Interim Analysis Suggest Azacitidine with Enasidenib More Effective Than Monotherapy


Results of an interim analysis of a phase 2 trial are suggesting enasidenib plus azacitidine may be more effective than azacitidine monotherapy alone.

Courtney DiNardo, MD

Courtney DiNardo, MD

Interim results of a phase 2 study from The University of Texas MD Anderson Cancer Center suggest that a combination of standard chemotherapy azacitidine with enasidenib could boost complete remission for newly diagnosed leukemia patients with IDH2 mutations.

Presented at the American Society of Hematology (ASH) 2019 annual meeting by Courtney DiNardo, MD, clinical researcher in the Department of Leukemia at the MD Anderson Cancer Center, results indicate enasidenib plus azacitidine was associated with significant improvements in complete remission and overall response rates and significant mutant IDH2 variant allele frequencies (VAF) reductions compared with azacitidine monotherapy.

"These findings are significant, given that the older a patient is, the more likely they are to have an IDH2 mutation," DiNardo said. "This combination treatment may offer an alternative option for older patients who may not be candidates for intensive chemotherapy or who have relapsed disease."

In an effort to assess the efficacy of the enasidenib, which is an oral, small-molecule inhibitor of mutant IDH2(mIDH2) that promotes myeloid cell differentiation, investigators enrolled 101 adult patients who were ineligible to receive intensive chemotherapy in a multicenter, randomized, open-label trial. For inclusion in the trial, patients needed newly diagnosed mIDH2 acute myeloid leukemia and had an Eastern Cooperative Oncology Group Performance Status score of 2 or less.

Patients included in the study were randomized in a 2:1 ratio to receive combination therapy with enasidenib or azacitidine monotherapy in repeated 28-day cycles. Investigators noted all patients received subcutaneous azacitidine 75mg/m2 daily for the first 7 days of each treatment cycle and patients receiving monotherapy received continuous enasidenib 100 mg daily during treatment cycles.

The primary endpoint of the trial is overall response rate, which, for the purpose of the study, includes complete remission, complete remission with incomplete blood or platelet count recovery, partial remission, and morphologic leukemia-free state. Investigators pointed out chi-square tests were used to calculate P values for comparisons and duration of response was estimated using the Kaplan-Meier method. mIDH2 VAF in bone marrow mononuclear cells was assessed by digital polymerase chain reaction.

Interim results of the analyses presented at ASH 2019 indicated response rate were significantly higher with combination therapy compared to azacitinide with overall response rates of 68% and 42%, respectively (P=0.0155). Additionally, the observed rates of complete response were 50% and 12%, respectively (P=0.0002).

In regard to treatment-related adverse events, investigators noted multiple grade 3 or 4 adverse events occurring in 10% or more of the combination therapy group. These included neutropenia (34%), thrombocytopenia (34%), anemia (21%), febrile neutropenia (12%), and IDH differentiation syndrome (10%). In comparison, these events occurred in 19%, 19%, 22%, 13%, and 0% of patients in the azacitinide monotherapy group.

Overall, the observed rate of treatment-related grade 3 or 4 adverse events was 16% in the enasidenib combination therapy group and 31% in the azacitinide monotherapy group. Investigators noted 5 deaths were reported in the combination therapy group—3 from infectious complications and 2 due to possible IDH differentiation syndrome—and 1 in the monotherapy group, which was caused by progressive disease.

"IDH2 mutations occur in 8% to 19% of patients with AML,” DiNardo said. “This is the first report of interim outcomes from this study, which represent at least one year of follow up for all participating patients. In general, the combination therapy was well tolerated."

This study, titled “Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study,” was presented at ASH 2019.

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