15 results on '"Willemze, Roel"'
Search Results
2. Long-term follow-up of a trial comparing post-remission treatment with autologous or allogeneic bone marrow transplantation or intensive chemotherapy in younger acute myeloid leukemia patients.
- Author
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Baron F, Efficace F, Cannella L, Willemze R, Vignetti M, Muus P, Marie JP, Ferrero D, Fazi P, La Sala E, Bourhis JH, Fabbiano F, Bosi A, Sborgia M, Martinelli G, Wittnebel S, Trisolini S, Petti MC, Halkes CJM, van der Velden WJFM, de Witte T, Amadori S, Zittoun RA, and Suciu S
- Subjects
- Antineoplastic Combined Chemotherapy Protocols adverse effects, Bone Marrow Transplantation, Cytarabine therapeutic use, Follow-Up Studies, Humans, Remission Induction, Transplantation, Autologous, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute drug therapy
- Published
- 2020
- Full Text
- View/download PDF
3. Generation and administration of HA-1-specific T-cell lines for the treatment of patients with relapsed leukemia after allogeneic stem cell transplantation: a pilot study.
- Author
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Meij P, Jedema I, van der Hoorn MA, Bongaerts R, Cox L, Wafelman AR, Marijt EW, Willemze R, and Falkenburg JH
- Subjects
- Hematopoietic Stem Cell Transplantation, Humans, Pilot Projects, Recurrence, Transplantation, Homologous, Treatment Outcome, Adoptive Transfer, CD8-Positive T-Lymphocytes immunology, Leukemia immunology, Leukemia therapy, Minor Histocompatibility Antigens immunology, Oligopeptides immunology
- Abstract
Since HA-1-specific T cells have been shown to make a significant contribution to the clinical responses in patients with relapsed leukemia, we investigated the feasibility of adoptive transfer of in vitro induced HA-1-specific CD8 positive T cells to patients with relapsed leukemia after allogeneic stem cell transplantation. The in vitro generation of clinical grade HA-1-specific T-cell lines from HA-1 negative donors was seen to be feasible and 3 patients were treated with HA-1-specific T-cell lines. No toxicity after infusion was observed. Although in one patient, during a period of stable disease, HA-1-specific T cells could be detected in the peripheral blood and bone marrow, these patients had no clear clinical response.
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- 2012
- Full Text
- View/download PDF
4. Combined CD8+ and CD4+ adenovirus hexon-specific T cells associated with viral clearance after stem cell transplantation as treatment for adenovirus infection.
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Zandvliet ML, Falkenburg JH, van Liempt E, Veltrop-Duits LA, Lankester AC, Kalpoe JS, Kester MG, van der Steen DM, van Tol MJ, Willemze R, Guchelaar HJ, Schilham MW, and Meij P
- Subjects
- Adenoviridae Infections blood, Adenoviridae Infections etiology, Adenoviridae Infections immunology, Adult, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Child, Child, Preschool, Female, Humans, Male, Transplantation, Homologous, Viremia immunology, Viremia therapy, Adenoviridae, Adenoviridae Infections therapy, Adoptive Transfer methods, CD4-Positive T-Lymphocytes transplantation, CD8-Positive T-Lymphocytes transplantation, Capsid Proteins immunology, Stem Cell Transplantation
- Abstract
Background: Human adenovirus can cause morbidity and mortality in immunocompromised patients after allogeneic stem cell transplantation. Reconstitution of adenovirus-specific CD4(+) T cells has been reported to be associated with sustained protection from adenovirus disease, but epitope specificity of these responses has not been characterized. Since mainly CD4(+) T cells and no CD8(+) T cells specific for adenovirus have been detected after allogeneic stem cell transplantation, the relative contribution of adenovirus-specific CD4(+) and CD8(+) T cells in protection from adenovirus disease remains to be elucidated., Design and Methods: The presence of human adenovirus hexon-specific T cells was investigated in peripheral blood of pediatric and adult allogeneic stem cell transplant recipients, who showed spontaneous resolution of disseminated adenovirus infection. Subsequently, a clinical grade method was developed for rapid generation of adenovirus-specific T-cell lines for adoptive immunotherapy., Results: Clearance of human adenovirus viremia coincided with emergence of a coordinated CD8(+) and CD4(+) T-cell response against adenovirus hexon epitopes in patients after allogeneic stem cell transplantation. Activation of adenovirus hexon-specific CD8(+) and CD4(+) T cells with a hexon protein-spanning peptide pool followed by interferon-γ-based isolation allowed rapid expansion of highly specific T-cell lines from healthy adults, including donors with very low frequencies of adenovirus hexon-specific T cells. Adenovirus-specific T-cell lines recognized multiple MHC class I and II restricted epitopes, including known and novel epitopes, and efficiently lysed human adenovirus-infected target cells., Conclusions: This study provides a rationale and strategy for the adoptive transfer of donor-derived human adenovirus hexon-specific CD8(+) and CD4(+) T cells for the treatment of disseminated adenovirus infection after allogeneic stem cell transplantation.
