170 results on '"Roel Willemze"'
Search Results
2. 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
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Pauline Meij, Inge Jedema, Menno A.W.G. van der Hoorn, Rian Bongaerts, Linda Cox, Amon R. Wafelman, Erik W.A. Marijt, Roel Willemze, and J.H. Frederik Falkenburg
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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
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3. 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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Maarten L. Zandvliet, J.H. Frederik Falkenburg, Ellis van Liempt, Louise A. Veltrop-Duits, Arjan C. Lankester, Jayant S. Kalpoe, Michel G.D. Kester, Dirk M. van der Steen, Maarten J. van Tol, Roel Willemze, Henk-Jan Guchelaar, Marco W. Schilham, and Pauline Meij
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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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4. 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
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Theo de Witte, Anne Hagemeijer, Stefan Suciu, Amin Belhabri, Michel Delforge, Guido Kobbe, Dominik Selleslag, Harry C. Schouten, Augustin Ferrant, Harald Biersack, Sergio Amadori, Petra Muus, Joop H. Jansen, Eva Hellström-Lindberg, Tibor Kovacsovics, Pierre Wijermans, Gert Ossenkoppele, Alois Gratwohl, Jean-Pierre Marie, and Roel Willemze
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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. (Eudract number: NCT00002926; http://www.cancer.gov/clinicaltrials/EORTC-06961)
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- 2010
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5. 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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Boris Labar, Stefan Suciu, Roel Willemze, Petra Muus, Jean-Pierre Marie, Georges Fillet, Zwi Berneman, Branimir Jaksic, Walter Feremans, Dominique Bron, Harm Sinnige, Martin Mistrik, Gerard Vreugdenhil, Robrecht De Bock, Damir Nemet, Caroline Gilotay, Sergio Amadori, and Theo de Witte
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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/m2 or prednisolone 60 mg/m2. 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.
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- 2010
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6. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy
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Marieke Griffioen, Esther H.M. van Egmond, Michel G.D. Kester, Roel Willemze, J.H. Frederik Falkenburg, and Mirjam H.M. Heemskerk
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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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7. Genetic engineering of virus-specific T cells with T-cell receptors recognizing minor histocompatibility antigens for clinical application
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Marieke Griffioen, H.M. Esther van Egmond, Helen Barnby-Porritt, Menno A.W.G. van der Hoorn, Renate S. Hagedoorn, Michel G.D. Kester, Nikolai Schwabe, Roel Willemze, J.H. Frederik Falkenburg, and Mirjam H.M. Heemskerk
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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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8. 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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Jeltje F. de Vries, Peter A. von dem Borne, Simone A.P. van Luxemburg-Heijs, Mirjam H.M. Heemskerk, Roel Willemze, J.H. Frederik Falkenburg, and Renèe M.Y. Barge
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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 (~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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9. 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
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Erik Marijt, Amon Wafelman, Menno van der Hoorn, Cornelis van Bergen, Rian Bongaerts, Simone van Luxemburg-Heijs, Joost van den Muijsenberg, Judith Olde Wolbers, Nicole van der Werff, Roel Willemze, and Frederik Falkenburg
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Diseases of the blood and blood-forming organs ,RC633-647.5 - 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 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.
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- 2007
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10. Supplementary Figure 1 from High-Throughput Characterization of 10 New Minor Histocompatibility Antigens by Whole Genome Association Scanning
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Marieke Griffioen, J.H. Frederik Falkenburg, Roel Willemze, Arend Mulder, Michel G.D. Kester, Jeanine J. Houwing-Duistermaat, Ellie G.A. Lurvink, Simone A.P. Van Luxemburg-Heijs, Edith D. Van Der Meijden, Caroline E. Rutten, and Cornelis A.M. Van Bergen
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Supplementary Figure 1 from High-Throughput Characterization of 10 New Minor Histocompatibility Antigens by Whole Genome Association Scanning
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- 2023
11. Supplementary Tables 1-3 from High-Throughput Characterization of 10 New Minor Histocompatibility Antigens by Whole Genome Association Scanning
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Marieke Griffioen, J.H. Frederik Falkenburg, Roel Willemze, Arend Mulder, Michel G.D. Kester, Jeanine J. Houwing-Duistermaat, Ellie G.A. Lurvink, Simone A.P. Van Luxemburg-Heijs, Edith D. Van Der Meijden, Caroline E. Rutten, and Cornelis A.M. Van Bergen
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Supplementary Tables 1-3 from High-Throughput Characterization of 10 New Minor Histocompatibility Antigens by Whole Genome Association Scanning
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- 2023
12. Data from High-Throughput Characterization of 10 New Minor Histocompatibility Antigens by Whole Genome Association Scanning
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Marieke Griffioen, J.H. Frederik Falkenburg, Roel Willemze, Arend Mulder, Michel G.D. Kester, Jeanine J. Houwing-Duistermaat, Ellie G.A. Lurvink, Simone A.P. Van Luxemburg-Heijs, Edith D. Van Der Meijden, Caroline E. Rutten, and Cornelis A.M. Van Bergen
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Patients with malignant diseases can be effectively treated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Polymorphic peptides presented in HLA molecules, the so-called minor histocompatibility antigens (MiHA), play a crucial role in antitumor immunity as targets for alloreactive donor T cells. Identification of multiple MiHAs is essential to understand and manipulate the development of clinical responses after allo-SCT. In this study, CD8+ T-cell clones were isolated from leukemia patients who entered complete remission after allo-SCT, and MiHA-specific T-cell clones were efficiently selected for analysis of recognition of a panel of EBV-transformed B cells positive for the HLA restriction elements of the selected T-cell clones. One million single nucleotide polymorphisms (SNP) were determined in the panel cell lines and investigated for matching with the T-cell recognition data by whole genome association scanning (WGAs). Significant association with 12 genomic regions was found, and detailed analysis of genes located within these genomic regions revealed SNP disparities encoding polymorphic peptides in 10 cases. Differential recognition of patient-type, but not donor-type, peptides validated the identification of these MiHAs. Using tetramers, distinct populations of MiHA-specific CD8+ T cells were detected, demonstrating that our WGAs strategy allows high-throughput discovery of relevant targets in antitumor immunity after allo-SCT. Cancer Res; 70(22); 9073–83. ©2010 AACR.
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- 2023
13. 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
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Walter J.F.M. van der Velden, Laura Cannella, Theo de Witte, Jean-Pierre Marie, Maria Concetta Petti, Dario Ferrero, Edoardo La Sala, Sebastian Wittnebel, Paola Fazi, Roel Willemze, Marco Sborgia, Fabio Efficace, Sergio Amadori, Alberto Bosi, Marco Vignetti, Jean-Henri Bourhis, Francesco Fabbiano, Robert Zittoun, Frédéric Baron, Giovanni Martinelli, Petra Muus, Silvia Maria Trisolini, Stefan Suciu, and Constantijn J.M. Halkes
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Oncology ,medicine.medical_specialty ,Long term follow up ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Intensive chemotherapy ,Transplantation, Autologous ,Text mining ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Autogenous bone ,Online Only Articles ,Bone Marrow Transplantation ,Marrow transplantation ,business.industry ,Remission Induction ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,Myeloid leukemia ,Hematology ,Leukemia, Myeloid, Acute ,Inflammatory diseases Radboud Institute for Health Sciences [Radboudumc 5] ,business ,Follow-Up Studies - Abstract
Contains fulltext : 218286.pdf (Publisher’s version ) (Open Access)
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- 2020
14. Comparative value of post-remission treatment in cytogenetically normal AML subclassified by NPM1 and FLT3-ITD allelic ratio
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Marie-Christiane Vekemans, Wim H. van der Putten, Johan Maertens, Florentien E. M. in ’t Hout, Raynier Devillier, Bart J. Biemond, Jurjen Versluis, Thomas Pabst, Gert J. Ossenkoppele, Jan J. Cornelissen, Peter J. M. Valk, Roel Willemze, Bob Löwenberg, Markus G. Manz, Frédéric Baron, Giovanna Meloni, Bert A. van der Reijden, Harry C. Schouten, Gerwin Huls, Marie-Cecile Legdeur, Edo Vellenga, Jakob Passweg, Jürgen Kuball, CCA - Cancer Treatment and Quality of Life, Clinical Haematology, CCA -Cancer Center Amsterdam, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Stem Cell Aging Leukemia and Lymphoma (SALL), UCL - (SLuc) Service d'hématologie, Hematology, CCA - Cancer Treatment and quality of life, University of Zurich, Cornelissen, J J, MUMC+: MA Hematologie (9), RS: GROW - R3 - Innovative Cancer Diagnostics & Therapy, and Interne Geneeskunde
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Oncology ,Male ,Cancer Research ,Transplantation Conditioning ,medicine.medical_treatment ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,2720 Hematology ,Hematopoietic stem cell transplantation ,UK MRC AML-10 ,Allelic ratio ,0302 clinical medicine ,hemic and lymphatic diseases ,1306 Cancer Research ,Cumulative incidence ,ALLOGENEIC TRANSPLANTATION ,Precision Medicine ,610 Medicine & health ,ACUTE MYELOGENOUS LEUKEMIA ,NO-DONOR ANALYSIS ,Hazard ratio ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Nuclear Proteins ,Hematology ,1ST COMPLETE REMISSION ,Middle Aged ,Survival Rate ,Leukemia ,Leukemia, Myeloid, Acute ,Tandem Repeat Sequences ,030220 oncology & carcinogenesis ,2730 Oncology ,Female ,Nucleophosmin ,REDUCED-INTENSITY ,Flt3 itd ,Adult ,NPM1 ,medicine.medical_specialty ,Adolescent ,MINIMAL RESIDUAL DISEASE ,ACUTE MYELOID-LEUKEMIA ,Risk Assessment ,03 medical and health sciences ,Young Adult ,Internal medicine ,Journal Article ,medicine ,Humans ,Comparative Study ,Survival rate ,business.industry ,STEM-CELL TRANSPLANTATION ,medicine.disease ,Minimal residual disease ,INTERNAL TANDEM DUPLICATION ,Anesthesiology and Pain Medicine ,fms-Like Tyrosine Kinase 3 ,10032 Clinic for Oncology and Hematology ,Immunology ,Fms-Like Tyrosine Kinase 3 ,Mutation ,business ,Value (mathematics) ,030215 immunology - Abstract
Contains fulltext : 169931.pdf (Publisher’s version ) (Closed access) Post-remission treatment (PRT) in patients with cytogenetically normal (CN) acute myeloid leukemia (AML) in first complete remission (CR1) is debated. We studied 521 patients with CN-AML in CR1, for whom mutational status of NPM1 and FLT3-ITD was available, including the FLT3-ITD allelic ratio. PRT consisted of reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (alloHSCT) (n=68), myeloablative conditioning (MAC) alloHSCT (n=137), autologous hematopoietic stem cell transplantation (autoHSCT) (n=168) or chemotherapy (n=148). Favorable overall survival (OS) was found for patients with mutated NPM1 without FLT3-ITD (71+/-4%). Outcome in patients with a high FLT3-ITD allelic ratio appeared to be very poor with OS and relapse-free survival (RFS) of 23+/-8% and 12+/-6%, respectively. Patients with wild-type NPM1 without FLT3-ITD or with a low allelic burden of FLT3-ITD were considered as intermediate-risk group because of similar OS and RFS at 5 years, in which PRT by RIC alloHSCT resulted in better OS and RFS as compared with chemotherapy (hazard ratio (HR) 0.56, P=0.022 and HR 0.50, P=0.004, respectively) or autoHSCT (HR 0.60, P=0.046 and HR 0.60, P=0.043, respectively). The lowest cumulative incidence of relapse (23+/-4%) was observed following MAC alloHSCT. These results suggest that alloHSCT may be preferred in patients with molecularly intermediate-risk CN-AML, while the choice of conditioning type may be personalized according to risk for non-relapse mortality.
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- 2017
15. Idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) for untreated patients with high-risk MDS or AML evolved from MDS: a phase II study from the EORTC and GIMEMA Leukemia Groups (protocol 06013)
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Roel Willemze, Dominik Selleslag, Liv Meert, Theo de Witte, Frédéric Baron, Petra Muus, Sergio Amadori, Dominique Bron, Constantijn J.M. Halkes, and Stefan Suciu
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Adult ,Male ,medicine.medical_specialty ,Secondary acute myeloid leukemia ,Adolescent ,Gemtuzumab ozogamicin ,Liver toxicity ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,medicine.medical_treatment ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Phases of clinical research ,Hematopoietic stem cell transplantation ,Antibodies, Monoclonal, Humanized ,Gastroenterology ,Disease-Free Survival ,Chronic myelomonocytic leukemia ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Idarubicin ,Cytogenetic risk score ,Autografts ,Survival rate ,Aged ,Chemotherapy ,business.industry ,Cytarabine ,Hematopoietic Stem Cell Transplantation ,General Medicine ,Hematology ,Middle Aged ,High-risk myelodysplastic syndromes ,Allografts ,Gemtuzumab ,Surgery ,Survival Rate ,Leukemia, Myeloid, Acute ,Regimen ,Aminoglycosides ,Myelodysplastic Syndromes ,Original Article ,Female ,business ,Hématologie ,medicine.drug - Abstract
The primary objective of this trial was to assess the feasibility, toxicity profile, and antitumor activity of gemtuzumab ozogamicin (GO) combined with a chemotherapy remission-induction regimen in adults with untreated high-risk myelodysplastic syndrome (HR-MDS) or secondary acute myeloid leukemia (sAML). In this phase II trial, 30 patients with median age of 58 years received 1 day of GO as a 1-h infusion at the dose level of 5 mg/m2 on day 7 of the remission-induction course further consisting of a continuous infusion of cytarabine 100 mg/m2/day for 10 days and idarubicin 12 mg/m2/day on days 1, 3, and 5. A consolidation course, consisting of intermediate-dose cytarabine (A) and idarubicin (I) followed by hematopoietic stem cell transplantation (HSCT) was planned for patients in complete remission (CR). The primary endpoints were response rate (CR/CRi) and severe toxicity rate. The secondary endpoint(s) were survival and progression-free survival (PFS) from start of treatment. Thirteen patients (43 %) achieved CR (eight patients) or CR with incomplete hematopoietic recovery (CRi) (five patients). In patients who achieved CR or CRi, the median time to recovery of neutrophils to 0.5 × 109/l and of platelets to >50 × 109/l was 29 and 30 days, respectively. Grade 3 to 4 severe toxicities occurred in nine patients. The most prominent was liver toxicity, as shown by elevated bilirubin levels in 16 patients and one case of nonfatal veno-occlusive disease (VOD). All 13 patients with CR/CRi received consolidation therapy, which was followed by allogeneic HSCT in five patients and autologous HSCT in three patients. According to the statistical design of the study, the idarubicin and cytarabine in combination with gemtuzumab ozogamicin (IAGO) regimen did not show sufficient activity to warrant further exploration of this regimen in adult patients with HR-MDS or sAML., SCOPUS: ar.j, info:eu-repo/semantics/published
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- 2015
16. Clinical and biological impact of TET2 mutations and expression in younger adult AML patients treated within the EORTC/GIMEMA AML-12 clinical trial
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Roel Willemze, Mariam G Aslanyan, Sergio Amadori, Petra Muus, Leonie I. Kroeze, Evelyn Tönnissen, Pedro da Silva-Coelho, Jean-Pierre Marie, Stefan Suciu, Marion Massop, Theresia N. Koorenhof-Scheele, Erik W.A. Marijt, Adrian van der Heijden, Louis van de Locht, Saskia Langemeijer, Ellen Stevens-Linders, Giuseppe Saglio, Ruoping Tang, Bert A. van der Reijden, Patricia van Hoogen, Daniela Cilloni, Boris Labar, Theo de Witte, and Joop H. Jansen
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Male ,Oncology ,Pathology ,Myeloid ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Kaplan-Meier Estimate ,medicine.disease_cause ,DNA Methyltransferase 3A ,Chlorocebus aethiops ,TET2 expression ,Multicenter Studies as Topic ,Missense mutation ,DNA (Cytosine-5-)-Methyltransferases ,Prospective Studies ,RNA, Neoplasm ,Prospective cohort study ,Clinical Trials as Topic ,Mutation ,Hematology ,Gene Expression Regulation, Leukemic ,General Medicine ,Prognosis ,Isocitrate Dehydrogenase ,Neoplasm Proteins ,DNA-Binding Proteins ,Leukemia, Myeloid, Acute ,Leukemia ,medicine.anatomical_structure ,COS Cells ,5-Methylcytosine ,Female ,Adult ,medicine.medical_specialty ,Adolescent ,Recombinant Fusion Proteins ,Transfection ,Dioxygenases ,Cytosine ,Young Adult ,Proto-Oncogene Proteins ,Internal medicine ,medicine ,Animals ,Humans ,RNA, Messenger ,Acute myeloid leukemia ,TET2 mutations ,business.industry ,Cancer ,medicine.disease ,Clinical trial ,business - Abstract
Item does not contain fulltext We assessed the prognostic impact of TET2 mutations and mRNA expression in a prospective cohort of 357 adult AML patients < 60 years of age enrolled in the European Organization For Research and Treatment of Cancer (EORTC)/Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) AML-12 06991 clinical trial. In addition the co-occurrence with other genetic defects and the functional consequences of TET2 mutations were investigated. TET2 mutations occurred in 7.6 % of the patients and were an independent marker of poor prognosis (p = 0.024). TET2 and IDH1/2 mutations strongly associated with aberrations in the DNA methyltransferase DNMT3A. Functional studies confirmed previous work that neither nonsense truncations, nor missense TET2 mutations, induced 5-hydroxymethylcytosine formation. In addition, we now show that mutant TET2 forms did not act in a dominant negative manner when co-expressed with the wild-type protein. Finally, as loss-of-function TET2 mutations predicted poor outcome, we questioned whether low TET2 mRNA expression in cases of AML without TET2 mutations would affect overall survival. Notably, also AML patients with low TET2 mRNA expression levels showed inferior overall survival.
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- 2014
17. Gemtuzumab Ozogamicin Versus Best Supportive Care in Older Patients With Newly Diagnosed Acute Myeloid Leukemia Unsuitable for Intensive Chemotherapy: Results of the Randomized Phase III EORTC-GIMEMA AML-19 Trial
- Author
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Adriano Venditti, Marco Mancini, Domenico Magro, Sergio Amadori, Carla Mazzone, Petra Muus, Safaa M. Ramadan, Maurizio Musso, Luciana Annino, Theo de Witte, Frédéric Baron, Paolo de Fabritiis, Giuliana Alimena, Paola Fazi, Dominik Selleslag, Stefan Suciu, Franco Aversa, Maria Teresa Voso, Anne Hagemeijer, Roel Willemze, Gianluca Gaidano, Liv Meert, Francesca Paoloni, and Marco Vignetti
- Subjects
0301 basic medicine ,Myeloid ,Male ,Cancer Research ,Pediatrics ,medicine.medical_specialty ,Randomization ,Gemtuzumab ozogamicin ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,CD33 ,Antineoplastic Agents ,Enasidenib ,Acute ,Antibodies, Monoclonal, Humanized ,Age Factors ,Aged ,Aged, 80 and over ,Aminoglycosides ,Female ,Humans ,Hydroxyurea ,Leukemia, Myeloid, Acute ,Middle Aged ,Antibodies ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,law ,Monoclonal ,Clinical endpoint ,medicine ,80 and over ,Humanized ,Leukemia ,business.industry ,Hazard ratio ,Myeloid leukemia ,Gemtuzumab ,030104 developmental biology ,Oncology ,030220 oncology & carcinogenesis ,business ,Settore MED/15 - Malattie del Sangue ,medicine.drug - Abstract
Purpose To compare single-agent gemtuzumab ozogamicin (GO) with best supportive care (BSC) including hydroxyurea as first-line therapy in older patients with acute myeloid leukemia unsuitable for intensive chemotherapy. Patients and Methods In this trial, patients at least 61 years old were centrally randomized (1:1) to receive either a single induction course of GO (6 mg/m2 on day 1 and 3 mg/m2 on day 8) or BSC. Patients who did not progress after GO induction could receive up to eight monthly infusions of the immunoconjugate at 2 mg/m2. Randomization was stratified by age, WHO performance score, CD33 expression status, and center. The primary end point was overall survival (OS) by intention-to-treat analysis. Results A total of 237 patients were randomly assigned (118 to GO and 119 to BSC). The median OS was 4.9 months (95% CI, 4.2 to 6.8 months) in the GO group and 3.6 months (95% CI, 2.6 to 4.2 months) in the BSC group (hazard ratio, 0.69; 95% CI, 0.53 to 0.90; P = .005); the 1-year OS rate was 24.3% with GO and 9.7% with BSC. The OS benefit with GO was consistent across most subgroups, and was especially apparent in patients with high CD33 expression status, in those with favorable/intermediate cytogenetic risk profile, and in women. Overall, complete remission (CR [complete remission] + CRi [CR with incomplete recovery of peripheral blood counts]) occurred in 30 of 111 (27%) GO recipients. The rates of serious adverse events (AEs) were similar in the two groups, and no excess mortality from AEs was observed with GO. Conclusion First-line monotherapy with low-dose GO, as compared with BSC, significantly improved OS in older patients with acute myeloid leukemia who were ineligible for intensive chemotherapy. No unexpected AEs were identified and toxicity was manageable.
- Published
- 2016
18. 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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Roel Willemze, Pauline Meij, J.H. Frederik Falkenburg, Linda Cox, Rian Bongaerts, Erik W.A. Marijt, Amon R. Wafelman, Inge Jedema, and Menno A. W. G. van der Hoorn
- Subjects
Oncology ,minor histocompatibility antigen ,medicine.medical_specialty ,Adoptive cell transfer ,T cell ,medicine.medical_treatment ,Pilot Projects ,Hematopoietic stem cell transplantation ,CD8-Positive T-Lymphocytes ,Minor Histocompatibility Antigens ,Recurrence ,allogeneic stem cell transplantation ,HA-1 ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,adoptive cellular immunotherapy ,Leukemia ,business.industry ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Adoptive Transfer ,Transplantation ,Treatment Outcome ,medicine.anatomical_structure ,CTL ,Immunology ,Bone marrow ,Original Articles and Brief Reports ,Stem cell ,business ,Oligopeptides ,CD8 - 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.
- Published
- 2012
19. High-Throughput Characterization of 10 New Minor Histocompatibility Antigens by Whole Genome Association Scanning
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Ellie Lurvink, Arend Mulder, J.H. Frederik Falkenburg, Marieke Griffioen, Simone A.P. van Luxemburg-Heijs, Edith D. van der Meijden, Roel Willemze, Cornelis A.M. van Bergen, Caroline E. Rutten, Michel G.D. Kester, and Jeanine J. Houwing-Duistermaat
- Subjects
Male ,Cancer Research ,Epitopes, T-Lymphocyte ,CD8-Positive T-Lymphocytes ,Biology ,Polymerase Chain Reaction ,Polymorphism, Single Nucleotide ,Genome ,Minor Histocompatibility Antigens ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Minor histocompatibility antigen ,medicine ,Humans ,Transplantation, Homologous ,Cells, Cultured ,Genetics ,Genome, Human ,Anemia, Refractory ,Hematopoietic Stem Cell Transplantation ,food and beverages ,Cancer ,Sequence Analysis, DNA ,medicine.disease ,SNP genotyping ,Oncology ,Myelodysplastic Syndromes ,Female ,Cellular immunotherapy ,hematopoietic-cell transplantation t-cells relapsed leukemia identification gene graft polymorphism target hla ,Genome-Wide Association Study - Abstract
Patients with malignant diseases can be effectively treated with allogeneic hematopoietic stem cell transplantation (allo-SCT). Polymorphic peptides presented in HLA molecules, the so-called minor histocompatibility antigens (MiHA), play a crucial role in antitumor immunity as targets for alloreactive donor T cells. Identification of multiple MiHAs is essential to understand and manipulate the development of clinical responses after allo-SCT. In this study, CD8+ T-cell clones were isolated from leukemia patients who entered complete remission after allo-SCT, and MiHA-specific T-cell clones were efficiently selected for analysis of recognition of a panel of EBV-transformed B cells positive for the HLA restriction elements of the selected T-cell clones. One million single nucleotide polymorphisms (SNP) were determined in the panel cell lines and investigated for matching with the T-cell recognition data by whole genome association scanning (WGAs). Significant association with 12 genomic regions was found, and detailed analysis of genes located within these genomic regions revealed SNP disparities encoding polymorphic peptides in 10 cases. Differential recognition of patient-type, but not donor-type, peptides validated the identification of these MiHAs. Using tetramers, distinct populations of MiHA-specific CD8+ T cells were detected, demonstrating that our WGAs strategy allows high-throughput discovery of relevant targets in antitumor immunity after allo-SCT. Cancer Res; 70(22); 9073–83. ©2010 AACR.
- Published
- 2010
20. HLA-DPB1 Mismatching Results in the Generation of a Full Repertoire of HLA-DPB1-Specific CD4+ T Cell Responses Showing Immunogenicity of all HLA-DPB1 Alleles
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Marieke Griffioen, Machteld Oudshoorn, Simone A.P. van Luxemburg-Heijs, Edith D. van der Meijden, J.H. Frederik Falkenburg, Roel Willemze, and Caroline E. Rutten
- Subjects
CD4-Positive T-Lymphocytes ,HLA-DP Antigens ,Epitopes, T-Lymphocyte ,Cross Reactions ,Biology ,Immune system ,Antigen ,HLA Antigens ,Transduction, Genetic ,Humans ,Allele ,Alleles ,HLA-DP beta-Chains ,Genetics ,Transplantation ,HLA-DPB1 ,Immunogenicity ,Hematology ,In vitro ,Mismatch ,Treatment Outcome ,Immunology ,Stem cell ,HeLa Cells ,Stem Cell Transplantation - Abstract
Clinical studies have indicated that HLA-DPB1 functions as a classical transplantation antigen in allogeneic stem cell transplantation. Mismatching for HLA-DPB1 was associated with an increased risk of graft-versus-host disease (GVHD), but also a decreased risk of disease relapse. However, specific HLA-DPB1 mismatches were associated with poor clinical outcome. It was suggested that this unfavorable effect was caused by a difference in immunogenicity between HLA-DPB1 alleles. To analyze whether immunogenicity of HLA-DPB1 mismatches could be predicted based on the presence or absence of specific amino acid sequences we developed a model to generate allo-HLA-DPB1 responses in vitro. We tested in total 48 different stimulator/responder combinations by stimulating CD4(+) T cells from 5 HLA-DPB1 homozygous individuals with the same antigen-presenting cells transduced with different allo-HLA-DPB1 molecules. HLA-DPB1 molecules used for stimulation comprised 76% to 99% of HLA-DPB1 molecules present in different ethnic populations. We show that all HLA-DPB1 mismatches as defined by allele typing resulted in high-frequency immune responses. Furthermore, we show that crossrecognition of different HLA-DPB1 molecules is a broadly observed phenomenon. We confirm previously described patterns in crossrecognition, and demonstrate that a high degree in similarity between HLA-DPB1 molecules is predictive for crossrecognition, but not for immunogenicity.
- Published
- 2010
21. 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
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Harald Biersack, Jean-Pierre Marie, Stefan Suciu, Joop H. Jansen, Petra Muus, Alois Gratwohl, Pierre W. Wijermans, Dominik Selleslag, Roel Willemze, Anne Hagemeijer, Eva Hellström-Lindberg, Tibor Kovacsovics, Sergio Amadori, Amin Belhabri, Gert J. Ossenkoppele, Harry C. Schouten, Augustin Ferrant, Michel Delforge, Guido Kobbe, Theo de Witte, Interne Geneeskunde, and RS: GROW - School for Oncology and Reproduction
- Subjects
Oncology ,medicine.medical_specialty ,autologous stem cell transplantation ,medicine.medical_treatment ,Medizin ,Autologous stem-cell transplantation ,allogeneic stem cell transplantation ,Immune Regulation [NCMLS 2] ,Translational research [ONCOL 3] ,Internal medicine ,Medicine ,Survival analysis ,Chemotherapy ,business.industry ,intensive chemotherapy ,Myelodysplastic syndromes ,Hazard ratio ,Hematology ,cytogenetic characteristics ,medicine.disease ,myelodysplastic syndromes ,Surgery ,Transplantation ,Leukemia ,Cytarabine ,Original Article ,secondary acute myeloid leukemia ,business ,medicine.drug - Abstract
Contains fulltext : 87519.pdf (Publisher’s version ) (Open Access) 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. 01 oktober 2010
- Published
- 2010
22. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy
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J.H. Frederik Falkenburg, Esther H.M. van Egmond, Michel G.D. Kester, Mirjam H.M. Heemskerk, Marieke Griffioen, and Roel Willemze
- Subjects
T-Lymphocytes ,T cell ,medicine.medical_treatment ,Genetic enhancement ,Antineoplastic Agents ,Immunotherapy, Adoptive ,Cell Line ,Antibodies, Monoclonal, Murine-Derived ,Interleukin 21 ,Antigen ,Transduction, Genetic ,immune system diseases ,Neoplasms ,hemic and lymphatic diseases ,medicine ,Humans ,Cytotoxic T cell ,IL-2 receptor ,business.industry ,Genes, Transgenic, Suicide ,Antibodies, Monoclonal ,Hematology ,Immunotherapy ,Suicide gene ,Antigens, CD20 ,Retroviridae ,medicine.anatomical_structure ,Immunology ,Brief Reports ,Rituximab ,business - 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.
- Published
- 2009
23. Identification of Varicella-Zoster Virus-Specific CD8 T Cells in Patients after T-Cell-Depleted Allogeneic Stem Cell Transplantation
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Catherine Elizabeth Napper, J.H. Frederik Falkenburg, Renate de Boer, Mirjam H.M. Heemskerk, Dirk M. van der Steen, Michel G.D. Kester, Jeremy William Fry, Roel Willemze, Erik W.A. Marijt, Pim L.J. van der Heiden, Wilmy M. E. Haarman, Helen E. Barnby-Porritt, and Menno W. A. G. van der Hoorn
- Subjects
Herpesvirus 3, Human ,viruses ,T cell ,Immunology ,CD8-Positive T-Lymphocytes ,Biology ,medicine.disease_cause ,Herpes Zoster ,Microbiology ,Herpesviridae ,Virus ,Epitope ,Immediate-Early Proteins ,Cohort Studies ,Postoperative Complications ,Viral Envelope Proteins ,Virology ,HLA-A2 Antigen ,medicine ,Humans ,Transplantation, Homologous ,Cytotoxic T cell ,integumentary system ,Varicella zoster virus ,virus diseases ,biochemical phenomena, metabolism, and nutrition ,eye diseases ,Transplantation ,medicine.anatomical_structure ,Insect Science ,Trans-Activators ,Pathogenesis and Immunity ,Stem cell ,Stem Cell Transplantation - Abstract
To study the role of CD8 T cells in the control of varicella-zoster virus (VZV) reactivation, we developed multimeric major histocompatibility complexes to identify VZV-specific CD8 T cells. Potential HLA-A2 binding peptides from the putative immediate-early 62 protein (IE62) of VZV were tested for binding, and peptides with sufficient binding capacity were used to generate pentamers. Patients with VZV reactivation following stem cell transplantation were screened with these pentamers, leading to the identification of the first validated class I-restricted epitope of VZV. In 42% of HLA-A2 patients following VZV reactivation, these IE62-ALW-A2 T cells could be detected ex vivo.
- Published
- 2009
24. Kinetic Preservation of Dual Specificity of Coprogrammed Minor Histocompatibility Antigen-Reactive Virus-Specific T Cells
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Renate S. Hagedoorn, J.H. Frederik Falkenburg, Manja Hoogeboom, Michel G.D. Kester, Roel Willemze, Marleen M. van Loenen, and Mirjam H.M. Heemskerk
- Subjects
Cancer Research ,T-Lymphocytes ,ZAP70 ,Receptors, Antigen, T-Cell ,Cytomegalovirus ,hemic and immune systems ,chemical and pharmacologic phenomena ,Streptamer ,Biology ,Natural killer T cell ,Neoplasm Proteins ,Cell biology ,Minor Histocompatibility Antigens ,Kinetics ,Interleukin 21 ,Oncology ,Immunology ,Humans ,Cytotoxic T cell ,IL-2 receptor ,Antigen-presenting cell ,Interleukin 3 - Abstract
Adoptive transfer of antigen-specific T cells is an attractive strategy for the treatment of hematologic malignancies. It has been shown that T cells recognizing minor histocompatibility antigens (mHag) selectively expressed on hematopoietic cells mediate antileukemic reactivity after allogeneic stem cell transplantation. However, large numbers of T cells with defined specificity are difficult to attain. An attractive strategy to obtain large numbers of leukemia-reactive T cells is retroviral transfer of mHag-specific T-cell receptors (TCR). TCR transfer into T cells specific for persistent viruses may enable these T cells to proliferate both after encountering with viral antigens as well as mHags, increasing the possibility of in vivo survival. We analyzed whether the dual specificity of the TCR-transferred T cells after repetitive stimulation via either the introduced antileukemic HA-2-TCR or the endogenous cytomegalovirus (CMV) specific CMV-TCR was preserved. We show that after repetitive stimulation, T cells skew to a population predominantly expressing the triggered TCR. However, HA-2-TCR–transferred CMV-specific T cells with high antileukemic HA-2-TCR expression but low CMV-TCR expression were able to persist and proliferate after repetitive stimulation with pp65. Moreover, HA-2-TCR–transferred CMV-specific T cells remained dual specific after repetitive stimulation and TCR expression could be reverted after additional stimulation via the previously nonstimulated TCR, restoring high-avidity interactions. These data imply persistence of TCR-transferred virus-specific T cells with both antileukemic and antivirus reactivity in vivo. [Cancer Res 2009;69(5):2034–41]
- Published
- 2009
25. Long–term culture of primary human lymphoblastic leukemia cells in the absence of serum or hematopoietic growth factors
- Author
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Erik W.A. Marijt, H. M. Goselink, Marja van der Burg, Karoly Szuhai, Oliver G. Ottmann, Danielle de Jong, Bart A. Nijmeijer, J.H. Frederik Falkenburg, Roel Willemze, and Marianke L.J. van Schie
- Subjects
Cancer Research ,Time Factors ,Cell Culture Techniques ,Blastic Phase ,Biology ,Culture Media, Serum-Free ,hemic and lymphatic diseases ,Leukemia, B-Cell ,Genetics ,medicine ,Humans ,Molecular Biology ,Cell Proliferation ,ABL ,breakpoint cluster region ,Myeloid leukemia ,Imatinib ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Leukemia ,Haematopoiesis ,Cell culture ,Immunology ,Intercellular Signaling Peptides and Proteins ,medicine.drug - Abstract
Objective B–lineage acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia in lymphatic blastic phase in adults have poor prognoses despite intensive chemotherapy. Novel targeted treatment modalities emerge, but their evaluation requires relevant in vitro models of lymphoblastic leukemia. Presently available cell lines do not fully represent this heterogeneous disease. Available in vitro culturing protocols do not support long–term proliferation of primary cells. We therefore aimed to develop a culture system that allows long–term proliferation of primary human B–lineage lymphoblastic leukemia. Materials and Methods Primary lymphoblastic leukemia cells were cultured in a defined serum–free medium, in the absence or presence of human hematopoietic growth factors or serum. Results In the defined serum–free medium, cells from 12 of 34 cases immediately proliferated in vitro. In the absence of hematopoietic growth factors and serum these cases proliferated for more than 1 year without signs of exhaustion. The culturing system supported different subtypes of lymphoblastic leukemia. Two chronic myeloid leukemia in lymphatic blastic phase, four bcr/abl–positive ALL, one etv6/abl–positive ALL, 2 e2a–pbx1−positive ALL, and one t(9;11)–positive ALL could be long–term expanded, as well as two ALL that displayed nontypical cytogenetics. Not all bcr/abl– or e2a–pbx1−positive ALL proliferated in vitro, demonstrating heterogeneity within these subtypes. The proliferating bcr/abl– and etv6/abl–positive cells displayed sensitivity to imatinib, demonstrating that their proliferation depended on the activity of these oncoproteins. Conclusion The serum–free culturing system may be a valuable instrument in the study of ALL cell biology, as well as in the evaluation of novel targeted therapeutics.
