Treatment of myeloproliferative neoplasms: Exploring new horizons of who and when to cytoreduce in patients with polycythemia vera and essential thrombocytosis.

Treatment for the classical Philadelphia-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV) and essential thrombocythemia (ET), has long relied on reducing thrombotic risk without a focus on underlying disease modification. The simplified framework of age and thrombosis history inadequately captures the biological complexity of these diseases with emerging data identifying leukocytosis, elevated neutrophil-to-lymphocyte ratio, and high JAK2 V617F variant allele frequency as independent predictors of thrombotic risk. Furthermore, prognostic models such as MIPSS-PV and MIPSS-ET incorporate somatic mutations to better predict survival. Despite these advances, real-world practice remains anchored to traditional risk categories, with over 30% of high-risk patients receiving no cytoreductive therapy. In this evidence-based review, we trace the evolution of risk stratification in PV and ET and examine the clinical evidence supporting current cytoreductive options, specifically hydroxyurea, interferons, ruxolitinib, and anagrelide. We argue for a paradigm shift away from binarily driven thrombosis-centric risk stratification toward a personalized, proactive approach that integrates molecular and inflammatory biomarkers, expands the population offered cytoreduction, and prioritizes disease-modifying therapies. Prospective studies are needed to validate the incorporation of these markers into risk-adapted algorithms and to define the long-term impact of early disease modification on transformation, survival, and quality of life.