6 results on '"Willekens, Christophe"'
Search Results
2. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.
- Author
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Stein EM, DiNardo CD, Pollyea DA, Fathi AT, Roboz GJ, Altman JK, Stone RM, DeAngelo DJ, Levine RL, Flinn IW, Kantarjian HM, Collins R, Patel MR, Frankel AE, Stein A, Sekeres MA, Swords RT, Medeiros BC, Willekens C, Vyas P, Tosolini A, Xu Q, Knight RD, Yen KE, Agresta S, de Botton S, and Tallman MS
- Subjects
- Adult, Aged, Aged, 80 and over, Aminopyridines adverse effects, Aminopyridines pharmacokinetics, Antineoplastic Agents adverse effects, Antineoplastic Agents pharmacokinetics, Bone Marrow drug effects, Bone Marrow metabolism, Bone Marrow pathology, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Female, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Maximum Tolerated Dose, Middle Aged, Mutation, Neoplasm Recurrence, Local drug therapy, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local pathology, Triazines adverse effects, Triazines pharmacokinetics, Young Adult, Aminopyridines therapeutic use, Antineoplastic Agents therapeutic use, Enzyme Inhibitors therapeutic use, Isocitrate Dehydrogenase antagonists & inhibitors, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute drug therapy, Triazines therapeutic use
- Abstract
Recurrent mutations in isocitrate dehydrogenase 2 ( IDH2 ) occur in ∼12% of patients with acute myeloid leukemia (AML). Mutated IDH2 proteins neomorphically synthesize 2-hydroxyglutarate resulting in DNA and histone hypermethylation, which leads to blocked cellular differentiation. Enasidenib (AG-221/CC-90007) is a first-in-class, oral, selective inhibitor of mutant-IDH2 enzymes. This first-in-human phase 1/2 study assessed the maximum tolerated dose (MTD), pharmacokinetic and pharmacodynamic profiles, safety, and clinical activity of enasidenib in patients with mutant- IDH2 advanced myeloid malignancies. We assessed safety outcomes for all patients and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML, from the phase 1 dose-escalation and expansion phases of the study. In the dose-escalation phase, an MTD was not reached at doses ranging from 50 to 650 mg per day. Enasidenib 100 mg once daily was selected for the expansion phase on the basis of pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3 to 4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with a median response duration of 5.8 months. Responses were associated with cellular differentiation and maturation, typically without evidence of aplasia. Median overall survival among relapsed/refractory patients was 9.3 months, and for the 34 patients (19.3%) who attained complete remission, overall survival was 19.7 months. Continuous daily enasidenib treatment was generally well tolerated and induced hematologic responses in patients for whom prior AML therapy had failed. Inducing differentiation of myeloblasts, not cytotoxicity, seems to drive the clinical efficacy of enasidenib. This trial was registered at www.clinicaltrials.gov as #NCT01915498., (© 2017 by The American Society of Hematology.)
- Published
- 2017
- Full Text
- View/download PDF
3. Characteristic repartition of monocyte subsets as a diagnostic signature of chronic myelomonocytic leukemia.
- Author
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Selimoglu-Buet D, Wagner-Ballon O, Saada V, Bardet V, Itzykson R, Bencheikh L, Morabito M, Met E, Debord C, Benayoun E, Nloga AM, Fenaux P, Braun T, Willekens C, Quesnel B, Adès L, Fontenay M, Rameau P, Droin N, Koscielny S, and Solary E
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Sensitivity and Specificity, Flow Cytometry methods, Leukemia, Myelogenous, Chronic, BCR-ABL Positive blood, Leukemia, Myelogenous, Chronic, BCR-ABL Positive diagnosis, Lipopolysaccharide Receptors blood, Monocytes metabolism, Monocytes pathology, Receptors, IgG blood
- Abstract
Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/ myeloproliferative neoplasm whose diagnosis is currently based on the elevation of peripheral blood monocytes to >1 × 10(9)/L, measured for ≥3 months. Diagnosis can be ambiguous; for example, with prefibrotic myelofibrosis or reactive monocytosis. We set up a multiparameter flow cytometry assay to distinguish CD14(+)/CD16(-) classical from CD14(+)/CD16(+) intermediate and CD14(low)/CD16(+) nonclassical monocyte subsets in peripheral blood mononucleated cells and in total blood samples. Compared with healthy donors and patients with reactive monocytosis or another hematologic malignancy, CMML patients demonstrate a characteristic increase in the fraction of CD14(+)/CD16(-) cells (cutoff value, 94.0%). The associated specificity and sensitivity values were 95.1% and 90.6% in the learning cohort (175 samples) and 94.1% and 91.9% in the validation cohort (307 samples), respectively. The accumulation of classical monocytes, which demonstrate a distinct gene expression pattern, is independent of the mutational background. Importantly, this increase disappears in patients who respond to hypomethylating agents. We conclude that an increase in the fraction of classical monocytes to >94.0% of total monocytes is a highly sensitive and specific diagnostic marker that rapidly and accurately distinguishes CMML from confounding diagnoses., (© 2015 by The American Society of Hematology.)
- Published
- 2015
- Full Text
- View/download PDF
4. Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome-Positive Leukemia: 25 Years' Experience at Gustave Roussy Cancer Campus.
