Omacetaxine and venetoclax in relapsed/refractory acute myeloid leukemia or myelodysplastic syndrome with mutant RUNX1.

Mutations in RUNX1 (RUNX1 mut) occur in 10% to 20% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and are associated with poor outcomes to standard therapy. Omacetaxine mepesuccinate (OM), a semisynthetic analog of homoharringtonine, has been shown to be lethal to RUNX1 mut AML cells in vitro through reduction of MCL1 and BCL-XL, and synergizes with venetoclax (VEN) in RUNX1 mut AML models. We investigated the safety and efficacy of OM + VEN in relapsed/refractory RUNX1 mut MDS/AML in a Bayesian Optimal Interval design. VEN 400 mg daily from days 1 to 14 and OM 1.25 mg/m2 twice daily from days 2 to 4 was selected as the recommended phase 2 dose. Twenty-four patients were treated, 22 with AML and 2 with MDS with excess blasts. There were no dose-limiting toxicities or episodes of tumor lysis syndrome. The most common grade ≥3 toxicity was infection. There were no responses in our heavily pretreated cohort of patients with AML. Both patients with MDS achieved composite complete remission and transitioned to allogeneic stem cell transplant. Treatment-induced downregulation in gene expression in the β-catenin and hedgehog signaling pathway genes were identified in peripheral blood mononuclear cells from patients who responded. As compared to nonresponders, samples from responders also exhibited reduced antiapoptotic and increased proapoptotic protein expression. OM can synergize with VEN to promote loss of viability of myeloid cells. Clinical responses were seen exclusively in patients with MDS, which suggests that dose optimization or combination with cytoreductive agents may be necessary for eliciting clinical activity in AML. This trial was registered at www.ClinicalTrials.gov as #NCT04874194.