Targeted Therapy With the Mutant IDH2 Inhibitor Enasidenib for High-Risk IDH2-Mutant Myelodysplastic Syndrome

Authors

Courtney D DiNardo
Sangeetha Venugopal
Curtis Lachowiez
Koichi Takahashi
Sanam Loghavi
Guillermo Montalban-Bravo
Xuemei Wang
Hetty Carraway
Mikkael Sekeres
Ameenah Sukkur
Danielle Hammond
Kelly Chien
Abhishek Maiti
Lucia Masarova
Koji Sasaki
Yesid Alvarado
Tapan Kadia
Nicholas J Short
Naval Daver
Gautam Borthakur
Farhad Ravandi
Hagop M Kantarjian
Bhumika Patel
Amy Dezern
Gail Roboz
Guillermo Garcia-Manero

Publication Date

6-13-2023

Journal

Blood Advances

Abstract

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 hypomethylating agent (HMA) therapy. Fifty patients with mIDH2 MDS enrolled: 27 in arm A and 23 in arm B. Median age of patients 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% of patients (8%; grades 3 and 4), and IDH-inhibitor-associated differentiation syndrome (IDH-DS) in 8 patients (16%). In the combination arm, the overall response rate (ORR: complete remission [CR] + marrow CR [mCR] + partial remission) 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 overall survival (OS) was 26 months (range, 14 to not reached). In the enasidenib monotherapy cohort after HMA failure, ORR and CRc were both 35% (n = 8), with 22% CR (n = 5). Median time to first response was 27 days, and time 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 to not reached). 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.

Keywords

Humans, Aged, Isocitrate Dehydrogenase, Mutation, Myelodysplastic Syndromes, Azacitidine

Comments

Supplementary Materials

PMID: 35973199