Background
Phase 3, open-label, randomized controlled trial. 222 patients with polycythemia vera (PV) who were phlebotomy-dependent with splenomegaly and had an inadequate response to or unacceptable side effects from hydroxyurea. Randomized 1:1. Ruxolitinib is a selective JAK1/2 inhibitor targeting the dysregulated JAK/STAT pathway in PV.
Interventions and follow up
Arm A: Ruxolitinib 10 mg orally twice daily (n=110)
Arm B: Standard therapy (investigator's choice: hydroxyurea at tolerated dose, interferon/pegylated interferon, anagrelide, or observation; n=112)
Primary endpoint: Composite of hematocrit (HCT) control AND ≥35% spleen volume reduction at week 32 (both criteria required)
mFollow up: Not stated (primary analysis at week 32)
Arm B: Standard therapy (investigator's choice: hydroxyurea at tolerated dose, interferon/pegylated interferon, anagrelide, or observation; n=112)
Primary endpoint: Composite of hematocrit (HCT) control AND ≥35% spleen volume reduction at week 32 (both criteria required)
mFollow up: Not stated (primary analysis at week 32)
Results
Primary composite (HCT control + ≥35% SVR): 21% vs 1%, P<.001
HCT control alone: 60% vs 20%
Spleen volume reduction ≥35% (SVR35): 38% vs 1%
Complete hematologic remission: 24% vs 9%, P=.003
TSS ≥50% improvement at week 32 (TSS50): 49% vs 5%
Thromboembolic events: 1 (ruxolitinib) vs 6 (standard therapy)
HCT control alone: 60% vs 20%
Spleen volume reduction ≥35% (SVR35): 38% vs 1%
Complete hematologic remission: 24% vs 9%, P=.003
TSS ≥50% improvement at week 32 (TSS50): 49% vs 5%
Thromboembolic events: 1 (ruxolitinib) vs 6 (standard therapy)
Adverse events
Hematologic (grade 3–4): anemia 2% (ruxolitinib) vs 0% (standard); thrombocytopenia 5% vs 4%
Infectious: herpes zoster 6% vs 0% (all grade 1–2; no grade 3–4 cases)
Vascular: fewer thromboembolic events with ruxolitinib (1 vs 6 patients)
Infectious: herpes zoster 6% vs 0% (all grade 1–2; no grade 3–4 cases)
Vascular: fewer thromboembolic events with ruxolitinib (1 vs 6 patients)
Conclusions
Ruxolitinib was superior to standard therapy in PV patients with hydroxyurea failure or intolerance, achieving the composite primary endpoint of hematocrit control and spleen reduction in 21% vs 1%, with substantially better rates of each component individually and improved symptom burden. The lower rate of thromboembolic events with ruxolitinib was clinically noteworthy.
Key Limitations
Composite primary endpoint requiring both HCT control AND spleen reduction is stringent; individual component benefits were much larger (60% vs 20% for HCT; 38% vs 1% for spleen). Open-label design introduces performance and assessment bias. No OS analysis at the primary endpoint; long-term survival impact unproven. Standard therapy arm was heterogeneous, precluding comparison to individual therapies. Herpes zoster risk (6%) requires vigilance and vaccination consideration. Long-term follow-up needed to assess AML/MF transformation risk.
Clinical Context
RESPONSE established ruxolitinib as standard second-line therapy for hydroxyurea-refractory/intolerant PV with splenomegaly and received FDA approval in 2014. It is endorsed by ELN guidelines for high-risk PV uncontrolled with or intolerant to hydroxyurea. Long-term follow-up (5 years) confirmed durable HCT control and low rates of disease transformation. Ropeginterferon alfa-2b and rusfertide (subcutaneous hepcidin mimetic) are emerging alternatives in ongoing trials.
References