Enasidenib: A Promising Option for IDH2-Mutated Acute Myeloid Leukemia?

Enasidenib is a promising therapy option with a generally favorable side effect profile for patients with acute myeloid leukemia (AML), and should be considered for all patients with IDH2-mutated disease, according to a new review article published in Core Evidence.

However, enasidenib’s role in upfront AML therapy with induction remains to be seen, as does its use in combination with hypomethylating agents (HMA) or with other targeted therapies, concluded the investigators, from the University of California Davis School of Medicine, Sacramento, California. In addition, it is still unknown what role the agent may play in post-consolidation or transplant maintenance, they added.

This review puts the latest evidence on treating patients with agents that target IDH1/IDH2 mutations into perspective, Mark James Levis, MD, PhD, program leader of the Hematologic Malignancies and Bone Marrow Transplant Program at Sidney Kimmel Comprehensive Cancer Center and a professor of oncology  at Johns Hopkins, told Cancer Network.

“They have actually changed care in the field of AML over the past 1 to 2 years, and will continue to change care as we move the drugs into treatment regimens upfront,” Levis said.

The authors reviewed the evidence for the use of enasidenib in patients with relapsed/refractory AML and outlined future directions of enasidenib therapy. Based on their findings, molecular testing should be done for all newly diagnosed patients with AML, they wrote. In addition, they advocate that testing be conducted throughout treatment and relapse in order to identify responses with minimal/measurable residual disease (MRD) and treatment-emergent targetable mutations.

Enasidenib was approved by the US Food and Drug Administration in August 2017, after researchers found an overall response rate of 40.3% was achieved in patients with relapsed/refractory disease. In addition, 19.3% of patients who received treatment with enasidenib achieved a complete remission. Additional studies are underway investigating enasidenib’s role in combination with other agents and in patients with newly-diagnosed disease.

It is estimated that IDH1/IDH2 mutations occur in approximately 20% of patients with AML. A second agent called ivosidenib, an IDH1 inhibitor, was FDA-approved in 2018. “Given the availabilities of new targeted therapies, molecular testing should be standard in all newly diagnosed AML and include testing for IDH2. Not only the availability, but also the timeliness of such testing is becoming increasingly important,” write the authors.

The BEAT AML trial reported that 52% of patients were successfully entered into an appropriate sub-study arm based on molecular testing and received treatment. According to the authors of the current review, the findings from the BEAT AML trial also demonstrated that 91% of patients were able to undergo molecular testing used for clinical decision-making within 7 days, suggesting that rapid identification of targetable mutations in AML appears to be both possible and practical.

Enasidenib has a half-life of 137 hours after multiple doses, and in a phase I/II study, it reached steady-state by cycle 2 (28-day cycles). The latest data suggest that 100 mg may be the optimal dose, the authors wrote.

To date, no specific analyses have been done on the effect of enasidenib on quality of life. However, this oral agent is generally well-tolerated, even in unfit patients, they concluded.