Somatic gene mutation patterns and burden influence outcomes with enasidenib in relapsed/refractory IDH2-mutated AML.

Autor: Risueño A; Bristol Myers Squibb, Lawrenceville, 3401 Princeton Pike, Lawrence Township, NJ 08648, United States., See WL; Bristol Myers Squibb, Summit, 86 Morris Avenue, Summit, NJ 07901, United States., Bluemmert I; Celgene International Sàrl, a Bristol-Myers Squibb Company, Route de Perreux 1, Boudry 2017, Switzerland., de Botton S; Institut Gustave Roussy, 114 Rue Edouard Vaillant, Villejuif 94805, France., DiNardo CD; The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, United States., Fathi AT; Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114, United States., Schuh AC; Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON M5G 2C4, Canada., Montesinos P; Hospital Universitario y Politécnico La Fe, Avinguda de Fernando Abril Martorell, 106, Valencia 46026, Spain., Vyas P; MRC Molecular Haematology Unit and Oxford Biomedical Research Centre, University of Oxford and Oxford University Hospitals, Headley Way, Headington, Oxford OX3 9DS, United Kingdom., Prebet T; Bristol Myers Squibb, Summit, 86 Morris Avenue, Summit, NJ 07901, United States., Gandhi A; Bristol Myers Squibb, Summit, 86 Morris Avenue, Summit, NJ 07901, United States., Hasan M; Bristol Myers Squibb, Summit, 86 Morris Avenue, Summit, NJ 07901, United States. Electronic address: maroof.hasan@bms.com.
Jazyk: angličtina
Zdroj: Leukemia research [Leuk Res] 2024 May; Vol. 140, pp. 107497. Date of Electronic Publication: 2024 Mar 27.
DOI: 10.1016/j.leukres.2024.107497
Abstrakt: 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.
Competing Interests: Declaration of Competing Interest AR reports current employment, equity ownership, and patents with Bristol Myers Squibb. WLS is a contractor with Bristol Myers Squibb. IB, TP, AG, and MH report current employment and equity ownership with Bristol Myers Squibb. SdB reports receiving honoraria from AbbVie, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, Loxo, and Servier; serving in a consultancy position with Bristol Myers Squibb, GlaxoSmithKline, Remix, Servier, and Syndax; speakers’ bureau participation for AbbVie, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, and Servier; receiving research funding from Auron and Forma; and having travel expenses paid by AbbVie and Servier. CDD is a V Foundation Lloyd Family Scholar and Scholar in Clinical Research of The Leukemia & Lymphoma Society receiving research funding from AbbVie, Astex, Bristol Myers Squibb, Cleave, Forma, Foghorn, ImmuneOnc, Loxo, and Servier; receiving honoraria from Astellas, bluebird bio, Bristol Myers Squibb, Foghorn, Gilead, ImmuneOnc, Jazz Pharmaceuticals, Kura, Novartis, Servier, and Takeda; receiving support as a LLS Scholar in Clinical Research; serving in an advisory position for GenMab, GlaxoSmithKline, Kura, and Notable Labs; serving in a consultancy position for AbbVie and Servier; and equity ownership with Notable Labs. ATF reports receiving clinical trial support from AbbVie, Agios/Servier, and Celgene/Bristol Myers Squibb; advisory board participation with AbbVie, Agios/Servier, Amgen, Astellas, Blueprint, Celgene/Bristol Myers Squibb, Daiichi Sankyo, EnClear, Foghorn, Genentech, Immunogen, Kite, Kura Oncology, Mablytics, Menarini, Morphosys, Novartis, Orum, Pfizer, PureTech, Remix, Rigel, Seattle Genetics, Takeda, and Trillium; and serving in a consultancy position for Daiichi Sankyo, Forma, Ipsen, Menarini, Remix, and Rigel. ACS reports advisory board membership with AbbVie, Amgen, Astellas, Bristol Myers Squibb, GlycoMimetics, Jazz Pharmaceuticals, Kite/Gilead, Loxo, Novartis, Paladin, Pfizer, Servier, Syndax, and Teva; and serving as Chair of the Canadian Leukemia Study Group (CLSG). PM reports serving in a consultancy position with Astellas, Agios, Glycomimetics, Celgene/Bristol Myers Squibb, and Daiichi Sankyo; advisory board participation with AbbVie, Astellas, Celgene/Bristol Myers Squibb, Daiichi Sankyo, Incyte, Janssen, Novartis, and Pfizer; and receiving research support from AbbVie, Astellas, Celgene/Bristol Myers Squibb, Daiichi Sankyo, Janssen, Novartis, and Pfizer. PV reports receiving research funding from Bristol Myers Squibb.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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