General AML,   IDH1/2

Enasidenib found to induce molecular remissions in IDH2-mutated, relapsed/refractory acute myeloid leukemia

Lead authors Eytan M. Stein, MD, of the Memorial Sloan Kettering Cancer Center, New York, NY, USA; Courtney D. DiNardo of the University of Texas MD Anderson Cancer Center, Houston, TX, USA; Amir T. Fathi of the Massachusetts General Hospital Cancer Center, Boston, MA, USA; and colleagues published their findings of a first-in-human trial of patients with relapsed and/or refractory (R/R), IDH2-mutated acute myeloid leukemia (AML) (NCT01915498) in the journal Blood. The authors provided updated results from the study, looking specifically at molecular remissions.

The phase I/II study evaluated enasidenib in adults with IDH2-mutated AML (n = 345) that had relapsed after allogeneic hematopoietic cell transplantation (alloHCT); were in second or later relapse; were refractory to initial induction or re-induction treatment, or had relapsed within one year of initial treatment. Enasidenib at a dose of 100 mg/day was administered in 214/345 patients (62%; median age: 68 years [range, 19–100]) in the phase II portion of the study. To monitor mutation clearance and hematologic response, the investigators collected bone marrow biopsies and peripheral blood samples at screening, on day 1 of cycle 2, and then every 28 days for a total of 12 months, followed by every 56 days thereafter.

Key findings
  • The most common any-grade adverse events (AEs) included indirect hyperbilirubinemia (40.3%), nausea (28%), decreased appetite (17.7%)

  • The most commonly reported grade 3-4 treatment-emergent AEs included hyperbilirubinemia (10.4%), IDH differentiation syndrome (IDH-DS; 6.4%), anemia (5.5%)

  • At a median follow-up of 7.8 months (estimate medium), response rates were similar between the enasidenib 100-mg/day cohort and the entire study population

  • The overall response rate (defined as complete remission [CR], CR with incomplete count recovery [CRi/CRp], and partial remission [PR]) was 33.2% in the 100-mg/day cohort and 33.9% across all dosing cohorts

  • Approximately 19% of patients in each group experienced a CR

  • Response rates did not appear to differ based on relapsed or refractory disease status, the authors reported

  • Survival outcomes also were similar in the 100-mg/day and all dosing groups: the median overall survival (OS) was 8.8 months (95% CI, 7.7–9.6 months and 7.8–9.9 months, respectively), and median event-free survival (EFS) was 4.7 months (95% CI, 3.7–5.6 months) and 4.6 months (95% CI, 3.7–5.6 months), respectively

  • Achieving a CR was associated with longer median OS, compared with those with less than a CR or no response (22.9 months vs. 10.6 months and 5.6 months; P value not reported), respectively

  • In addition, the median OS was longer in patients who had received one versus two or three previous AML treatments prior to enrolment (11.8 months vs. 7.8 months and 7.0 months, respectively; P = 0.001)

  • Among the 101 patients in the 100-mg/day group who had variant allele frequency (VAF) data available, 12 (11.9%) achieved mutant-IDH2 molecular remission (defined as IDH2 VAF <0.02%-0.04% at one or more time point), and achieving this endpoint was significantly associated with response to treatment, compared with no molecular remission (P = 0.0003)

  • Attaining molecular remission was also associated with “a significant survival advantage,” the investigators wrote (median OS = 22.9 months vs. 8.8 months, respectively; P = 0.0153)

Enasidenib also led to transfusion independence. Among the patients in the 100-mg/day group who were transfusion-dependent at baseline, 43.1% (n=66/153) achieved red blood cell transfusion independence and 40.2% (n=53/132) achieved platelet transfusion independence.

Limitations of the study include the relatively small number of patients enrolled, as well as the lack of a placebo and/or active treatment comparator arm. Enasidenib is now being evaluated in a randomized, phase III study of older patients with late-stage, IDH2-mutated, R/R AML, in which it will be compared with conventional care regimens.


1. Eytan M. S. et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. Blood. 2019 Feb 08; 133(7):676-687; DOI:

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