Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML
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Open Access
- 7 May 2020
- journal article
- research article
- Published by American Society of Hematology in Blood Advances
- Vol. 4 (9), 1894-1905
- https://doi.org/10.1182/bloodadvances.2020001503
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 #NCT02074839Keywords
This publication has 46 references indexed in Scilit:
- Terminal myeloid differentiation in vivo is induced by FLT3 inhibition in FLT3/ITD AMLBlood, 2012
- Potential application ofIDH1andIDH2mutations as prognostic indicators in non-promyelocytic acute myeloid leukemia: a meta-analysisLeukemia & Lymphoma, 2012
- IDH mutation impairs histone demethylation and results in a block to cell differentiationNature, 2012
- The sodium‐dependent di‐ and tricarboxylate transporter, NaCT, is not responsible for the uptake of D‐, L‐2‐hydroxyglutarate and 3‐hydroxyglutarate into neuronsJournal of Inherited Metabolic Disease, 2011
- Oncometabolite 2-Hydroxyglutarate Is a Competitive Inhibitor of α-Ketoglutarate-Dependent DioxygenasesCancer Cell, 2011
- Acute Myeloid Leukemia With IDH1 or IDH2 MutationAmerican Journal of Clinical Pathology, 2011
- IDH1 and IDH2 Mutations Are Frequent Genetic Alterations in Acute Myeloid Leukemia and Confer Adverse Prognosis in Cytogenetically Normal Acute Myeloid Leukemia With NPM1 Mutation Without FLT3 Internal Tandem DuplicationJournal of Clinical Oncology, 2010
- The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting α-Ketoglutarate to 2-HydroxyglutarateCancer Cell, 2010
- Cancer-associated IDH1 mutations produce 2-hydroxyglutarateNature, 2009
- Recurring Mutations Found by Sequencing an Acute Myeloid Leukemia GenomeThe New England Journal of Medicine, 2009