Treatment and clinical endpoints in polycythemia vera: seeking the best obtainable version of the truth

Abstract

Polycythemia vera (PV) is a Philadelphia chromosome-negative myeloproliferative neoplasm driven by the JAK2 V617F (or rarely exon 12) mutation. Its natural history can extend over a few decades, and therefore treatment planning is predicated on continual reassessment of traditional risk features (age, prior thrombosis) to evaluate the need for cytoreduction besides foundational therapy with low-dose aspirin and stringent phlebotomy. Shorter- and longer-term patient goals should be considered in light of several variables such as comorbid conditions (especially cardiovascular risk factors), disease symptoms, and the risk-benefit profile of available drugs. While hydroxyurea has been the pro forma choice of cytoreduction for many practitioners over the last half-century, the more recent regulatory approvals of ruxolitinib and ropeginterferon-alfa-2b, based on phase 3 randomized trials, highlight an expanding portfolio of active drugs. Obtaining high-level evidence for short-term clinical trial endpoints such as hematocrit control, symptom burden/quality of life, splenomegaly, and JAK2 V617F allele burden lies within the timeline of most studies. However, in many cases, it may not be possible to adequately power trials to capture significant differences in the typically low event rates of thrombosis as well as longer-horizon endpoints such as evolution to myelofibrosis and acute myeloid leukemia and survival. This Perspective highlights the challenges of addressing these data gaps and outstanding questions in the emerging treatment landscape of PV.