Abstract
Chronic systemic inflammation is a key driver of polycythemia vera (PV) progression, but the immunomodulatory effects of current treatments remain poorly defined. The neutrophil-to-lymphocyte ratio (NLR) is an accessible biomarker of systemic inflammation proven in other contexts, but its role in monitoring PV disease activity has not been established. Using data from three of the largest PV clinical trials, we evaluated the effects of PV therapies on NLR and its relationship with molecular response and clinical outcomes. In 404 hematocrit-controlled patients from the ECLAP study, hydroxyurea (HU) failed to significantly lower NLR (p = 0.11) due to the parallel declines in ANC and ALC. Neither leukocyte counts nor NLR were significantly reduced by phlebotomy in ECLAP patients treated without cytoreductive therapy. In contrast, the Low-PV study showed that while phlebotomy tended to increase NLR, low-dose ropeginterferon alfa-2b (Ropeg) significantly reduced NLR (-18.2% and -36.3% in patients with low and high baseline NLR, respectively) by suppressing ANC rather than lymphocytes. NLR reduction correlated with the primary Low-PV endpoint (p = 0.021) and reduction of JAK2 variant allele frequency (VAF) [1]. The PROUD-PV/CONTINUATION-PV study confirmed the superior effect of Ropeg over HU, with a significantly greater NLR reduction at 60 months (-56.5% versus -33.6%, respectively, p = 0.019) in patients with high baseline NLR. Moreover, NLR reduction was associated with decreased JAK2(V617F) VAF (p < 0.0001) and improved event-free survival (p = 0.010). These findings identify NLR as a dynamic biomarker of treatment response and prognosis in PV and support its incorporation into routine monitoring.