Towards New Therapy Endpoints in Polycythemia Vera: Targeting Clonal and Inflammatory Pathways

Although phlebotomy and hydroxyurea (HU) are standard first-line therapies for polycythaemia vera (PV), they do not adequately address clonal expansion and chronic inflammation - key drivers of thrombosis, myelofibrosis and mortality. Biomarkers such as JAK2 V617F VAF and the neutrophil-to-lymphocyte ratio (NLR) are emerging as valuable tools for guiding therapy. Ropeginterferon alfa-2b has been shown to reduce both JAK2 VAF and NLR, improving event-free survival as demonstrated in the Low-PV and PROUD-PV/CONTINUATION-PV trials. In contrast, propensity score matching of the ECLAP trial showed that HU has limited effect on these biomarkers, suggesting weaker disease-modifying potential. Although no data on NLR dynamics with ruxolitinib have been published, the anti-inflammatory effects of ruxolitinib and its suppression of JAK2 VAF suggest it may exert similar biological activity. These findings support a shift towards biology-guided treatment in PV, recognising that inflammation and JAK2 VAF could serve as surrogate endpoints in future clinical trials.