Background
Phase 2, 2-arm, multicenter, open-label study. 50 patients with IDH2-mutated MDS (IDH2 mutated in ~5% of MDS). Arm A: 27 patients with newly diagnosed higher-risk IDH2-mutated MDS; Arm B: 23 patients with IDH2-mutated MDS after prior HMA failure. Enasidenib is an oral selective mutant-IDH2 inhibitor approved for R/R IDH2-mutated AML. Median age 73 years.
Interventions and follow up
Arm A: Enasidenib 100 mg orally once daily + azacitidine 75 mg/m² SC/IV days 1–7 of 28-day cycles (treatment-naïve higher-risk IDH2-mutated MDS; n=27)
Arm B: Enasidenib 100 mg orally once daily monotherapy after prior HMA failure (n=23)
Primary endpoint: Safety and overall response rate (ORR; IWG 2006)
Median follow up: NR
Arm B: Enasidenib 100 mg orally once daily monotherapy after prior HMA failure (n=23)
Primary endpoint: Safety and overall response rate (ORR; IWG 2006)
Median follow up: NR
Results
Arm A — ORR: 74% (20/27)
Arm A — CRc (CR + marrow CR): 70%
Arm A — Median time to best response: 1 month (range 1–4)
Arm A — Median OS: 26 months (range 14 to NR)
Arm B — ORR: 35% (8/23)
Arm B — CRc: 35%; CR rate 22% (5/23)
Arm B — Median time to best response: 4.6 months
Arm B — Median OS: 20 months (range 11 to NR)
Arm A — CRc (CR + marrow CR): 70%
Arm A — Median time to best response: 1 month (range 1–4)
Arm A — Median OS: 26 months (range 14 to NR)
Arm B — ORR: 35% (8/23)
Arm B — CRc: 35%; CR rate 22% (5/23)
Arm B — Median time to best response: 4.6 months
Arm B — Median OS: 20 months (range 11 to NR)
Adverse events
Hematologic: Neutropenia 40%.
Gastrointestinal/Constitutional: Nausea 36%, constipation 32%, fatigue 26%.
Hepatic: Hyperbilirubinemia (off-target UGT1A1 inhibition) 14% any grade, 8% grade 3–4.
Differentiation syndrome: IDH-DS in 16% (8/50); manageable with steroids and/or dose interruption.
Gastrointestinal/Constitutional: Nausea 36%, constipation 32%, fatigue 26%.
Hepatic: Hyperbilirubinemia (off-target UGT1A1 inhibition) 14% any grade, 8% grade 3–4.
Differentiation syndrome: IDH-DS in 16% (8/50); manageable with steroids and/or dose interruption.
Conclusions
Enasidenib demonstrates clinically meaningful activity in IDH2-mutated MDS. Combined with azacitidine it achieved 74% ORR with 70% composite CR in treatment-naïve higher-risk MDS. As monotherapy after HMA failure, a 35% CRc rate with durable responses (median OS 20 months) supports enasidenib's use in this molecularly selected relapsed/refractory population.
Key Limitations
Small phase 2, non-randomized, 2-arm design (n=50) without a comparator; cross-arm comparisons are descriptive only. Arm A combines enasidenib with azacitidine, so single-agent contribution cannot be isolated. Highly selected IDH2-mutated population limits generalizability. Median follow-up not reported; survival estimates have wide confidence intervals. No prospective MRD assessment.
Clinical Context
Enasidenib is FDA-approved for relapsed/refractory IDH2-mutated AML; its use in IDH2-mutated MDS remains investigational/off-label and is not yet a labeled indication. IDH2 mutation testing should be incorporated into MDS molecular work-up. ELN and MDS expert recommendations support consideration of IDH-targeted therapy in molecularly defined subsets, particularly after HMA failure where prognosis is otherwise poor.