@article{fb6ad421618849d69f7eda7c54e28727,
title = "Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML",
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",
author = "Sung Choe and Hongfang Wang and DiNardo, {Courtney D.} and Stein, {Eytan M.} and {de Botton}, St{\'e}phane and Roboz, {Gail J.} and Altman, {Jessica K.} and Mims, {Alice S.} and Watts, {Justin M.} and Pollyea, {Daniel A.} and Fathi, {Amir T.} and Tallman, {Martin S.} and Kantarjian, {Hagop M.} and Stone, {Richard M.} and Lynn Quek and Zenon Konteatis and Lenny Dang and Brandon Nicolay and Parham Nejad and Guowen Liu and Vickie Zhang and Hua Liu and Meredith Goldwasser and Wei Liu and Kevin Marks and Chris Bowden and Biller, {Scott A.} and Attar, {Eyal C.} and Bin Wu",
note = "Funding Information: Medical writing assistance was provided by Helen Varley of Excel Medical Affairs, Horsham, United Kingdom, and funded by Agios. Funding Information: Conflict-of-interest disclosure: S.C., H.W., Z.K., L.D., B.N., P.N., G.L., V.Z., H.L., M.G., W.L., K.M., C.B., S.A.B., and B.W. are employees of and have equity ownership in Agios. C.D.D. has received honoraria and research funding from AbbVie, Agios, Cel-gene, and Daiichi Sankyo, and honoraria from MedImmune. E.M.S. has membership on the board of directors or advisory committee for Agios, Astellas, Celgene, Daiichi Sankyo, Genentech, Novartis, PTC Therapeutics, and Syros, and has acted as consultant for Agios. S.d.B. has acted as consultant for AbbVie, Agios, Astellas, Bayer, Celgene, Daiichi Sankyo, Forma, Janssen, Novartis, Pfizer, Pierre Fabre, Servier, and Syros; has received research funding from Agios and Forma; and is on a speaker bureau for Celgene. G.J.R. has acted as consultant or member of a data and safety monitoring committee for AbbVie, Actinium, Agios, Amphivena, Argenx, Astellas, Astex, Bayer, Celgene, Celltrion, Daiichi Sankyo, Eisai, Janssen, Jazz, MEI Pharma, Novartis, Orsenix, Otsuka, Pfizer, Roche/Genentech, Sandoz, Takeda, and Trovagene, and has Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology",
year = "2020",
month = may,
day = "12",
doi = "10.1182/bloodadvances.2020001503",
language = "English (US)",
volume = "4",
pages = "1894--1905",
journal = "Blood advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "9",
}