110 results on '"Willekens, Christophe"'
Search Results
102. Clonal Heterogeneity in Differentiation Response and Resistance to the IDH2Inhibitor Enasidenib in Acute Myeloid Leukemia
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Quek, Lynn, David, Muriel, Kennedy, Alison, Metzner, Marlen, Amatangelo, Michael, Shih, Alan H., Stoilova, Bilyana, Karamitros, Dimitris, Quivoron, Cyril, Heiblig, Mael, Willekens, Christophe, Saada, Veronique, Peniket, Andrew, Bernard, Olivier, Agresta, Sam, Yen, Katharine, Stein, Eytan M., De Botton, Stephane, Thakurta, Anjan, Levine, Ross L., Penard-Lacronique, Virginie, and Vyas, Paresh
- Abstract
Background
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- 2017
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103. Serum 2-Hydroxyglutarate Level Can Predict IDH2Mutation in Myeloid Sarcoma
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Willekens, Christophe, Micol, Jean-Baptiste, Poinsignon, Vianney, Quivoron, Cyril, Saada, Véronique, Broutin, Sophie, Terroir-Cassou-Mounat, Marie, Ghez, David, Bourhis, Jean-Henri, Bosq, Jacques, Ribrag, Vincent, Paci, Angelo, Lacronique-Penard, Virginie, and De Botton, Stéphane
- Abstract
Myeloid sarcoma (MS) is defined as a tumor mass consisting of myeloid blasts with or without maturation occurring at an anatomical site other than bone marrow (BM). MS may occur before, concurrently or after a characterized acute myeloid leukemia (AML). Cytogenetic abnormalities are found in 50% of the cases but molecular alterations are less well described and involved FLT3and/or NPM1mutations. Mutations in IDH1and IDH2genes are found in 15% to 20% of patients with AML but have never been described in MS. Mutated IDH enzymes produce in vast excess D-2-hydroxyglutarate (2-HG) in leukemic cells, which can act as a biomarker predictive of the presence of IDH1and IDH2mutations. As availability of DNA sequencing techniques on paraffin samples are limited, molecular characterization of MS remained difficult. We asked whether in MS, serum 2-HG would predict the presence of IDH1/2mutations at diagnosis, and could provide a biomarker for follow up.
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- 2015
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104. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.
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Levine, Ross L., Stein, Eytan M., Tallman, Martin S., Flinn, Ian W., Collins, Robert, Frankel, Arthur E., Patel, Manish R., Stein, Anthony, Sekeres, Mikkael A., Swords, Ronan T., Medeiros, Bruno C., Willekens, Christophe, de Botton, Stephane, Vyas, Paresh, Roboz, Gail J., Tosolini, Alessandra, Qiang Xu, Knight, Robert D., Yen, Katharine E., and Agresta, Sam
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ISOCITRATE dehydrogenase , *ACUTE myeloid leukemia , *HYPERBILIRUBINEMIA , *PHARMACOKINETICS , *BONE marrow - 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 doseescalation 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. [ABSTRACT FROM AUTHOR]
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- 2017
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105. RAS mutations in myeloid malignancies: revisiting old questions with novel insights and therapeutic perspectives.
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Alawieh D, Cysique-Foinlan L, Willekens C, and Renneville A
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- Humans, Prognosis, Myeloproliferative Disorders genetics, Myeloproliferative Disorders therapy, Myeloproliferative Disorders drug therapy, Molecular Targeted Therapy, Proto-Oncogene Proteins p21(ras) genetics, Mutation
- Abstract
NRAS and KRAS activating point mutations are present in 10-30% of myeloid malignancies and are often associated with a proliferative phenotype. RAS mutations harbor allele-specific structural and biochemical properties depending on the hotspot mutation, contributing to variable biological consequences. Given their subclonal nature in most myeloid malignancies, their clonal architecture, and patterns of cooperativity with other driver genetic alterations may potentially have a direct, causal influence on the prognosis and treatment of myeloid malignancies. RAS mutations overall tend to be associated with poor clinical outcome in both chronic and acute myeloid malignancies. Several recent prognostic scoring systems have incorporated RAS mutational status. While RAS mutations do not always act as independent prognostic factors, they significantly influence disease progression and survival. However, their clinical significance depends on the type of mutation, disease context, and treatment administered. Recent evidence also indicates that RAS mutations drive resistance to targeted therapies, particularly FLT3, IDH1/2, or JAK2 inhibitors, as well as the venetoclax-azacitidine combination. The investigation of novel therapeutic strategies and combinations that target multiple axes within the RAS pathway, encompassing both upstream and downstream components, is an active field of research. The success of direct RAS inhibitors in patients with solid tumors has brought renewed optimism that this progress will be translated to patients with hematologic malignancies. In this review, we highlight key insights on RAS mutations across myeloid malignancies from the past decade, including their prevalence and distribution, cooperative genetic events, clonal architecture and dynamics, prognostic implications, and therapeutic targeting., (© 2024. The Author(s).)
