Ruxolitinib versus best available therapy in inadequately controlled polycythaemia vera without splenomegaly (RESPONSE-2): 5-year follow up of a randomised, phase 3b study

Background: The phase 3b, randomised, open-label RESPONSE-2 study in patients with inadequately controlled polycythaemia vera without splenomegaly showed superiority of the Janus kinase (JAK) 1 and JAK2 inhibitor ruxolitinib versus best available therapy for the primary endpoint of haematocrit control at week 28. Here, we present secondary endpoints of the RESPONSE-2 study after 5 years of follow-up. Methods: RESPONSE-2 was an open-label, randomised, phase 3b study done at 48 hospitals or clinics across 12 countries in Asia, Australia, Europe, and Canada. Patients (aged ≥18 years) with polycythaemia vera without splenomegaly, who were intolerant of, or resistant to hydroxyurea, with an Eastern Cooperative Oncology Group performance status of 2 or less were randomly assigned (1:1) to receive ruxolitinib or best available therapy for up to 80 weeks. Patients received oral ruxolitinib at a starting dose of 10 mg twice a day or best available therapy. Patients assigned to best available therapy could cross over to ruxolitinib at week 28 if the primary endpoint was not met, or after week 28 and up to week 80 if best available therapy was ineffective or not tolerated. Patients receiving ruxolitinib at week 80, including crossover patients, could continue ruxolitinib treatment up to week 260. We assessed secondary endpoints at week 260, including durable haematocrit control, median duration of haematocrit control, median haematocrit level over time, number of phlebotomies, and overall survival. Analyses were based on the intention-to-treat principle. This study is registered with ClinicalTrials.gov, NCT02038036 and was completed on April 7, 2020. Findings: Patients were enrolled between March 25, 2014 and Feb 11, 2015. 149 patients were randomly assigned to ruxolitinib (n=74) or best available therapy (n=75). The median follow-up was 67 months (IQR 65–70). At randomisation, best available therapy regimens included hydroxyurea (n=38), interferon or pegylated interferon (n=9), pipobroman (n=5), lenalidomide (n=1), or no treatment (n=22). Between weeks 28 and 80, 58 (77%) of 75 patients in the best available therapy group crossed over to ruxolitinib; no patients continued best available therapy after week 80 per protocol. 97 patients received ruxolitinib until week 260, including 59 (80%) of 74 patients in the ruxolitinib group and 38 (66%) of 58 patients in the crossover groups. At week 260, 16 (22%; 95% CI 13–33) of 74 patients in the ruxolitinib group had achieved durable haematocrit control, with estimated median duration not reached (NR; 95% CI 144 to NR). Median duration of haematocrit control was not reported for patients in the best available therapy group due to the small number of responders by week 80. During the 5-year follow-up, median haematocrit level among patients in the ruxolitinib group remained below 45%. 60 phlebotomies were required among 74 patients in the ruxolitinib group in 260 weeks, and 106 phlebotomies among 75 patients in the best available therapy group in 80 weeks. 5-year overall survival was 96% (95% CI 87–99) in the ruxolitinib group and 91% (80–96) in the best available therapy group. The most common grade 3–4 adverse events (exposure-adjusted per 100 patient-years) in the ruxolitinib group (n=74) and best available therapy group (n=75) were hypertension (eight [2·4%] vs three [5·6%]), thrombocytopenia (one [0·3%] vs three [5·6%]), and thrombocytosis (0 vs four [7·5%]). Exposure-adjusted rates of any-grade thromboembolic events were 1·5% per 100 person-years (five of 74 patients) in the ruxolitinib group and 3·7% per 100 person-years (two of 75 patients) in the best available therapy group. No treatment-related deaths occurred during the study. Interpretation: 5-year results from the RESPONSE-2 study support the use of ruxolitinib as a second-line therapy of choice for patients with inadequately controlled polycythaemia vera without splenomegaly. Funding: Novartis.