Background
Phase 3b, randomized, open-label study. 149 patients with polycythemia vera (PV), NO palpable splenomegaly, and hydroxyurea resistance or intolerance requiring second-line therapy. Randomized 1:1. Complementary to RESPONSE, which was restricted to patients with splenomegaly. 48 sites in 12 countries.
Interventions and follow up
Arm A: Ruxolitinib 10 mg orally twice daily (n=74)
Arm B: Best available therapy (BAT; hydroxyurea, interferon/pegylated interferon, pipobroman, anagrelide, or no cytoreductive treatment; n=75)
Primary endpoint: Hematocrit control at week 28
mFollow up: Not stated (primary analysis at week 28)
Arm B: Best available therapy (BAT; hydroxyurea, interferon/pegylated interferon, pipobroman, anagrelide, or no cytoreductive treatment; n=75)
Primary endpoint: Hematocrit control at week 28
mFollow up: Not stated (primary analysis at week 28)
Results
HCT control at week 28: 62% (46/74) vs 19% (14/75), OR 7.28 (95% CI 3.43–15.45), P<.0001
Complete hematologic remission at week 28: higher with ruxolitinib (key secondary)
Symptom burden: improved with ruxolitinib vs BAT
Durability: 78% of week-28 HCT responders maintained response to week 80
Complete hematologic remission at week 28: higher with ruxolitinib (key secondary)
Symptom burden: improved with ruxolitinib vs BAT
Durability: 78% of week-28 HCT responders maintained response to week 80
Adverse events
Hematologic (any grade): anemia 14% vs 3%; thrombocytopenia 3% vs 8%
Hematologic (grade 3–4): anemia 0% (ruxolitinib) vs 1% (BAT); thrombocytopenia 0% vs 4%
Other: grade 3–4 hypertension 7% vs 4%
Deaths: 2 deaths occurred, both in the BAT arm
Hematologic (grade 3–4): anemia 0% (ruxolitinib) vs 1% (BAT); thrombocytopenia 0% vs 4%
Other: grade 3–4 hypertension 7% vs 4%
Deaths: 2 deaths occurred, both in the BAT arm
Conclusions
Ruxolitinib achieved superior hematocrit control versus BAT in PV patients without splenomegaly who failed hydroxyurea, meeting the primary endpoint with a 3.3-fold higher rate of HCT control (62% vs 19%), along with higher complete hematologic remission and improved symptom burden. The results support ruxolitinib use in PV regardless of splenomegaly status.
Key Limitations
Phase 3b designation reflects a confirmatory/labeling-extension rather than pivotal trial. No spleen endpoint was assessed (patients had no splenomegaly). Open-label design. Symptom improvement was not a coprimary endpoint here (unlike RESPONSE). The BAT arm included patients receiving no cytoreductive treatment, a heterogeneous control group that may underestimate ruxolitinib's comparative benefit. Longer follow-up data on OS, transformation, and thromboembolic events were needed (later addressed at 80-week and 5-year follow-up).
Clinical Context
RESPONSE-2 extended ruxolitinib's indication to hydroxyurea-refractory/intolerant PV without splenomegaly, broadening its eligible population, and the FDA labeling was updated accordingly. It is the supporting trial that most closely mirrors common clinical practice, where many PV patients present without significant splenomegaly. Ropeginterferon alfa-2b is an approved alternative for high-risk PV with superior molecular response (VAF reduction) and is increasingly used in earlier lines.