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

ABSTRACT: Although phlebotomy and hydroxyurea (HU) are standard first-line therapies for polycythemia vera (PV), they do not adequately address clonal expansion and chronic inflammation, which are key drivers of thrombosis, myelofibrosis, and mortality. Biomarkers such as JAK2 V617F variant allele frequency (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 European Collaborative Low-Dose Aspirin trial showed that HU has a 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 toward biology-guided treatment in PV, recognizing that inflammation and JAK2 VAF could serve as surrogate end points in future clinical trials.