Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Blood advances	4	9	2020 05 12	1894-1905	Blood Adv

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 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
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 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	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 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 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 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 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 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 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 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