in reciprocal translocations that is detected in acute leukemia. The MLL gene, coomonly known as mixed lineage leukemia or myeloid lymphoid leukemia, has been independently identified and cloned from the 11q23 breakpoint of acute leukemia. We describe a patient with acute lymphoblastic leukemia whose cells had shown reciprocal translocation between short arm (p21) of chromosome 2 and long arm (q23) of chromoso...

  9. Steroid resistance in leukemia

    OpenAIRE

    Shah, Darshan S; Kumar, Raj

    2013-01-01

    There are several types of leukemia which are characterized by the abnormal growth of cells from the myeloid or lymphoid lineage. Because of their lympholytic actions, glucocorticoids (GCs) are included in many therapeutic regimens for the treatment of various forms of leukemia. Although a significant number of acute lymphoblastic leukemia patients respond well to GC treatment during initial phases; prolonged treatments sometimes results in steroid-resistance. The exact mechanism of this resi...

  10. 混合造血干细胞移植联合DLI-IL-2治疗急性髓性白血病的疗效%Efficacy of mixed hematopoietic stem cell transplantation combined with donor lymphocyte infusion and IL-2 in treatment of acute myelogenous leukemia

    Institute of Scientific and Technical Information of China (English)

    王存邦; 白海; 葸瑞; 潘耀柱; 张茜; 周进茂; 吴涛; 徐淑芬

    2011-01-01

    目的:探讨急性髓性白血病(acute myelogenous leukemia,AML)患者采用自体外周血干细胞混合HLA半相合异体骨髓移植(autologous peripheral blood stem cell mixed with HLA haploidentieai allogeneic bone marrow transplantation,Mixed-HSCT)联合供体淋巴细胞输注+白介素2(donor lymphocyte infusion combined interleukin-2,DLI-IL-2)治疗的疗效.方法:采用联合治疗方案的试验组23例AML患者中男性15例、女性8例,中位年龄22(17~41)岁;采用单纯移植治疗的对照组14例AML患者中男性10例、女性4例,中位年龄21(19~4JD)岁.两组患者在完全缓解期采用TBI+VEMAC方案预处理,对照组患者接受单纯Mixed-HSCT移植,试验组患者接受Mixed-HSCT且造血重建后继续DLI-1L-2治疗1~8次;各组在治疗前后进行染色体核型分析及骨髓检查.随访时间>3年.结果:两组患者均获得造咀重建,无移植物抗宿主病(graft-versus-host disease,GVHD)发生.试验组有6例形成混合嵌合体(46XX/46XY),随访显示存活15例,长期无病存活率(disease.free survival,DFS)为65.2%;对照组有3例形成混合嵌合体(46XX/46XY),随访显示存活7例,DFS为50.O%.两组患者治疗后的不良反应(口腔溃疡、出血性膀胱炎、发热等)相似.结论:Mixed-HSCT联合DLI-IL-2治疗对AML患者长期无病生存有积极意义,无严重不良反应.%Objective:To study the efficacy of mixed-HSCT (autologous peripheral blood stem cell mixed with HLA haploidentical allogeneic bone marrow transplantation ) combined with donor lymphocyte infusion plus interleukin-2 (DLI + IL-2) in treatment of acute myelogenous leukemia (AML) patients.Methods: Twenty-three AML patients (15 males and 8 females, median age 22 years) were enrolled in this study as mixed-HSCT combined DLI + IL-2 group, and 14 AML patients ( 10 males and 4 females, median age 21 years) were enrolled as control group.All patients in the two groups received TBI + VEMAC therapy after complete remission, patients

  11. Congenital acute megakaryocytic leukemia

    Directory of Open Access Journals (Sweden)

    N B Mathur

    2011-01-01

    Full Text Available Congenital leukemia (CL is an extremely rare disorder in the newborn, significant proportion of which is of myeloid origin, primarily of M4 or M5 morphology. As compared to pediatric leukemia, CL is a more aggressive disease. Acute myeloid leukemia (AML-M7 or acute megakaryocytic leukemia is a rare type of AML with an incidence of 0.5 per million per year. Median age of presentation is 6 years, and children may present with a broad variety of symptoms including low-grade fever, diarrhea, easy bruising, failure to gain weight and life-threatening conditions.

  12. Idiopathic thrombocytopenic purpura following successful treatment of acute lymphoblastic leukemia.

    Science.gov (United States)

    Tannir, N M; Kantarjian, H

    2001-03-01

    Thrombocytopenia is common in patients with acute lymphocytic leukemia (ALL) at diagnosis. It is a universal side effect of dose-intensive regimens employed in the treatment of adult ALL. In patients with ALL who achieve remission, thrombocytopenia frequently indicates relapse. We report three adult patients successfully treated for ALL who developed thrombocytopenia and were found to have immune-mediated thrombocytopenia (ITP). Possible pathophysiologic mechanisms underlying the association of ALL and ITP are discussed. PMID:11342378

  13. Concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma in an anterior mediastinal mass.

    Science.gov (United States)

    Ito, Junko; Yoshida, Akihiko; Maeshima, Akiko Miyagi; Nakagawa, Kazuo; Watanabe, Shun-ichi; Kobayashi, Yukio; Fukuhara, Suguru; Tsuta, Koji

