Predicting Molecular Response through Half Reduction of Neutrophil-to-Lymphocyte Ratio (NLR) in Polycythemia Vera Treatment with Ropeginterferon
Authors: Yoon Seug Yun , Won Jong-Ho , Lee Sung-Eun , Yoon Sung-Soo , Yang Deok-Hwan , Lee Gyeong Won , Sohn Sang Kyun , Shin Ho-Jin , Bae Sung Hwa , Choi Chul Won , Choi Yunsuk , Cheong June-won , Bang Soo-Mee , Park Joon Seong , Oh Sukjoong , Park Yong , Park Young Hoon 
Published: December 2024

Background
Polycythemia vera (PV) is a one of myeloproliferative neoplasm (MPN) s. In MPNs, the malignant clone of hematopoietic cells drives the production of inflammatory cytokines, creating a self-perpetuating inflammatory cycle that sustains the disease process. This chronic inflammation contributes to the pathogenesis and progression of the disease. The neutrophil-to-lymphocyte ratio (NLR) is calculated by dividing the neutrophil count by the lymphocyte count. The NLR is a quick and simple method for assessing inflammatory status, widely used in various diseases to predict inflammation and mortality. In a previous studies, we have demonstrated that the NLR is elevated in patients with MPNs compared to the normal population. Especially, in PV, panmyelosis causes an increase in myeloid cells, leading to a relative decrease in lymphocytes and resulting in an elevated NLR. The NLR serves as a marker reflecting the inflammatory status, and a decrease in NLR can indicate an improvement in PV. Therefore, we aimed to investigate how well a half reduction in NLR can predict and molecular response (MR).
Methods
We analyzed data from a phase 2 clinical study conducted in Korea, which assessed the efficacy of ropeginterferon alfa-2b in patients with PV. The NLR reduction rate was defined as the percentage reduction in NLR from baseline to assessment visits compared to the baseline NLR. Receiver Operating Characteristic (ROC) curves were utilized to determine the optimal cut-off values for the NLR reduction rate, aiming to predict molecular response at each assessment visit. A logistic regression model was applied to calculate odds ratios (OR). Statistical significance was defined as a p-value less than or equal to 0.05, and R software was used for data analysis.
Results
A total of 95 patients were included in the full analysis set, all of whom received at least one dose of ropeginterferon alfa-2b. The median age was 58 years (range, 26-81), with 51 (54%) male participants. Among these patients, 46 (48%) had high-risk PV, and 52 (54.7%) were hydroxyurea-naïve. The median disease duration was 907 days (range, 0-6,321), and the median NLR was 4.87 (range, 1.17-32.34).
The optimal cut-off value for the NLR reduction rate to predict molecular response at each assessment visit. was -0.49, with a sensitivity of 73% and specificity of 77%. ROC curve analysis demonstrated an area under the ROC Curve (AUC) of 0.803 [95% CI 0.754-0.852, p&lt;0.001], leading to the classification of patients into groups based on achieving over half NLR reduction.
At VISIT 3 (12 weeks), achieving an NLR reduction of over half increased the odds of achieving a molecular response (MR) by 7.49 times (OR = 7.49, 95% CI [2.41-23.27], p = 0.0005). Among hydroxyurea-naïve patients, the odds of achieving MR at VISIT 3 were 4.24 times higher compared to those who were hydroxyurea-resistant or intolerant (OR = 4.24, 95% CI [1.05-17.19], p = 0.0429). At VISIT 4 (24 weeks), achieving a greater than half NLR reduction increased the odds of achieving MR by 27.77 times (OR = 27.77, 95% CI [5.83-132.41], p &lt; 0.0001). Notably, each additional year of age was associated with a 10% decrease in the odds of achieving MR at VISIT 4 (OR = 0.90, 95% CI [0.85-0.96], p = 0.018). At VISIT 5 (36 weeks), a greater than half reduction in NLR increased the odds of achieving MR by 22.71 times (OR = 22.71, 95% CI [5.69-90.71], p &lt; 0.0001). Similarly, at VISIT 6 (48 weeks), achieving a greater than half NLR reduction increased the odds of achieving MR by 15.26 times (OR = 15.26, 95% CI [1.17-13.84], p = 0.0224).
Conclusions
A significant finding was that a greater than half reduction in the NLR significantly increased the odds of achieving MR at various assessment points. Hydroxyurea-naïve patients showed higher odds of achieving MR compared to those resistant or intolerant to hydroxyurea. Additionally, older age was associated with decreased odds of MR at 24 weeks. These results suggest that monitoring NLR reduction can be a valuable predictor of treatment efficacy with ropeginterferon alfa-2b, particularly in younger and hydroxyurea-naïve patients.