Enasidenib as maintenance following allogeneic hematopoietic cell transplantation for IDH2-mutated myeloid malignancies

Amir T Fathi, Haesook T Kim, Robert J Soiffer, Mark J Levis, Shuli Li, Annette S Kim, Alice S Mims, Zachariah DeFilipp, Areej El-Jawahri, Steven L McAfee, Andrew M Brunner, Rupa Narayan, Laura W Knight, Devon Kelley, Aj S Bottoms, Lindsey H Perry, Jonathan L Wahl, Jennifer Brock, Elayne Breton, Vincent T Ho, Yi-Bin Chen, Amir T Fathi, Haesook T Kim, Robert J Soiffer, Mark J Levis, Shuli Li, Annette S Kim, Alice S Mims, Zachariah DeFilipp, Areej El-Jawahri, Steven L McAfee, Andrew M Brunner, Rupa Narayan, Laura W Knight, Devon Kelley, Aj S Bottoms, Lindsey H Perry, Jonathan L Wahl, Jennifer Brock, Elayne Breton, Vincent T Ho, Yi-Bin Chen

Abstract

IDH2 (isocitrate dehydrogenase 2) mutations occur in approximately 15% of patients with acute myeloid leukemia (AML). The IDH2 inhibitor enasidenib was recently approved for IDH2-mutated relapsed or refractory AML. We conducted a multi-center, phase I trial of maintenance enasidenib following allogeneic hematopoietic cell transplantation (HCT) in patients with IDH2-mutated myeloid malignancies. Two dose levels, 50mg and 100mg daily were studied in a 3 × 3 dose-escalation design, with 10 additional patients treated at the recommended phase 2 dose (RP2D). Enasidenib was initiated between days 30 and 90 following HCT and continued for twelve 28-day cycles. Twenty-three patients were enrolled, of whom 19 initiated post-HCT maintenance. Two had myelodysplastic syndrome, and 17 had AML. All but 3 were in first complete remission. No dose limiting toxicities were observed, and the RP2D was established at 100mg daily. Attributable grade ≥3 toxicities were rare, with the most common being cytopenias. Eight patients stopped maintenance before completing 12 cycles, due to adverse events (n=3), pursuing treatment for graft-vs-host disease (GVHD) (n=2), clinician choice (n=1), relapse (n=1), and COVID infection (n=1). No cases of grade ≥3 acute GVHD were seen, and 12-month cumulative incidence of moderate/severe chronic GVHD was 42% (20-63%). Cumulative incidence of relapse was 16% (95% CI: 3.7-36%); 1 subject relapsed while receiving maintenance. Two-year progression-free and overall survival were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively. Enasidenib is safe, well-tolerated, with preliminary activity as maintenance therapy following HCT, and merits additional study. The study was registered at www.clinicaltrials.gov (#NCT03515512).

Conflict of interest statement

Conflicts-of-interest disclosure: A.T.F. has consulted for Agios, Celgene, Bristol Myers Squibb, Servier Pharmaceuticals, Forma Pharmaceuticals, Astellas, Amgen, Takeda, Immunogen, AbbVie, Mablytics, Ipsen, Genentech, EnClear, Orum, and Novartis. Z.D. has consulted for Syndax Pharmaceuticals, Kadmon, Omeros, Incyte, and MorphoSys. A.E.-J. has consulted for Novartis, GSK, and Incyte. A.M.B. has consulted for Acceleron, Agios, BMS/Celgene, CTI BioPharma, Gilead, Keros Therapeutics, Novartis, Taiho, and Takeda. Y.-B.C. has consulted for Incyte, Magenta, Moderna, Novartis, Gamida Cell, T-Scan, Actinium, and Equilium. The remaining authors declare no competing financial interests.

© 2022 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.

Figures

Graphical abstract
Graphical abstract
Figure 1.
Figure 1.
Number of patients with concurrentmutations on study.
Figure 2.
Figure 2.
Incidence of graft-vs-host disease. (A) cumulative incidence of grade II-IV aGVHD. (B) Cumulative incidence of cGVHD.
Figure 3.
Figure 3.
Survival, relapse, and non-relapse mortality. (A) OS, PFS, and GRFS. (B) Cumulative incidence of relapse and NRM.
Figure 4.
Figure 4.
Swim plot of post-HCT outcomes among patients receiving enasidenib maintenance therapy. On the left, a panel shows a heatmap for the status of IDH2 mutational burden before HCT and before enasidenib maintenance. The right panel shows a swim plot for time from HCT to death or last seen alive. Orange triangle indicates relapse, plus sign indicates death.

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