PRJNA801230
Transcriptomic analysis of AML bone marrow biopsies in a Phase II trial of cytarabine and mitoxantrone with devimistat
Devimistat is a novel TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory acute myeloid leukemia (AML) showed promising response rates. A single arm phase II study (NCT02484391) of AML patients to assess the feasibility of maintenance devimistat, response, survival and safety is now complete. A dose response was observed in older patients, but not younger patients. RNAseq analysis of pre-treatment bone marrow biopsies revealed an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis, and there is a direct correlation between mitochondrial membrane potential and chemotherapy sensitization. Devimistat induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. Pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These data support a model where devimistat may benefit older patients as a consequence of age related decline in mitochondrial quality and autophagy.