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- 2010
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- View/download PDF
5. Value of allogeneic versus autologous stem cell transplantation and chemotherapy in patients with myelodysplastic syndromes and secondary acute myeloid leukemia. Final results of a prospective randomized European Intergroup Trial.
- Author
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de Witte T, Hagemeijer A, Suciu S, Belhabri A, Delforge M, Kobbe G, Selleslag D, Schouten HC, Ferrant A, Biersack H, Amadori S, Muus P, Jansen JH, Hellström-Lindberg E, Kovacsovics T, Wijermans P, Ossenkoppele G, Gratwohl A, Marie JP, and Willemze R
- Subjects
- Adult, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Humans, Leukemia, Myeloid, Acute mortality, Middle Aged, Myelodysplastic Syndromes mortality, Neoplasms, Second Primary mortality, Neoplasms, Second Primary therapy, Survival Analysis, Transplantation, Autologous, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods, Leukemia, Myeloid, Acute therapy, Myelodysplastic Syndromes therapy
- Abstract
Background: Allogeneic stem cell transplantation is usually considered the only curative treatment option for patients with advanced or transformed myelodysplastic syndromes in complete remission, but post-remission chemotherapy and autologous stem cell transplantation are potential alternatives, especially in patients over 45 years old., Design and Methods: We evaluated, after intensive anti-leukemic remission-induction chemotherapy, the impact of the availability of an HLA-identical sibling donor on an intention-to treat basis. Additionally, all patients without a sibling donor in complete remission after the first consolidation course were randomized to either autologous peripheral blood stem cell transplantation or a second consolidation course consisting of high-dose cytarabine., Results: The 4-year survival of the 341 evaluable patients was 28%. After achieving complete remission, the 4-year survival rates of patients under 55 years old with or without a donor were 54% and 41%, respectively, with an adjusted hazard ratio of 0.81 (95% confidence interval [95% CI], 0.49-1.35) for survival and of 0.67 (95% CI, 0.42-1.06) for disease-free survival. In patients with intermediate/high risk cytogenetic abnormalities the hazard ratio in multivariate analysis was 0.58 (99% CI, 0.22-1.50) (P=0.14) for survival and 0.46 (99% CI, 0.22-1.50) for disease-free survival (P=0.03). In contrast, in patients with low risk cytogenetic characteristics the hazard ratio for survival was 1.17 (99% CI, 0.40-3.42) and that for disease-free survival was 1.02 (99% CI, 0.40-2.56). The 4-year survival of the 65 patients randomized to autologous peripheral blood stem cell transplantation or a second consolidation course of high-dose cytarabine was 37% and 27%, respectively. The hazard ratio in multivariate analysis was 1.22 (95% CI, 0.65-2.27) for survival and 1.02 (95% CI, 0.56-1.85) for disease-free survival., Conclusions: Patients with a donor and candidates for allogeneic stem cell transplantation in first complete remission may have a better disease-free survival than those without a donor in case of myelodysplastic syndromes with intermediate/high-risk cytogenetics. Autologous peripheral blood stem cell transplantation does not provide longer survival than intensive chemotherapy.
- Published
- 2010
- Full Text
- View/download PDF
6. Dexamethasone compared to prednisolone for adults with acute lymphoblastic leukemia or lymphoblastic lymphoma: final results of the ALL-4 randomized, phase III trial of the EORTC Leukemia Group.
