April 20, 2021

New therapeutic strategy for leukemia syndrome

Using primary cells from patients with chronic myelomonocytic leukemia, Vanderbilt researchers found synergistic inhibition of cell viability and proliferation, suggesting a new treatment strategy.

Chronic myelomonocytic leukemia (CMML) — a blood cancer with characteristics of both myeloproliferative and myelodysplastic syndromes — has a poor prognosis and limited treatment options. 

PI3K enzymes are a family of signaling proteins involved in cell growth and proliferation. VUMC Harrison Fellow Matt Villaume, MD, and colleagues from the groups of Michael Savona, MD, and P. Brent Ferrell, MD, demonstrated increased expression of the PI3K-delta isoform relative to other PI3K isoforms in multiple myeloid leukemia cell lines. 

In addition, they tested the PI3K-delta inhibitor umbralisib as a single agent and in combination with ruxolitinib, an inhibitor of another cell signaling pathway, in primary CMML patient samples. The research team found synergistic inhibition of cell viability and proliferation with the drug combination, and they characterized biochemical changes that suggest a mechanism for the enhanced efficacy. 

The preclinical findings, reported in the journal Experimental Hematology, support the use of umbralisib and ruxolitinib combination therapy in CMML, which has been tested in a multicenter clinical trial led by Savona at VUMC.

This research was supported by the Biff Ruttenberg Foundation, Beverly and George Rawlings Directorship, and National Institutes of Health (grant CA068485). Savona is a Clinical Scholar for the Leukemia and Lymphoma Society. TG Therapeutics provided umbralisib and other support for this work.