Forty Percent of Patients With Previously Treated IDH2-Mutated AML Respond to Enasidenib

For the approximately 12 percent of patients with acute myeloid leukemia (AML) with the IDH2 mutation, the oral, selective, small-molecule inhibitor enasidenib could become a new treatment option, according to results of a phase I/II trial presented at the 2017 ASCO Annual Meeting.1

Among the 239 patients with relapsed/refractory IDH2-mutant AML enrolled in the trial, the overall response rate (ORR) was 40 percent, and patients achieved a median overall survival (OS) of 9.3 months (range = 8.2-10.9 months).

“I’m extraordinarily optimistic about [these response rates] in this heavily pretreated patient population,” lead author Eytan M. Stein, MD, from Memorial Sloan Kettering Cancer Center in New York, told ASH Clinical News. “I’m encouraged that this drug will make a real difference to patients.” Dr. Stein presented results from the dose-escalation and dose-expansion phases of the multicenter, open-label trial, which were also published recently in Blood.2

Patients with AML have increased levels of 2-hydroxyglutarate (2HG), Dr. Stein explained, “which freezes myeloid cells in an undifferentiated state and the IDH2-mutant protein keeps those cells from growing.” By blocking IDH2 and lowering levels of 2HG, enasidenib “allows those immature cells to start maturing. It’s a differentiation therapy, rather than a cytotoxic therapy.”

All patients (median age = 70 years; range = 19-100 years) received enasidenib. In the dose-escalation phase, which included 113 patients, the maximum tolerated dose was not reached at doses of up to 650 mg daily. Median 2HG reductions from baseline were 92 percent, 90 percent, and 93 percent in patients receiving enasidenib <100 mg, 100 mg, or >100 mg daily; respectively. Based on the drug’s pharmacodynamic profile and efficacy, the researchers selected enasidenib 100 mg once-daily, administered in 28-day treatment cycles, for the dose-expansion phase (n=126).

This phase included four subgroups of patients: patients ≥60 years or <60 years with relapsed/refractory AML following a hematopoietic cell transplantation; patients ≥60 years with previously untreated AML who declined standard-of-care chemotherapy; and those ineligible for other arms.

In the 176 patients with relapsed/refractory AML, the ORR was 40.3 percent, including 34 complete remissions (CRs; for a CR rate of 20.2%). For the 109 patients who received enasidenib 100 mg/day, the ORR was 38.5 percent (TABLE).

The median duration of response was 5.8 months (range = 3.9-7.4 months) in the overall population and 5.6 months (range = 3.8-9.7 months) in the 100 mg/day group.

Overall, 36.3 percent of relapsed/refractory patients achieved RBC transfusion-independence and 36.4 percent achieved platelet transfusion-independence. For patients in CR, these rates were 95.5 percent and 94.1 percent, respectively.

“The median overall survival of longer than 9 months was impressive for a group of patients with relapsed/refractory AML,” Dr. Stein noted. Patients in CR with enasidenib also had longer median OS (19.7 months; range = 11.6 months to not estimable), compared with non-responders (7.0 months; range = 5.0-8.3 months; p value not reported).

Patients received a median of five treatment cycles (range = 1-25). The most common any-grade adverse events (AEs) were: nausea (46%), hyperbilirubinemia (45%), diarrhea (40%), and fatigue (40%). Treatment-related grade 3/4 AEs included: indirect hyperbilirubinemia (12%), thrombocytopenia (6%), and anemia (5%). Serious treatment-related IDH-inhibitor-associated differentiation syndrome was reported in 8 percent of patients, and two of these patients died during study follow-up.

Response also was associated with myeloid differentiation, though baseline 2HG levels and mIDH2 variant allele frequency were similar between responders and non-responders. “Unlike cytotoxic chemotherapy, responses to enasidenib may require several treatment cycles and responses can improve over time with continued treatment,” the authors concluded.

The study’s findings are limited by the lack of a comparator arm.

Dr. Stein noted that enasidenib is being compared with standard-of-care therapies (either induction chemotherapy or azacitidine) in an ongoing, randomized, phase III trial of patients with relapsed/refractory, IDH2-mutant AML. “We’re hoping that [enasidenib] combined with standard-of-care therapies will be more effective than standard-of-care therapies alone,” he said.

Dr. Stein reports research funding from Celgene.


Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia (R/R AML): Results of a phase I dose-escalation and expansion study. Abstract #7004. Presented at the 2017 ASCO Annual Meeting; June 6, 2017; Chicago, Illinois.

TABLE. Response Rates for Patients With IDH2-Mutant Relapsed/Refractory AML


100 mg/day

Overall response rate

71 (40.3%)

42 (38.5%)

Complete remission

34 (19.3%)

22 (20.2%)

Complete remission with incomplete hematologic recovery

12 (6.8%)

7 (6.4%)

Morphologic leukemia-free state

14 (8.0%)

10 (9.2%)

Partial remission

11 (6.3%)

3 (2.8%)

Stable disease

85 (48.3%)

58 (53.2%)

Progressive disease

9 (5.1%)

5 (4.6%)

Not evaluable

3 (1.7%)

2 (1.8%)