Discussion
MDS or CMML, toxicity, AML, myelosuppression, Myelosuppression
AML, SECONDARY AML, HYPOPHOSPHATEMIA, DISEASES, MYELOSUPPRESSION
Azacitidine plus venetoclax is standard of care for older adults with newly diagnosed AML who are unfit for intensive chemotherapy, although the outcomes for the substantial proportion of these patients who whose AML has adverse cytomolecular features remain suboptimal [Overall 84% of patients in the AML cohort had one or more poor-risk cytogenetic or molecular feature, including 34% with a This study was also enriched with patients with treated secondary AML (accounting for 53% of the AML cohort). In one retrospective analysis, only 24% of older adults with treated secondary AML achieved CR/CRi with frontline induction therapy, which translated to a dismal median OS of 4.7 months [Effective treatment options for patients with MDS or CMML after HMA failure are limited. While previous studies have suggested clinical activity of HMA plus venetoclax, there is still no standard of care in this population [Using CyTOF analysis, we observed an early increase in NOXA levels, followed decrease in MCL-1 levels, a finding that is consistent with preclinical data suggesting that pevonedistat may synergize with azacitidine and venetoclax by increasing NOXA levels, leading to downstream neutralization of MCL-1 [Across both cohorts, the addition of pevonedistat was safe and did not appear to impair delivery of the intended doses of azacitidine or venetoclax. Hypophosphatemia, a known pevonedistat-induced electrolyte abnormality, was observed in 47% of patients but was manageable with oral or IV supplementation. Myelosuppression with the triplet regimen appeared consistent with historical expectations with azacitidine plus venetoclax. The lack of myelosuppression with pevonedistat is supported by two randomized studies in MDS/CMML of azacitidine plus pevonedistat versus azacitidine alone, where the pevonedistat-containing arm had a similar incidence of hematologic toxicity and was able to maintain dose intensity of azacitidine [In summary, the triplet combination of azacitidine, venetoclax and pevonedistat was active in this very poor-risk population of older adults with newly diagnosed secondary AML and in patients with MDS or CMML after HMA failure. While the response rates and survival in patients with MDS or CMML after HMA failure are encouraging, the added clinical benefit of pevonedistat in this setting is questionable considering a negative randomized study of pevonedistat in these diseases. A randomized phase 2 study of azacitidine, venetoclax and pevonedistat versus azacitidine and venetoclax in patients with newly diagnosed AML who are unfit for intensive chemotherapy has fully accrued (NCT04266795) and will help to clarify the potential role of pevonedistat in this population.