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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MSK Authors
  1. Emily Margaret Stein
    3 Stein
  2. Martin Stuart Tallman
    408 Tallman
  3. Ross Levine
    469 Levine