Neutrophil-to-lymphocyte Ratio (nlr) In Polycythemia Vera (pv): Correlation With Ropeg-interferon Response In Low Pv Trial
Topic: Myeloproliferative neoplasms — Clinical
Background:In PV, the JAK2V617F mutation activates circulating neutrophils, inducing chronic systemic inflammation. Thisleads to impaired function of T lymphocytes and natural killer (NK) cells, fostering immune dysfunction, clonalexpansion, and immune evasion. The neutrophil-to-lymphocyte ratio (NLR) reflects this dual immune process,serving as a potential inflammatory biomarker for critical outcomes in PV. Interferon-alpha (IFN-alpha) therapyshowed a significant favorable impact on lymphocyte subsets and neutrophil reduction compared tohydroxyurea in PV patients.
Aims:To assess the impact of interferon therapy on inflammation in PV patients, we examined NLR levels in theRopeg-interferon alpha-2b arm versus phlebotomy alone (Ph-O) in the phase II low-PV trial.
Methods:In 126 patients, we analyzed (i) patient profiles based on NLR levels at randomization, (ii) NLR variations in thetwo arms at 12 and 24 months, and (iii) the correlation between NLR levels, patient response, and JAK2 V617Fallele burden (NEJM Evid 2023).
Results:i. Patients were stratified according to NLR < or > 3.5 (median value at baseline). Patients with NLR > 3.5had a longer history of PV prior to enrolment (21.4 vs. 7.2 months; p=0.004), were more likelysplenomegalic (41.5% vs. 20.0%; p=0.012) and had a higher JAK2 V617F VAF (56% vs. 20% p=0.001).Cases with NLR > 3.5 had laboratory tests confirming a more proliferative disease (higher leukocytes, LDHand bone marrow hipercellularity).ii. In Ropeg patients a decrease in NLR levels was found; it occurred within the first 3 months and wasmainly due to the decrease in neutrophils (60%) rather than lymphocytes (34%)(Fig 1). After 12 months,the difference between Ropeg and Phl-O in the % of subjects with NLR improvement (i.e. ❤.5) wassignificant (68.3% vs. 43.9%, respectively, p=0.008). This trend was also substantially confirmed at 24months in responders.iii. By protocol, responders were defined as those who maintained HCT <45% in the first year, and were 81%vs. 51% for Ropeg vs. Phl-O, respectively. Phl-O non-responders had higher baseline NLR values and 6/8of them met the definition of progressive disease. In contrast, NLR levels were ❤.5 in Phl-O respondersat baseline and after 12 months. In the Ropeg arm, both responders and non-responders had a decreasein NLR compared to baseline, but this drop was statistically significant at 12 months only in responders(p=0.019, Fig. 1). In this arm, the decrease in JAK2 VAF from baseline was found to be linearly associatedwith the decrease in NLR (beta=1.65, p=0.025) with a Pearson correlation coefficient (r) of 0.307. Thisassociation was more pronounced for the decrease in neutrophils (beta=1.72, p=0.016, r=0.323) than forthe decrease in lymphocytes (beta=1.22, p=0.044, r=0.236). In the Phl-O arm, as expected, no changesbetween two markers at 12 months were found.
Summary/Conclusion:In chemotherapy-naïve PV patients enrolled in the Low-PV trial, high NLR reflects hyper-inflammation, more
proliferative disease and is associated with higher VAF levels of JAK2-V617F. Ropeginterferon was able tosignificantly reduce the inflammatory biomarker NLR, indicating modulation of the immune response, whichwas associated with improved therapeutic efficacy.