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Labar B, Suciu S, Willemze R, Muus P, Marie JP, Fillet G, Berneman Z, Jaksic B, Feremans W, Bron D, Sinnige H, Mistrik M, Vreugdenhil G, De Bock R, Nemet D, Gilotay C, Amadori S, and de Witte T
- Subjects
- Adolescent, Adult, Aged, Antineoplastic Agents, Hormonal, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Combined Modality Therapy, Disease-Free Survival, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Male, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Remission Induction, Young Adult, Dexamethasone administration & dosage, Prednisolone administration & dosage
- Abstract
Background: Corticosteroids are a standard component of the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma. Our aim was to determine whether dexamethasone results in a better outcome than prednisolone., Design and Methods: Adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma were randomized to receive, as part of their induction therapy on days 1-8 and 15-22, either dexamethasone 8 mg/m(2) or prednisolone 60 mg/m(2). Those who reached complete remission were given two courses of consolidation therapy with high-dose cytarabine and mitoxantrone and methotrexate and asparaginase. Subsequently patients younger than 50 years, with a suitable donor, were to undergo allogeneic stem cell transplantation, whereas the others were planned to receive either an autologous stem cell transplant or high-dose maintenance chemotherapy with prophylactic central nervous system irradiation. Randomization was done with a minimization technique. The primary endpoint was event-free survival and the analyses was conducted on an intention-to-treat basis., Results: Between August 1995 and October 2003, 325 patients between 15 to 72 years of age were randomized to receive either dexamethasone (163 patients) or prednisolone (162 patients). After induction and the course of first consolidation therapy, 131 (80.4%) patients in the dexamethasone group and 124 (76.5%) in the prednisolone group achieved complete remission. No significant difference was observed between the two treatment groups with regards to 6-year event-free survival rates (+/-SE) which were 25.9% (3.6%) and 28.7% (3.5%) in the dexamethasone and prednisolone groups, respectively (P=0.82, hazard ratio 0.97; 95% confidence interval, 0.75-1.25). Disease-free survival after complete remission was also similar in the dexamethasone and prednisolone groups, the 6-year rates being 32.3% and 37.5%, respectively (hazard ratio 1.03; 95% confidence interval 0.76-1.40). The 6-year cumulative incidences of relapse were 49.8% and 53.5% (Gray's test: P=0.30) while the 6-year cumulative incidences of death were 18% and 9% (Gray's test: P=0.07)., Conclusions: In the ALL-4 trial in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma, treatment with dexamethasone did not show any advantage over treatment with prednisolone.
- Published
- 2010
- Full Text
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7. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy.
- Author
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Griffioen M, van Egmond EH, Kester MG, Willemze R, Falkenburg JH, and Heemskerk MH
- Subjects
- Antibodies, Monoclonal, Murine-Derived, Antigens, CD20 immunology, Cell Line, Humans, Neoplasms immunology, Neoplasms metabolism, Rituximab, T-Lymphocytes immunology, T-Lymphocytes metabolism, Antibodies, Monoclonal pharmacology, Antigens, CD20 biosynthesis, Antineoplastic Agents pharmacology, Genes, Transgenic, Suicide, Immunotherapy, Adoptive, Neoplasms therapy, Retroviridae, T-Lymphocytes transplantation, Transduction, Genetic
- Abstract
The aim of adoptive T-cell therapy of cancer is to selectively confer immunity against tumor cells. Autoimmune side effects, however, remain a risk, emphasizing the relevance of a suicide mechanism allowing in vivo elimination of infused T cells. We investigated the use of human CD20 as suicide gene in T-lymphocytes. Potential effects of forced CD20 expression on T-cell function were investigated by comparing CD20- and mock-transduced cytomegalovirus (CMV) specific T cells for cytolysis, cytokine release and proliferation. The use of CD20 as suicide gene was investigated in CMV specific T cells and in T cells genetically modified with an antigen specific T-cell receptor. No effect of CD20 on T-cell function was observed. CD20-transduced T cells with and without co-transferred T-cell receptor were efficiently eliminated by complement dependent cytotoxicity induced by therapeutic anti-CD20 antibody rituximab. The data support the broad value of CD20 as safety switch in adoptive T-cell therapy.
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- 2009
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8. Genetic engineering of virus-specific T cells with T-cell receptors recognizing minor histocompatibility antigens for clinical application.
