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

   

Authors:	Choe, S.; Wang, H.; DiNardo, C. D.; Stein, E. M.; de Botton, S.; Roboz, G. J.; Altman, J. K.; Mims, A. S.; Watts, J. M.; Pollyea, D. A.; Fathi, A. T.; Tallman, M. S.; Kantarjian, H. M.; Stone, R. M.; Quek, L.; Konteatis, Z.; Dang, L.; Nicolay, B.; Nejad, P.; Liu, G.; Zhang, V.; Liu, H.; Goldwasser, M.; Liu, W.; Marks, K.; Bowden, C.; Biller, S. A.; Attar, E. C.; Wu, B.
Article 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 © 2020 by The American Society of Hematology
Journal Title:	Blood Advances
Volume:	4
Issue:	9
ISSN:	2473-9529
Publisher:	American Society of Hematology
Date Published:	2020-05-12
Start Page:	1894
End Page:	1905
Language:	English
DOI:	10.1182/bloodadvances.2020001503
PUBMED:	32380538
PROVIDER:	scopus
PMCID:	PMC7218420
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85085010187&doi=10.1182%2fbloodadvances.2020001503&partnerID=40&md5=a991635b47623d971ce3e35dd4d099ab
Notes:	Article -- Source: Scopus

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