Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML

Sung Choe, Hongfang Wang, Courtney D. DiNardo, Eytan M. Stein, Stéphane de Botton, Gail J. Roboz, Jessica K. Altman, Alice S. Mims, Justin M. Watts, Daniel A. Pollyea, Amir T. Fathi, Martin S. Tallman, Hagop M. Kantarjian, Richard M. Stone, Lynn Quek, Zenon Konteatis, Lenny Dang, Brandon Nicolay, Parham Nejad, Guowen LiuVickie Zhang, Hua Liu, Meredith Goldwasser, Wei Liu, Kevin Marks, Chris Bowden, Scott A. Biller, Eyal C. Attar, Bin Wu

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2hydroxyglutarate (2-HG) and impaired cellular differentiation. Ivosidenib, a targeted mutant IDH1 (mIDH1) enzyme inhibitor, can restore normal differentiation and results in clinical responses in a subset of patients with mIDH1 relapsed/refractory (R/R) acute myeloid leukemia (AML). We explored mechanisms of ivosidenib resistance in 174 patients with confirmed mIDH1 R/R AML from a phase 1 trial. Receptor tyrosine kinase (RTK) pathway mutations were associated with primary resistance to ivosidenib. Multiple mechanisms contributed to acquired resistance, particularly outgrowth of RTK pathway mutations and 2-HG–restoring mutations (second-site IDH1 mutations, IDH2 mutations). Observation of multiple concurrent mechanisms in individual patients underscores the complex biology of resistance and has important implications for rational combination therapy design. This trial was registered at www.clinicaltrials.gov as #NCT02074839

Original languageEnglish (US)
Pages (from-to)1894-1905
Number of pages12
JournalBlood Advances
Volume4
Issue number9
DOIs
StatePublished - May 12 2020

ASJC Scopus subject areas

  • Hematology

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