Promising Results of a Phase 1/2 Clinical Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia

Introduction: Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by GM-CSF hypersensitivity, marrow dysplasia, blood monocytosis, and a propensity for acute myeloid leukemia transformation. The overall survival is estimated at 34 months with no drug therapies known to improve survival. We previously reported results of a phase 1 study demonstrating that ruxolitinib, a JAK1/2 inhibitor, is safe and has clinical activity in CMML at doses up to 20mg BID. To confirm efficacy we performed a phase 2 clinical trial and here report the combined results of the phase 1 and 2 clinical studies. Methods: All CMML WHO subtypes were included without regard to previous therapy. Key exclusion criteria included an ANC < 0.25x10³ c/dL and a platelet count < 35x10³c/dL. The use of GM-CSF analogs was prohibited. The Kaplan-Meier method was used to estimate survival and log-rank test to determine statistical significance. Somatic mutations were identified at baseline using a 49 gene targeted next generation sequencing panel (RainDance Technologies) and a custom 46-plex Luminex assay was used to profile baseline cytokine levels (R&D). The study was registered at clinicaltrials.gov NCT01776723 Results: Between April 2015 and October 2016, 29 patients were enrolled in the phase 2 study resulting in a combined 49 CMML patients treated with ruxolitinib. In phase 2, 56 percent of patients had the proliferative subtype (MPN-CMML) defined by WBC >13x10⁹/L and 28% had higher-risk disease by the Global MD Anderson Scoring System. Six patients (20%) received a prior hypomethylating agent and 85% of patients were WHO subtype CMML-1. Therapy-emergent toxicities were similar to those reported in phase 1. The mean duration of therapy was 219 days (range, 6-675 days). Three hematologic responses, including bi- or trilineage responses (2 HI-E, 2 HI-P, 1 HI-N), one marrow CR, and one partial bone marrow response per 2006 IWG criteria were observed. Six of 13 patients (46%) with splenomegaly had a 50% or greater reduction in spleen size by physical exam. When combining IWG and spleen responses, the overall response rate was 46% (n=11 of 24), including clinical benefit by MDS/MPN IWG response criteria. Using the Myeloproliferative Symptom Assessment Form (MPN-SAF) administered electronically daily, a reduction in total symptom score was noted. The median OS (mOS) from start of treatment was 28 months (95% CI 18-38), and, for CMML-MDS and CMML-MPN, was 32 months and 28 months respectively, (p=0.3). To evaluate whether ruxolitinib may have disease-modifying properties in CMML, analysis of mOS from time of diagnosis was performed comparing all ruxolitinib treated patients (n=49) to an historical dataset with over 1800 CMML patients (Padron et al 2015). The mOS at the time of diagnosis in CMML ruxolitinib-treated CMML patients was 69 months compared to 31 months in the historical CMML cohort (p=0.03). Adjusting for age, Global MD Anderson model, CMML WHO subtype, CMML-MPN, and the interval from diagnosis, treatment with ruxolitinib was associated with improved OS (HR 0.42, p <0.005). Although no mutation or class of mutations was associated with response, peripheral blood plasma levels of CXCL9 (p=0.02) and decreased levels of CCL5 (p=0.018) and RAGE (p=0.016) were statistically associated with higher likelihood of response. Conclusions: Ruxolitinib has promising activity in CMML patients with particular benefit in those with proliferative symptoms and may have disease-modifying activity. The MPN-SAF may be a useful tool to measure symptom burden in the context of ruxolitinib therapy for CMML. Overexpression of cytokines and soluble innate immune receptors is associated with a higher likelihood of response to ruxolitinib therapy. Further clinical study is warranted to validate the biomarkers of response and disease modifying capacity of ruxolitinib in CMML.