A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML)

Abstract

Purpose To conduct a phase I clinical trial exploring the safety and efficacy of ruxolitinib, a JAK1/2 inhibitor, for chronic myelomonocytic leukemia (CMML). Experimental Design Patients with CMML-1 were included without regard to previous therapy. Key exclusion criteria included an absolute neutrophil count (ANC) <0.25 × 103 cells/dL and a platelet count <35 × 103 cells/dL. Four cohorts were enrolled using a "rolling six" study design, with doses ranging from 5 to 20 mg twice daily of ruxolitinib in 5-mg dose escalations. Results Between March 2013 and January 2015, 20 patients were enrolled and treated with ruxolitinib. Seventy percent of patients had the proliferative subtype and 47% had higher risk disease by the Global MD Anderson Scoring System. Eight patients (42%) received a prior hypomethylating agent. No dose-limiting toxicities for ruxolitinib were identified. One subject had grade (G)3 thrombocytopenia with no other drug-associated G3 or G4 adverse events. The mean duration of therapy was 122 days (range, 28–409 days). Four had hematologic improvement and one patient had a partial response per 2006 International Working Group (IWG) criteria. Five of 9 patients with splenomegaly had a reduction in spleen size. Ten of 11 patients with reported disease-related symptoms had clinically meaningful or complete resolution. When combining IWG and spleen responses, a total response rate of 35% (n = 7) was identified. Correlative analysis demonstrated a reduction in inflammatory cytokines and GM-CSF–dependent STAT5 phosphorylation. Conclusions The recommended phase II dose of ruxolitinib is 20 mg twice daily. We demonstrate that ruxolitinib has promising activity in CMML with particular benefit in those with disease-related B symptoms that warrants further study.

JAK2 inhibitors for myeloproliferative neoplasms: what is next?

“…Objective responses using MDS response criteria (mostly hematologic improvement) occurred in 5 patients, and the majority of patients had improvement or resolution in splenomegaly and diseaserelated symptoms. 151 The combination of ruxolitinib and azacitidine seems promising in patients with unclassifiable MDS/ MPNs. 152 …”

CMML: Clinical and molecular aspects

“…To date there is no validated questionnaire for CMML patients, but recent biological findings suggest that plasma levels of inflammatory cytokines can also be elevated in CMML [28], paving the way for dedicated therapeutic intervention such as JAK inhibition [29].…”

Engraftment of chronic myelomonocytic leukemia cells in immunocompromised mice supports disease dependency on cytokines

“…GM-CSF neutralization was therefore proposed as a potential therapeutic strategy in this difficult-to-treat disease. 4,5 Genetically modified mouse models only partially recapitulate the phenotypic heterogeneity of CMML. 6 An alternative approach is the xenotransplantation of human diseased cells in immunocompromised mice.…”