A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.

Enasidenib is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML sub-study, we applied a risk-adapted approach to assess the efficacy of enasidenib monotherapy for patients 60 years and older with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated mutant IDH2 was in the dominant leukemic clone. Patients for whom enasidenib monotherapy did not induce a complete response (CR) or CR with incomplete blood count recovery (CRi) enrolled on a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to enasidenib alone demonstrated efficacy, with a composite CR/CRi (cCR) rate of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and one dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of enasidenib monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML.