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Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia

Author

Listed:
  • Rebecca Anderson

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Lance D. Miller

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Scott Isom

    (Wake Forest Public Health Sciences)

  • Jeff W. Chou

    (Wake Forest Public Health Sciences)

  • Kristin M. Pladna

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Nathaniel J. Schramm

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Leslie R. Ellis

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Dianna S. Howard

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Rupali R. Bhave

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Megan Manuel

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Sarah Dralle

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Susan Lyerly

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Bayard L. Powell

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist)

  • Timothy S. Pardee

    (Comprehensive Cancer Center of Atrium Health Wake Forest Baptist
    Comprehensive Cancer Center of Atrium Health Wake Forest Baptist
    Rafael Pharmaceuticals Inc)

Abstract

Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design.

Suggested Citation

  • Rebecca Anderson & Lance D. Miller & Scott Isom & Jeff W. Chou & Kristin M. Pladna & Nathaniel J. Schramm & Leslie R. Ellis & Dianna S. Howard & Rupali R. Bhave & Megan Manuel & Sarah Dralle & Susan L, 2022. "Phase II trial of cytarabine and mitoxantrone with devimistat in acute myeloid leukemia," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29039-4
    DOI: 10.1038/s41467-022-29039-4
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    References listed on IDEAS

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    1. Jeffrey W. Tyner & Cristina E. Tognon & Daniel Bottomly & Beth Wilmot & Stephen E. Kurtz & Samantha L. Savage & Nicola Long & Anna Reister Schultz & Elie Traer & Melissa Abel & Anupriya Agarwal & Auro, 2018. "Functional genomic landscape of acute myeloid leukaemia," Nature, Nature, vol. 562(7728), pages 526-531, October.
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