Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome

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, 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

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.

Conflict of interest statement

Conflict-of-interest disclosure: C.D.D. reports research grants from AbbVie, Servier, Astex, BMS, Cleave, Daiichi-Sankyo, ImmuneOnc, and Loxo, and receives honoraria/consulting fee from AbbVie, Servier, Astellas, BMS, Celgene, Cleave, Foghorn, Genentech, Gilead, Novartis, Notable Labs, and Takeda. K.T. reports consultancy and an advisory fee from Symbio Pharmaceuticals, Novartis, Celegene/BMS, Agios, GSK, and Otsuka, and received honoraria from Mission Bio and Illumina. S.L. owns stock in AbbVie. N.J.S. reports receiving research grants from Takeda Oncology, Astellas Pharma Inc., Stemline Therapeutics Inc., and Xencor, and has received honoraria from Amgen, Jazz Pharmaceuticals, Novartis, and Pfizer. F.R. reports research funding, consultancy, and honoraria from Celgene/BMS, Astex/Taiho, Genentech, Syros, and Astellas; research funding from Prelude and Hutchison Pharma; and consultancy/honoraria from Novartis, AstraZeneca, and Mablytics. A.D. has previously acted as a consultant and served in advisory roles for BMS, Novartis, Takeda, Geron, Taiho, and CTI Biopharma. G.G.M. reports funding from BMS. The remaining authors declare no competing financial interests.

© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.

Figures

Figure 1.
Figure 1.
Baseline mutational features of study cohort. (A) Dot plot showing the IDH2 variant allele frequency in each treatment arm. (B) Violin plot showing the frequency of genes mutated per patient in each treatment arm. (C) Complex heatmap of the entire cohort; each column represents a patient. Treatment arm, IPSS-R risk group, cytogenetic risk group, indicated mutations, and response are shown for each patient. Shown to the right of the plot are the percentage of patients in each labeled row. AZA, azacitidine; ENA, enasidenib; NR, not reported; SD, stable disease.
Figure 2.
Figure 2.
AEs attributable to study therapy by grade and treatment arm. AZA, azacitidine; ENA, enasidenib.
Figure 3.
Figure 3.
Swim plot and response outcomes of the study population by treatment arm. (A) Swim plot showing individual patient, treatment duration, response, and patient disposition. (B) Proportion of responses in arm A (ENA + AZA). (C) Proportion of responses in arm B (ENA). AZA, azacitidine; ENA, enasidenib; SD, stable disease.
Figure 4.
Figure 4.
OS and DOR by treatment arm. (A) Kaplan-Meier curves showing OS in arm A (ENA + AZA). (B) Kaplan-Meier curves showing OS in arm B (ENA). (C) Kaplan-Meier curves showing the DOR in arm A (ENA + AZA). (D) Kaplan-Meier curves showing the DOR in arm B (ENA). AZA, azacitidine; ENA, enasidenib.

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