Somatic Gene Mutation Patterns and Burden Influence Outcomes With Enasidenib in Relapsed/Refractory IDH2-Mutated AML

Authors

Alberto Risueño
Wendy L See
Iryna Bluemmert
Stéphane de Botton
Courtney D DiNardo
Amir T Fathi
Andre C Schuh
Pau Montesinos
Paresh Vyas
Thomas Prebet
Anita Gandhi
Maroof Hasan

Language

English

Publication Date

5-1-2024

Journal

Leukemia Research

DOI

10.1016/j.leukres.2024.107497

PMID

38564986

Abstract

Limited treatment options are available for patients with relapsed/refractory acute myeloid leukemia (R/R AML). We recently reported results from the phase 3 IDHENTIFY trial (NCT02577406) showing improved response rates and event-free survival with enasidenib monotherapy compared with conventional care regimens (CCR) in heavily pretreated, older patients with late-stage R/R AML bearing IDH2 mutations. Here we investigated the prognostic impact of mutational burden and different co-mutation patterns at study entry within the predominant IDH2 variant subclasses, IDH2-R140 and IDH2-R172. The prognostic relevance of these variants is well documented in newly diagnosed AML, but data are lacking in R/R AML. In this large R/R AML patient cohort, targeted next-generation sequencing at baseline (screening) revealed distinct co-mutation patterns and mutational burden between subgroups bearing different IDH2 variants: variant IDH2-R140 was associated with greater mutational burden and was enriched predominantly with poor-risk mutations, including FLT3, RUNX1, and NRAS, while variant IDH2-R172 was associated with lower mutational burden and was preferentially co-mutated with DNMT3A. In multivariable analyses, RAS and RTK pathway mutations were significantly associated with decreased overall survival, after adjusting for treatment arm, IDH2 variant, and mutational burden. Importantly, enasidenib-mediated survival benefit was more pronounced in patients with IDH2-R172 variants.

Keywords

Adult, Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Aminopyridines, Drug Resistance, Neoplasm, Isocitrate Dehydrogenase, Leukemia, Myeloid, Acute, Mutation, Neoplasm Recurrence, Local, Prognosis, Triazines, Acute myeloid leukemia; Enasidenib; Gene mutation; IDH2-mutated; IDHENTIFY; Relapsed/refractory

Published Open-Access

yes

Recommended Citation

Risueño, Alberto; See, Wendy L; Bluemmert, Iryna; et al., "Somatic Gene Mutation Patterns and Burden Influence Outcomes With Enasidenib in Relapsed/Refractory IDH2-Mutated AML" (2024). Faculty, Staff and Student Publications. 5548.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5548