Changes in neutrophil-to-lymphocyte ratio in patients with polycythemia vera treated with ruxolitinib reflect JAK2 variant allele frequency

The neutrophil-to-lymphocyte ratio (NLR) has received interest as potential biomarker of diseases where sustained inflammation plays a major role, including cardiovascular diseases and tumors1. In cancer, tumor growth and dissemination is facilitated by chronic inflammation promoted by activated neutrophils, while systemic and tumor-infiltrating T-lymphocytes are supposed to counteract cancer development by activating immunosurveillance. Similar processes may occur in the vascular system, resulting in atherosclerosis and vascular occlusion. Capturing balance between factors promoting and inhibiting cancer and atherosclerosis, NLR may serve as simple and reliable prognostic biomarker of such different diseases1. In polycythemia vera (PV), a myeloproliferative neoplasm (MPN) where sustained inflammatory condition and abnormal neutrophil count and functions are fueled by uncontrolled activation of JAK/STAT pathway caused by JAK2V617F mutation, higher NLR was associated with risk of venous thrombosis2, reduced survival3, and response to ropeg-interferon4. In a Danish population-based longitudinal analysis, increasing NLR was associated with shorter survival in patients with PV and other MPN, compared to unaffected population5. A comparative analysis of PV patients treated with hydroxyurea or phlebotomy (ECLAP study, n=202 each), ropeg-interferon or phlebotomy (LOW-PV trial, n= 63 and 64, respectively), and ropeg-interferon or hydroxyurea (PROUD-PV/CONTINUATION-PV study, n= 127 each), showed unique kinetics patterns of NLR upon different treatments. In fact, NLR resulted unchanged from baseline in patients managed with phlebotomy only and hydroxyurea, in the latter instance owing to parallel decline of neutrophils and lymphocytes, while in ropeg-interferon-treated patients, the reduction of NLR was due to preferential lowering of neutrophils6. Recent data indicate that neutrophils in PV express reduced levels of Kruppel-like factor 2 in a JAK2V617F VAF-inverse manner, that were largely reverted by pegylated interferon alfa7. Furthermore, tissue factor synthesis and activity was described in PV neutrophils, possibly contributing to thrombotic risk8. An additional explanation for abnormally increased NLR levels and the differential effects of drugs, may be related to the expression of JAK2V617F mutation also in lymphoid lineage, that in preclinical model caused an impaired lymphoid differentiation9. Reduction of NLR in patients receiving ropeg-interferon significantly correlated with decrease of JAK2V617F VAF, and molecular responses to ropeg-interferon were predictive of improved event-free survival6, 10. Also relevant to the interpretation of those findings is the evidence, obtained in animals expressing ruxolitinib resistant mutations, that the action of ruxolitinib was independent of JAK2V617F signaling, rather it appeared to be mediated by reduction 4 of pro-inflammatory cytokines produced by stromal cells and non-malignant hematopoietic cells 11. Another drug currently used for second-line treatment of PV patients is ruxolitinib, a JAK1 and JAK2 inhibitor12, 13. Recent data from the MAJIC study and a real-world cohort have shown that progressive decline of JAK2V617F VAF under ruxolitinib treatment correlated with improved overall and event-free survival, particularly myelofibrosis-free survival