- Published
- 2009
26. Genetic engineering of virus-specific T cells with T-cell receptors recognizing minor histocompatibility antigens for clinical application
- Author
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Nikolai Schwabe, Menno A. W. G. van der Hoorn, Michel G.D. Kester, J.H. Frederik Falkenburg, Marieke Griffioen, H. M. Esther van Egmond, Mirjam H.M. Heemskerk, Roel Willemze, Renate S. Hagedoorn, and Helen E. Barnby-Porritt
- Subjects
biology ,T-Lymphocytes ,Genetic Vectors ,Antigen presentation ,Receptors, Antigen, T-Cell ,CD1 ,Hematology ,Streptamer ,Protein Engineering ,Major histocompatibility complex ,Natural killer T cell ,Cell biology ,Minor Histocompatibility Antigens ,Retroviridae ,Immunology ,biology.protein ,Minor histocompatibility antigen ,Humans ,Cytotoxic T cell ,Antigen-presenting cell ,Cells, Cultured - 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.
- Published
- 2008
27. 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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Simone A.P. van Luxemburg-Heijs, Renee M.Y. Barge, Jeltje F. de Vries, Peter A. von dem Borne, Roel Willemze, J.H. Frederik Falkenburg, and Mirjam H.M. Heemskerk
- Subjects
Programmed cell death ,Time Factors ,T-Lymphocytes ,CASP8 and FADD-Like Apoptosis Regulating Protein ,Apoptosis ,Granzymes ,Receptors, Tumor Necrosis Factor ,Transduction, Genetic ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Tumor Cells, Cultured ,Humans ,Cytotoxic T cell ,Caspase 8 ,Immunity, Cellular ,Cell Death ,biology ,Perforin ,Hematology ,Caspase Inhibitors ,Granzyme B ,CTL ,Retroviridae ,Cell killing ,Immunology ,Cancer research ,biology.protein ,Clone (B-cell biology) - 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 (~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.
- Published
- 2007
28. Post-remission Treatment for Adult Patients With Acute Lymphoblastic Leukemia in First Remission: Is There a Role for Autologous Stem Cell Transplantation?
- Author
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Boris Labar and Roel Willemze
- Subjects
Adult ,Oncology ,medicine.medical_specialty ,Transplantation Conditioning ,Allogeneic transplantation ,Transplantation, Autologous ,Disease-Free Survival ,law.invention ,Autologous stem-cell transplantation ,Randomized controlled trial ,law ,Internal medicine ,Acute lymphocytic leukemia ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,Survival rate ,Randomized Controlled Trials as Topic ,Acute leukemia ,Evidence-Based Medicine ,business.industry ,Remission Induction ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Combined Modality Therapy ,Chemotherapy regimen ,Surgery ,Survival Rate ,Transplantation ,Acute Lymphoblastic Leukemia ,Autologous stem cell transplantation ,Treatment Outcome ,business ,Whole-Body Irradiation ,Stem Cell Transplantation - Abstract
Allogeneic stem cell transplantation (alloSCT) or autologous SCT (autoSCT) and intensive consolidation/intensification courses plus maintenance chemotherapy for 1 to 2 years are currently the major options for post-remission treatment of adult patients with acute lymphoblastic leukemia (ALL) in first remission. Comparison of their value with respect to relapse prevention, disease-free survival, and overall survival has been impossible until recently when the results of several randomized trials became available. Herein, we try to dissect data from these randomized trials to evaluate the role of autoSCT in patients with ALL in complete remission. Five prospectively randomized trials were found in which patients with a family donor were eligible for an alloSCT and the remaining patients were randomized between autoSCT and continuation chemotherapy. In addition, in two prospectively randomized trials all patients with a donor were eligible for an alloSCT and the remaining patients were eligible for autoSCT. Using intention to treat, in the majority of ALL studies alloSCT is superior to autoSCT or intensive continuation chemotherapy. It still has to be determined which subgroups of ALL benefit most of allogeneic transplantation, since in some trials the advantage of allogeneic transplantation was confined to the standard-risk ALL patients and in other trials to the high-risk patients. With respect to the role of autoSCT compared to continuation chemotherapy, both treatment modalities show equal, although for high-risk ALL inferior, overall survival chances. In one large trial the disease-free survival in the autoSCT arm was inferior to that in the chemotherapy arm. This finding may eventually have an impact on the overall survival rate. Currently, the main benefit of autoSCT may be its short duration compared with the continuation chemotherapy regimen.
- Published
- 2007
29. Repeated Hematopoietic Stem and Progenitor Cell Mobilization Without Depletion of the Bone Marrow Stem and Progenitor Cell Pool in Mice After Repeated Administration of Recombinant Murine G-CSF
- Author
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Evert-Jan F. M. de Kruijf, Graham Molineux, Henny Hagoort, Melissa van Pel, Roel Willemze, Donnée Kruysdijk, and Willem E. Fibbe
- Subjects
Filgrastim ,Neutrophils ,Immunology ,Bone Marrow Cells ,Cell Count ,Spleen ,Antibodies ,law.invention ,Andrology ,Mice ,law ,Granulocyte Colony-Stimulating Factor ,Animals ,Humans ,Immunology and Allergy ,Medicine ,Progenitor cell ,Mice, Inbred BALB C ,Mobilization ,biology ,business.industry ,Stem Cells ,Granulocyte-Macrophage Colony-Stimulating Factor ,General Medicine ,Hematopoietic Stem Cells ,Hematopoietic Stem Cell Mobilization ,Recombinant Proteins ,Haematopoiesis ,medicine.anatomical_structure ,Antibody Formation ,biology.protein ,Recombinant DNA ,Female ,Bone marrow ,Antibody ,Stem cell ,business - Abstract
Administration of recombinant-human G-CSF (rhG-CSF) is highly efficient in mobilizing hematopoietic stem and progenitor cells (HSC/HPC) from the bone marrow (BM) toward the peripheral blood. This study was designed to investigate whether repeated G-CSF-induced HSC/HPC mobilization in mice could lead to a depletion of the bone marrow HSC/HPC pool with subsequent loss of mobilizing capacity. To test this hypothesis Balb/c mice were treated with a maximum of 12 repeated 5-day cycles of either 10 μg rhG-CSF/day or 0.25 μg rmG-CSF/day. Repeated administration of rhG-CSF lead to strong inhibition of HSC/HPC mobilization toward the peripheral blood and spleen after >4 cycles because of the induction of anti–rhG-CSF antibodies. In contrast, after repeated administration of rmG-CSF, HSC/HPC mobilizing capacity remained intact for up to 12 cycles. The number of CFU-GM per femur did not significantly change for up to 12 cycles. We conclude that repeated administration of G-CSF does not lead to depletion of the bone marrow HSC/HPC pool.
- Published
- 2007
30. 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
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Judith Olde Wolbers, Joost W. van den Muijsenberg, Cornelis A.M. van Bergen, Nicole M. van der Werff, Roel Willemze, Frederik Falkenburg, Rian Bongaerts, Menno A. W. G. van der Hoorn, Amon R. Wafelman, Simone A.P. van Luxemburg-Heijs, and Erik W.A. Marijt
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Antigen-Presenting Cells ,Immunotherapy, Adoptive ,Donor lymphocyte infusion ,Recurrence ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Transplantation, Homologous ,Cytotoxic T cell ,Child ,In Situ Hybridization, Fluorescence ,Leukemia ,Hematology ,business.industry ,Immunotherapy ,Middle Aged ,medicine.disease ,Transplantation ,CTL ,Phenotype ,Treatment Outcome ,Immunology ,Cancer research ,Female ,Stem cell ,business ,Stem Cell Transplantation ,T-Lymphocytes, Cytotoxic - Abstract
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.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.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.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
31. Stimulatory and Inhibitory Interactions of Granulocyte-Macrophage Colony-Stimulating Factor with Other Cytokines1
- Author
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Willem E. Fibbe, J. Mark J. M. Zijlmans, and Roel Willemze
- Subjects
Granulocyte macrophage colony-stimulating factor ,Chemistry ,medicine ,Inhibitory postsynaptic potential ,medicine.drug ,Microbiology - Published
- 2015
32. Specific scoring systems to predict survival of patients with high-risk myelodysplastic syndrome (MDS) and de novo acute myeloid leukemia (AML) after intensive antileukemic treatment based on results of the EORTC-GIMEMA AML-10 and intergroup CRIANT studies
- Author
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Franco Mandelli, Jean-Pierre Marie, Marco Vignetti, Petra Muus, Eva Hellström-Lindberg, Carlo Aul, Theo de Witte, Dominik Selleslag, Boris Labar, Roel Willemze, Sergio Amadori, Songuel Cakmak-Wollgast, Stefan Suciu, M. Oosterveld, Amin Belhabri, Augustin Ferrant, Ulrich Jehn, Ulrich Germing, Michel Delforge, and Uwe Hess
- Subjects
Oncology ,Adult ,Male ,medicine.medical_specialty ,Myeloid ,Adolescent ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Severity of Illness Index ,Young Adult ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Secondary Acute Myeloid Leukemia ,Humans ,Survival rate ,Hematology ,Performance status ,business.industry ,Myelodysplastic syndromes ,Myeloid leukemia ,General Medicine ,Middle Aged ,medicine.disease ,Europe ,Survival Rate ,Leukemia ,Leukemia, Myeloid, Acute ,medicine.anatomical_structure ,Treatment Outcome ,Myelodysplastic Syndromes ,Immunology ,Female ,business - Abstract
Item does not contain fulltext High-risk myelodysplastic syndrome (MDS) patients have usually a less favorable outcome after intensive treatment compared with de novo acute myeloid leukemia (AML) patients. This may reflect different disease-related and patient-related factors. The purpose of this analysis is to identify disease-specific prognostic factors and to develop prognostic scores for both patient groups. A total of 692 patients in the EORTC/GIMEMA AML-10 study and 289 patients in the CRIANT study received identical remission-induction and consolidation treatment. Estimated 5-year survival rate was 34 % in the AML-10 versus 27 % in the CRIANT study, and estimated disease-free survival was 40 % versus 28 %, respectively. In multivariate analysis, cytogenetic characteristics, white blood count, and age appeared prognostic for survival in both studies. French-American-British (FAB) subtype and performance status were prognostic in the AML-10 study only, whereas number of cytopenias and duration of antecedent hematologic disorder >6 months were prognostic in the CRIANT study only. The prognostic scores distinguish three groups with a 5-year survival rate of 54, 38, and 19 % in the AML-10 study versus 69, 37, and 5 % in the CRIANT study. The prognostic value of these scores has been validated on two external series. The new scoring systems form a practical tool to predict the outcome of individual MDS and AML patients treated with intensive antileukemic therapy.
