Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome.

The isocitrate dehydrogenase enzyme 2 (IDH2) gene is mutated in ~5% of patients with myelodysplastic syndrome (MDS). Enasidenib is an oral, selective, mutant IDH2 inhibitor approved for IDH2-mutated (mIDH2) relapsed/refractory acute myeloid leukemia. We designed a 2-arm multicenter study to evaluate safety and efficacy of (A) the combination of enasidenib with azacitidine for newly diagnosed mIDH2 MDS, and (B) enasidenib monotherapy for mIDH2 MDS after prior HMA therapy. 50 patients with mIDH2 MDS enrolled; 27 in Arm A and 23 in Arm B. Median age was 73 years. The most common adverse events were neutropenia (40%), nausea (36%), constipation (32%) and fatigue (26%). Hyperbilirubinemia from off-target UGT1A1 inhibition occurred in 14% (8% grade 3-4), and IDH-inhibitor-associated differentiation syndrome (IDH-DS) in 8 patients (16%). In the combination arm, the overall response rate (ORR: CR+mCR+PR) was 74%, including 70% composite CR (CRc: CR+mCR). Median time to best response was 1 month (range 1-4) and a median of 4 cycles was received (1-32). The median OS was 26 months (range 14-NE). In the enasidenib monotherapy cohort post HMA failure, ORR and CRc were both 35% (n=8), with 22% CR (n=5). Median time to first response was 27 days, and to best response was 4.6 months (2.7-7.6 months). A median of 7 cycles was received (range 1-29) and the median OS was 20 months (range 11-NR). Enasidenib is an effective treatment option for mIDH2 MDS, both in combination with azacitidine for treatment naïve high-risk MDS, and as a single agent after prior HMA therapy. This trial is registered at www.clinicaltrials.gov as NCT03383575.