Adding enasidenib to azacitidine significantly improved responses in older patients with newly diagnosed, IDH2-mutant acute myeloid leukemia (AML), according to research published in The Lancet Oncology.

In a phase 1b/2 trial (ClinicalTrials.gov Identifier: NCT02677922), researchers compared enasidenib plus azacitidine with azacitidine monotherapy. The trial enrolled 107 patients with newly diagnosed, IDH2-mutant AML who were not eligible for intensive chemotherapy.

In the phase 1b portion of the trial, 6 patients received enasidenib at 100 mg (3 patients) or 200 mg (3 patients) per day, in combination with azacitidine. There were no dose-limiting toxicities, and a 100 mg dose of enasidenib was selected as the phase 2 dose.


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In phase 2, 101 patients were randomly assigned to receive enasidenib plus azacitidine (68 patients) or azacitidine alone (33 patients). The patients’ median age was 75 years (range, 71-78 years), and 53% were men.

The overall response rate was significantly higher in the enasidenib arm than in the azacitidine-alone arm — 74% and 36%, respectively (odds ratio, 4.9; 95% CI, 2.0-11.9; P =.0003). The rate of complete remission was 54% and 12%, respectively (P <.0001).

The duration of response was 24.1 months in the enasidenib arm and 9.9 months in the azacitidine-alone arm. The duration of complete remission was not reached and 12.7 months, respectively.

Hematologic improvement in erythroid, platelet, or neutrophil lineages was observed in 71% of patients in the combination arm and 58% of patients in the monotherapy arm (P =.19).

The median event-free survival was 15.9 months in the enasidenib arm and 11.9 months in the azacitidine-alone arm (hazard ratio [HR], 0.59; 95% CI, 0.30-1.13; P =.11). The median overall survival was 22.0 months and 22.3 months, respectively (HR, 0.99; 95% CI, 0.52-1.87; P =.97).

The most common treatment-related grade 3-4 adverse events (AEs) were thrombocytopenia (37% in the combination arm and 19% in the monotherapy arm) and neutropenia (37% and 25%, respectively).

Serious treatment-related AEs occurred in 43% of patients in the combination arm and 44% of those in the monotherapy arm. There were no treatment-related deaths.

“The overall response rate with enasidenib and azacitidine in combination was greater than historical response rates for either agent when used as monotherapy,” the researchers wrote. “It is unknown whether adding or sequencing enasidenib with a venetoclax-azacitidine combination regimen would be tolerable and improve efficacy outcomes even further in a similar patient population.”

Disclosures: This research was supported by Celgene, a subsidiary of Bristol Myers Squibb. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

DiNardo CD, Schuh AC, Stein EM, et al. Enasidenib plus azacitidine versus azacitidine alone in patients with newly diagnosed, mutant-IDH2 acute myeloid leukaemia (AG221-AML-005): A single-arm, phase 1b and randomised, phase 2 trial. Lancet Oncol. Published online October 18, 2021. doi:10.1016/S1470-2045(21)00494-0