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

• Omacetaxine can synergize with venetoclax to promote loss of viability of myeloblasts.

• Clinical responses were seen in MDS patients, suggesting dose optimization or combination therapy with cytoreduction is necessary in AML.

Mutations in RUNX1 (RUNX1^mut) occur in 10-20% of patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) and are associated with poor outcomes to standard therapy. Omacetaxine mepesuccinate (OM) is a semi-synthetic analogue of homoharringtonine, which has been shown to be lethal to RUNX1^mut AML cells in vitro through reduction of MCL1 and BCL-XL and has demonstrated synergy with venetoclax (VEN) in models of RUNX1^mut AML. We investigated the safety and efficacy of OM + VEN in relapsed/refractory (R/R) RUNX1^mut MDS/AML in a Bayesian optimal interval (BOIN) design (NCT04874194). VEN 400 mg daily days 1-14 and OM 1.25 mg/m² twice daily days 2-4 was selected as the recommended phase 2 dose. Twenty-four patients were treated, 22 AML and 2 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 pre-treated cohort of AML patients. Both patients with MDS achieved composite complete remission and transitioned to allogeneic stem cell transplant. Treatment-induced downregulation in gene expression in the beta-catenin and hedgehog signaling pathway genes was identified in PBMNCs from responding patients. As compared to non-responders, samples from responders also exhibited reduced anti-apoptotic and increased pro-apoptotic protein expressions. OM can synergize with VEN to promote loss of viability of myeloid cells. Clinical responses were seen exclusively in MDS patients, which suggests that dose optimization or combination with cytoreductive agents may be necessary for eliciting clinical activity in AML. NCT04874194