1. A study to assess the efficacy of enasidenib and risk-adapted addition of azacitidine in newly diagnosed IDH2-mutant AML.
- Author
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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, and Stein EM
- Subjects
- Humans, Isocitrate Dehydrogenase genetics, Mutation, Pathologic Complete Response, Azacitidine adverse effects, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute genetics, Aminopyridines, Triazines
- Abstract
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 ENA monotherapy 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. This trial is registered at www.clinicaltrials.gov as #NCT03013998., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2024
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