Synergistic Therapeutic Effects of DS-1594b and Venetoclax on AML with MLL Rearrangements and NPM1 Mutations

The abstract discusses the role of the MLL gene in the development of aggressive leukemias, particularly in the context of AML, where it is often associated with poor outcomes. The interaction between Menin and MLL proteins is highlighted as a crucial factor in the pathogenesis of AML, and the use of Menin inhibitors has shown promise in treating both MLL-rearranged and NPM1-mutated leukemias. However, due to the transient nature of these responses, there is a need to explore additional therapeutic strategies.

Our research has identified that cells from patients with MLL-rearranged acute lymphoblastic leukemia exhibit elevated levels of the BCL-2 protein and are sensitive to venetoclax, a BCL-2 antagonist. This study investigates the potential of a novel Menin-MLL inhibitor, DS-1594b, in combination with venetoclax for the treatment of MLL-rearranged and NPM1-mutated acute leukemias.

Using various AML cell lines and primary leukemia samples, the study evaluates the effects of DS-1594b and venetoclax, both as single agents and in combination, on cell viability, apoptosis induction, and cell differentiation. The results indicate that DS-1594b reduces viability in affected cell lines at low concentrations and induces differentiation without causing apoptosis, suggesting its primary mechanism is promoting cell differentiation. The combination treatment with venetoclax leads to synergistic lethality and growth inhibition, particularly in primary leukemia samples.

The study concludes that DS-1594b demonstrates in vitro efficacy as a single agent and in combination with venetoclax for treating MLL-rearranged and NPM1-mutated leukemias. The combination treatment induces significant apoptosis in primary samples, and ongoing in vivo studies are expected to provide further insights into the potential of this therapeutic approach for AML patients with MLL rearrangements and/or NPM1 mutations.