Promising Results of a Phase 1/2 Clinical Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (2017)

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 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 Disclosures Padron: Incyte: Honoraria, Research Funding. Lancet: Bio-Path Holdings: Consultancy; Celgene: Consultancy; Boehringer Ingelheim: Consultancy; Jazz Pharmaceuticals: Consultancy; BioSight: Consultancy; Erytech: Consultancy; Janssen: Consultancy; Pfizer: Other: Institutional research funding, Research Funding; Novartis: Consultancy. Mesa: Promedico: Research Funding; Ariad: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy; Gilead Sciences, Inc.: Research Funding; Celgene Corporation: Research Funding; Galena Biopharma, Inc.: Consultancy; Incyte Corporation: Research Funding; CTI BioPharma Corp.: Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Steensma: Amgen: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity9s Board of Directors or advisory committees; Incyte: Equity Ownership; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy, Research Funding; H3 Biosciences: Consultancy; Onconova: Consultancy; Pfizer: Consultancy. Sekeres: Celgene: Membership on an entity9s Board of Directors or advisory committees. Komrokji: Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria.