Enasidenib, an inhibitor of mutant IDH2 proteins, induces durable remissions in older patients with newly diagnosed acute myeloid leukemia

Daniel A Pollyea, Martin S Tallman, Stéphane de Botton, Hagop M Kantarjian, Robert Collins, Anthony S Stein, Mark G Frattini, Qiang Xu, Alessandra Tosolini, Wendy L See, Kyle J MacBeth, Samuel V Agresta, Eyal C Attar, Courtney D DiNardo, Eytan M Stein, Daniel A Pollyea, Martin S Tallman, Stéphane de Botton, Hagop M Kantarjian, Robert Collins, Anthony S Stein, Mark G Frattini, Qiang Xu, Alessandra Tosolini, Wendy L See, Kyle J MacBeth, Samuel V Agresta, Eyal C Attar, Courtney D DiNardo, Eytan M Stein

Abstract

Older adults with acute myeloid leukemia (AML) who are not fit for standard chemotherapy historically have poor outcomes. Approximately 12-15% of older patients with AML harbor isocitrate dehydrogenase 2 (IDH2) gene mutations. Enasidenib is an oral inhibitor of mutant IDH2 proteins. Among 39 patients with newly diagnosed mutant-IDH2 AML who received enasidenib monotherapy in this phase I/II trial, median age was 77 years (range 58-87) and 23 patients (59%) had had an antecedent hematologic disorder. The median number of enasidenib treatment cycles was 6.0 (range 1-35). The most common treatment-related adverse events were indirect hyperbilirubinemia (31%), nausea (23%), and fatigue, decreased appetite, and rash (18% each). Treatment-related grade 3-4 cytopenias were reported for eight patients (21%); there was no treatment-related grade 3-4 infections. Twelve patients achieved a response (overall response rate 30.8% [95% CI 17.0%, 47.6%]), including seven patients (18%) who attained complete remission. At a median follow-up of 8.4 months, the median duration of any response was not reached (NR). Median overall survival for all patients was 11.3 months (95% CI 5.7, 15.1), and was NR for responders. Oral, outpatient targeted treatment with enasidenib may benefit older adults with newly diagnosed mutant-IDH2 AML who are not candidates for cytotoxic regimens.

Conflict of interest statement

Compliance with ethical standards

Conflict of interest

DAP receives research funding from Agios, AbbVie, and Pfizer, and serves on advisory boards for Celgene, Pfizer, Argenx, Agios, AbbVie, Agios, Celyad, and Gilead. MST received research funding from AROG, Cellerant, ADC Therapeutics, Celgene, Daiichi-Sankyo, and Orsenix, and participated in advisory boards for Orsenix, Biosight, and Daiichi-Sankyo. SdB received research funding from Agios Pharmaceuticals, Inc. and served on advisory boards for Agios Pharmaceuticals, Inc., Celgene, Pfizer, Novartis, Servier, Pierre Fabre, Bayer, Seagen, Carthagenetics, and Forma. HMK received research funding from Amgen, Ariad, Astex, BMS, Novartis, and Pfizer, and received honoraria from AbbVie, Amgen, Ariad, BMS, Immunogen, Orsinex, and Pfizer. RC received honoraria and received research funding from Agios Pharmaceuticals, Inc. ASS served on the speakers’ bureaus for Amgen and Celgene. MGF, QX, AT, and KJM are employed by and hold stock in Celgene. WLS is a contractor with Celgene. ECA and SVA are employed by and hold stock in Agios Pharmaceuticals, Inc. CDD is a consultant for Agios and Celgene, and served on the advisory board for Bayer, Karyopharm, MedImmune, and AbbVie. EMS has served on advisory boards for Astellas Pharma, Daiichi, Bayer, Novartis, Syros, Pfizer, PTC Therapeutics, AbbVie, Agios, and Celgene and has received research support from Agios, Celgene, Syros and Bayer.

Figures

Fig. 1
Fig. 1
Treatment durations, hematologic responses and patient dispositions
Fig. 2
Fig. 2
Baseline gene co-mutations, organized by functional category, IDH2 mutation, and clinical response status
Fig. 3
Fig. 3
Kaplan–Meier survival estimates. a Overall survival (OS); and b event-free survival (EFS)

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