Background
Phase 2, randomized, open-label trial. 180 patients with polycythemia vera (PV) resistant or intolerant to hydroxycarbamide (HC-INT/RES). Ruxolitinib vs best available therapy (BAT). Primary outcome was complete response (CR) within 1 year. Molecular response (JAK2 V617F VAF reduction) was a prespecified secondary endpoint. UK multicenter trial.
Interventions and follow up
Arm A: Ruxolitinib (dose per label) (n≈93)
Arm B: Best available therapy (BAT; investigator's choice) (n≈87)
Primary endpoint: Complete response (CR) within 1 year (European LeukemiaNet criteria)
mFollow up: Not stated
Arm B: Best available therapy (BAT; investigator's choice) (n≈87)
Primary endpoint: Complete response (CR) within 1 year (European LeukemiaNet criteria)
mFollow up: Not stated
Results
CR within 1 year: 43% (40 patients, ruxolitinib) vs 26% (23 patients, BAT), OR 2.12 (90% CI 1.25–3.60), P=.02
Duration of CR: superior for ruxolitinib; HR 0.38 (95% CI 0.24–0.61), P<.001
EFS (major thrombosis, hemorrhage, transformation, death): superior with ruxolitinib (HR 0.58, 95% CI 0.35–0.94, P=.03)
JAK2 V617F molecular response: more frequent with ruxolitinib; associated with improved PFS (P=.001), EFS (P=.001), and OS (P=.01)
CALR1 mutation: adverse predictor of EFS (HR 3.02, 95% CI 1.47–6.17, P=.003)
Duration of CR: superior for ruxolitinib; HR 0.38 (95% CI 0.24–0.61), P<.001
EFS (major thrombosis, hemorrhage, transformation, death): superior with ruxolitinib (HR 0.58, 95% CI 0.35–0.94, P=.03)
JAK2 V617F molecular response: more frequent with ruxolitinib; associated with improved PFS (P=.001), EFS (P=.001), and OS (P=.01)
CALR1 mutation: adverse predictor of EFS (HR 3.02, 95% CI 1.47–6.17, P=.003)
Adverse events
Hematologic: anemia and thrombocytopenia were the most common AEs, typically manageable with dose adjustment
Overall: safety profile consistent with prior ruxolitinib data; no new safety signals
Overall: safety profile consistent with prior ruxolitinib data; no new safety signals
Conclusions
MAJIC-PV demonstrated ruxolitinib's superiority over BAT for CR, duration of CR, and event-free survival in HC-INT/RES PV. Critically, it was the first trial to demonstrate that achieving molecular response (JAK2 V617F VAF reduction) with ruxolitinib is associated with improved long-term outcomes (PFS, EFS, OS), validating molecular response as a clinically meaningful endpoint in PV.
Key Limitations
Phase 2 trial; not powered to definitively assess OS. Open-label design with BAT heterogeneity. The 90% CI for the primary endpoint is non-standard and widens the uncertainty interval relative to conventional 95% CI reporting. EFS and OS benefits are secondary/exploratory. The molecular response–outcome association is correlative; causality not established. CALR1's adverse EFS impact needs prospective validation. Limited generalizability to non-European populations.
Clinical Context
MAJIC-PV provides additional phase 2 evidence for ruxolitinib in HC-INT/RES PV and uniquely establishes molecular response as a surrogate outcome. The JAK2 VAF data support the hypothesis that deeper molecular control may improve disease trajectory. MAJIC-PV complements RESPONSE/RESPONSE-2 and supports current ELN and BSH guidance. Ruxolitinib is established second-line standard of care in PV, with interferon and ropeginterferon alfa-2b preferred in younger or first-line patients where disease modification and pregnancy safety are prioritized.
References