In an integrated human and murine clinical study of chronic myelomonocytic leukemia (CMML), treatment with ruxolitinib led to overall response rates of 38%, according to results published in Clinical Cancer Research.
“CMML is a rare leukemia characterized by peripheral monocytosis with no disease-modifying therapies,” the authors explained. “CMML cells are uniquely hypersensitive to [granulocyte-macrophage colony-stimulating factor, or GM-CSF] and robustly engraft in immunocompromised mice that secrete human cytokines.”
Investigators leveraged these unique biologic features in an integrated human and murine study evaluating ruxolitinib, a JAK1/2 inhibitor that downregulates intracellular GM-CSF signaling. This open-label, phase I/II study enrolled 50 patients with CMML, who were treated with ruxolitinib 20 mg twice daily. The researchers conducted a parallel study of 49 patient-derived xenografts from 13 study participants that were randomized to received ruxolitinib or control.
In safety analysis, the most common grade 3/4 treatment-related adverse events were anemia (10%) and thrombocytopenia (6%). The clinical overall response rate was 38%. In addition, 43% of patients with baseline splenomegaly achieved a spleen response. Analyses of PDX models derived from screening samples of study participants demonstrated similar response rates to those seen in humans, particularly spleen responses.
Based on these findings, ruxolitinib “is a potential novel therapeutic in this rare malignancy,” the authors concluded. They added that these findings demonstrate the feasibility of patient-derived xenograft modeling, “recapitulating responses of patients treated on clinical trial and representing a novel correlative study that corroborates clinical efficacy seen in humans.”