Pre-Treatment Derived Neutrophil to Lymphocyte Ratio As a Prognostic Factor in Extranodal Natural Killer/T-Cell Lymphoma
Authors: Zhou Xiangxiang , Zhang Lingyan , Li Ying , Fang Xiaosheng , Lv Xiao , Lu Kang , Wang Xin 
Published: October 2019

Abstract
Introduction: Extranodal natural killer/T-cell lymphoma (ENKTL) is an aggressive type of non-Hodgkin lymphoma (NHL), which is relatively more common in Asia. Accumulating evidence suggested that tumor microenvironment and inflammatory response played important roles in determining the clinical course and outcome of human malignancies. Recently, the derived neutrophil to lymphocyte ratio (dNLR) was demonstrated to act as prognostic factor in several malignancies. Nevertheless, the significance of dNLR in ENKTL has not been elucidated to date. The aim of this study is to investigate the prognostic value of dNLR in ENKTL.
Methods: We included patients with pathological diagnosis of ENKTL from February 2002 to June 2018 at Shandong Provincial Hospital Affiliated to Shandong University. All the diagnoses were based on the criteria of the WHO 2016 Classifications of the Tumors and Hematopoietic and Lymphoid Tissues. The pretreatment clinical-pathological data, such as age, gender, stage, performance status, serum lactate dehydrogenase (LDH) levels, bone marrow involvement, and neutrophil count and leukocyte count were collected. The dNLR was calculated by absolute neutrophil count divided by (leukocyte count - neutrophil count).The primary end point was overall survival (OS). The secondary end point was progression-free survival (PFS). Survival analyses were performed using the Kaplan-Meier method and log-rank test. Multivariate analyses were performed using Cox proportional-hazards regression model. This study was approved by the Medical Ethical Committee of Shandong Provincial Hospital Affiliated to Shandong University. P<0.05 was considered statistically significant.
Results: A total of 33 patients with pathological diagnosis of ENKTL were included in this study, including 26 (78.8%) male patients and 7 (21.1%) female patients. The median age at diagnosis was 50 years (range 13-75 years), and 6 (18.2%) of them were more than 60 years old. Among them, 13 (39.4%) patients were diagnosed at stage I/II with mean dNLR of 1.801 ± 0.832, versus 20 (60.6%) at stage III/IV with mean dNLR of 2.834 ± 1.962 (P=0.047). In addition, elevated serum LDH (P=0.026), distant lympho-node involvement (P=0.013), high β2-microglobulin (β2-MG, P=0.035) and high International Prognostic Index (IPI) score (P=0.044) were also significantly associated with high dNLR at diagnosis of ENKTL (Table 1).
To determine the clinical significance of dNLR, cutoff value of 3.6 for dNLR, which was determined by receiver operating characteristic (ROC) analysis, was selected as the best discriminate between patients' survival and death (AUC 0.714, 95%CI 0.524-0.904, P=0.043, Figure 1). Patients were divided into dNLR<3.6 and dNLR≥3.6 groups. Patients with elevated dNLR (≥3.6) presented adverse pre-treatment factors, including elevated serum LDH (P<0.001), high Eastern Cooperative Oncology Group performance status (ECOG PS) score (P=0.004), increased β2-MG (P=0.008) and high IPI score (P=0.018). Kaplan-Meier curve revealed that high dNLR (≥3.6) was related to shorter OS (P=0.001) and PFS (P=0.047) of ENKTL patients (Figure 2-3).
We next explored the correlation between clinical characteristics and survival of ENKTL patients by univariate and multivariate analysis. Univariate Cox proportional analysis revealed that high ECOG PS score (≥2, P=0.004), elevated β2-MG (P=0.014), high IPI score (≥2, P=0.007) and elevated dNLR (>3.6, P=0.001) as prognostic factors of poor outcome of patients. To further assess whether dNLR could act as an independent prognostic value for OS, multivariate analysis with Cox proportional hazard model was performed. In the multivariate analysis, which included all independent parameters significantly associated with clinical outcome in univariate analysis, we identified that high dNLR (≥3.6) as an independent prognostic factor for OS in patients with ENKTL (P=0.004).
Conclusions: In this study, we validated for the first time the prognostic value of dNLR in ENKTL patients. High dNLR was associated with poor survival of ENKTL. The dNLR may serve as a novel and convenient prognostic factor for untreated ENKTL patients. Further validation of these results in larger cohorts of patients with ENKTL is warranted.

Disclosures
No relevant conflicts of interest to declare.