- Author
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Griffioen M, van Egmond HM, Barnby-Porritt H, van der Hoorn MA, Hagedoorn RS, Kester MG, Schwabe N, Willemze R, Falkenburg JH, and Heemskerk MH
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- Cells, Cultured, Genetic Vectors genetics, Humans, Minor Histocompatibility Antigens genetics, Minor Histocompatibility Antigens metabolism, Protein Engineering, Minor Histocompatibility Antigens immunology, Receptors, Antigen, T-Cell immunology, Retroviridae genetics, T-Lymphocytes immunology, T-Lymphocytes virology
- Abstract
Background: Donor lymphocyte infusion is an effective form of adoptive immunotherapy for hematologic malignancies after allogeneic stem cell transplantation. Graft-versus-host disease, however, often develops due to recognition of ubiquitously-expressed minor histocompatibility antigens. Transfer of T-cell receptors recognizing hematopoiesis-restricted minor histocompatibility antigens to virus-specific T cells may be a powerful anti-tumor therapy with a low risk of graft-versus-host disease. The purpose of this study was to develop an optimal T-cell receptors-encoding multi-cistronic retroviral vector and an efficient method for generating T-cell receptors-engineered virus-specific T cells., Design and Methods: Retroviral vectors encoding the T-cell receptors for the hematopoiesis-restricted minor histocompatibility antigen HA-2 with and without selection markers were compared for T-cell receptors surface expression and HA-2-specific lysis. In addition, two different methods, i.e. peptide stimulation of CD8(+) cells and Pro5 MHC pentamer-based isolation of antigen-specific T cells, were investigated for their efficiency to generate T-cell receptors-transduced virus-specific T cells., Results: Bi-cistronic vectors without selection markers most efficiently mediated T-cell receptors surface expression and HA-2-specific lysis. Furthermore, both methods were useful for generating gene-modified cells, but the purity of virus-specific T cells was higher after pentamer isolation. Finally, the capacity of gene-modified cells to express the transgenic T-cell receptors at the cell surface markedly differed between virus-specific T cells and was correlated with lysis of relevant target cells., Conclusions: Our data support T-cell receptors gene transfer to pentamer-isolated virus-specific T cells using bi-cistronic retroviral vectors and illustrate the relevance of selection of gene-modified T cells with appropriate transgenic T-cell receptors surface expression for clinical gene therapy.
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- 2008
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9. Differential activation of the death receptor pathway in human target cells induced by cytotoxic T lymphocytes showing different kinetics of killing.
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de Vries JF, von dem Borne PA, van Luxemburg-Heijs SA, Heemskerk MH, Willemze R, Falkenburg JH, and Barge RM
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- Apoptosis genetics, CASP8 and FADD-Like Apoptosis Regulating Protein genetics, CASP8 and FADD-Like Apoptosis Regulating Protein immunology, Caspase 8 immunology, Caspase Inhibitors, Cell Death genetics, Cell Death immunology, Humans, Immunity, Cellular genetics, Immunity, Cellular immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Receptors, Tumor Necrosis Factor immunology, Retroviridae, Time Factors, Transduction, Genetic, Tumor Cells, Cultured, Apoptosis immunology, Granzymes immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, Perforin immunology, T-Lymphocytes immunology
- Abstract
Background and Objectives: Cytotoxic T lymphocytes (CTL) may use two effector mechanisms to kill their target cells: perforin (PFN) and granzyme B (GrB)-dependent granule-mediated cell death and death receptor-mediated cell death. Controversy exists whether, in addition to PFN/GrB-mediated apoptosis, death receptor-induced apoptosis contributes to the elimination of human tumor cells by CTL., Design and Methods: Since the two CTL-mediated effector mechanisms differ in time required to eliminate target cells, lysis of target cells was analyzed using CTL clones with slow and rapid kinetics of killing derived from a patient with chronic myeloid leukemia. To determine the involvement of the death receptor pathway, a retroviral construct encoding the antiapoptotic gene FLICE inhibitory protein (FLIP) was introduced into these target cells., Results: A CTL clone capable of killing 50% of the target cells within 2 hours of incubation primarily acted by release of PFN and GrB. In contrast, two CTL clones showing slower target cell killing kinetics partially used the death receptor pathway (approximately 30% inhibition by FLIP)., Interpretation and Conclusions: We demonstrated that the death receptor pathway contributes to T-cell-mediated cell death if not all target cells are destroyed by release of PFN and GrB.
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- 2007
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10. Phase I/II feasibility study evaluating the generation of leukemia-reactive cytotoxic T lymphocyte lines for treatment of patients with relapsed leukemia after allogeneic stem cell transplantation.
