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

2021; Elsevier BV; Volume: 21; Linguagem: Inglês

10.1016/s2152-2650(21)01791-2

2152-2650

Sangeetha Venugopal, Courtney D. DiNardo, Koichi Takahashi, Marina Konopleva, Sanam Loghavi, Gautam Borthakur, Amy E. DeZern, Lucia Masárová, Naval Daver, Nicholas J. Short, Yesid Alvarado, Farhad Ravandi, Guillermo Montalban‐Bravo, Koji Sasaki, Ricardo Delumpa, Mikkael A. Sekeres, Bhumika J. Patel, Gail J. Roboz, Hagop M. Kantarjian, Guillermo Garcia‐Manero,

Multiple Myeloma Research and Treatments

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-naïve 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. 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. 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). Multi-institutional, open-label, two-arm, non-randomized, phase II study. 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. 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. 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-naïve 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. ENA is well-tolerated and shows promising efficacy in IDH2-mutated higher-risk MDS. Follow-up and accrual are ongoing.