Comparative Analysis of Major Polycythemia Vera Clinical Trials: PROUD-PV, MAJIC-PV, RESPONSE, and CYTO-PV

Summary of Clinical Trials Guiding Polycythemia Vera Management

Key Clinical Trials

1. CYTO-PV Study:
   1. 365 randomized patients comparing strict (<45%) vs lenient (45%-50%) hematocrit control
   2. Results: 4-fold higher risk of cardiovascular death and thrombosis with lenient control
   3. Key finding: Just a 3% difference in hematocrit targets led to significantly worse outcomes
   4. Established the importance of maintaining hematocrit <45% consistently
2. RESPONSE Trial:
   1. Phase 3 study of ruxolitinib vs best available therapy (mostly hydroxyurea) in hydroxyurea-resistant/intolerant polycythemia vera patients requiring phlebotomies
   2. All patients had splenomegaly
   3. Results: 21% vs 1% achieved composite response (hematocrit control plus ≥35% spleen volume reduction)
   4. Higher individual rates of hematocrit control and spleen response with ruxolitinib
3. MAJIC-PV Study (2023):
   1. Similar population to RESPONSE: hydroxyurea-resistant/intolerant PV requiring phlebotomies
   2. Key difference: No crossover allowed between arms
   3. Results:
      1. 39% complete response rate with ruxolitinib
      2. Improved event-free survival with ruxolitinib vs hydroxyurea
      3. Molecular responses correlated with clinical outcomes
   4. Key finding: Early switch to ruxolitinib in hydroxyurea-resistant/intolerant patients is beneficial
4. PROUD-PV/CONTINUATION-PV:
   1. Patients diagnosed with PV within 3 years
   2. Ropeginterferon alfa-2b vs hydroxyurea
   3. Results:
      1. Similar complete hematologic response at 12 months
      2. Long-term outcomes favored ropeginterferon
      3. Molecular responses with hydroxyurea diminished over time while ropeginterferon responses deepened

Clinical Implications

• The critical importance of maintaining hematocrit <45% is strongly supported by evidence
• For hydroxyurea-resistant/intolerant patients, early switch to ruxolitinib improves outcomes
• Ropeginterferon offers superior long-term molecular responses compared with hydroxyurea
• Clinical and molecular response correlations suggest value in monitoring both parameters

These trial results provide a data-driven framework for risk-adapted management of polycythemia vera patients, supporting the treatment algorithm presented earlier and highlighting the importance of prompt recognition and management of hydroxyurea resistance or intolerance.