Toward new therapy end points in polycythemia vera: targeting clonal and inflammatory pathways

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• Polycythaemia vera (PV) treatments like phlebotomy and hydroxyurea (HU) do not fully control disease drivers: clonal expansion and inflammation.
• These drivers contribute to thrombosis, myelofibrosis, and mortality in PV patients.
• Biomarkers such as JAK2 V617F variant allele frequency (VAF) and neutrophil-to-lymphocyte ratio (NLR) are crucial for monitoring disease and guiding therapy.

Purpose of the Study:

• To compare the effects of ropeginterferon alfa-2b and hydroxyurea on key biomarkers in polycythaemia vera.
• To evaluate the potential of ropeginterferon alfa-2b in modifying disease progression by targeting clonal expansion and inflammation.
• To explore the role of JAK2 VAF and NLR as surrogate endpoints for future PV clinical trials.

Main Methods:

• Analysis of data from the Low-PV, PROUD-PV, and CONTINUATION-PV trials for ropeginterferon alfa-2b.
• Propensity score matching of data from the ECLAP trial to assess hydroxyurea's effects.
• Comparison of biomarker changes (JAK2 V617F VAF and NLR) between treatment groups.

Main Results:

• Ropeginterferon alfa-2b significantly reduced both JAK2 V617F VAF and NLR, correlating with improved event-free survival.
• Hydroxyurea demonstrated limited impact on these biomarkers, suggesting less potent disease-modifying capacity.
• While not directly studied, ruxolitinib's known anti-inflammatory actions and JAK2 VAF suppression suggest potential for similar biological activity.

Conclusions:

• Ropeginterferon alfa-2b offers superior control over key polycythaemia vera drivers compared to hydroxyurea.
• Biomarker modulation by targeted therapies supports a move towards biology-guided treatment strategies in PV.
• JAK2 VAF and NLR hold promise as surrogate endpoints for assessing treatment efficacy in future PV research.