- Author
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Marijt E, Wafelman A, van der Hoorn M, van Bergen C, Bongaerts R, van Luxemburg-Heijs S, van den Muijsenberg J, Wolbers JO, van der Werff N, Willemze R, and Falkenburg F
- Subjects
- Adolescent, Adult, Antigen-Presenting Cells metabolism, Cell Line, Tumor, Child, Female, Humans, In Situ Hybridization, Fluorescence, Leukemia therapy, Male, Middle Aged, Phenotype, Recurrence, T-Lymphocytes, Cytotoxic metabolism, Transplantation, Homologous, Treatment Outcome, Immunotherapy, Adoptive methods, Leukemia immunology, Stem Cell Transplantation methods, T-Lymphocytes, Cytotoxic immunology
- Abstract
Background and Objectives: Graft-versus-host-disease may be avoided and the likelihood of a graft-versus-leukemia reaction increased by infusion of in vitro generated, leukemia-reactive, cytotoxic T lymphocyte (CTL) lines as treatment for patients with relapsed leukemia after allogeneic stem cell transplantation, instead of donor lymphocyte infusion. The aim of this study phase I/II study was to assess the feasibility of large-scale in vitro generation of leukemia-reactive CTL for clinical use., Design and Methods: Using a modified limiting dilution culture system donor T cells were stimulated with HLA-identical leukemic antigen presenting cells. Feasibility experiments demonstrated that in 16 of 27 donor-recipient pairs tested a CTL line could be generated. Twelve of these 16 patients developed a relapse and for 11 of these 12 patients a CTL line was generated under Good Manufacturing Practice conditions., Results: The CTL lines showed moderate to high cytotoxic activity against original recipient leukemic cells in vitro. Eight patients with a relapse received from one to seven CTL lines. One patient entered a complete remission after CTL infusion only, one entered a complete remission after combined CTL infusion and donor lymphocyte infusion, two patients had temporarily stable disease, and in four patients no response was observed., Interpretation and Conclusions: Although the current procedure to generate these CTL lines is feasible, the strategy is logistically complex and time-consuming, and needs further improvement. Key words: cellular immunotherapy, CTL, leukemia, allogeneic stem cell transplantation.
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- 2007
- Full Text
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11. Outcomes after myeloablative unrelated donor stem cell transplantation using both in vitro and in vivo T-cell depletion with alemtuzumab.
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von dem Borne PA, Beaumont F, Starrenburg CW, Oudshoorn M, Hale G, Falkenburg JH, Fibbe WE, Willemze R, and Barge RM
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- Adolescent, Adult, Alemtuzumab, Antibodies, Monoclonal, Humanized, Female, Humans, Male, Middle Aged, T-Lymphocytes immunology, Transplantation Conditioning methods, Treatment Outcome, Antibodies, Monoclonal pharmacology, Antibodies, Neoplasm pharmacology, Lymphocyte Depletion methods, Stem Cell Transplantation methods, Tissue Donors
- Abstract
HLA-matched unrelated donor (MUD) stem cell transplantation (MUD) is complicated by a high incidence of graft-versus-host-disease (GVHD) resulting in significant morbidity and mortality. To circumvent this problem we included alemtuzumab for in vivo and in vitro T-cell depletion in a myeloablative MUD-SCT regimen. After SCT, no severe acute GVHD was observed in the 30 transplanted patients. Donor lymphocyte infusion administered at a later time point resulted in sustained anti-tumor responses in most patients with chronic myeloid leukemia. After donor lymphocyte infusion three patients developed severe acute GVHD. Due to good responsiveness to immunosuppressive therapy only two patients developed persistent chronic GVHD. The main advantage of the transplantation regimen including alemtuzumab is that not only mortality due to GVHD is limited but also extensive chronic GVHD, which potentially leads to chronic morbidity and diminished quality of life, is hardly observed.
