Enasidenib Effective Treatment for Refractory Acute Myeloid Leukemia

The FDA approval of enasidenib for the treatment of IDH2-mutated relapsed/refractory acute myeloid leukemia (AML) marks a new era for patients who previously had few options, says Mikkael Sekeres, MD, MS, Director of Cleveland Clinic Cancer Center’s Leukemia Program and site leader for clinical trials testing the drug.

The precision therapy inhibits the mutation of the IDH2 protein that blocks myeloid differentiation, which occurs in about 12 percent of patients with AML. Enasidenib at doses of 50 mg to 650 mg daily produced an overall response rate (ORR) of 40.3 percent (95% CI, 33-38) and a 19.3 percent (95% CI, 13.8-25.9) rate of complete remission (CR), according to results from a phase 1/2 clinical trial recently published in Blood.

“For many decades, we’ve only had limited advances in the treatment of refractory AML, and 5-year survival for these patients was in the single digits,” says Dr. Sekeres. “Enasidenib reshapes the treatment landscape; it induces durable complete remissions and extends survival benefit substantially.”

Increased OS, if clinicians are patient

The two-part study included dose escalation and dose expansion cohorts to test the maximum tolerable dose, pharmacologic profiles and safety for all patients (n = 293). Clinical efficacy was assessed for patients with relapsed/refractory disease (n = 176), and results for this group show a median overall survival (OS) of 9.3 months, and 19.7 months for patients who reached CR.

Adverse events were generally tolerable with grade 3/4 events including hyperbilirubinemia (12 percent), thrombocytopenia (6 percent) and anemia (5 percent).

Because enasidenib works by inducing myeloblast differentiation, first response is a bit delayed compared to cytotoxic therapies. “Patience is key,” says Dr. Sekeres. “Our results show that it takes about two months to show a response and about four months to complete response. We need to give the therapy time to work, because the payoff can be significant.”

Further trials are planned or underway at Cleveland Clinic and other sites to compare enasidenib with conventional treatments for older patients with relapsed/refractory AML, to establish optimal dosing, and to expand the treatment to other disorders like myelodysplastic syndrome.