Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study

Eytan M. Stein*, Courtney D. DiNardo, Amir T. Fathi, Alice S. Mims, Keith W. Pratz, Michael R. Savona, Anthony S. Stein, Richard M. Stone, Eric S. Winer, Christopher S. Seet, Hartmut Döhner, Daniel A. Pollyea, James K. McCloskey, Olatoyosi Odenike, Bob Löwenberg, Gert J. Ossenkoppele, Prapti A. Patel, Mikhail Roshal, Mark G. Frattini, Frederik LerschAleksandra Franovic, Salah Nabhan, Bin Fan, Sung Choe, Hongfang Wang, Bin Wu, Lei Hua, Caroline Almon, Michael Cooper, Hagop M. Kantarjian, Martin S. Tallman

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

120 Citations (Scopus)


Ivosidenib (AG-120) and enasidenib (AG-221) are targeted oral inhibitors of the mutant isocitrate dehydrogenase (mIDH) 1 and 2 enzymes, respectively. Given their effectiveness as single agents in mIDH1/2 relapsed or refractory acute myeloid leukemia (AML), this phase 1 study evaluated the safety and efficacy of ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed mIDH1/2 AML. Ivosidenib 500 mg once daily and enasidenib 100 mg once daily were well tolerated in this setting, with safety profiles generally consistent with those of induction and consolidation chemotherapy alone. The frequency of IDH differentiation syndrome was low, as expected given the concurrent administration of cytotoxic chemotherapy. In patients receiving ivosidenib, the frequency and grades of QT interval prolongation were similar to those observed with ivosidenib monotherapy. Increases in total bilirubin were more frequently observed in patients treated with enasidenib, consistent with this inhibitor's known potential to inhibit UGT1A1, but did not appear to have significant clinical consequences. In patients receiving ivosidenib (n = 60) or enasidenib (n = 91), end-of-induction complete remission (CR) rates were 55% and 47%, respectively, and CR/CR with incomplete neutrophil or platelet recovery (CR/CRi/CRp) rates were 72% and 63%, respectively. In patients with a best overall response of CR/CRi/CRp, 16/41 (39%) receiving ivosidenib had IDH1 mutation clearance and 15/64 (23%) receiving enasidenib had IDH2 mutation clearance by digital polymerase chain reaction; furthermore, 16/20 (80%) and 10/16 (63%), respectively, became negative for measurable residual disease by multiparameter flow cytometry. This trial was registered at www.clinicaltrials.gov as #NCT02632708.

Original languageEnglish
Pages (from-to)1792-1803
Number of pages12
Issue number13
Publication statusPublished - 1 Apr 2021

Bibliographical note

Editorial assistance was provided to the authors by Helen Varley, CMPP,
Excel Medical Affairs, Horsham, United Kingdom, and supported by
This work was supported by Agios Pharmaceuticals, Inc., in collaboration
with Bristol-Myers Squibb. Agios provided financial support for the study
and participated in the design, study conduct, and analysis and in-
terpretation of data, as well as the writing, review, and approval of the

Publisher Copyright: © 2021 American Society of Hematology


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