- Published
- 2015
33. High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT
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Boris Labar, Stefan Suciu, J-P. Marie, Paola Fazi, T. de Witte, Giuseppe Fioritoni, Anne Hagemeijer, Marco Vignetti, M. Hengeveld, Y. Chelgoum, Fabrizio Pane, Roel Willemze, F. Lefrère, Frédéric Baron, Franco Mandelli, Sergio Amadori, Jaroslav Cermak, G. Storti, J. H. Bourhis, Petra Muus, Hengeveld, M, Suciu, S., Chelgoum, Y., Marie, J. P., Muus, P., Lefrère, F., Mandelli, F., Pane, Fabrizio, Amadori, S., Fioritoni, G., Labar, B., Baron, F., Cermak, J., Bourhis, J. H., Storti, G., Fazi, P., Hagemeijer, A., Vignetti, M., Willemze, R., and De Witte, T.
- Subjects
Adult ,Male ,medicine.medical_specialty ,Randomization ,Transplantation Conditioning ,Adolescent ,Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2] ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,CD34 ,Antigens, CD34 ,Gastroenterology ,Transplantation, Autologous ,Disease-Free Survival ,Young Adult ,Recurrence ,Risk Factors ,Internal medicine ,medicine ,Humans ,Bone Marrow Transplantation ,Transplantation ,business.industry ,Risk Factor ,Incidence (epidemiology) ,Hazard ratio ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,medicine.disease ,Confidence interval ,Hematopoietic Stem Cell Mobilization ,Surgery ,Transplantation, Autologou ,Leukemia ,Leukemia, Myeloid, Acute ,Graft-versus-host disease ,Female ,Renal disorders Radboud Institute for Health Sciences [Radboudumc 11] ,business ,Human - Abstract
Item does not contain fulltext The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.
- Published
- 2015
34. Efficiency of T-cell receptor expression in dual-specific T cells is controlled by the intrinsic qualities of the TCR chains within the TCR-CD3 complex
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Roel Willemze, J.H. Frederik Falkenburg, Manja Hoogeboom, Renate S. Hagedoorn, Lars T. van der Veken, Menno A. W. G. van der Hoorn, Michel G.D. Kester, and Mirjam H.M. Heemskerk
- Subjects
Cytotoxicity, Immunologic ,Receptors, Antigen, T-Cell, alpha-beta ,Recombinant Fusion Proteins ,CD3 ,T cell ,Genetic Vectors ,Molecular Sequence Data ,Immunology ,Antigen presentation ,Immunoglobulin Variable Region ,Cytomegalovirus ,T-Cell Antigen Receptor Specificity ,chemical and pharmacologic phenomena ,Biology ,Ligands ,Biochemistry ,HLA-B7 Antigen ,Antigen ,Genes, Reporter ,Transduction, Genetic ,HLA-DQ Antigens ,HLA-A2 Antigen ,Minor histocompatibility antigen ,medicine ,Humans ,Cytotoxic T cell ,Amino Acid Sequence ,Promoter Regions, Genetic ,Cells, Cultured ,Antigen Presentation ,T-cell receptor ,Receptors, Antigen, T-Cell, gamma-delta ,hemic and immune systems ,Cell Biology ,Hematology ,Flow Cytometry ,Cell biology ,Retroviridae ,medicine.anatomical_structure ,Receptor-CD3 Complex, Antigen, T-Cell ,Genes, T-Cell Receptor beta ,biology.protein ,Moloney murine leukemia virus ,Genes, T-Cell Receptor alpha ,Protein Binding ,T-Lymphocytes, Cytotoxic - Abstract
Genetic engineering of T lymphocytes is an attractive strategy to specifically redirect T-cell immunity toward viral infections and malignancies. We previously demonstrated redirected antileukemic reactivity of cytomegalovirus (CMV)–specific T cells by transfer of minor histocompatibility antigen HA-2–specific T-cell receptors (TCRs). HA-2–TCR-transferred CMV-specific T cells were potent effectors against HA-2–expressing leukemic cells, as well as CMV-expressing cells. Functional activity of these T cells correlated with TCR cell-surface expression. In the present study we analyzed which properties of transferred and endogenous TCRs are crucial for efficient cell-surface expression. We demonstrate that expression of the introduced TCR is not a random process but is determined by characteristics of both the introduced and the endogenously expressed TCR. The efficiency of TCR cell-surface expression is controlled by the intrinsic quality of the TCR complex. In addition, we demonstrate that chimeric TCRs can be formed and that efficiency of TCR expression is independent of whether TCRs are retrovirally introduced or naturally expressed. In conclusion, introduced, endogenous, and chimeric TCRs compete for cell-surface expression in favor of the TCR-CD3 complex with best-pairing properties.
- Published
- 2006
35. αβ T-Cell Receptor Engineered γδ T Cells Mediate Effective Antileukemic Reactivity
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Renate S. Hagedoorn, Marleen M. van Loenen, Roel Willemze, J.H. Frederik Falkenburg, Mirjam H.M. Heemskerk, and Lars T. van der Veken
- Subjects
Cancer Research ,education.field_of_study ,medicine.medical_treatment ,Population ,T-cell receptor ,Immunotherapy ,T lymphocyte ,Human leukocyte antigen ,Biology ,Cell biology ,Oncology ,Immunology ,medicine ,Minor histocompatibility antigen ,Cytotoxic T cell ,education ,CD8 - Abstract
Retroviral transfer of T-cell receptors (TCR) to peripheral blood–derived T cells generates large numbers of T cells with the same antigen specificity, potentially useful for adoptive immunotherapy. One drawback of this procedure is the formation of mixed TCR dimers with unknown specificities due to pairing of endogenous and introduced TCR chains. We investigated whether γδ T cells can be an alternative effector population for TCR gene transfer because the γδTCR is not able to form dimers with the αβTCR. Peripheral blood–derived γδ T cells were transduced with human leukocyte antigen (HLA) class I– or HLA class II–restricted minor histocompatibility antigen (mHag) or virus-specific TCRs. Because most γδ T cells do not express CD4 and CD8, we subsequently transferred these coreceptors. The TCR-transduced γδ T cells exerted high levels of antigen-specific cytotoxicity and produced IFN-γ and IL-4, particularly in the presence of the relevant coreceptor. γδ T cells transferred with a TCR specific for the hematopoiesis-specific mHag HA-2 in combination with CD8 displayed high antileukemic reactivity against HA-2–expressing leukemic cells. These data show that transfer of αβTCRs to γδ T cells generated potent effector cells for immunotherapy of leukemia, without the expression of potentially hazardous mixed TCR dimers. (Cancer Res 2006; 66(6): 3331-7)
- Published
- 2006
36. Serpina1 is a potent inhibitor of IL-8-induced hematopoietic stem cell mobilization
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Gerjo A. Velders, Melissa van Pel, Ivan J. D. Lindley, Willem E. Fibbe, Roel Willemze, Henny Hagoort, Peter M. H. Heegaard, Ronald van Os, Damage and Repair in Cancer Development and Cancer Treatment (DARE), and Stem Cell Aging Leukemia and Lymphoma (SALL)
- Subjects
Male ,ALPHA-1-PROTEINASE INHIBITOR ,Proteases ,INTERLEUKIN-8 ,Time Factors ,bone marrow ,BLOOD ,BONE-MARROW ,Blotting, Western ,protease inhibitors ,Biology ,Pharmacology ,Granulocyte ,Models, Biological ,RADIOPROTECTIVE CAPACITY ,Mice ,THIOPHILIC ADSORPTION ,medicine ,Cell Adhesion ,Animals ,adhesion molecules ,RNA, Messenger ,Progenitor cell ,Hematopoietic Stem Cell Mobilization ,Mice, Inbred BALB C ,Multidisciplinary ,Pancreatic Elastase ,Reverse Transcriptase Polymerase Chain Reaction ,Stem Cells ,RAPID MOBILIZATION ,Elastase ,Hematopoietic stem cell ,Antibodies, Monoclonal ,Dose-Response Relationship, Radiation ,protease ,Biological Sciences ,COLONY-STIMULATING FACTOR ,Colony-stimulating factor ,Hematopoietic Stem Cells ,Molecular biology ,Mice, Inbred C57BL ,medicine.anatomical_structure ,PROGENITOR CELLS ,alpha 1-Antitrypsin ,Cytokines ,Bone marrow ,RHESUS-MONKEYS - Abstract
Here, we report that cytokine-induced (granulocyte colony-stimulating factor and IL-8) hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) mobilization is completely inhibited after low-dose (0.5 Gy) total-body irradiation (TBI). Because neutrophil granular proteases are regulatory mediators in cytokine-induced HSC/HPC mobilization, we considered a possible role for protease inhibitors in the induction of HSC/HPC mobilization. Bone marrow (BM) extracellular extracts that were obtained from murine femurs after 0.5 Gy of TBI contained an inhibitor of elastase. Also, after low-dose TBI, both Serpina1 mRNA and protein concentrations were increased in BM extracts, compared with extracts that were obtained from controls. The inhibitory activity in BM extracts of irradiated mice was reversed by addition of an Ab directed against Serpina1. To further study a possiblein vivorole of Serpina1 in HSC/HPC mobilization, we administered Serpina1 before IL-8 injection. This administration resulted in an almost complete inhibition of HSC/HPC mobilization, whereas heat-inactivated Serpina1 had no effect. These results indicate that low-dose TBI inhibits cytokine-induced HSC/HPC mobilization and induces Serpina1 in the BM. Because exogenous administration of Serpina1 inhibits mobilization, we propose that radiation-induced Serpina1 is responsible for the inhibition of HSC/HPC mobilization. Also, we hypothesize that cytokine-induced HSC/HPC mobilization is determined by a critical balance between serine proteases and serine protease inhibitors.
