Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib

Eytan M. Stein, Courtney D. DiNardo, Amir T. Fathi, Daniel A. Pollyea, Richard M. Stone, Jessica K. Altman, Gail J. Roboz, Manish R. Patel, Robert Collins, Ian W. Flinn, Mikkael A. Sekeres, Anthony S. Stein, Hagop M. Kantarjian, Ross L. Levine, Paresh Vyas, Kyle J. MacBeth, Alessandra Tosolini, Jason VanOostendorp, Qiang Xu, Ira Gupta, Thomas Lila, Alberto Risueno, Katharine E. Yen, Bin Wu, Eyal C. Attar, Martin S. Tallman and Stéphane de Botton

Key points

  • Reductions in IDH2 variant allele frequency and molecular clearance with enasidenib were associated with attainment of complete remission.

  • Enasidenib induced responses in ~40% of patients with mutant-IDH2 R/R AML, with similar response rates in relapsed or refractory patients.


Approximately 8-19% 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), that leads to DNA and histone hypermethylation and impaired hematopoietic differentiation. Enasidenib is an oral inhibitor of mutant-IDH2 proteins. This first-in-human phase I/II study evaluated enasidenib doses of 50-650 mg/day, administered in continuous 28-day cycles, in patients with mutant-IDH2 hematologic malignancies (, NCT01915498). Overall, 214/345 patients (62%) with relapsed/refractory AML received enasidenib 100 mg/day. 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 overall response rate was 38.8% (95%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 non-intensive (43.2%) therapies. Sixty-six RBC transfusion-dependent (43.1%) and 53 platelet transfusion-dependent (40.2%) 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 3-4 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 to as NCT01915498.

  • Submitted August 10, 2018.
  • Accepted November 19, 2018.