The delta isoform of PI3K predominates in chronic myelomonocytic leukemia and can be targeted effectively with umbralisib and ruxolitinib

Abstract Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome/myeloproliferative neoplasm overlap syndrome characterized by monocytic proliferation in the presence of dysplastic bone marrow changes, inflammatory symptoms and propensity for transformation to AML, with a poor prognosis and limited treatment options. Unlike the α and β isoforms, the PI3K-δ signaling protein is predominantly expressed by hematopoietic cells and therefore has garnered interest as a potential target for the treatment of lymphomas and leukemias. We revealed a pattern of increased PIK3CD : PIK3CA ratio in monocytic M5 AML patients and cell lines and this ratio correlated with responsiveness to pharmacological PI3K-δ inhibition in vitro . As CMML is a disease defined by monocytic clonal proliferation, we tested the PI3K-δ inhibitor, umbralisib, as a single agent, and in combination with the JAK1/2 inhibitor, ruxolitinib in CMML. Our ex vivo experiments with primary CMML patient samples showed synergistic inhibition of viability and clonogenicity with this combination. Phospho-specific flow cytometry revealed that dual inhibition had the unique ability to decrease STAT5, ERK, AKT and S6 phosphorylation simultaneously, which offers a mechanistic hypothesis for the enhanced efficacy of the combination treatment. These preclinical data demonstrate promising activity by co-inhibition of PI3K-δ and JAK1/2 and support the use of ruxolitinib + umbralisib combination therapy in CMML under active clinical investigation.