- Published
- 2006
37. Ex Vivo Expansion and Engraftment Potential of Cord Blood-Derived CD34+ Cells in NOD/SCID Mice
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Willy A. Noort, Frank Schipper, Roel Willemze, and Willem E. Fibbe
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Allogeneic transplantation ,Transplantation, Heterologous ,Antigens, CD34 ,Mice, SCID ,Nod ,Umbilical cord ,General Biochemistry, Genetics and Molecular Biology ,Mesoderm ,Polyploidy ,Mice ,History and Philosophy of Science ,Fetal Tissue Transplantation ,Mice, Inbred NOD ,medicine ,Animals ,Humans ,Progenitor cell ,Lung ,Cells, Cultured ,Bone Marrow Transplantation ,Blood Cells ,business.industry ,General Neuroscience ,Graft Survival ,Mesenchymal stem cell ,Hematopoietic Stem Cell Transplantation ,Cell Differentiation ,Fetal Blood ,Hematopoietic Stem Cells ,Haematopoiesis ,surgical procedures, operative ,medicine.anatomical_structure ,Thrombopoietin ,Organ Specificity ,Radiation Chimera ,Cord blood ,Immunology ,Severe Combined Immunodeficiency ,Stem cell ,business ,Megakaryocytes ,Cell Division - Abstract
For more than 10 years umbilical cord blood (UCB) has been used as an alternative source of hematopoietic stem cells for allogeneic transplantation. Although the clinical results are encouraging, UCB is associated with delayed engraftment. To address these issues we have used the NOD/SCID mouse model to study the engraftment potential of cord blood cells in more detail, to assess the engraftment potential of expanded megakaryocytic progenitor cells, and to study the effect of co-transplantation of mesenchymal stem cells on engraftment.
- Published
- 2006
38. Enhanced engraftment of umbilical cord blood-derived stem cells in NOD/SCID mice by cotransplantation of a second unrelated cord blood unit
- Author
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Ellie Lurvink, Frans H.J. Claas, Alma J. Nauta, Willy A. Noort, Arend Mulder, Alwine B. Kruisselbrink, Willem E. Fibbe, and Roel Willemze
- Subjects
Adult ,Cancer Research ,Cord ,Transplantation, Heterologous ,CD34 ,Antigens, CD34 ,Blood Donors ,Mice, SCID ,Umbilical cord ,Mice ,Mice, Inbred NOD ,Genetics ,Animals ,Humans ,Transplantation, Homologous ,Medicine ,Molecular Biology ,business.industry ,Histocompatibility Testing ,Graft Survival ,Recovery of Function ,Cell Biology ,Hematology ,Fetal Blood ,Hematopoietic Stem Cells ,Hematopoiesis ,Transplantation ,Haematopoiesis ,surgical procedures, operative ,medicine.anatomical_structure ,Cord blood ,Immunology ,Cord Blood Stem Cell Transplantation ,Bone marrow ,Stem cell ,business - Abstract
Objective Umbilical cord blood (UCB) is considered as an attractive alternative source of hematopoietic stem cells for allogeneic stem cell transplantations in patients who lack human leukocyte antigen (HLA)-matched donors. However, the low cell dose adversely affects hematopoietic recovery and therefore limits application of UCB transplantation in adults. Transplantation of multiple UCB units could be a strategy to overcome cell dose limitations. Materials and Methods To investigate the effect of double cord transplantation, nonobese diabetic/severe combined immunodeficient mice were transplanted with human hematopoietic progenitor cells (CD34 + ) derived from two UCB units with HLA disparity. Human cell engraftment and donor origin was determined by flow cytometry. Results Double CB transplantation resulted in increased engraftment levels in the bone marrow and peripheral blood in comparison with recipients of a single unit. Because this effect could be due to the higher cell dose (2.10 5 vs 1.10 5 cells), double CB transplantation was compared with single units containing equal cell numbers (2.10 5 ). In some cases, engraftment levels in recipients of single units containing 2.10 5 cells were significantly higher than after transplantation of 1.10 5 cells. These engraftment levels were similar to those observed after double CB transplantation. Chimerism analysis indicated that increased engraftment in recipients of two units was predominantly derived from one unit, whereas in other cases the contribution of the two units was similar. Conclusion These results indicate that engraftment may be enhanced by addition of a second unrelated CB that might be attributed to a cell dose effect or due to a graft-facilitating effect.
- Published
- 2005
39. Responses to donor lymphocyte infusion for acute lymphoblastic leukemia may be determined by both qualitative and quantitative limitations of antileukemic T-cell responses as observed in an animal model for human leukemia
- Author
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Marianke L.J. van Schie, J.H. Frederik Falkenburg, Roel Willemze, Perry Verzaal, and Bart A. Nijmeijer
- Subjects
Adult ,Cytotoxicity, Immunologic ,Male ,Cancer Research ,T-Lymphocytes ,T cell ,Graft vs Leukemia Effect ,Mice, SCID ,Human leukocyte antigen ,Nod ,Donor lymphocyte infusion ,Mice ,Antigen ,Mice, Inbred NOD ,Living Donors ,Genetics ,medicine ,Animals ,Humans ,Transplantation, Homologous ,Molecular Biology ,Cell Proliferation ,Immunity, Cellular ,Leukemia, Experimental ,business.industry ,Cell Biology ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Transplantation ,Leukemia ,medicine.anatomical_structure ,Lymphocyte Transfusion ,Immunology ,Female ,Stem cell ,business ,Neoplasm Transplantation ,Stem Cell Transplantation - Abstract
Objective Donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation is largely unsuccessful in the treatment of acute lymphoblastic leukemia (ALL). To allow identification of the causes of this failure, we established an animal model of DLI in human ALL. Methods NOD/scid mice were inoculated with primary human ALL cells. Cells from five different patients were studied. After engraftment, DLI was performed by infusion of human leukocyte antigen (HLA)-identical donor T cells or HLA-disparate donor T cells. Results DLI resulted in expansion of activated, leukemia-reactive T cells in all donor–patient combinations. After 40 days of expansion, T cells abruptly declined in numbers and displayed loss of cytotoxicity. At this moment, remissions were observed in three of five donor–patient combinations. In animals engrafted with the two unresponsive ALL, remissions could be achieved when HLA-disparate DLI was given. Conclusion Our results indicate that the inefficacy of DLI in ALL may be due to the limitation of the proliferative capacity of ALL-reactive T cells and that the antileukemic efficacy during the limited time span of proliferation depends on the antigenic disparity between the donor and the patient. The model can be used to study whether alternative strategies may result in more sustained antileukemic responses after DLI in ALL.
- Published
- 2005
40. Primary Allogeneic T-Cell Responses against Mantle Cell Lymphoma Antigen-Presenting Cells for Adoptive Immunotherapy after Stem Cell Transplantation
- Author
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J.H. Frederik Falkenburg, Roel Willemze, Willem M. Smit, Mels Hoogendoorn, M. Ronald Schaafsma, Inge Jedema, Renee M.Y. Barge, and Judith Olde Wolbers
- Subjects
Adult ,Male ,Cancer Research ,Adoptive cell transfer ,T-Lymphocytes ,T cell ,Antigen-Presenting Cells ,Lymphoma, Mantle-Cell ,Immunotherapy, Adoptive ,immune system diseases ,hemic and lymphatic diseases ,Humans ,Transplantation, Homologous ,Medicine ,Antigen-presenting cell ,neoplasms ,Aged ,CD40 ,biology ,business.industry ,Graft vs Tumor Effect ,Middle Aged ,Transplantation ,CTL ,medicine.anatomical_structure ,Oncology ,Immunology ,biology.protein ,Cytokines ,Female ,Stem cell ,business ,CD8 ,Stem Cell Transplantation - Abstract
Purpose: In patients treated with allogeneic stem cell transplantation for advanced mantle cell lymphoma (MCL), complete sustained remissions have been observed illustrating susceptibility of MCL cells to a graft-versus-lymphoma effect. To potentiate this graft-versus-lymphoma effect, adoptive transfer of in vitro selected MCL-specific CTL can be an attractive approach. The lack of expression of costimulatory molecules on MCL cells hampers the generation of MCL-reactive T-cell responses. The purpose of this study was to modify MCL cells into antigen-presenting cells (APC) and to use these MCL-APCs to induce allogeneic MCL-reactive T-cell responses. Experimental Design: Interleukin (IL)-4, IL-10, CpG, and CD40 activation were tested for their capacity to up-regulate costimulatory molecules on MCL cells. Primary MCL cells or the modified MCL-APCs were then used to evaluate the induction of MCL-reactive T-cell responses in HLA-matched donors. Results: Ligation of CD40 on MCL cells was essential to up-regulate costimulatory molecules and to induce production of high amounts of IL-12. In contrast to primary MCL cells, MCL-APC cells as stimulators were capable of inducing CD8+ CTL lines from HLA class I–matched donors. High numbers of CTL clones could be generated capable of efficiently killing the primary MCL cells and MCL-APC but not donor-specific targets. Conclusion: These results show the feasibility to generate primary allogeneic T-cell responses against MCL-APC, and may provide new immunotherapeutic tools to further exploit the graft-versus-lymphoma effect following allogeneic stem cell transplantation in patients with MCL.
- Published
- 2005
41. Minor histocompatibility antigens as targets of cellular immunotherapy in leukaemia
- Author
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Roel Willemze and J. H. Frederik Falkenburg
- Subjects
Leukemia ,Allogeneic transplantation ,T-Lymphocytes ,Clinical Biochemistry ,Hematopoietic Stem Cell Transplantation ,Biology ,Immunotherapy, Adoptive ,In vitro ,Minor Histocompatibility Antigens ,Transplantation ,Haematopoiesis ,Immune system ,Oncology ,Transplantation Immunology ,Immunology ,Minor histocompatibility antigen ,Humans ,Autologous transplantation ,Stem cell - Abstract
Allogeneic human-leukocyte-antigen-matched stem cell transplantation is associated with a lower risk of relapse of leukaemia than autologous transplantation due to a T-cell-mediated graft-vs.-leukaemia effect. Replacement of patient haematopoiesis by donor haematopoiesis allows the application of donor-derived specifically targeted cellular immunotherapy for the treatment of leukaemia. Following allogeneic transplantation, donor-derived T cells recognizing minor histocompatibility antigens expressed on haematopoietic cells from the patient may result in eradication of all haematopoietic cells of recipient origin. Since after transplantation, normal haematopoiesis is of donor origin, these T-cell responses may result in establishment of full donor chimerism associated with elimination of the haematological malignancy. By targeting the immune response to minor histocompatibility antigens that are not expressed on non-haematopoietic tissues, graft-vs.-host reactions may be limited. Several methods can be used for in vitro selection of T-cell responses with high specificity for malignant cells, and in vitro manipulation of donor T cells including transfer of antigen-specific T-cell receptors may greatly enhance specificity and efficacy of donor-derived cellular immunotherapy of haematological malignancies.
