Background: Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by dysregulation of the Janus kinase (JAK) pathway resulting in bone marrow fibrosis, splenomegaly, and debilitating symptoms. Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor that decreased spleen volume, improved symptoms, and prolonged survival in phase 3 studies. Panobinostat (PAN) is a potent pan-deacetylase inhibitor (DACi) that has shown splenomegaly reduction and improvement of marrow fibrosis in phase 1/2 studies. RUX and PAN demonstrated synergistic anti-MF activity in preclinical studies. Here, we present the updated results of a phase 1b study of the combination of RUX and PAN in MF patients (pts). Methods: Eligible pts had intermediate-1, -2, or high-risk MF by International Prognostic Scoring System criteria with palpable splenomegaly. Pts received RUX (5-15 mg) twice daily, every day (BID) and PAN (10-25 mg) once daily, 3 times a week (TIW; days 2, 4, and 6), every other week (QOW) in a 28-day cycle. The primary objective was determination of the recommended phase 2 dose (RP2D) and/or maximum tolerated dose (MTD). Dose escalation was guided by a Bayesian logistic regression model with overdose control based on cycle 1 dose-limiting toxicities (DLTs) and other safety results. Additional pts were enrolled and treated at the RP2D in the expansion phase. Results: A total of 48 pts were enrolled (38 escalation phase and 10 expansion phase). Preliminary RP2D was identified at RUX 15 mg BID/PAN 25 mg TIW/QOW. Grade 3/4 adverse events (AEs) included anemia (42%), thrombocytopenia (21%), abdominal pain (8%), and diarrhea (8%) in the escalation phase and anemia (20%) and asthenia (10%) in the expansion phase. Preliminary activity in the dose escalation phase was demonstrated by a ≥ 50% decrease in palpable spleen length at any time in 76% of pts and 50% of patients demonstrating a 100% (non-palpable spleen) response. In the expansion phase, all 4 evaluable pts demonstrated a best spleen response of 100% (non-palpable spleen). Conclusions: The combination of RUX and PAN has a tolerable safety profile and encouraging efficacy as demonstrated by spleen responses. Additional safety and efficacy data from the expansion phase will be presented. Clinical trial information: NCT01433445.