Background: PV is a myeloproliferative neoplasm characterized by clonal stem cell proliferation, hyperviscous blood, significant morbidity, and reduced life span. Advanced PV results in splenomegaly, severe constitutional symptoms, and possible evolution to myelofibrosis and acute myeloid leukemia (AML). Nearly all patients (pts) have a mutation in JAK2, and > 95% have the JAK2 V617F allele. HU is the myelosuppressive agent of choice in high-risk pts, but it often loses efficacy over time and may cause unacceptable skin toxicities. Therapeutic options in the case of HU resistance are limited, and survival is significantly reduced. A phase 2 study in HU-resistant/-intolerant PV pts showed that ruxolitinib, a potent and selective JAK1/JAK2 inhibitor, was well tolerated and achieved rapid and durable clinical responses, including hematocrit (Hct) normalization, phlebotomy independence, resolution of splenomegaly, and improvements in symptoms (Verstovsek et al, Cancer, 2013). RESPONSE, a phase 3 trial, was designed to compare the efficacy and safety of ruxolitinib with best available therapy (BAT) in HU-resistant/-intolerant PV pts with splenomegaly. Methods: RESPONSE 2 is an open-label, randomized (1:1), phase 3b study (NCT02038036) designed to compare the efficacy and safety of ruxolitinib with BAT in PV pts (per revised WHO criteria) who require phlebotomy and are HU-resistant/-intolerant. Target enrollment is 104 pts and includes pts without splenomegaly, expanding the RESPONSE patient population. The primary endpoint is the achievement of Hct control, defined as Hct < 45% at week 16 and maintained until week 28, and no phlebotomy from week 4 to week 28, with ≤ 1 phlebotomy postrandomization and prior to week 4. Secondary endpoints include peripheral blood count remission, partial remission (ELN and IWG-MRT criteria), and resolution of symptoms in MPN-SAF TSS at week 28. The BAT group may cross over to ruxolitinib on or after week 28 if they have Hct > 45%, receive phlebotomy, or need to discontinue BAT. Pts will be treated for 52 weeks to assess safety and durability of response. Clinical trial information: NCT02038036.