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

JAMA Oncol. 2018 Aug 1;4(8):1106-1110. doi: 10.1001/jamaoncol.2017.4695.


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.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Aminopyridines / adverse effects*
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / genetics
  • Enzyme Inhibitors / adverse effects
  • Female
  • Follow-Up Studies
  • Humans
  • Isocitrate Dehydrogenase / antagonists & inhibitors*
  • Isocitrate Dehydrogenase / genetics
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Middle Aged
  • Molecular Targeted Therapy / adverse effects*
  • Mutation*
  • Neoplasm Recurrence, Local / drug therapy*
  • Neoplasm Recurrence, Local / pathology
  • Prognosis
  • Retrospective Studies
  • Syndrome
  • Triazines / adverse effects*


  • Aminopyridines
  • Enzyme Inhibitors
  • Triazines
  • enasidenib
  • IDH2 protein, human
  • Isocitrate Dehydrogenase

Associated data

  • ClinicalTrials.gov/NCT01915498