Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib Journal Article
| Authors: | Stein, E. M.; DiNardo, C. D.; Fathi, A. T.; Pollyea, D. A.; Stone, R. M.; Altman, J. K.; Roboz, G. J.; Patel, M. R.; Collins, R.; Flinn, I. W.; Sekeres, M. A.; Stein, A. S.; Kantarjian, H. M.; Levine, R. L.; Vyas, P.; MacBeth, K. J.; Tosolini, A.; VanOostendorp, J.; Xu, Q.; Gupta, I.; Lila, T.; Risueno, A.; Yen, K. E.; Wu, B.; Attar, E. C.; Tallman, M. S.; de Botton, S. |
| Article Title: | Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib |
| Abstract: | Approximately 8% to 19% of patients with acute myeloid leukemia (AML) have isocitrate dehydrogenase-2 (IDH2) mutations, which occur at active site arginine residues R140 and R172. IDH2 mutations produce an oncometabolite, 2-hydroxyglutarate (2-HG), which leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase 1/2 study evaluated enasidenib doses of 50 to 650 mg/d, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies. Overall, 214 of 345 patients (62%) with relapsed or refractory (R/R) AML received enasidenib, 100 mg/d. Median age was 68 years. Forty-two patients (19.6%) attained complete remission (CR), 19 patients (10.3%) proceeded to an allogeneic bone marrow transplant, and the overall response rate was 38.8% (95% confidence interval [CI], 32.2-45.7). Median overall survival was 8.8 months (95% CI, 7.7-9.6). Response and survival were comparable among patients with IDH2-R140 or IDH2-R172 mutations. Response rates were similar among patients who, at study entry, were in relapse (37.7%) or were refractory to intensive (37.5%) or nonintensive (43.2%) therapies. Sixty-six (43.1%) red blood cell transfusion–dependent and 53 (40.2%) platelet transfusion–dependent patients achieved transfusion independence. The magnitude of 2-HG reduction on study was associated with CR in IDH2-R172 patients. Clearance of mutant-IDH2 clones was also associated with achievement of CR. Among all 345 patients, the most common grade 3 or 4 treatment-related adverse events were hyperbilirubinemia (10%), thrombocytopenia (7%), and IDH differentiation syndrome (6%). Enasidenib was well tolerated and induced molecular remissions and hematologic responses in patients with AML for whom prior treatments had failed. The study is registered at www.clinicaltrials.gov as #NCT01915498. © 2019 by The American Society of Hematology. |
| Journal Title: | Blood |
| Volume: | 133 |
| Issue: | 7 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2019-02-14 |
| Start Page: | 676 |
| End Page: | 687 |
| Language: | English |
| DOI: | 10.1182/blood-2018-08-869008 |
| PUBMED: | 30510081 |
| PROVIDER: | scopus |
| PMCID: | PMC6384189 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2019 -- Source: Scopus |
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