MDS-090: Phase II Study of the IDH2 Inhibitor Enasidenib in Patients with High-Risk IDH2-Mutated Myelodysplastic Syndromes (MDS)

Context: Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral mutant-IDH2 inhibitor with single-agent activity in relapsed/refractory AML. Objective: To evaluate the efficacy and tolerability of ENA, as monotherapy or in combination with azacitidine (AZA), in pts with higher-risk IDH2-mutated MDS (NCT03383575). Design and Setting: Multi-institutional, open-label, two-arm, non-randomized, phase II study. Patients and Interventions: Pts with higher-risk (R-IPSS > 3, or high-molecular-risk MDS/CMML, or RAEB-T MDS) enrolled in Arm A and received ENA100 mg orally daily for 14 or 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1–7 of each cycle (ENA+AZA). ENA duration was decreased to 14 d of each cycle, per amendment, to mitigate cytopenias. Pts with refractory or progressive MDS prior to HMA therapy enrolled in Arm B and received ENA alone (ENA), continuously, in 28-d cycles. Main Outcome Measures: The primary endpoint was overall response rate (ORR) [complete remission (CR), marrow CR (mCR), partial remission (PR), and hematologic improvement (HI)]. Other endpoints include safety and survival outcomes. Results: 48 pts received ENA+AZA (n = 26) or ENA (n = 22). The median age was 73 yrs (range, 46–83). Most pts (72%) had HMR: ASXL1 (39%) and RUNX1 (17%). Common Tx-related grade 3–4 AEs in the ENA+AZA arm were neutropenia (64%), thrombocytopenia (28%), and anemia (8%); these occurred in 10%, 0%, and 5%, in the ENA arm, respectively. IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. In response-evaluable pts (n = 46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment-naive Arm A and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm B. After a median follow-up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA arm and 21.3 mo in the ENA arm. Conclusions: ENA is well-tolerated and shows promising efficacy in IDH2-mutated higher-risk MDS. Follow-up and accrual are ongoing.