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

Sung Choe; Hongfang Wang; Courtney D. DiNardo; Eytan M. Stein; Stéphane de Botton; Gail J. Roboz; Jessica K. Altman; Alice S. Mims; Justin M. Watts; Daniel A. Pollyea; Amir T. Fathi; Martin S. Tallman; Hagop M. Kantarjian; Richard M. Stone; Lynn Quek; Zenon Konteatis; Lenny Dang; Brandon Nicolay; Parham Nejad; Guowen Liu; Vickie Zhang; Hua Liu; Meredith Goldwasser; Wei Liu; Kevin Marks; Chris Bowden; Scott A. Biller; Eyal C. Attar; Bin Wu

doi:10.1182/bloodadvances.2020001503

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

Sung Choe, Hongfang Wang, Courtney D. DiNardo, Eytan M. Stein, Stéphane de Botton, Gail J. Roboz, Jessica K. Altman, Alice S. Mims, Justin M. Watts, Daniel A. Pollyea, Amir T. Fathi, Martin S. Tallman, Hagop M. Kantarjian, Richard M. Stone, Lynn Quek, Zenon Konteatis, Lenny Dang, Brandon Nicolay, Parham Nejad, Guowen LiuVickie Zhang, Hua Liu, Meredith Goldwasser, Wei Liu, Kevin Marks, Chris Bowden, Scott A. Biller, Eyal C. Attar, Bin Wu

Leukemia

Research output: Contribution to journal › Article › peer-review

120 Scopus citations

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

Original language	English (US)
Pages (from-to)	1894-1905
Number of pages	12
Journal	Blood Advances
Volume	4
Issue number	9
DOIs	https://doi.org/10.1182/bloodadvances.2020001503
State	Published - May 12 2020

ASJC Scopus subject areas

Hematology

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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., ... Wu, B. (2020). Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML. Blood Advances, 4(9), 1894-1905. https://doi.org/10.1182/bloodadvances.2020001503

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 2020, 'Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML', Blood Advances, vol. 4, no. 9, pp. 1894-1905. https://doi.org/10.1182/bloodadvances.2020001503

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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",

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AU - Choe, Sung

AU - Wang, Hongfang

AU - DiNardo, Courtney D.

AU - Stein, Eytan M.

AU - de Botton, Stéphane

AU - Roboz, Gail J.

AU - Altman, Jessica K.

AU - Mims, Alice S.

AU - Watts, Justin M.

AU - Pollyea, Daniel A.

AU - Fathi, Amir T.

AU - Tallman, Martin S.

AU - Kantarjian, Hagop M.

AU - Stone, Richard M.

AU - Quek, Lynn

AU - Konteatis, Zenon

AU - Dang, Lenny

AU - Nicolay, Brandon

AU - Nejad, Parham

AU - Liu, Guowen

AU - Zhang, Vickie

AU - Liu, Hua

AU - Goldwasser, Meredith

AU - Liu, Wei

AU - Marks, Kevin

AU - Bowden, Chris

AU - Biller, Scott A.

AU - Attar, Eyal C.

AU - Wu, Bin

PY - 2020/5/12

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N2 - 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

AB - 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

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

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