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Ref Type Journal Article
PMID (32380538)
Authors Choe S, Wang H, DiNardo CD, Stein EM, de Botton S, Roboz GJ, Altman JK, Mims AS, Watts JM, Pollyea DA, Fathi AT, Tallman MS, Kantarjian HM, Stone RM, 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 SA, Attar EC, Wu B
Title Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML.
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
IDH1 D279N missense unknown IDH1 D279N does not lie within any known functional domains of the Idh1 protein (UniProt.org). D279N results in cellular transformation in the context of IDH1 R132H (PMID: 36056177) and has been associated with acquired IDH1 inhibitor resistance with IDH1 R132C (PMID: 32380538; PMID: 36056177), but has not been individually characterized and therefore, its effect on Idh1 protein function is unknown (PubMed, Jan 2024).
IDH1 G131A missense unknown IDH1 G131A does not lie within any known functional domains of the Idh1 protein (UniProt.org). G131A has been associated with acquired IDH1 inhibitor resistance with IDH1 R132C (PMID: 32380538), but has not been biochemically characterized and therefore, its effect on Idh1 protein function is unknown (PubMed, Mar 2024).
IDH1 G289D missense unknown IDH1 G289D does not lie within any known functional domains of the Idh1 protein (UniProt.org). G289D has been associated with acquired IDH1 inhibitor resistance (PMID: 32380538), but has not been biochemically characterized and therefore, its effect on Idh1 protein function is unknown (PubMed, Apr 2024).
IDH1 R119P missense unknown IDH1 R119P does not lie within any known functional domains of the Idh1 protein (UniProt.org). R119P has been associated with acquired IDH1 inhibitor resistance with IDH1 R132C/L (PMID: 32380538), but has not been biochemically characterized and therefore, its effect on Idh1 protein function is unknown (PubMed, Apr 2024). Y
IDH1 S280F missense no effect - predicted IDH1 S280F does not lie within any known functional domains of the Idh1 protein (UniProt.org). S280F confers resistance to an IDH1 inhibitor in the presence of IDH1 R132C/H (PMID: 29950729, PMID: 32380538, PMID: 36222845), but does not lead to increased production of the oncometabolite 2HG (R(-)-2-hydroxyglutarate) in cell culture (PMID: 36222845), and therefore, is predicted to have no effect on Idh1 protein function. Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
IDH1 R132C IDH1 D279N IDH1 H315D acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 H315D and D279N were identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132C who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R132C IDH1 D279N IDH2 R140Q acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 D279N and IDH2 R140Q were identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132C who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 G131A IDH1 R132C acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 G131A was identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132C who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R132H IDH2 R140Q acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH2 R140Q was identified at progression in 4 patients with acute myeloid leukemia harboring IDH1 R132H who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R119P IDH1 R132L acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 R119P was identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132L who previously had a response of stable disease with Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R132L IDH2 R140Q acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH2 R140Q was identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132L who previously had a response of stable disease with Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R132G IDH1 D279N IDH1 G289D acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 G289D and D279N were identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132G who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R132C IDH2 R140Q acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH2 R140Q was identified at progression in 5 patients with acute myeloid leukemia harboring IDH1 R132C who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R132C IDH1 S280F acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 S280F was identified at progression in 3 patients with acute myeloid leukemia harboring IDH1 R132C who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R119P IDH1 R132L IDH2 R140Q acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 R119P and IDH2 R140Q were identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132L who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538
IDH1 R119P IDH1 R132S acute myeloid leukemia predicted - resistant Ivosidenib Case Reports/Case Series Actionable In a Phase I trial, IDH1 R119P was identified at progression in a patient with acute myeloid leukemia harboring IDH1 R132S who previously responded to Tibsovo (ivosidenib) treatment (PMID: 32380538; NCT02074839). 32380538