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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 12  |  Issue : 4  |  Page : 189-194

Assessment of neutrophil/lymphocyte ratio in relation to presentation and prognosis of diffuse large B-cell nonhodgkin lymphoma


1 Department of Medicine (Hematology), College of Medicine, Al-Nahrain University, Baghdad, Iraq
2 Department of Medicine (Hematology) Al-Imamain Al-Kadhumain, Medical City, Baghdad, Iraq

Date of Submission17-Feb-2021
Date of Decision30-Mar-2021
Date of Acceptance10-Apr-2021
Date of Web Publication18-Jan-2022

Correspondence Address:
Prof. Waseem F Al-Tameemi
Department of Medicine (Hematology), College of Medicine, Al-Nahrain University, P. O. Box: 70044, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/joah.joah_16_21

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  Abstract 


BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is representing 30%–40% of all lymphomas. It is an aggressive lymphoma with heterogeneous clinicopathological features. Inflammatory processes have been identified to play an important role in the pathogenesis of lymphoma including the neutrophil-lymphocyte ratio (NL ratio) was associated with a poor prognosis.
AIM OF STUDY: The aim of this study is to assess neutrophil/lymphocyte (N/L) ratio in relation to clinical presentation, and other prognosticators in DLBCL, and to study the effect of these markers with response rate and early outcome.
PATIENTS AND METHODS: This is a cohort prospective study with data obtained from May 2018 to November 2019. Data collected from multiple hematological centers in Baghdad, Iraq. A total of 58 adult patients who are newly diagnosed with DLBCL were enrolled. In addition to demographic features, international prognostic index (IPI) score, complete blood parameters (white blood cell count, N/L ratio, had assessed.
RESULTS: The mean age was 53.54 ± 14.95 years. Twenty-two (45.83%) had extranodal involvement at the presentation. Advanced stage was reported in 34 (70.83%). Median N/L ratio was 3.39 with cut-off values 4.41. There was no significant association with the N/L ratio neither with progression-free survival (PFS) nor with the advanced stage presentation (P = 0.238, 0.343, respectively). It is found also that higher median N/L ratio was significantly associated with high and high-intermediate IPI score (P = 0.03).
CONCLUSION: The NL ratio has a significant association with the IPI score, but not with the disease PFS.

Keywords: Lymphocyte, neutrophil, nonHodgkin lymphoma, prognosis


How to cite this article:
Al-Tameemi WF, Mahmmood AJ. Assessment of neutrophil/lymphocyte ratio in relation to presentation and prognosis of diffuse large B-cell nonhodgkin lymphoma. J Appl Hematol 2021;12:189-94

How to cite this URL:
Al-Tameemi WF, Mahmmood AJ. Assessment of neutrophil/lymphocyte ratio in relation to presentation and prognosis of diffuse large B-cell nonhodgkin lymphoma. J Appl Hematol [serial online] 2021 [cited 2022 Sep 25];12:189-94. Available from: https://www.jahjournal.org/text.asp?2021/12/4/189/335938




  Introduction Top


Diffuse large B-cell lymphomas (DLBCLs) comprise heterogeneous group of aggressive malignancies of large, transformed B cell which causes diffuse effacement of the normal lymph node structure.[1]

Numerous studies have demonstrated that the ratio of different kinds of peripheral blood cells can be used to predict the prognosis of lymphomas such as neutrophil-to-lymphocyte ratio (N/L ratio) and platelet-to-lymphocyte ratio.[2],[3]

The N/L ratio, a biomarker for systematic inflammation, has been recently identified as a prognostic factor for various types of both solid and hematologic malignancies and it was analyzed whether can be served as a prognostic biomarker in DLBCL. Electronic databases for relevant studies were searched and enrolled 11 studies with a total of 25 DLBCL patients were included in the meta-analysis.[4] The results revealed that elevated pretreatment N/L ratio was significantly associated with elder age, advanced Ann Arbor stage, higher incidence rate of B symptoms and bone marrow involvement, and higher lactate dehydrogenase level, etc., Moreover, increased N/L ratio also predicted poorer overall survival (OS) and progression-free survival (PFS)/event-free survival.[4] This meta-analysis revealed nonlinear association between increased N/L ratio and risk of mortality in DLBCL patients and concluded that patients with higher N/L ratio were more likely to have poorer prognosis than those with lower N/L ratio.[5]

Several studies have shed light on the association between N/L ratio and the prognosis of cancer patients. However, these results are not comparable because of the heterogeneity on design and population, and the diversity in cut-off values defining “elevated N/L ratio.” A meta-analysis combining nine studies has shown that N/L ratio was a significant indicator for poor OS and PFS from a total of 2297 individuals.[6]

Aim of the study

  1. To define neutrophil/lymphocyte (N/L) ratio in relation to clinical presentation in DLBCL
  2. To assess its role in relation to the international prognostic index (IPI) and other prognosticators.



  Patients and Methods Top


Study design

This is a cohort prospective study with data obtained from September 2018 to October 2019, from hematology wards of Medical city complex, The National Center of Haematology and Al Kadhimain medical city in Baghdad, Iraq.

