IDH2 Inhibitor Plus HMA Leads to Durable Responses in IDH2-Mutated MDS

Enasidenib, a selective inhibitor of the mutated IDH2 enzyme, plus a hypomethylating agent led to an overall response rate (ORR) of 74% in patients with newly diagnosed IDH2-mutated myelodysplastic syndrome (MDS), according to a recent study.

Enasidenib is approved for use in patients with IDH2-mutated relapsed/refractory acute myeloid leukemia, but around 5% of patients with MDS have IDH2 mutations.

Courtney DiNardo, MD, MSCE, of The University of Texas MD Anderson Cancer Center, and colleagues conducted the two-arm multicenter study and published its findings in Blood Advances.

The study was designed to evaluate the safety and efficacy of enasidenib plus azacitidine for patients with newly diagnosed mutated-IDH2 MDS (n=27) and enasidenib monotherapy for patients with mutated-IDH2 MDS who previously received hypomethylating agent therapy (n=23). The median patient age was 73 years.

Patients treated with the combination treatment had an ORR of 74%, including a 70% composite complete response rate. The median time to best response was one month, with a median overall survival (OS) of 26 months. Patients received a median of four cycles (range, one to 32).

Patients treated with enasidenib alone had an ORR and composite complete response rate of 35%, with a complete response reported in 22% of patients. The median time to first response was 27 days and the median time to best response was 4.6 months (range, 2.7 to 2.6). The median OS was 20 months. Patients received a median of seven cycles (range, one to 29).

Neutropenia was reported in 40% of patients, nausea was reported in 36% of patients, constipation was reported in 32% of patients, and fatigue was reported in 26% of patients. Hyperbilirubinemia from off-target UGT1A1 inhibition occurred in 14% of patients, and IDH-inhibitor-associated differentiation syndrome was reported in 16% of patients.

“Enasidenib is an effective treatment option for [mutated]-IDH2 MDS, both in combination with azacitidine for treatment-naïve high-risk MDS, and as a single agent after prior [hypomethylating agent] therapy,” Dr. DiNardo and colleagues concluded.

DiNardo CD, Venugopal S, Lachowiez CA, et al. Targeted therapy with the mutant IDH2 inhibitor enasidenib for high-risk IDH2-mutant myelodysplastic syndrome. Blood Adv. 2022. doi:10.1182/bloodadvances.2022008378