Differentiation Syndrome Associated With Enasidenib, a Selective Inhibitor of Mutant Isocitrate Dehydrogenase 2: Analysis of a Phase 1/2 Study

Abstract

Importance: Enasidenib mesylate, a mutant isocitrate dehydrogenase 2 (IDH2) protein inhibitor that promotes differentiation of leukemic myeloblasts, was recently approved by the US Food and Drug Administration for use in relapsed/refractory (R/R) mutant IDH2 acute myeloid leukemia (AML). During the first study of enasidenib in humans, a minority of patients with advanced myeloid neoplasms experienced unexpected signs/symptoms of a differentiation syndrome (DS), a potentially lethal entity.

Objective: To characterize IDH-inhibitor-associated DS (IDH-DS) and its effective management.

Design, setting, and participants: Using data obtained from a multicenter, open-label, pivotal phase 1/2 study of enasidenib, a differentiation syndrome review committee retrospectively evaluated potential cases of IDH-DS in enasidenib-treated patients with R/R AML. Data were collected between August 27, 2013, and October 14, 2016. The committee identified and agreed on signs and symptoms characteristic of IDH-DS and developed an algorithm for identification and treatment. Among 281 patients with R/R AML enrolled in the trial, the committee identified 72 patients for review based on investigator-reported cases of DS (n = 33) or reported adverse events or signs and symptoms characteristic of IDH-DS.

Interventions: Treatment with enasidenib at a dosage of 50 to 650 mg/d was evaluated during the dose-escalation phase, and a dosage of 100 mg/d was used in the phase 1 expansion and phase 2, all in continual 28-day cycles.

Main outcomes and measures: Unexpected adverse events of IDH-DS during the phase 1/2 study.

Results: Thirty-three of the 281 patients (11.7%) were identified as having possible or probable IDH-DS. Median age of those 33 patients was 70 years (range, 38-80 years); 20 (60.6%) were male. The most frequent manifestations were dyspnea, fever, pulmonary infiltrates, and hypoxia. Median time to onset was 30 days (range, 7-129 days). Patients who experienced IDH-DS were less likely to have less than 20% bone marrow blasts (6% vs 22%, P = .04) and more likely to have undergone fewer previous anticancer regimens (median, 1.0 [range, 1-4] vs 2.0 [range, 1-14], P = .05) at study entry than those who did not. Thirteen patients (39.4%) had concomitant leukocytosis. Isocitrate dehydrogenase differentiation syndrome was effectively managed with systemic corticosteroids. The enasidenib regimen was interrupted for 15 patients (45.5%), but permanent discontinuation of treatment was not required.

Conclusions and relevance: Isocitrate dehydrogenase differentiation syndrome is a recognizable and potentially lethal clinical entity, occurring in approximately 12% of enasidenib-treated patients with mutant-IDH2 R/R AML. It requires prompt recognition and management. As use of mutant IDH inhibitors increases, these findings and recommendations are increasingly germane to care of patients with mutant-IDH neoplasms.

Trial registration: clinicaltrials.gov Identifier: NCT01915498.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Fathi reported serving as a consultant for and receiving clinical trial support from Celgene Corporation and Seattle Genetics; serving on advisory boards for Agios Pharmaceuticals, Inc, Merck, Juno, Torero, and Bexalata; and receiving clinical trial support from Takeda and Exelixis. Dr DiNardo reported receiving compensation for serving on advisory boards for Agios, Daiichi Sankyo, Celgene, and Novartis, speakers fees from AbbVie, and receiving clinical research support from Agios Pharmaceuticals, Inc, AbbVie, Daiichi Sankyo, Novartis, and Celgene Corporation. Drs Kline, Kenvin, and Gupta are employees and hold stock in Celgene Corporation. Dr Attar is an employee of Agios Pharmaceuticals, Inc. Dr Stein reported receiving grants and personal fees from Celgene Corporation and Agios Pharmaceuticals. Dr de Botton reported receiving personal fees from Agios Pharmaceuticals, Inc, Celgene Corporation, Novartis, Pfizer, and Servier. No other disclosures were reported.

Figures

Figure.. Differentiation Syndrome Review Committee Amended Protocol for Isocitrate Dehydrogenase Differentiation Syndrome (IDH-DS) Diagnosis and Management

DIC indicates disseminated intravascular coagulation; WBC, white blood cells. aTypical onset is between 7 to 10 days and 5 months from start of enasidenib treatment or reinitiation of enasidenib after prolonged treatment interruption. bOwing to the long half-life of enasidenib, treatment may not immediately reverse symptoms of IDH-DS.