Evaluating Enasidenib, With or Without Azacitidine, in Patients with IDH2-Mutated MDS

Enasidenib was had a tolerable safety profile and showed promising clinical activity in patients with IDH2-mutated, high-risk myelodysplastic syndromes (MDS), according to results from a phase II trial presented at EHA2021 Virtual, the annual congress of the European Hematology Association, by Sangeetha Venugopal, MD, of the University of Texas MD Anderson Cancer Center.

The study included 48 patients with refractory or progressive MDS who had previously received hypomethylating agent therapy. Participants received enasidenib 100 mg daily in 28-day cycles until disease progression, unacceptable toxicity, relapse, or transformation to acute myeloid leukemia (AML). Meanwhile, the 22 patients with higher-risk or high molecular-risk MDS, chronic myelomonocytic leukemia (CMML) or low-blast AML naïve to hypomethylating agents received enasidenib 100 mg daily plus 75 mg/m2 intravenous or subcutaneous azacitidine on days 1 through 7 of each 28-day cycle. Higher-risk disease was defined as a Revised International Prognostic Scoring System risk score of >3.

The median age of patients enrolled in the study was 73 years (range = 46-83). Most patients (72%) had high molecular-risk disease (39% had ASXL1 mutations and 17% had RUNX1 mutations). In the combination therapy group, patients were treated for a median of four 28-day cycles (range = 2-32), compared with seven treatment cycles (range = 1-23) in the monotherapy arm.

The primary endpoint of the study was overall response rate (ORR), and secondary endpoints included safety and survival outcomes.

Two COVID-19–related deaths occurred during the trial. Common treatment-related grade 3-4 adverse events (AEs) included neutropenia (64% in the enasidenib plus azacitidine group vs. 10% in the enasidenib monotherapy group), thrombocytopenia (28% vs. 0%), and anemia (8% vs. 5%). Most patients who discontinued treatment did so because of disease progression (20% in the enasidenib plus azacitidine group; 33% in the enasidenib monotherapy arm).

In the combination group, the ORR was 84%, which included a complete response (CR) rate of 24% and a partial response (PR) rate of 8%. In the enasidenib-only arm, the ORR was nearly half – at 43%. This included CR and PR rates of 24% and 5%, respectively. At data cutoff on December 31, 2020, seven patients were still receiving enasidenib plus azacitidine and five were still receiving enasidenib only.

Median overall survival was 32.2 months for patients receiving enasidenib plus azacitidine and 21.3 months for patients receiving enasidenib alone. “Follow up and accrual is ongoing to better define duration and biomarkers of response,” the authors concluded.

The study authors report no relevant conflicts of interest.


Venugopal S, DiNardo C, Takahashi K, et al. Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS). Abstract #S167. Presented at the EHA2021 Virtual Congress, June 9-17, 2021.