- Published
- 2006
12. The mechanisms of Ara-C-induced apoptosis of resting B-chronic lymphocytic leukemia cells.
- Author
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de Vries JF, Falkenburg JH, Willemze R, and Barge RM
- Subjects
- Arabinofuranosylcytosine Triphosphate metabolism, Cell Proliferation drug effects, Cytarabine metabolism, Female, Humans, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Male, RNA antagonists & inhibitors, RNA biosynthesis, Apoptosis drug effects, Cytarabine pharmacology, Leukemia, Lymphocytic, Chronic, B-Cell pathology
- Abstract
Background and Objectives: Cytarabine (Ara-C) is commonly used for the treatment of acute leukemia. Incorporation of Ara-C into DNA is a key event in the mechanism of killing of proliferating leukemic cells. Previously, we demonstrated that Ara-C was cytotoxic to proliferating but not to resting (G(O)) malignant cells from patients with acute leukemia. In contrast, here we show unexpected apoptosis of G(O) B-chronic lymphocytic leukemia (CLL) cells by Ara-C in a dose-dependent manner. In this study we analyzed which cellular processes were involved in Ara-C-mediated killing of G(O)-B-CLL cells., Design and Methods: Using primary B-CLL cells (>98% in G(O)), we examined the mechanisms of Ara-C-mediated apoptosis in resting G(O) cells. CFSE-based cytotoxicity assays combined with cell cycle analysis were used to perform a long-term analysis of Ara-C-mediated killing of B-CLL cells. The effects of Ara-C on DNA and RNA synthesis were studied using various 3H-incorporation experiments., Results: Ara-C-mediated cell death of B-CLL cells showed the characteristics of normal apoptosis, such as phosphatidyl serine exposure and caspase activation. The mechanism of killing of quiescent B-CLL cells by Ara-C was shown not to be dependent on DNA replication. In contrast, CD40L-activated B-CLL cells showed S-phase-specific depletion of proliferating CLL cells. We demonstrated that Ara-C was converted into its active triphosphate by G(O)-B-CLL cells, coinciding with a 30% inhibition of RNA synthesis., Interpretation and Conclusions: In conclusion, our data indicate that Ara-C can induce apoptosis in resting G(O)-B-CLL cells using a mechanism independent of cell proliferation and DNA replication but associated with inhibition of RNA synthesis and downregulation of Mcl-1.
- Published
- 2006
13. Proteosomal degradation of BCR/ABL protein can generate an HLA-A*0301-restricted peptide, but high-avidity T cells recognizing this leukemia-specific antigen were not demonstrated.
- Author
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Posthuma EF, van Bergen CA, Kester MG, de Paus RA, van Veelen PA, de Ru AH, Drijfhout JW, Lurvink EG, Willemze R, and Falkenburg JH
- Subjects
- Amino Acid Sequence, Antigen Presentation, Antigens, Neoplasm metabolism, Clone Cells immunology, Dendritic Cells immunology, Fusion Proteins, bcr-abl metabolism, HLA-A3 Antigen, HLA-B8 Antigen, Humans, K562 Cells, Mass Spectrometry, Molecular Sequence Data, Peptide Fragments chemical synthesis, Peptide Fragments immunology, Peptide Fragments metabolism, Proteasome Endopeptidase Complex metabolism, Protein Binding, Protein Interaction Mapping, Antigens, Neoplasm immunology, Fusion Proteins, bcr-abl immunology, HLA-A Antigens immunology, HLA-B Antigens immunology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology, T-Cell Antigen Receptor Specificity
- Abstract
Background and Objectives: Cytotoxic T-lymphocytes (CTL) have been generated in vitro against chronic myeloid leukemia (CML)-associated BCR/ABL-specific peptides. We analyzed the existence of high-avidity T cells recognizing endogenously processed BCR/ABL-specific proteins., Design and Methods: We performed binding studies of BCR/ABL-specific peptides, proteosomal digestion of BCR/ABL breakpoint overlapping protein, mass spectrometry of eluates from HLA-*0301-transduced K562 cells, and tried to isolate peptide-specific T-cells using tetramers., Results: We confirmed the binding of the BCR/ABL-specific peptides KQSSKALQR to HLA-A*0301 and GFKQSSKAL to HLA-B*0801. Proteasomal digestion showed cleavage sites leading to KQSSKALQR but not to GFKQSSKAL. Using mass spectrometry KQSSKALQR could not be detected in the eluates from HLA-A*0301-transduced K562 cells. We attempted to induce BCR/ABL-specific CTL lines from 4 healthy donors using dendritic cells pulsed with KQSSKALQR and performed single cell sorting to isolate tetramer-positive T cells. None of 31 generated clones showed BCR/ABL-specific cytotoxicity. Isolation of tetramer-positive cells from peripheral blood of relapsed CML patients after allogeneic transplantation treated with donor lymphocyte infusion resulted in 38 T-cell clones which did not show peptide-specific cytotoxicity., Interpretation and Conclusions: We provide evidence that BCR/ABL protein processing can lead to KQSSKALQR peptide binding to HLA-A*0301. However, KQSSKALQR could not be detected in HLA-A*0301-transduced K562 cells, and KQSSKALQR could not be demonstrated to induce high-avidity BCR/ABL-specific CTL.
