Mutation Status Impacts Efficacy of Enasidenib in Patients with AML

By Kerri Fitzgerald - Last Updated: October 3, 2022

A phase III study compared the efficacy of enasidenib versus conventional care regimens in patients with IDH2-relapsed/refractory acute myeloma leukemia (AML) and did not observe a significant improvement in overall survival (OS) with enasidenib. However, the researchers observed a trend for improved OS with enasidenib in patients with IDH2-R172 mutations.

Courtney D. DiNardo, MD, of the University Texas MD Anderson Cancer Center, discussed the findings during the Society of Hematologic Oncology (SOHO) Annual Meeting.

IDH2 mutations occur in approximately 8% to 19% of patients with AML, most commonly R140Q (~75%) or R172K (~25%) point mutations.

The randomized, open-label IDHENTIFY trial enrolled 319 patients aged 60 years or older who had received two to three prior therapies for AML. Patients were randomized 1:1 to receive enasidenib 100 mg per day or conventional care regimens, which included azacitidine, intermediate- or low-dose cytarabine, or supportive care.

Of the patients included, 88 (28%) had IDH2-R172 mutations, and 229 (72%) had IDH2-R140 mutations. Median baseline 2-hydroxyglutarate level and IDH2 variant allele frequency were similar between arms and IDH2 mutation subgroups. Patients with IDH2-R172 mutations had fewer baseline mutations (median, 4 mutations; range, 2-8 mutations) than those with IDH2-R140 mutations (median, 5 mutations; range, 1-11 mutations; P<.0001).

The researchers found that presence of IDH2-R172 mutation was significantly associated with improved OS in the enasidenib cohort compared with those with IDH2-R140 mutation (P<.04). In addition, the number of baseline mutations significantly impacted OS in the conventional care regimen cohort (P<.01).

Median OS in the IDH2-R172 group was 14.6 months with enasidenib versus 7.8 months with conventional care (hazard ratio [HR], 0.69; 95% CI, 0.35-0.98; P=.039). One-year survival rates were 62% and 30%, respectively.

The trial “highlighted the fact that IDH2-R172 patients actually derived significant benefit with enasidenib, with essentially a doubling of overall survival to about 14 months in the relapsed setting, which is pretty impressive for an oral outpatient single-daily oral therapy,” Dr. DiNardo told Blood Cancers Today.

Median OS in the IDH2-R140 group was 5.7 months in both treatment cohorts (HR, 0.93; 95% CI, 0.70-1.24; P=.61), and the one-year survival rates were 29% in the enasidenib cohort and 25% in the conventional care group.

“The key takeaway is that if you have a patient with relapsed AML, the most important thing to do is to check the mutational and the genomic profile of your patient at relapse because there are effective treatment options for AML patients based on those mutations,” said Dr. DiNardo. “You want to make sure that you know the kind of fingerprint of the leukemia at any treatment time point so that you know the best way to treat it.”


DiNardo CD, de Botton S, Risueño A, et al. Overall survival (OS) by IDH2 mutant allele (R140 or R172) in patients with late-stage, mutant-IDH2 relapsed/refractory acute myeloid leukemia (AML) treated with enasidenib or conventional care regimens (CCR) in the randomized, open-label, phase 3 IDHENTIFY trial. Abstract #AML-432. Presented at the 2022 Society of Hematologic Oncology (SOHO) Annual Meeting, September 28-October 1, 2022.

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