AML-432 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

Courtney D. DiNardo, Stéphane de Botton, Alberto Risueño, Andre C. Schuh, Bob Löwenberg, Hee Je Kim, Paresh Vyas, Andrew H. Wei, Eytan M. Stein, Hartmut Döhner, Amir T. Fathi, Patricia Martin-Regueira, Lilia Taningco, Iryna Bluemmert, Xin Yu, Wendy L. See, Maroof Hasan

Research output: Contribution to journalMeeting AbstractAcademicpeer-review

Abstract

Context: IDH2 mutations (mIDH2) occur in ~8%-19% of patients with AML, typically as R140Q (~75%) or R172K (~25%) point mutations, which have distinct functional effects and prognostic relevance. In the phase 3 IDHENTIFY trial, enasidenib did not significantly improve OS vs CCR in older patients with mIDH2 relapsed/refractory AML, but a trend for improved OS with enasidenib was detected in patients with IDH2-R172. Objective: Investigate molecular profiles and OS in mIDH2 variant subgroups (R140/R172). Methods: IDHENTIFY (NCT02577406) enrolled patients aged ≥60 years who had received 2-3 prior AML-directed therapies. Patients were randomized 1:1 to enasidenib 100-mg/day or CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care). Co-occurring mutations were identified by targeted NGS of BMMC DNA. Total 2-hydroxyglutarate was determined by LC/MS. Results: Of 319 patients enrolled, 88 (28%; 43 enasidenib, 45 CCR) had mIDH2-R172 and 229 (72%; 115 enasidenib, 114 CCR) had mIDH2-R140. Median baseline 2-hydroxyglutarate level and IDH2 VAF were similar between arms and mIDH2 subgroups. Patients with mIDH2-R172 had fewer baseline mutations (median 4 [range 2-8]) than those with mIDH2-R140 (5 [1-11]) (P<0.0001). Common co-mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with R172, R140 was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2, whereas DNMT3A and TP53 were more common with R172. In Cox multivariate analysis including mIDH2 variant, DNMT3A status, and number of baseline mutations, mIDH2-R172 was significantly correlated with improved OS (P=0.04 vs R140) in the enasidenib arm, and number of baseline mutations was significantly (P<0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 months with enasidenib vs 7.8 months with CCR (HR, 0.59 [95%CI 0.35-0.98]; P=0.039); 1-year survival rates were 62% and 30%. In the R140 subgroup, median OS was 5.7 months in both arms (0.93 [0.70-1.24]; P=0.61), and 1-year survival rates were 29% and 25% with enasidenib and CCR. Conclusions: Mutational burden and co-mutational profiles differed between patients with mIDH2-R140 and mIDH2-R172 relapsed/refractory AML. In the R172 subgroup, median OS and 1-year survival rate with enasidenib were approximately double those with CCR.

Original languageEnglish
Pages (from-to)S249-S250
JournalClinical Lymphoma, Myeloma and Leukemia
Volume22
DOIs
Publication statusPublished - 1 Oct 2022

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