A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML

Sheng F. Cai; Ying Huang; Jennie R. Lance; Hsiaoyin Charlene Mao; Andrew J. Dunbar; Samantha N. McNulty; Todd Druley; Yan Li; Maria R. Baer; Wendy Stock; Tibor Kovacsovics; William G. Blum; Gary J. Schiller; Rebecca L. Olin; James M. Foran; Mark Litzow; Tara Lin; Prapti Patel; Matthew C. Foster; Michael Boyiadzis; Robert H. Collins; Jordan Chervin; Abigail Shoben; Jo Anne Vergilio; Nyla A. Heerema; Leonard Rosenberg; Timothy L. Chen; Ashley O. Yocum; Franchesca Druggan; Sonja Marcus; Mona Stefanos; Brian J. Druker; Alice S. Mims; Uma Borate; Amy Burd; John C. Byrd; Ross L. Levine; Eytan M. Stein

doi:10.1182/bloodadvances.2023010563

A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML

Sheng F. Cai, Ying Huang, Jennie R. Lance, Hsiaoyin Charlene Mao, Andrew J. Dunbar, Samantha N. McNulty, Todd Druley, Yan Li, Maria R. Baer, Wendy Stock, Tibor Kovacsovics, William G. Blum, Gary J. Schiller, Rebecca L. Olin, James M. Foran, Mark Litzow, Tara Lin, Prapti Patel, Matthew C. Foster, Michael BoyiadzisRobert H. Collins, Jordan Chervin, Abigail Shoben, Jo Anne Vergilio, Nyla A. Heerema, Leonard Rosenberg, Timothy L. Chen, Ashley O. Yocum, Franchesca Druggan, Sonja Marcus, Mona Stefanos, Brian J. Druker, Alice S. Mims, Uma Borate, Amy Burd, John C. Byrd, Ross L. Levine, Eytan M. Stein

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2 Scopus citations

Abstract

Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENAmonotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML.

Original language	English (US)
Pages (from-to)	429-440
Number of pages	12
Journal	Blood Advances
Volume	8
Issue number	2
DOIs	https://doi.org/10.1182/bloodadvances.2023010563
State	Published - Jan 23 2024
Externally published	Yes

ASJC Scopus subject areas

Hematology

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Cai, S. F., Huang, Y., Lance, J. R., Mao, H. C., Dunbar, A. J., McNulty, S. N., Druley, T., Li, Y., Baer, M. R., Stock, W., Kovacsovics, T., Blum, W. G., Schiller, G. J., Olin, R. L., Foran, J. M., Litzow, M., Lin, T., Patel, P., Foster, M. C., ... Stein, E. M. (2024). A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML. Blood Advances, 8(2), 429-440. https://doi.org/10.1182/bloodadvances.2023010563

Cai, SF, Huang, Y, Lance, JR, Mao, HC, Dunbar, AJ, McNulty, SN, Druley, T, Li, Y, Baer, MR, Stock, W, Kovacsovics, T, Blum, WG, Schiller, GJ, Olin, RL, Foran, JM, Litzow, M, Lin, T, Patel, P, Foster, MC, Boyiadzis, M, Collins, RH, Chervin, J, Shoben, A, Vergilio, JA, Heerema, NA, Rosenberg, L, Chen, TL, Yocum, AO, Druggan, F, Marcus, S, Stefanos, M, Druker, BJ, Mims, AS, Borate, U, Burd, A, Byrd, JC, Levine, RL & Stein, EM 2024, 'A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML', Blood Advances, vol. 8, no. 2, pp. 429-440. https://doi.org/10.1182/bloodadvances.2023010563

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title = "A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML",

abstract = "Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENAmonotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML.",

author = "Cai, {Sheng F.} and Ying Huang and Lance, {Jennie R.} and Mao, {Hsiaoyin Charlene} and Dunbar, {Andrew J.} and McNulty, {Samantha N.} and Todd Druley and Yan Li and Baer, {Maria R.} and Wendy Stock and Tibor Kovacsovics and Blum, {William G.} and Schiller, {Gary J.} and Olin, {Rebecca L.} and Foran, {James M.} and Mark Litzow and Tara Lin and Prapti Patel and Foster, {Matthew C.} and Michael Boyiadzis and Collins, {Robert H.} and Jordan Chervin and Abigail Shoben and Vergilio, {Jo Anne} and Heerema, {Nyla A.} and Leonard Rosenberg and Chen, {Timothy L.} and Yocum, {Ashley O.} and Franchesca Druggan and Sonja Marcus and Mona Stefanos and Druker, {Brian J.} and Mims, {Alice S.} and Uma Borate and Amy Burd and Byrd, {John C.} and Levine, {Ross L.} and Stein, {Eytan M.}",

note = "Publisher Copyright: {\textcopyright} 2024 by The American Society of Hematology.",

year = "2024",

month = jan,

day = "23",

doi = "10.1182/bloodadvances.2023010563",

language = "English (US)",

volume = "8",

pages = "429--440",

journal = "Blood Advances",

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T1 - A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML

AU - Cai, Sheng F.

AU - Huang, Ying

AU - Lance, Jennie R.

AU - Mao, Hsiaoyin Charlene

AU - Dunbar, Andrew J.

AU - McNulty, Samantha N.

AU - Druley, Todd

AU - Li, Yan

AU - Baer, Maria R.

AU - Stock, Wendy

AU - Kovacsovics, Tibor

AU - Blum, William G.

AU - Schiller, Gary J.

AU - Olin, Rebecca L.

AU - Foran, James M.

AU - Litzow, Mark

AU - Lin, Tara

AU - Patel, Prapti

AU - Foster, Matthew C.

AU - Boyiadzis, Michael

AU - Collins, Robert H.

AU - Chervin, Jordan

AU - Shoben, Abigail

AU - Vergilio, Jo Anne

AU - Heerema, Nyla A.

AU - Rosenberg, Leonard

AU - Chen, Timothy L.

AU - Yocum, Ashley O.

AU - Druggan, Franchesca

AU - Marcus, Sonja

AU - Stefanos, Mona

AU - Druker, Brian J.

AU - Mims, Alice S.

AU - Borate, Uma

AU - Burd, Amy

AU - Byrd, John C.

AU - Levine, Ross L.

AU - Stein, Eytan M.

PY - 2024/1/23

Y1 - 2024/1/23

N2 - Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENAmonotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML.

AB - Enasidenib (ENA) is an inhibitor of isocitrate dehydrogenase 2 (IDH2) approved for the treatment of patients with IDH2-mutant relapsed/refractory acute myeloid leukemia (AML). In this phase 2/1b Beat AML substudy, we applied a risk-adapted approach to assess the efficacy of ENAmonotherapy for patients aged ≥60 years with newly diagnosed IDH2-mutant AML in whom genomic profiling demonstrated that mutant IDH2 was in the dominant leukemic clone. Patients for whom ENA monotherapy did not induce a complete remission (CR) or CR with incomplete blood count recovery (CRi) enrolled in a phase 1b cohort with the addition of azacitidine. The phase 2 portion assessing the overall response to ENA alone demonstrated efficacy, with a composite complete response (cCR) rate (CR/CRi) of 46% in 60 evaluable patients. Seventeen patients subsequently transitioned to phase 1b combination therapy, with a cCR rate of 41% and 1 dose-limiting toxicity. Correlative studies highlight mechanisms of clonal elimination with differentiation therapy as well as therapeutic resistance. This study demonstrates both efficacy of ENA monotherapy in the upfront setting and feasibility and applicability of a risk-adapted approach to the upfront treatment of IDH2-mutant AML.

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A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML

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