| Literature DB >> 32380538 |
Sung Choe1, Hongfang Wang1, Courtney D DiNardo2, Eytan M Stein3, Stéphane de Botton4, Gail J Roboz5, Jessica K Altman6, Alice S Mims7, Justin M Watts8, Daniel A Pollyea9, Amir T Fathi10, Martin S Tallman3, Hagop M Kantarjian2, Richard M Stone11, Lynn Quek12, Zenon Konteatis1, Lenny Dang1, Brandon Nicolay1, Parham Nejad1, Guowen Liu1, Vickie Zhang1, Hua Liu1, Meredith Goldwasser1, Wei Liu1, Kevin Marks1, Chris Bowden1, Scott A Biller1, Eyal C Attar1, Bin Wu1.
Abstract
Isocitrate dehydrogenase (IDH) 1 and 2 mutations result in overproduction of D-2-hydroxyglutarate (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.Entities:
Year: 2020 PMID： 32380538 PMCID： PMC7218420 DOI： 10.1182/bloodadvances.2020001503
Source DB: PubMed Journal: Blood Adv ISSN： 2473-9529