- Author
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Chamseddine AN, Willekens C, De Botton S, and Bourhis JH
- Subjects
- Adolescent, Adult, Female, Humans, Male, Middle Aged, Philadelphia Chromosome, Precursor Cell Lymphoblastic Leukemia-Lymphoma mortality, Retrospective Studies, Young Adult, Hematopoietic Stem Cell Transplantation methods, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Transplantation Conditioning methods, Transplantation, Homologous methods
- Abstract
The introduction of tyrosine kinase inhibitor (TKI) therapy has markedly reduced the use of allogeneic (allo) hematopoietic stem cell transplantation (HSCT), which is no longer standard practice in the first chronic phase in chronic myelogenous leukemia and is currently reserved after failure of TKI or in advanced phase of disease. We compared the outcome of Philadelphia chromosome-positive (Ph+) leukemia patients who received a first allo-HSCT in our center in both the pre-TKI era and the TKI era. The primary end point was to compare the 2 groups' overall survival (OS), leukemia-free survival (LFS), cumulative incidence of nonrelapse mortality, and relapse incidence. The secondary end point was to underline in the TKI era the impact of the pretransplantation minimal residual disease (MRD) on the outcomes. A total of 69 patients with Ph+ leukemia were included and their outcomes analyzed. For the purpose of this analysis, we defined 2 groups: group A (n = 39) included patients treated in the pre-TKI era, treated from January 1989 until December 2001, and group B (n = 30) included patients treated in the TKI era, treated from January 2002 until December 2013. Additional analysis was performed in group B for whom detailed TKIs and MRD data were collected. The study took place in our cancer center in the department of HSCT, Villejuif, France. The median follow-up duration for group A was 116.1 months (range, 1.1 to 240.1 months) and for group B was 8.3 months (range, 3.5 to 141.7 months). At 3 years, the LFS and OS were higher in group B (respectively, 66% and 71%) than in group A (respectively, 63% and 57%) (P > .05). The LFS and OS at 3 years of the pretransplantation MRD-negative (< 0.01%) patients were significantly (P < .05) higher (respectively, 83% and 94%) than the pretransplantation MRD-positive patients (respectively, 43% and 46%). Our data, although statistically not significant, suggest better outcomes for Ph+ leukemia patients undergoing allo-HSCT in the TKI era. Mostly TKI does not adversely affect the transplantation outcomes and can be used successfully as a bridge to allo-HSCT, especially in advanced disease. In addition, we highlight the importance of obtaining deep pretransplantation MRD negativity., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
- Full Text
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5. JAK2 and MPL protein levels determine TPO-induced megakaryocyte proliferation vs differentiation.
- Author
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Besancenot R, Roos-Weil D, Tonetti C, Abdelouahab H, Lacout C, Pasquier F, Willekens C, Rameau P, Lecluse Y, Micol JB, Constantinescu SN, Vainchenker W, Solary E, and Giraudier S
- Subjects
- Animals, Autoantigens genetics, Blood Platelets metabolism, Cell Cycle Checkpoints genetics, Cell Line, Cell Proliferation, Gene Expression, Humans, Iodide Peroxidase genetics, Iron-Binding Proteins genetics, Janus Kinase 2 genetics, Mice, Phenotype, Primary Myelofibrosis genetics, Primary Myelofibrosis metabolism, RNA, Small Interfering genetics, Receptors, Thrombopoietin genetics, Thrombocythemia, Essential genetics, Thrombocythemia, Essential metabolism, Autoantigens metabolism, Cell Differentiation genetics, Iodide Peroxidase metabolism, Iron-Binding Proteins metabolism, Janus Kinase 2 metabolism, Megakaryocytes cytology, Megakaryocytes metabolism, Receptors, Thrombopoietin metabolism
- Abstract
Megakaryopoiesis is a 2-step differentiation process, regulated by thrombopoietin (TPO), on binding to its cognate receptor myeloproliferative leukemia (MPL). This receptor associates with intracytoplasmic tyrosine kinases, essentially janus kinase 2 (JAK2), which regulates MPL stability and cell-surface expression, and mediates TPO-induced signal transduction. We demonstrate that JAK2 and MPL mediate TPO-induced proliferation arrest and megakaryocytic differentiation of the human megakaryoblastic leukemia cell line UT7-MPL. A decrease in JAK2 or MPL protein expression, and JAK2 chemical inhibition, suppress this antiproliferative action of TPO. The expression of JAK2 and MPL, which progressively increases along normal human megakaryopoiesis, is decreased in platelets of patients diagnosed with JAK2- or MPL-mutated essential thrombocytemia and primary myelofibrosis, 2 myeloproliferative neoplasms in which megakaryocytes (MKs) proliferate excessively. Finally, low doses of JAK2 chemical inhibitors are shown to induce a paradoxical increase in MK production, both in vitro and in vivo. We propose that JAK2 and MPL expression levels regulate megakaryocytic proliferation vs differentiation in both normal and pathological conditions, and that JAK2 chemical inhibitors could promote a paradoxical thrombocytosis when used at suboptimal doses., (© 2014 by The American Society of Hematology.)
- Published
- 2014
- Full Text
- View/download PDF
6. Bone marrow necrosis: a culture medium for bacteria.
- Author
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Willekens C and Boyer T
- Subjects
- Adenocarcinoma complications, Aged, Bone Marrow Diseases microbiology, Culture Media, Fatal Outcome, Humans, Male, Necrosis, Pleural Effusion pathology, Shock, Septic complications, Shock, Septic microbiology, Stomach Neoplasms complications, Streptococcal Infections complications, Streptococcus, Blood microbiology, Bone Marrow pathology, Bone Marrow Diseases pathology, Shock, Septic diagnosis, Streptococcal Infections pathology
- Published
- 2013
- Full Text
- View/download PDF
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