Enasidenib Induces Molecular Remissions in IDH2-Mutated, Relapsed/Refractory AML

A first-in-human trial of patients with relapsed and/or refractory, IDH2-mutated acute myeloid leukemia (AML) found that the IDH2 inhibitor enasidenib was an effective salvage therapy, inducing . In a recent article published in Blood, the authors provided updated results from the study, looking specifically at molecular remissions.

“In our study, approximately 30 percent of patients with a best response of stable disease at 90 days (after three cycles of therapy) went on to have a response, suggesting that in the absence of clear evidence of progressive disease, patients who have stable disease on day 90 should continue on therapy, as they may achieve a response,” lead author Eytan M. Stein, MD, of the Memorial Sloan Kettering Cancer Center in New York, told ASH Clinical News. “Enasidenib also is able to clear the IDH2 mutant clone in a subset of patients who enter a complete remission.”

The phase I/II study evaluated enasidenib (administered in continuous 28-day cycles) in adults with IDH2-mutated AML that had relapsed after allogeneic hematopoietic cell transplantation (alloHCT), was in second or later relapse, was refractory to initial induction or reinduction treatment, or had relapsed within one year of initial treatment.

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.

A total of 280 patients with relapsed/refractory AML from 21 sites were enrolled, all of whom received a median of five cycles of enasidenib (range = 1-38 cycles). The authors also reported results for a subgroup of patients who received enasidenib 100 mg/day (n=214; 76.2% of entire study population). Median age in this group was 68 years (range = 19-100 years), and 48 (22.4%) had received at least three prior therapies for AML.

“Safety outcomes for all patients were consistent with those reported previously,” the investigators reported. 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%)

The development of IDH-DS is an AE unique to treatment with enasidenib, Dr. Stein explained, advising that clinicians be aware of this risk. “As opposed to reinduction chemotherapy, enasidenib is a differentiation agent and leads to maturation of malignant myeloblasts into neutrophils,” he said. “Failure to recognize and promptly administer corticosteroids for differentiation syndrome can lead to respiratory failure from pulmonary edema.”

At a median follow-up of 7.8 months (range not reported), 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 percent in the 100-mg/day cohort and 33.9 percent across all dosing cohorts. Approximately 19 percent 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 (ranges = 7.7-9.6 months and 7.8-9.9 months, respectively), and median event-free survival (EFS) was 4.7 months (range = 3.7-5.6 months) and 4.6 months (range = 3.7-5.6 months), respectively. See more response and survival data in the TABLE. 

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 enrollment (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 served as a bridge to transplant for several patients with relapsed or refractory disease,” the authors added, with 19 patients in the 100-mg/day group who achieved a CR subsequently undergoing alloHCT.

Enasidenib also led to transfusion independence. Among the patients in the 100-mg/day group who were transfusion-dependent at baseline, 43.1 percent (n=66/153) achieved red blood cell transfusion independence and 40.2 percent (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. Dr. Stein added that enasidenib is now being evaluated in a randomized, phase III study of older patients with late-stage, IDH2-mutated, relapsed/refractory AML, in which it will be compared with conventional care regimens.

The study authors report financial relationships with Agios and Celgene, which cosponsored the trial.


Stein EM, DiNardo CD, Fathi AT, et al. Molecular remission and response patterns in patients with mutant-IDH2 acute myeloid leukemia treated with enasidenib. 2018 December 3. [Epub ahead of print]