Treatment options for acute myeloid leukemia (AML) are limited, and prognosis, is poor, particularly for older patients, those with secondary AML, and those with relapsed or refractory disease. Recurrent mutations in the isocitrate dehydrogenase 2 gene (IDH2) occur in approximately 12% of patients with AML and may contribute to AML development by blocking myeloid cell differentiation.
Enasidenib is a first-in-class, oral, selective inhibitor of mutant IDH2 enzymes which can induce terminal differentiation of leukemic myeloblasts and lead to normal hematopoiesis. This agent was evaluated in a large phase I/II dose-escalation and expansion study involving 239 patients with IDH2-mutated myeloid malignancies, including 176 patients with relapsed/refractory AML. Enasidenib was well-tolerated in all patients with IDH2 mutations and showed impressive efficacy in the subgroup of patients with AML for whom prior therapy had failed.
The maximum tolerated dose was not reached at doses ranging from 50 mg to 650 mg daily.
Enasidenib was associated with mostly mild, manageable adverse events (AEs). However, grade 3/4 treatment-related AEs occurred in 41% of patients, including indirect hyperbilirubinemia (12%) and IDH-inhibitor associated differentiation syndrome (7%). In addition, non–dose-dependent, noninfectious leukocytosis was reported in 17% of patients, occurring mostly in the first 2 cycles. Of note, enasidenib is not myeloblative and rates of grade 3/4 infections were low (1%).
In patients with relapsed/refractory AML, the overall response rate (ORR) was 40.3%, with 19.3% achieving complete remission (CR). Median event-free survival was 6.4 months and median overall survival (OS) was 9.3 months. In patients who achieved CR, the median OS was 19.7 months. Patients who had received 2 or more prior treatments for AML had a median OS of 8.0 months on enasidenib.
Though the clinical activity of enasidenib was observed at all doses, a dose of 100 mg daily was selected for future studies based on steady-state drug concentrations, tolerability, and an associated ORR of 38.5%.
The authors concluded that data from this study indicate single-agent enasidenib is safe and is associated with clinically meaningful outcomes in patients with relapsed or refractory IDH2-mutant AML. Efficacy and safety of this agent will be evaluated further in the ongoing international, phase III randomized IDHENTIFY trial comparing enasidenib with current standard therapy in patients 60 years or older with IDH2-mutant relapsed/refractory AML.