    2015-09-01

    We report a case of a 62-year-old man with concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Computed tomography revealed a 5.5-cm anterior mediastinal mass, and surgical resection was performed. Histologically, the mass showed concurrent thymoma (type AB), thymic carcinoma, and T lymphoblastic leukemia/lymphoma. Lymphoma cells infiltrated in the left lung, pulmonary hilar lymph nodes, and involved bone marrow. The patient underwent chemotherapy for T lymphoblastic leukemia/lymphoma and achieved remission. One year after surgery, he remains free of both thymoma and thymic carcinoma, and T lymphoblastic leukemia/lymphoma remains complete remission under maintenance therapy. Thymoma and T lymphoblastic leukemia/lymphoma can combine in the same mass, although this is quite rare. At the time of the diagnosis of thymoma, additional attention should be directed toward lymphocytes in the background. PMID:26150396

  14. Drug screen in patient cells suggests quinacrine to be repositioned for treatment of acute myeloid leukemia

    International Nuclear Information System (INIS)

    To find drugs suitable for repositioning for use against leukemia, samples from patients with chronic lymphocytic, acute myeloid and lymphocytic leukemias as well as peripheral blood mononuclear cells (PBMC) were tested in response to 1266 compounds from the LOPAC1280 library (Sigma). Twenty-five compounds were defined as hits with activity in all leukemia subgroups (<50% cell survival compared with control) at 10 μM drug concentration. Only one of these compounds, quinacrine, showed low activity in normal PBMCs and was therefore selected for further preclinical evaluation. Mining the NCI-60 and the NextBio databases demonstrated leukemia sensitivity and the ability of quinacrine to reverse myeloid leukemia gene expression. Mechanistic exploration was performed using the NextBio bioinformatic software using gene expression analysis of drug exposed acute myeloid leukemia cultures (HL-60) in the database. Analysis of gene enrichment and drug correlations revealed strong connections to ribosomal biogenesis nucleoli and translation initiation. The highest drug–drug correlation was to ellipticine, a known RNA polymerase I inhibitor. These results were validated by additional gene expression analysis performed in-house. Quinacrine induced early inhibition of protein synthesis supporting these predictions. The results suggest that quinacrine have repositioning potential for treatment of acute myeloid leukemia by targeting of ribosomal biogenesis

  15. What Should You Ask Your Doctor about Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... copies of your medical records, pathology reports, and radiology reports may be useful in case you wish ... Statistics News About Cancer Expert Voices Blog Programs & Services Breast Cancer Support TLC Hair Loss & Mastectomy Products ...

  16. Treatment of Chronic Lymphocytic Leukemia by Risk Group

    Science.gov (United States)

    ... Local Offices Volunteer Employment Become a Supplier Report Fraud or ... reserved. The American Cancer Society is a qualified 501(c)(3) tax-exempt organization. Cancer.org is provided courtesy of ...

  17. Chronic Lymphocytic Leukemia (CLL) in Adults (Beyond the Basics)

    Science.gov (United States)

    ... cells then re-establish the blood cell production process in the bone marrow. (See "Patient information: Stem cell transplantation (bone marrow transplantation) (Beyond the Basics)" .) The type of stem cell ...

  18. What Are the Risk Factors for Chronic Lymphocytic Leukemia?

    Science.gov (United States)

    ... CLL). These include: Exposure to certain chemicals Family history Gender Race/ethnicity The risk of getting CLL does not seem to be affected by smoking, diet, or infections. Certain chemical exposures Some studies have linked exposure to Agent Orange, an herbicide used during the Vietnam War, to ...

  19. Atomic bomb and leukemia

    International Nuclear Information System (INIS)

    Characteristic features of the leukemia among atomic bomb survivors were studied. Dose estimates of atomic bomb radiation were based on T65D, but the new dosimetry system DS86 was used for some analyses. The ratio of a single leukemia type to all leukemias was highest for chronic myelogenous leukemia (CML) in Hiroshima, and the occurrence of CML was thought to be most characteristic to atomic bomb radiation induced leukemia. The threshold of CML occurrence in Hiroshima is likely to be between 0.5∼0.09 Gy. However, the threshold of acute leukemia appears to be nearly 1 Gy. In the distribution of acute myeloid leukemia (AML) subtypes by French-American-British classification, there was no M3 case in 1 Gy or more group, although several atypical AML cases of survivors were observed. Although aplastic anemia has not increased as a late effect of the atomic bomb radiation exposure, many atypical leukemia or other myeloproliferative diseases who had been diagnosed as aplastic anemia or its related diseases have been experienced among atomic bomb survivors. Chromosome study was conducted using colony forming cells induced by hemopoietic stem cells of peripheral blood of proximal survivors. Same chromosome aberrations were observed in colony forming cells and peripheral T-cells in several atomic bomb survivors. (author)

  20. What Is Childhood Leukemia?

    Science.gov (United States)

    ... red blood cells, or platelets. Hybrid or mixed lineage leukemia: In these rare leukemias, the cells have ... from too many white blood cells in the lungs), and an enlarged spleen and lymph nodes. Last Medical Review: ... Information Cancer Basics Cancer Prevention & Detection Signs & Symptoms ...