- Published
- 2004
14. Sequential administration of gemtuzumab ozogamicin and conventional chemotherapy as first line therapy in elderly patients with acute myeloid leukemia: a phase II study (AML-15) of the EORTC and GIMEMA leukemia groups.
- Author
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Amadori S, Suciu S, Willemze R, Mandelli F, Selleslag D, Stauder R, Ho A, Denzlinger C, Leone G, Fabris P, Muus P, Vignetti M, Hagemeijer A, Beeldens F, Anak O, and De Witte T
- Subjects
- Acute Disease, Aged, Aminoglycosides administration & dosage, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Cisplatin administration & dosage, Drug Administration Schedule, Female, Gemtuzumab, Humans, Ifosfamide administration & dosage, Infusions, Intravenous, Leukemia, Myeloid mortality, Male, Middle Aged, Mitomycin administration & dosage, Reproducibility of Results, Survival Analysis, Vindesine administration & dosage, Aminoglycosides therapeutic use, Aminoglycosides toxicity, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal toxicity, Antineoplastic Agents therapeutic use, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid drug therapy
- Abstract
Background and Objectives: Acute myeloid leukemia (AML) in the elderly is associated with low rates of response to conventional chemotherapy and long-term survival, highlighting the need for innovative treatment strategies. Gemtuzumab ozogamicin (GO) is an immunoconjugate that has shown activity in relapsed AML with a favorable safety profile. The aim of this collaborative trial was to assess the feasibility, safety, and antileukemic activity of administering GO followed by conventional chemotherapy as first line therapy in patients aged 61-75 years with AML., Design and Methods: Eligible patients received frontline treatment with GO 9 mg/m2 infused intravenously on days 1 and 15. Following response assessment to GO, patients were started on conventional chemotherapy consisting of the MICE regimen (mitoxantrone, cytarabine, etoposide). No further treatment was planned for complete responders., Results: Among the 57 evaluable patients, 38 (67%) completed the entire sequential treatment as planned. The overall response rate to the entire induction sequence was 54.4% (31/57), with complete remission (CR) in 35.1% and complete remission with incomplete platelet recovery (CRp) in 19.3%. Rates of failure due to treatment-related mortality or resistant disease were 14.1% (3 toxic deaths during the GO segment, 5 during MICE) and 29.9%, respectively. An initial response to GO was documented in 20 patients (35.1%), with CR in 22.8% and CRp in 12.3%; 6 additional patients entered a partial remission. Reversible myelosuppression and liver toxicity were the main adverse events during both segments of induction. Frontline GO was associated with modest mucosal and gastrointestinal toxicity, but grade 3-4 pancytopenia was universal and prolonged. Hepatic veno-occlusive disease developed in 3 patients after GO and 2 after MICE, resulting in 4 deaths from liver failure. One-year survival at follow-up was 34%. Twelve patients continue in CR/CRp after a median of 226 days., Interpretation and Conclusions: The sequential combination of GO and conventional chemotherapy is a feasible and active treatment strategy for older patients with untreated AML. This novel regimen is now being compared in a phase III trial (AML-17).
- Published
- 2004
15. Allogeneic stem cell transplantation in acute lymphoblastic leukemia and non-Hodgkin's lymphoma for patients <or=50 years old in first complete remission: results of the EORTC ALL-3 trial.
- Author
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Labar B, Suciu S, Zittoun R, Muus P, Marie JP, Fillet G, Peetermans M, Stryckmans P, Willemze R, Feremans W, Jaksic B, Bourhis JH, Burghouts JP, and de Witte T
- Subjects
- Adolescent, Adult, Age Factors, Bone Marrow Transplantation, Disease-Free Survival, Female, Humans, Leukocyte Count, Lymphoma, Non-Hodgkin drug therapy, Lymphoma, Non-Hodgkin mortality, Male, Middle Aged, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Remission Induction, Tissue Donors, Transplantation, Autologous, Transplantation, Homologous, Treatment Outcome, Hematopoietic Stem Cell Transplantation, Lymphoma, Non-Hodgkin therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy
- Abstract
Background and Objectives: In the EORTC ALL-3 trial, the efficacy of allogeneic transplantation was compared with that of autologous marrow transplantation and maintenance chemotherapy in patients
- Published
- 2004
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