- Published
- 2004
42. New CFSE-based assay to determine susceptibility to lysis by cytotoxic T cells of leukemic precursor cells within a heterogeneous target cell population
- Author
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J.H. Frederik Falkenburg, Roel Willemze, Inge Jedema, Renee M.Y. Barge, and Nicole M. van der Werff
- Subjects
Cell type ,T-Lymphocytes ,Immunology ,Population ,Cell ,Succinimides ,Carboxyfluorescein diacetate succinimidyl ester ,Biology ,Biochemistry ,chemistry.chemical_compound ,Precursor cell ,medicine ,Humans ,Preleukemia ,Cytotoxic T cell ,education ,Cytotoxicity ,Fluorescent Dyes ,HLA-D Antigens ,education.field_of_study ,Histocompatibility Antigens Class I ,Cell Biology ,Hematology ,Fluoresceins ,Leukemia, Lymphocytic, Chronic, B-Cell ,Molecular biology ,Clone Cells ,Cell biology ,Leukemia, Myeloid, Acute ,Cytolysis ,medicine.anatomical_structure ,chemistry ,Cell Division ,T-Lymphocytes, Cytotoxic - Abstract
For the clinical evaluation of the efficacy of cellular immunotherapy it is necessary to analyze the effector functions of T cells against primary leukemic target cell populations which are usually considerably heterogeneous caused by differential maturation stages of the leukemic cells. An appropriate assay should not only allow the quantitative analysis of rapid cell death induction as measured by the conventional 51Cr release assay but also of the more slowly executing pathways of T-cell-induced apoptosis occurring within days instead of hours which cannot be measured using this method. Furthermore, it should dissect the differential susceptibility to T-cell-induced cell death of various target cell subpopulations and characterize the malignant precursor cells capable of producing malignant progeny. To fulfill these requirements we developed a new assay based on carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling of the target cell population combined with antibody staining of specific cell populations and addition of fluorescent microbeads to quantitatively monitor target cell death occurring within a longer time frame up to at least 5 days. This new assay facilitates the analysis of differential recognition of distinct cell types within a heterogeneous target cell population and allows simultaneously evaluation of the proliferative status of surviving target cells in response to relevant cytokines. (Blood. 2004;103: 2677-2682)
- Published
- 2004
43. Reprogramming of Virus-specific T Cells into Leukemia-reactive T Cells Using T Cell Receptor Gene Transfer
- Author
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Michel G.D. Kester, J.H. Frederik Falkenburg, Manja Hoogeboom, Renate S. Hagedoorn, Mirjam H.M. Heemskerk, and Roel Willemze
- Subjects
Cytotoxicity, Immunologic ,minor histocompatibility antigen ,T-Lymphocytes ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,Cytomegalovirus ,Streptamer ,Biology ,virus-specific T cells ,Article ,Minor Histocompatibility Antigens ,Viral Matrix Proteins ,Interleukin 21 ,Cell Line, Tumor ,medicine ,Humans ,Immunology and Allergy ,Cytotoxic T cell ,Amino Acid Sequence ,IL-2 receptor ,gene transfer ,Antigen-presenting cell ,Antigens, Viral ,Leukemia ,ZAP70 ,Gene Transfer Techniques ,Phosphoproteins ,Natural killer T cell ,leukemia reactive ,Neoplasm Proteins ,medicine.anatomical_structure ,T cell receptor - Abstract
T cells directed against minor histocompatibility antigens (mHags) might be responsible for eradication of hematological malignancies after allogeneic stem cell transplantation. We investigated whether transfer of T cell receptors (TCRs) directed against mHags, exclusively expressed on hematopoietic cells, could redirect virus-specific T cells toward antileukemic reactivity, without the loss of their original specificity. Generation of T cells with dual specificity may lead to survival of these TCR-transferred T cells for prolonged periods of time in vivo due to transactivation of the endogenous TCR of the tumor-reactive T cells by the latent presence of viral antigens. Furthermore, TCR transfer into restricted T cell populations, which are nonself reactive, will minimize the risk of autoimmunity. We demonstrate that cytomegalovirus (CMV)-specific T cells can be efficiently reprogrammed into leukemia-reactive T cells by transfer of TCRs directed against the mHag HA-2. HA-2-TCR–transferred CMV-specific T cells derived from human histocompatibility leukocyte antigen (HLA)-A2+ or HLA-A2− individuals exerted potent antileukemic as well as CMV reactivity, without signs of anti–HLA-A2 alloreactivity. The dual specificity of these mHag-specific, TCR-redirected virus-specific T cells opens new possibilities for the treatment of hematological malignancies of HLA-A2+ HA-2–expressing patients transplanted with HLA-A2–matched or –mismatched donors.
- Published
- 2004
44. α-Interferon with very-low-dose donor lymphocyte infusion for hematologic or cytogenetic relapse of chronic myeloid leukemia induces rapid and durable complete remissions and is associated with acceptable graft-versus-host disease
- Author
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Ronald A. van Soest, Shama L. van Zelderen-Bhola, Willem E. Fibbe, J.H. Frederik Falkenburg, Roel Willemze, Wim M. Smit, C.W.J. Ingrid Starrenburg, Renee M.Y. Barge, Erik W.A. Marijt, Eduardus F. M. Posthuma, Inge O Baas, Human genetics, and Dermatology
- Subjects
Adult ,Male ,medicine.medical_specialty ,Graft vs Host Disease ,Gastroenterology ,Group A ,α-Interferon ,Group B ,Donor lymphocyte infusion ,Sepsis ,Recurrence ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Internal medicine ,medicine ,Humans ,Relapse ,CML ,Transplantation Chimera ,Transplantation ,business.industry ,Remission Induction ,Hematopoietic Stem Cell Transplantation ,Interferon-alpha ,Myeloid leukemia ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Surgery ,Graft-versus-host disease ,Lymphocyte Transfusion ,Female ,DLI ,business ,Complication - Abstract
Donor lymphocyte infusion (DLI) results in complete cytogenetic remission (CCR) of relapsed chronic-phase chronic myeloid leukemia (CML-CP) after allogeneic stem cell transplantation (SCT) in up to 80% of patients. The main complication of DLI is graft-versus-host disease (GVHD). Decreasing the dose of DLI is associated with less GVHD but also with a longer interval between treatment and CCR. We postulated that combining α-interferon (α-IFN) with DLI would enable us to decrease the dose of DLI, thereby limiting GVHD, and at the same time to decrease the interval between DLI and CCR for patients with either a hematologic or cytogenetic relapse. For molecular relapses, we hypothesized that because of a lower tumor load, very low doses of DLI without α-IFN could be an effective treatment. Two groups of CML-CP patients treated with DLI at a very low dose of 0.5 to 1.0 × 107 mononuclear cells per kilogram, containing 2 to 6 × 106 CD3+ T cells per kilogram, were analyzed: 13 patients with a cytogenetic or a hematologic relapse after allogeneic SCT (group A) were treated with additional α-IFN therapy at a dose of 3 × 106 U 5 d/wk, and 8 patients with a molecular relapse were treated without α-IFN (group B). Twelve patients from group A reached a CCR. The median interval between DLI and CCR was 7 weeks (range, 5-18 weeks) for group A. All patients with a CCR reached complete donor chimerism at a median of 10 weeks after DLI (range, 6-121 weeks). Eleven patients reached molecular remission at a median of 15 weeks after DLI (range, 8-34 weeks). In group B, all patients reached a molecular remission at a median of 14 weeks (range, 12-29 weeks). Five patients from group A developed acute GVHD grade II to IV and extensive chronic GVHD. In group B, 1 patient developed acute GVHD grade II to IV and subsequently developed extensive chronic GVHD. With a median follow-up of 62 months, 10 patients in group A are alive and in continuous CCR. One patient had a molecular relapse, for which she successfully received additional DLI; another patient reached molecular remission only after 5 doses of DLI. Two patients from group A died of a gram-negative sepsis, and 1 died of an acute myocardial infection. In group B, all patients are alive and in molecular remission with a median follow-up of 20 months. One patient's disease progressed but was successfully treated with DLI plus α-IFN. In conclusion, very-low-dose DLI in combination with α-IFN as treatment for cytogenetic or hematologic relapses of CML-CP after allogeneic SCT reduced the interval to obtain a CCR with acceptable GVHD when compared with the literature. Patients with a CCR also reached complete donor chimerism and complete molecular remissions. For patients with a molecular relapse, very-low-dose DLI alone is sufficient to induce molecular remissions in most patients and is associated with limited GVHD.
- Published
- 2004
45. Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region
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Roelof A. de Paus, Mirjam H.M. Heemskerk, Els Goulmy, J.H. Frederik Falkenburg, Roel Willemze, Menno A. W. G. van der Hoorn, Michel G.D. Kester, and Manja Hoogeboom
- Subjects
T cell receptor complex ,Receptors, Antigen, T-Cell, alpha-beta ,T cell ,Immunology ,Biology ,Immunotherapy, Adoptive ,Biochemistry ,Minor Histocompatibility Antigens ,Antigen ,Transduction, Genetic ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,HLA-A2 Antigen ,Minor histocompatibility antigen ,medicine ,Humans ,Cytotoxic T cell ,Amino Acid Sequence ,Conserved Sequence ,Blood Cells ,T-cell receptor ,Cell Biology ,Hematology ,T lymphocyte ,Cytotoxicity Tests, Immunologic ,Molecular biology ,Neoplasm Proteins ,medicine.anatomical_structure ,Immunoglobulin Joining Region ,Genes, T-Cell Receptor alpha ,Alpha chain ,T-Lymphocytes, Cytotoxic - Abstract
Donor-derived T lymphocytes directed against minor histocompatibility antigens (mHags) exclusively expressed on cells of the hematopoietic lineages can eliminate hematologic malignancies. Transfer of T-cell receptors (TCRs) directed against these mHags into T lymphocytes may provide a strategy to generate antileukemic T cells. To investigate the feasibility of this strategy the TCR usage of mHag HA-2-specific T-cell clones was characterized. Thirteen different types of HA-2-specific T-cell clones were detected, expressing TCRs with diversity in TCR α- and β-chain usage, however, containing in the TCR α chain a single conserved gene segment Jα42, indicating that Jα42 is involved in HA-2-specific recognition. We transferred various HA-2 TCRs into T lymphocytes from HLA-A2-positive HA-2-negative individuals resulting in T cells with redirected cytolytic activity against HA-2-expressing target cells. Transfer of chimeric TCRs demonstrated that the HA-2 specificity is not only determined by the Jα42 region but also by the N-region of the α chain and the CDR3 region of the β chain. Finally, when HA-2 TCRs were transferred into T cells from HLA-A2-negative donors, the HA-2 TCR-modified T cells exerted potent antileukemic reactivity without signs of anti-HLA-A2 alloreactivity. These results indicate that HA-2 TCR transfer may be used as an alternative strategy to generate HA-2-specific T cells to treat hematologic malignancies of HLA-A2-positive, HA-2-expressing patients that received transplants from HLA-A2-matched or -mismatched donors. (Blood. 2003;102:3530-3540)
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- 2003
46. Differential maturation of megakaryocyte progenitor cells from cord blood and mobilized peripheral blood
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Roel Willemze, Laurus F. Schipper, Anneke Brand, Willem E. Fibbe, Nathalie Reniers, and Cees J.J Melief
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Platelet Membrane Glycoprotein IIb ,Cancer Research ,Megakaryocyte Progenitor Cells ,CD34 ,Antigens, CD34 ,Cell Count ,Cell Separation ,Biology ,Immunophenotyping ,Megakaryocyte ,Genetics ,medicine ,Humans ,Progenitor cell ,Erythropoietin ,Molecular Biology ,Cells, Cultured ,Peripheral Blood Stem Cell Transplantation ,Stem Cell Factor ,Granulocyte-Macrophage Colony-Stimulating Factor ,Cell Biology ,Hematology ,Fetal Blood ,Flow Cytometry ,Molecular biology ,Endothelial stem cell ,Haematopoiesis ,medicine.anatomical_structure ,Thrombopoietin ,Cord blood ,Immunology ,Interleukin-3 ,Cord Blood Stem Cell Transplantation ,Stem cell ,Megakaryocytes ,Cell Division - Abstract
Objective In comparison with stem cell transplantation using bone marrow or cytokine-mobilized peripheral blood, cord blood transplantation is characterized by delayed engraftment, in particular platelet recovery. The differences in the kinetics of engraftment may be related to quantitative differences in the numbers of stem cells and megakaryocyte progenitor cells and/or to qualitative differences between megakaryocyte progenitor cells in these grafts. We compared the hematopoietic composition of these grafts and determined the distribution of mature and immature megakaryocyte progenitor cells in cord blood and mobilized peripheral blood and their in vitro kinetic behavior. Methods Megakaryocyte progenitor cell subpopulations from cord blood (CB) and mobilized peripheral blood (PBSC) were expanded in vitro in the presence of mpl -ligand. The developmental differences during expansion of megakaryocyte progenitors were analyzed by flow cytometry and progenitor assays. Results We found that the immature (CD34 + /CD41 − ) subpopulation from CB contains more than 98% of all megakaryocyte progenitor cells, responsible for 99% of all megakaryocytic cells cultured during 2 weeks. The CB CD34 + /CD41 + subpopulation shows no contribution to megakaryocytic cell formation. In contrast, in PBSC the mature (CD34 + /CD41 + ) subpopulation contains 7% of all megakaryocyte progenitor cells. Moreover, CD34 + cells from CB and PBSC also showed distinct phenotypic differences during maturation in vitro. PBSC megakaryocyte progenitor cells transiently express both CD34 and CD41 during maturation in vitro, whereas CB progenitor cells transiently lack expression of both markers before differention into (CD34 − /CD41 + ) megakaryocytic cells. Conclusion The in vitro data indicate the presence of different developmental stages of megakaryocyte progenitor cells in CB as compared to PBSC. These differences in composition and maturation between CB and PBSC may be related to the different kinetics of engraftment following transplantation of these stem cell sources.
