Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia

Eytan M. Stein, Courtney D. DiNardo, Daniel A. Pollyea, Amir T. Fathi, Gail J. Roboz, Jessica K. Altman, Richard M. Stone, Daniel J. DeAngelo, Ross L. Levine, Ian W. Flinn, Hagop M. Kantarjian, Robert Collins, Manish R. Patel, Arthur E. Frankel, Anthony Stein, Mikkael A. Sekeres, Ronan T. Swords, Bruno C. Medeiros, Christophe Willekens, Paresh Vyas, Alessandra Tosolini, Qiang Xu, Robert D. Knight, Katharine E. Yen, Sam Agresta, Stéphane de Botton and Martin S. Tallman

Key points

  • Enasidenib, a selective inhibitor of mutant-IDH2 enzymes, was safe and well-tolerated in patients with IDH2-mutated myeloid malignancies.

  • Enasidenib induced hematologic responses in patients with relapsed/refractory AML in this dose-escalation and expansion study.


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, leading 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 (N=239) and clinical efficacy in the largest patient subgroup, those with relapsed or refractory AML (n=176), 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 50-650 mg daily. Enasidenib 100 mg daily was selected for the expansion phase based on pharmacokinetic and pharmacodynamic profiles and demonstrated efficacy. Grade 3-4 enasidenib-related adverse events included indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (IDH-DS; 7%). Among patients with relapsed or refractory AML, overall response rate was 40.3%, with 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 was 19.7 months. Continuous daily enasidenib treatment was generally well-tolerated and induced hematologic responses in patients who had failed prior AML therapy. Inducing differentiation of myeloblasts, not cytotoxicity, appears to drive the clinical efficacy of enasidenib.

  • Submitted April 13, 2017.
  • Accepted May 19, 2017.