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- 2024
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106. Correction: Metabolomic analyses of COVID-19 patients unravel stage-dependent and prognostic biomarkers.
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Danlos FX, Grajeda-Iglesias C, Durand S, Sauvat A, Roumier M, Cantin D, Colomba E, Rohmer J, Pommeret F, Baciarello G, Willekens C, Vasse M, Griscelli F, Fahrner JE, Goubet AG, Dubuisson A, Derosa L, Nirmalathasan N, Bredel D, Mouraud S, Pradon C, Stoclin A, Rozenberg F, Duchemin J, Jourdi G, Ellouze S, Levavasseur F, Albigès L, Soria JC, Barlesi F, Solary E, André F, Pène F, Ackerman F, Mouthon L, Zitvogel L, Marabelle A, Michot JM, Fontenay M, and Kroemer G
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- 2024
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107. First-in-Human Phase I Study of Iadademstat (ORY-1001): A First-in-Class Lysine-Specific Histone Demethylase 1A Inhibitor, in Relapsed or Refractory Acute Myeloid Leukemia.
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Salamero O, Montesinos P, Willekens C, Pérez-Simón JA, Pigneux A, Récher C, Popat R, Carpio C, Molinero C, Mascaró C, Vila J, Arévalo MI, Maes T, Buesa C, Bosch F, and Somervaille TCP
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- Adult, Aged, Aged, 80 and over, Enzyme Inhibitors pharmacology, Female, Humans, Male, Middle Aged, Recurrence, Enzyme Inhibitors therapeutic use, Histone Demethylases antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: Iadademstat is a novel, highly potent, and selective inhibitor of LSD1 (KDM1A), with preclinical in vitro and in vivo antileukemic activity. This study aimed to determine safety and tolerability of iadademstat as monotherapy in patients with relapsed/refractory acute myeloid leukemia (R/R AML)., Methods: This phase I, nonrandomized, open-label, dose-escalation (DE), and extension-cohort (EC) trial included patients with R/R AML and evaluated the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antileukemic activity of this orally bioavailable first-in-class lysine-specific demethylase 1 inhibitor., Results: Twenty-seven patients were treated with iadademstat on days 1 to 5 (5-220 µg/m
2 /d) of each week in 28-day cycles in a DE phase that resulted in a recommended dose of 140 µg/m2 /d of iadademstat as a single agent. This dose was chosen to treat all patients (n = 14) in an EC enriched with patients with MLL/KMT2A-rearranged AML. Most adverse events (AEs) were as expected in R/R AML and included myelosuppression and nonhematologic AEs, such as infections, asthenia, mucositis, and diarrhea. PK data demonstrated a dose-dependent increase in plasma exposure, and PD data confirmed a potent time- and exposure-dependent induction of differentiation biomarkers. Reductions in blood and bone marrow blast percentages were observed, together with induction of blast cell differentiation, in particular, in patients with MLL translocations. One complete remission with incomplete count recovery was observed in the DE arm., Conclusion: Iadademstat exhibits a good safety profile together with signs of clinical and biologic activity as a single agent in patients with R/R AML. A phase II trial of iadademstat in combination with azacitidine is ongoing (EudraCT No.: 2018-000482-36).- Published
- 2020
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108. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.
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DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Swords R, Collins RH, Mannis GN, Pollyea DA, Donnellan W, Fathi AT, Pigneux A, Erba HP, Prince GT, Stein AS, Uy GL, Foran JM, Traer E, Stuart RK, Arellano ML, Slack JL, Sekeres MA, Willekens C, Choe S, Wang H, Zhang V, Yen KE, Kapsalis SM, Yang H, Dai D, Fan B, Goldwasser M, Liu H, Agresta S, Wu B, Attar EC, Tallman MS, Stone RM, and Kantarjian HM
- Subjects
- Administration, Oral, Adolescent, Adult, Aged, Aged, 80 and over, Cell Count, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Enzyme Inhibitors adverse effects, Enzyme Inhibitors pharmacokinetics, Female, Follow-Up Studies, Glycine administration & dosage, Glycine adverse effects, Glycine pharmacokinetics, Hemoglobins analysis, Humans, Isocitrate Dehydrogenase antagonists & inhibitors, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Mutation, Pyridines adverse effects, Pyridines pharmacokinetics, Recurrence, Remission Induction, Survival Rate, Young Adult, Enzyme Inhibitors administration & dosage, Glycine analogs & derivatives, Isocitrate Dehydrogenase genetics, Leukemia, Myeloid, Acute drug therapy, Pyridines administration & dosage
- Abstract
Background: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1., Methods: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up., Results: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment., Conclusions: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).
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- 2018
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109. Prospective long-term minimal residual disease monitoring using RQ-PCR in RUNX1-RUNX1T1-positive acute myeloid leukemia: results of the French CBF-2006 trial.
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Willekens C, Blanchet O, Renneville A, Cornillet-Lefebvre P, Pautas C, Guieze R, Ifrah N, Dombret H, Jourdan E, Preudhomme C, and Boissel N
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- Adaptor Proteins, Signal Transducing metabolism, Adolescent, Adult, Antineoplastic Agents therapeutic use, Biomarkers, Tumor metabolism, Blood Cells metabolism, Blood Cells pathology, Bone Marrow metabolism, Bone Marrow pathology, Chromosomes, Human, Pair 22, Chromosomes, Human, Pair 8, Consolidation Chemotherapy methods, Core Binding Factor Alpha 2 Subunit metabolism, Cytoskeletal Proteins metabolism, Female, France, Gene Expression, Humans, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Monitoring, Physiologic, Neoplasm, Residual, Prospective Studies, Proto-Oncogene Proteins metabolism, RUNX1 Translocation Partner 1 Protein, Real-Time Polymerase Chain Reaction, Recurrence, Remission Induction, Survival Analysis, Transcription Factors metabolism, Translocation, Genetic, Adaptor Proteins, Signal Transducing genetics, Biomarkers, Tumor genetics, Core Binding Factor Alpha 2 Subunit genetics, Cytoskeletal Proteins genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Proto-Oncogene Proteins genetics, Transcription Factors genetics
- Abstract
In t(8;21)(q22;q22) acute myeloid leukemia, the prognostic value of early minimal residual disease assessed with real-time quantitative polymerase chain reaction is the most important prognostic factor, but how long-term minimal residual disease monitoring may contribute to drive individual patient decisions remains poorly investigated. In the multicenter CBF-2006 study, a prospective monitoring of peripheral blood and bone marrow samples was performed every 3 months and every year, respectively, for 2 years following intensive chemotherapy in 94 patients in first complete remission. A complete molecular remission was defined as a (RUNX1-RUNX1T1/ABL1)×100 ≤ 0.001%. After the completion of consolidation therapy, a bone marrow complete molecular remission was observed in 30% of the patients, but was not predictive of subsequent relapse. Indeed, 8 patients (9%) presented a positive bone marrow minimal residual disease for up to 2 years of follow-up while still remaining in complete remission. Conversely, a peripheral blood complete molecular remission was statistically associated with a lower risk of relapse whatever the time-point considered after the completion of consolidation therapy. During the 2-year follow-up, the persistence of peripheral blood complete molecular remission was associated with a lower risk of relapse (4-year cumulative incidence, 8.2%), while molecular relapse confirmed on a subsequent peripheral blood sample predicted hematological relapse (4-year cumulative incidence, 86.9%) within a median time interval of 3.9 months. In t(8;21)(q22;q22) acute myeloid leukemia, minimal residual disease monitoring on peripheral blood every 3 months allows for the prediction of hematological relapse, and to identify patients who could potentially benefit from intervention therapy. (ClinicalTrials.gov ID #NCT00428558)., (Copyright© Ferrata Storti Foundation.)
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- 2016
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110. Linezolid induces ring sideroblasts.
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Willekens C, Dumezy F, Boyer T, Renneville A, Rossignol J, Berthon C, Cotteau-Leroy A, Mehiaoui L, Quesnel B, and Preudhomme C
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- Adult, Aged, Anemia, Sideroblastic diagnosis, Bone Marrow Cells drug effects, Bone Marrow Cells pathology, Cohort Studies, Female, Humans, Linezolid, Male, Middle Aged, Retrospective Studies, Acetamides adverse effects, Anemia, Sideroblastic blood, Anemia, Sideroblastic chemically induced, Anti-Infective Agents adverse effects, Oxazolidinones adverse effects
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- 2013
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