Neutrophil-to-lymphocyte ratio as a gene-specific biomarker of JAK2-driven inflammation across CHIP and myeloproliferative neoplasms.

The neutrophil-to-lymphocyte ratio (NLR) has emerged as a mechanistically informative biomarker in clonal hematopoiesis of indeterminate potential (CHIP) and myeloproliferative neoplasms (MPNs), although its clinical utility is strongly mutation dependent. NLR is markedly elevated in JAK2V617F-mutated CHIP and MPNs, reflecting neutrophil-driven myeloproliferation, whereas it remains largely unchanged in TET2, DNMT3A, and ASXL1 mutations despite substantial IL-1β- and IL-6-mediated inflammation. This apparent paradox highlights distinct inflammatory programs generated by different driver mutations, with JAK2 promoting neutrophilia and epigenetic mutations primarily activating macrophage-mediated innate immunity. In polycythemia vera, elevated NLR independently predicts thrombosis, myelofibrotic progression, and mortality. Similar prognostic value has been reported in essential thrombocythemia and myelofibrosis, particularly among patients with JAK2 mutations. Beyond risk stratification, NLR also functions as a pharmacodynamic biomarker. During treatment with ropeginterferon alfa-2b, reductions in NLR parallel decreases in JAK2V617F allele burden, whereas persistent NLR elevation during hydroxyurea therapy identifies patients at higher risk of thrombosis and adverse outcomes. Conversely, the CANTOS trial demonstrates that patients with TET2-mutated CHIP derived marked cardiovascular benefit from IL-1β inhibition despite NLR providing limited biological information, underscoring the need for complementary biomarkers in non-JAK2 CHIP. This review integrates mechanistic, clinical, and therapeutic evidence supporting mutation-specific inflammatory biomarkers and proposes NLR-guided strategies for risk assessment, treatment monitoring, and precision management in MPNs and CHIP.