The objective of this study was to evaluate the safety and efficacy of a combination of the isocitrate dehydrogenase-2 (IDH2) inhibitor enasidenib (Idhifa) and the hypomethylating agent azacitidine (Onureg) versus azacitidine alone in patients with mutant IDH2 newly diagnosed acute myeloid leukemia (AML). In addition, the effect of these therapies on 2-hydroxyglutarate (2-HG) and mutant IDH2 variant allele frequency (VAF) was examined. Enasidenib is an oral, small-molecule inhibitor of mutant IDH2 proteins that suppresses 2-HG, which in turn reduces DNA methylation. This restores function to the alpha-ketoglutarate–dependent ten-eleven translocation family of methylcytosine dioxygenases and other substrates of these enzymes. Azacitidine reduces DNA methylation by inhibiting DNA methyltransferases. Enasidenib and azacitidine individually induce an overall response rate (ORR) of approximately 30% and a complete remission rate of approximately 20% in patients with IDH2 mutation–positive newly diagnosed AML.
Patients were randomized 2:1 to receive enasidenib plus azacitidine (N = 68) or azacitidine only (N = 33). All cycles were 28 days. Patients received azacitidine 75 mg/m2 subcutaneously daily for a 7-day cycle. Patients in the enasidenib plus azacitidine arm also received enasidenib 100 mg daily. The primary end point was ORR defined as the proportion of patients achieving complete remission, complete remission with incomplete count recovery, partial remission, or morphologic leukemia-free state. Additional end points included duration of response (DOR), overall survival (OS), event-free survival (EFS), and changes in 2-HG levels and mutant IDH2 VAF.
Patient median age was 75 years (range, 57-85 years), and 83% had intermediate-risk cytogenetics. At data cutoff, 21 patients in the enasidenib plus azacitidine arm and 1 patient in the azacitidine-only arm were still on treatment, with the most common causes of discontinuation being disease progression (31% in the enasidenib plus azacitidine arm and 52% in the azacitidine-only arm). The median number of treatment cycles were 10 (range, 1-26) versus 6 (range, 1-28) for the enasidenib plus azacitidine and azacitidine monotherapy arms, respectively.
Enasidenib plus azacitidine resulted in significantly improved ORR and complete remission when compared with azacitidine only. ORRs were 48% (95% confidence interval [CI], 58-81) versus 14% (95% CI, 26-63) in favor of the enasidenib plus azacitidine arm. Median DOR was 24.1 months for those in the enasidenib plus azacitidine arm and 12.1 months for those in the azacitidine-only arm. Median OS was similar between the 2 arms at 22 months (hazard ratio [HR], 0.99; 95% CI, 0.52-1.87; P = .97). Median EFS was improved in the enasidenib plus azacitidine arm (17.2 months) versus the azacitidine-only arm (10.8 months; HR, 0.59; 95% CI, 0.30-1.17; P = .13). Enasidenib plus azacitidine was correlated with significantly greater maximal changes from baseline in mutant IDH2 VAF (median, –83.4% vs –17.7% with azacitidine only; P <.01) and 2-HG levels (median, –97.8% vs –54.3%; P <.01).
Common grade 3/4 treatment-related adverse events in the enasidenib plus azacitidine and azacitidine-only arms were thrombocytopenia (37% vs 19%, respectively), neutropenia (35% vs 22%, respectively), anemia (19% vs 22%, respectively), and febrile neutropenia (15% vs 16%, respectively). Infections (grade 3/4) occurred in 18% of enasidenib plus azacitidine patients and 31% of azacitidine-only patients. In the enasidenib plus azacitidine arm, 12 (18%) patients had IDH inhibitor–associated differentiation syndrome.
Authors concluded that response rates were significantly improved with enasidenib plus azacitidine compared with azacitidine alone, and the combination therapy also led to significant reductions in 2-HG concentrations and mutant IDH2, neither of which occurred in the azacitidine monotherapy arm. Enasidenib plus azacitidine was generally well-tolerated.
DiNardo C, Schuh A, Stein E, et al. Enasidenib plus Azacitidine Significantly Improves Complete Remission and Overall Response Rates versus Azacitidine Monotherapy in Mutant-IDH2 Newly Diagnosed Acute Myeloid Leukemia (ND-AML). Presented at: 25th European Hematology Association Congress Virtual; June 11-21, 2020. Abstract S139.