6 results on '"Willekens, Christophe"'
Search Results
2. Mutational profiling of isolated myeloid sarcomas and utility of serum 2HG as biomarker of IDH1/2 mutations.
- Author
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Willekens C, Renneville A, Broutin S, Saada V, Micol JB, Delahousse J, Poinsignon V, Bories C, Berthon C, Itzykson R, Boissel N, Quivoron C, Terroir-Cassou-Mounat M, Bosq J, Preudhomme C, Paci A, Penard-Lacronique V, and De Botton S
- Subjects
- Adolescent, Adult, Aged, Biomarkers, Biopsy, DNA Mutational Analysis, Female, Humans, Male, Middle Aged, Positron-Emission Tomography, Sarcoma, Myeloid diagnosis, Young Adult, Glutarates blood, Isocitrate Dehydrogenase genetics, Mutation, Sarcoma, Myeloid blood, Sarcoma, Myeloid genetics
- Published
- 2018
- Full Text
- View/download PDF
3. Clonal heterogeneity of acute myeloid leukemia treated with the IDH2 inhibitor enasidenib.
- Author
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Quek L, David MD, Kennedy A, Metzner M, Amatangelo M, Shih A, Stoilova B, Quivoron C, Heiblig M, Willekens C, Saada V, Alsafadi S, Vijayabaskar MS, Peniket A, Bernard OA, Agresta S, Yen K, MacBeth K, Stein E, Vassiliou GS, Levine R, De Botton S, Thakurta A, Penard-Lacronique V, and Vyas P
- Subjects
- Aminopyridines pharmacology, Cell Differentiation drug effects, Clone Cells, Cohort Studies, Hematopoiesis, Humans, Immunophenotyping, Isocitrate Dehydrogenase metabolism, Mutation genetics, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells drug effects, Neoplastic Stem Cells metabolism, Neoplastic Stem Cells pathology, Triazines pharmacology, Aminopyridines therapeutic use, Isocitrate Dehydrogenase antagonists & inhibitors, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Triazines therapeutic use
- Abstract
Mutations in the gene encoding isocitrate dehydrogenase 2 (IDH2) occur in several types of cancer, including acute myeloid leukemia (AML). In model systems, mutant IDH2 causes hematopoietic differentiation arrest. Enasidenib, a selective small-molecule inhibitor of mutant IDH2, produces a clinical response in 40% of treated patients with relapsed/refractory AML by promoting leukemic cell differentiation. Here, we studied the clonal basis of response and acquired resistance to enasidenib treatment. Using sequential patient samples, we determined the clonal structure of hematopoietic cell populations at different stages of differentiation. Before therapy, IDH2-mutant clones showed variable differentiation arrest. Enasidenib treatment promoted hematopoietic differentiation from either terminal or ancestral mutant clones; less frequently, treatment promoted differentiation of nonmutant cells. Analysis of paired diagnosis/relapse samples did not identify second-site mutations in IDH2 at relapse. Instead, relapse arose by clonal evolution or selection of terminal or ancestral clones, thus highlighting multiple bypass pathways that could potentially be targeted to restore differentiation arrest. These results show how mapping of clonal structure in cell populations at different stages of differentiation can reveal the response and evolution of clones during treatment response and relapse.
- Published
- 2018
- Full Text
- View/download PDF
4. Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.
- Author
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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 .).
- Published
- 2018
- Full Text
- View/download PDF
5. 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
6. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia.
- Author
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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
- Subjects
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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]
- Published
- 2017
- Full Text
- View/download PDF
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