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

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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
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
Publication status	Published - 12 May 2020

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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

@article{77df15175b1a48d4be48f87f69e3647a,

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",

author = "Sung Choe and Hongfang Wang and DiNardo, {Courtney D.} and Stein, {Eytan M.} and {de Botton}, St{\'e}phane and Roboz, {Gail J.} and Altman, {Jessica K.} and Mims, {Alice S.} and Watts, {Justin M.} and Pollyea, {Daniel A.} and Fathi, {Amir T.} and Tallman, {Martin S.} and Kantarjian, {Hagop M.} and Stone, {Richard M.} and Lynn Quek and Zenon Konteatis and Lenny Dang and Brandon Nicolay and Parham Nejad and Guowen Liu and Vickie Zhang and Hua Liu and Meredith Goldwasser and Wei Liu and Kevin Marks and Chris Bowden and Biller, {Scott A.} and Attar, {Eyal C.} and Bin Wu",

note = "Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology",

year = "2020",

month = may,

day = "12",

doi = "10.1182/bloodadvances.2020001503",

language = "English",

volume = "4",

pages = "1894--1905",

journal = "Blood Advances",

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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

TY - JOUR

T1 - Molecular mechanisms mediating relapse following ivosidenib monotherapy in IDH1-mutant relapsed or refractory AML

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

Y1 - 2020/5/12

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

UR - http://www.scopus.com/inward/record.url?scp=85085010187&partnerID=8YFLogxK

U2 - 10.1182/bloodadvances.2020001503

DO - 10.1182/bloodadvances.2020001503

M3 - Article

C2 - 32380538

AN - SCOPUS:85085010187

SN - 2473-9529

VL - 4

SP - 1894

EP - 1905

JO - Blood Advances

JF - Blood Advances

IS - 9

ER -

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

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