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

  • Stein, Eytan M1
  • DiNardo, Courtney D2
  • Fathi, Amir T3
  • Mims, Alice S4
  • Pratz, Keith W5
  • Savona, Michael R6
  • Stein, Anthony S7
  • Stone, Richard M8
  • Winer, Eric S8
  • Seet, Christopher S9
  • Döhner, Hartmut10
  • Pollyea, Daniel A11
  • McCloskey, James K12
  • Odenike, Olatoyosi13
  • Löwenberg, Bob14
  • Ossenkoppele, Gert J15
  • Patel, Prapti A16
  • Roshal, Mikhail17
  • Frattini, Mark G18
  • Lersch, Frederik19
  • And 11 more
  • 1 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 2 Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX.
  • 3 Dana-Faber/Harvard Cancer Center, Massachusetts General Hospital, Boston, MA.
  • 4 Ohio State University Wexner Medical Center, Columbus, OH.
  • 5 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
  • 6 Vanderbilt-Ingram Center, Vanderbilt University School of Medicine, Nashville, TN.
  • 7 Department of Hematology & Hematopoietic Cell Transplantation, City of Hope Medical Center, Duarte, CA.
  • 8 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
  • 9 Department of Medicine, University of California Los Angeles Medical Center, Los Angeles, CA.
  • 10 Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany. , (Germany)
  • 11 Department of Medicine, University of Colorado School of Medicine, Aurora, CO.
  • 12 John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, NJ.
  • 13 University of Chicago Medicine Comprehensive Cancer Center, Chicago, IL.
  • 14 Department of Hematology, Erasmus University Medical Centre, Rotterdam, The Netherlands. , (Netherlands)
  • 15 Department of Hematology, VUmc Cancer Center, Amsterdam, The Netherlands. , (Netherlands)
  • 16 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.
  • 17 Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY.
  • 18 Bristol-Myers Squibb, Summit, NJ.
  • 19 Celgene International, Boudry, Switzerland. , (Switzerland)
  • 20 Bristol-Myers Squibb, San Francisco, CA; and.
  • 21 Agios Pharmaceuticals, Inc., Cambridge, MA.
Published Article
American Society of Hematology
Publication Date
Apr 01, 2021
DOI: 10.1182/blood.2020007233
PMID: 33024987


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 as #NCT02632708. © 2021 by The American Society of Hematology.

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