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PMID
Authors Sangeetha Venugopal, Courtney Denton Dinardo, Koichi Takahashi, Marina Konopleva, Sanam Loghavi, Gautam Borthakur, Amy Elizabeth Dezern, Lucia Masarova, Naval Guastad Daver, Nicholas James 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
Title Phase II study of the IDH2-inhibitor enasidenib in patients with high-risk IDH2-mutated myelodysplastic syndromes (MDS).
URL https://ascopubs.org/doi/abs/10.1200/JCO.2021.39.15_suppl.7010
Abstract Text Background: Isocitrate dehydrogenase 2 (IDH2) mutations occur in 5% of patients (pts) with MDS. Enasidenib (ENA) is a selective oral inhibitor of the mutant IDH2 enzyme with single-agent activity in relapsed/refractory acute myeloid leukemia (AML). We report the results of the open label phase II study designed 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). Methods: Pts with higher-risk [Revised International Prognostic Scoring System risk > 3 or high molecular risk (HMR)] MDS/CMML or LB AML naïve to hypomethylating agents (HMA) received ENA100 mg orally daily for 28 d of each 28-d cycle + AZA 75 mg/m2 IV or SC on d 1-7 of each cycle (ENA+AZA), and pts with refractory or progressive MDS to prior HMA therapy received ENA alone (ENA), in 28-d cycles until unacceptable toxicity, relapse, transformation to AML, or progression. 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%). Median number Tx cycles was 4 (2–32) in the ENA+AZA, and 7 (1–23) in the ENA arm. 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. Grade 3–4 infections occurred in 32% (ENA+AZA) and 14% (ENA). IDH differentiation syndrome occurred in 3 pts (12%) in the ENA+AZA and 5 pts (24%) in the ENA arm. Two deaths occurred during the initial 60 d, both unrelated to study and due to COVID. In response-evaluable pts (n=46), ORR was 84% (n = 21/25; 24% CR + 8% PR+44% mCR+ 8% HI] in the treatment naïve ENA+AZA and 43% (n = 9/21; 24% CR+5%PR+5% mCR+10% HI) in the HMA failure ENA arm (Table). Most common reason for Tx discontinuation was disease progression (ENA+AZA 20%, ENA 33%).5 pts (20%) received HCT in the ENA+AZA and 1 (5%) in the ENA arm. 7 pts in the ENA+AZA and 5 in the ENA arm were ongoing at data cutoff (Dec 31, 2020). After a median follow up of 12.6 mo, median OS was 32.2 mo in the ENA+AZA 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 is ongoing to better define duration and biomarkers of response. Clinical trial information: NCT03383575.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH2 R140X myelodysplastic syndrome predicted - sensitive Azacitidine + Enasidenib Phase II Actionable In a Phase II trial, Idhifa (enasidenib) and Vidaza (azacitidine) combination treatment was well tolerated and resulted in an overall response rate of 68% (30/46, 11 complete remission (CR), 3 partial remission, 12 marrow CR, 4 hematological improvement only) in patients with higher-risk myelodysplastic syndrome harboring IDH2 R140 or R172 mutations who were naive to hypomethylating agents, with a median overall survival of 21.3 months (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7010-7010; NCT03383575). detail...
IDH2 R172X myelodysplastic syndrome predicted - sensitive Enasidenib Phase II Actionable In a Phase II trial, Idhifa (enasidenib) treatment was well tolerated and resulted in an overall response rate of 43% (9/21, 5 complete remission (CR), 1 partial remission, 1 marrow CR, 2 hematological improvement only) in patients with higher-risk myelodysplastic syndrome harboring IDH2 R140 or R172 mutations who were refractory to or progressed on hypomethylating agents, with a median overall survival of 21.3 months (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7010-7010; NCT03383575). detail...
IDH2 R172X myelodysplastic syndrome predicted - sensitive Azacitidine + Enasidenib Phase II Actionable In a Phase II trial, Idhifa (enasidenib) and Vidaza (azacitidine) combination treatment was well tolerated and resulted in an overall response rate of 68% (30/46, 11 complete remission (CR), 3 partial remission, 12 marrow CR, 4 hematological improvement only) in patients with higher-risk myelodysplastic syndrome harboring IDH2 R140 or R172 mutations who were naive to hypomethylating agents, with a median overall survival of 21.3 months (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7010-7010; NCT03383575). detail...
IDH2 R140X myelodysplastic syndrome predicted - sensitive Enasidenib Phase II Actionable In a Phase II trial, Idhifa (enasidenib) treatment was well tolerated and resulted in an overall response rate of 43% (9/21, 5 complete remission (CR), 1 partial remission, 1 marrow CR, 2 hematological improvement only) in patients with higher-risk myelodysplastic syndrome harboring IDH2 R140 or R172 mutations who were refractory to or progressed on hypomethylating agents, with a median overall survival of 21.3 months (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 7010-7010; NCT03383575). detail...