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- 2003
47. Hematopoiesis-restricted minor histocompatibility antigens HA-1- or HA-2-specific T cells can induce complete remissions of relapsed leukemia
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Freke M. Kloosterboer, Mirjam H.M. Heemskerk, Jan W. Drijfhout, Menno A. W. G. van der Hoorn, Michel G.D. Kester, Simone A. P. van Luxemburg-Heys, Manja Hoogeboom, Tuna Mutis, Els Goulmy, W. A. Erik Marijt, J. H. Frederik Falkenburg, Roel Willemze, and Jon J. van Rood
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Genetic Markers ,Male ,Time Factors ,CD8 Antigens ,medicine.medical_treatment ,Fusion Proteins, bcr-abl ,Genes, MHC Class I ,Bone Marrow Cells ,CD8-Positive T-Lymphocytes ,Biology ,Donor lymphocyte infusion ,Minor Histocompatibility Antigens ,Antigen ,Recurrence ,medicine ,Minor histocompatibility antigen ,Humans ,Transplantation, Homologous ,Cytotoxic T cell ,In Situ Hybridization, Fluorescence ,Chromosomes, Human, X ,Chromosomes, Human, Y ,Leukemia ,Multidisciplinary ,Models, Genetic ,Remission Induction ,Immunotherapy ,Biological Sciences ,Middle Aged ,medicine.disease ,Chromium Radioisotopes ,Hematopoiesis ,Neoplasm Proteins ,Phenotype ,Immunology ,Female ,Stem cell ,Peptides ,Oligopeptides ,Cell Division ,CD8 ,Stem Cell Transplantation - Abstract
Donor lymphocyte infusion (DLI) into patients with a relapse of their leukemia or multiple myeloma after allogeneic stem cell transplantation (alloSCT) has been shown to be a successful treatment approach. The hematopoiesis-restricted minor histocompatibility antigens (mHAgs) HA-1 or HA-2 expressed on malignant cells of the recipient may serve as target antigens for alloreactive donor T cells. Recently we treated three mHAg HA-1- and/or HA-2-positive patients with a relapse of their disease after alloSCT with DLI from their mHAg HA-1- and/or HA-2-negative donors. Using HLA-A2/HA-1 and HA-2 peptide tetrameric complexes we showed the emergence of HA-1- and HA-2-specific CD8+T cells in the blood of the recipients 5–7 weeks after DLI. The appearance of these tetramer-positive cells was followed immediately by a complete remission of the disease and restoration of 100% donor chimerism in each of the patients. Furthermore, cloned tetramer-positive T cells isolated during the clinical response specifically recognized HA-1 and HA-2 expressing malignant progenitor cells of the recipient and inhibited the growth of leukemic precursor cellsin vitro. Thus, HA-1- and HA-2-specific cytotoxic T lymphocytes emerging in the blood of patients after DLI demonstrate graft-versus-leukemia or myeloma reactivity resulting in a durable remission. This finding implies thatin vitrogenerated HA-1- and HA-2-specific cytotoxic T lymphocytes could be used as adoptive immunotherapy to treat hematological malignances relapsing after alloSCT.
- Published
- 2003
48. Allogeneic compared with autologous stem cell transplantation in the treatment of patients younger than 46 years with acute myeloid leukemia (AML) in first complete remission (CR1): an intention-to-treat analysis of the EORTC/GIMEMAAML-10 trial
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Franco Mandelli, Ulrich Jehn, Theo de Witte, Rosario Giustolisi, Gennaro De Rosa, Boris Labar, Giuseppe Leone, Paola Fazi, Anne Hagemeijer, Robert Zittoun, Giuseppe Fioritoni, Roel Willemze, Stefan Suciu, Richard Delarue, A Belhabri, Vincenzo Liso, Eugenio Gallo, Jean-Henri Bourhis, Salvatore Mirto, and Sergio Amadori
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Adult ,Male ,medicine.medical_specialty ,Tissue and Organ Procurement ,Adolescent ,medicine.medical_treatment ,Immunology ,Hematopoietic stem cell transplantation ,Biochemistry ,Transplantation, Autologous ,Disease-Free Survival ,Autologous stem-cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Transplantation, Homologous ,Survival rate ,Proportional Hazards Models ,Intention-to-treat analysis ,business.industry ,Hazard ratio ,Age Factors ,Myeloid leukemia ,Immunotherapy, gene therapy and transplantation [UMCN 1.4] ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Combined Modality Therapy ,Surgery ,Transplantation ,Leukemia ,Leukemia, Myeloid, Acute ,Treatment Outcome ,Female ,business ,Stem Cell Transplantation - Abstract
Item does not contain fulltext In the European Organization for Research and Treatment of Cancer Leukemia Group and Gruppo Italiano Malattie Ematologiche dell' Adulto (EORTC-LG/GIMEMA) acute myeloid leukemia (AML)-10 trial, patients in first complete remission (CR1) received a single intensive consolidation (IC) course. Subsequently, those patients younger than 46 years with an HLA-identical sibling donor were assigned to undergo allogeneic (allo) stem cell transplantation (SCT), and patients without such a donor were planned for autologous (auto) SCT. Between November 1993 and December 1999, of 1198 patients aged younger than 46 years, 822 achieved CR. The study group constituted 734 patients who received IC: 293 had a sibling donor and 441 did not. Allo-SCT and auto-SCT were performed in 68.9% and 55.8%, respectively. Cytogenetic determination was successfully performed in 446 patients. Risk groups were good (t(8;21), inv16), intermediate (NN or -Y only), and bad/very bad (all others). Median follow-up was 4 years; 289 patients relapsed, 66 died in CR1, and 293 died. Intention-to-treat analysis revealed that the 4-year disease-free survival (DFS) rate of patients with a donor versus those without a donor was 52.2% versus 42.2%, P =.044; hazard ratio = 0.80, 95% confidence interval (0.64, 0.995), the relapse incidence was 30.4% versus 52.5%, death in CR1 was 17.4% versus 5.3%, and the survival rate was 58.3% versus 50.8% (P =.18). The DFS rates in patients with and without a sibling donor were similar in patients with good/intermediate risk but were 43.4% and 18.4%, respectively, in patients with bad/very bad risk cytogenetics. In younger patients (15-35 years), the difference was more pronounced. The strategy to perform early allo-SCT led to better overall results than auto-SCT, especially for younger patients or those with bad/very bad risk cytogenetics.
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- 2003
49. Deoxycytidine kinase expression and activity in patients with resistant versus sensitive acute myeloid leukemia
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M. Willy Honders, Renee M.Y. Barge, Roel Willemze, and Marjan J. T. Veuger
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Chemotherapy ,medicine.drug_class ,medicine.medical_treatment ,Myeloid leukemia ,Biological activity ,Hematology ,General Medicine ,Deoxycytidine kinase ,Biology ,Antimetabolite ,medicine.anatomical_structure ,hemic and lymphatic diseases ,Immunology ,Cancer research ,medicine ,Cytarabine ,Bone marrow ,Protein kinase A ,medicine.drug - Abstract
Resistance to cytarabine (AraC) is a major problem in treatment of patients with acute myeloid leukemia (AML). In contrast to in vitro AraC resistance, deoxycytidine kinase (dCK) mutations are rarely found in patients with refractory or relapsed AML. Previously we have demonstrated alternatively spliced dCK mRNA predominantly expressed in leukemic blasts from patients with resistant AML. In this study we investigated wild-type (wt) dCK expression and activity to elucidate the possible role of decreased dCK expression or activity in unresponsiveness to AraC in patients with AML. No alterations in dCK mRNA and protein expression or in dCK activity were detected between patients with clinically resistant vs. sensitive AML. In addition, wt dCK expression and activity were not reduced in leukemic blasts expressing alternatively spliced dCK forms as compared to blasts with only wt dCK. Also, no major differences in wt dCK expression and activity were observed between samples obtained from patients with AML and bone marrow or peripheral blood samples from healthy donors. These data implicate that in our patient group of refractory or relapsed AML cases, alterations in dCK expression and/or activity cannot explain unresponsiveness to chemotherapy including AraC.
- Published
- 2002
50. Chemotherapy only compared to chemotherapy followed by transplantation in high risk myelodysplastic syndrome and secondary acute myeloid leukemia; two parallel studies adjusted for various prognostic factors
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Carlo Aul, Dominik Selleslag, D. Fiere, Gregor Verhoef, Boris Labar, T. de Witte, Jorge E. Cortes, Augustin Ferrant, Roel Willemze, M. Oosterveld, Franco Mandelli, Stefan Suciu, P. W. Wijermans, Charles Koller, Alois Gratwohl, Eli Estey, and P. Muus
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Adult ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,medicine.medical_treatment ,Hematopoietic stem cell transplantation ,Antimetabolite ,Disease-Free Survival ,Risk Factors ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Biomarkers, Tumor ,Odds Ratio ,medicine ,Humans ,Transplantation, Homologous ,Idarubicin ,Etoposide ,Chemotherapy ,business.industry ,Myelodysplastic syndromes ,Remission Induction ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Hematology ,Middle Aged ,Prognosis ,medicine.disease ,Combined Modality Therapy ,humanities ,Blood Cell Count ,Surgery ,Transplantation ,Leukemia, Myeloid ,Myelodysplastic Syndromes ,Acute Disease ,Cytogenetic Analysis ,Cytarabine ,business ,Haematology ,medicine.drug - Abstract
Item does not contain fulltext Comparisons of the effectiveness of chemotherapy and transplantation in AML in first complete remission (CR) have focused almost exclusively on patients with de novo disease. Here we used Cox modelling to compare these strategies in patients with MDS and s-AML treated by the Leukemia Group of the EORTC or at the MD Anderson Cancer Center. All patients were aged 15-60. The 184 EORTC patients received conventional dose ara-C + idarubicin + etoposide for remission induction, and after one consolidation course, were scheduled to receive an allograft, or an autograft if a sibling donor was unavailable. The 215 MDA patients received various high-dose ara-C containing induction regimens, and in CR, continued to receive these regimens at reduced dose for 6-12 months. CR rates were 54% EORTC and 63% MDA (P = 0.09). Sixty-five of the 100 EORTC patients who entered CR received a transplant in first CR. Disease-free survival in patients achieving CR was superior in the EORTC cohort, the 4-years DFS rates were 28.9% (s.e. = 4.8%) EORTC vs 17.3% (s.e. = 3.7%) MDA (P = 0.017). Survival from CR was not significantly different in the EORTC and MDA groups, as was survival from start of treatment. After accounting for prognostic factors the conclusions were unchanged. Despite various problems with the analysis discussed below, the data suggest that neither transplantation nor chemotherapy, as currently practised, can be unequivocally recommended for these patients in first CR and that questions as to the superior modality may be less important than the need to improve results with both.
- Published
- 2002
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