Patients selection

A total of 58 adult patients who were diagnosed with DLBCL and received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) were enrolled in this study. Ten patients lost their follow-up.

All patients received protocol that includes R-CHOP chemotherapy.

Those are excluded from the study are missed initial investigations, lost follow-up patients, and those with proved infections or other histopathological lymphoma types and relapsing patients.

All patients were informed about the study and consent taken. It is approved by the Iraqi board for medical specialty in adult clinical hematology.

Definitions

Absolute neutrophil count (ANC) is a measure of the number of neutrophil granulocytes present in the blood. The ANC is calculated from measurements of the total number of white blood cells (WBCs), usually based on the combined percentage of mature neutrophils sometimes called “segs,” or segmented cells and bands, which immature neutrophils.[7]

The reference range for ANC in adults considered as (1.5 − 8) × 109/l and for Lymphocytes as (1.0 − 3.0) × 109/l (20%–40%).[8]





Receiver operating characteristic (ROC) curve was used to determine the cut-off values of N/L ratio.[9]

Progression-free survival

Progression-free survival is defined as the time from random assignment in a clinical trial to disease progression or death from any cause.[10]

Outcome assessed according to the following definitions whenever they are available.

Complete response

Positron emission tomography-computed tomography (PET-CT), score 1, 2, or 3 with or without a residual mass on 5-point scale (1), no uptake above background; (2), uptake ≤mediastinum; (3), uptake >mediastinum but ≤liver; (4), uptake greater than liver; (5), uptake markedly higher than liver odds ratio (OR) on CT, target nodes/nodal masses must regress to ≤1.5 cm in longest diameter.[11]

Partial response

PET-CT score 4 or 5 with reduced uptake compared with baseline and residual mass (es) of any size. OR On CT ≥50% decrease in size of the nodes and extranodal sites.[11]

In this study, criteria for complete response (CR) were applied if available. In cases of partial response (PR), the criteria of response in PET scan were applied if available. In cases were CT scan that only available the PR determined if ≥50% reducti on in the size of the initial lymph nodes affected that not matched CR criteria.

Progressive disease

PET-CT score 4 or 5 with an increase in the intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma at interim or end-of-treatment assessment. OR On CT, an individual node/lesion must be abnormal with: longest diameter >1.5 cm and an increase in longest diameter or short diameter from nadir 0.5 cm for lesions ≤2 cm, 1.0 cm for lesions >2 cm.[11]

In the setting of splenomegaly, the splenic length must increase by >50% of the extent of its prior increase beyond baseline (e.g., a 15-cm spleen must increase to >16 cm). If no prior splenomegaly must increase by ≥2 cm from baseline. New or recurrent splenomegaly. New or clear progression of pre-existing non measured lesions. Regrowth of previously resolved lesions.

A new node >1.5 cm in any axis or a new extranodal site >1.0 cm in any axis; if <1.0 cm in any axis, its presence must be unequivocal and must be attributable to lymphoma.

Assessable disease of any size unequivocally attributable to lymphoma AND/OR new or recurrent involvement of the bone marrow.[12]

In this study, these criteria were applied for progression cases in the patients enrolled.

No response or stable disease

Score 4 or 5 with no significant change in FDG uptake from baseline at interim or end of treatment by PET scan or <50% decrease from baseline measurable nodes and extranodal sites; no criteria for progressive disease are met in target nodes/nodal masses, extranodal lesions, no increase in organ enlargement consistent with progression with no appearance of new lesions.[13]

Data collection

All data were taken from patient registry file concerning the diagnosis and duration of disease as well as treatment protocols details in addition to patient demographic data, method of diagnosis (bone marrow and lymph node), histopathological morphology and immunohistochemistry, clinical presentation and staging, IPI score, extranodal involvement, disease duration, disease outcome (complete remission, progression, relapse, stable disease, partial remission), duration of remission, and time till progression in addition to laboratory measures.

Clinical groups of lymphatic system were categorized for statistical purposes according to the regional anatomical sites into head and neck, axillary, intraabdominal, mediastinal, and groin.

Treatment protocols defined as standard or adjusted according to doses of the doxorubicin (50 vs. 25 mg/m2), cyclophosphamide (750 vs. 500 mg/m2), and vincristine (2 mg vs. 1 mg total dose) and rituximab repeated every 21 days.

Duration of follow-up for each patient has been defined from diagnosis up to the interim evaluation, the end of treatment, and the end of the study. The durations were classified according to the outcome of each patient. In case complete remission the follow-up period was from the diagnosis till the end of the study including the remission duration. Progression, partial remission, and stable disease, the follow-up period was calculated from the diagnosis till the assessment at the midcourse evaluation and at the end of treatment. In relapse cases, the duration of follow-up was from the diagnosis till date of proven relapse.

Statistical analysis

Statistical analyses were performed by using SPSS software version 25.0 (SPSS, Chicago, Illinois, USA). Continuous data were subjected to normality test (Shapiro–Wilk test), and accordingly, these data were expressed as median and range.

Mann–Whitney U test was used to find the significant differences between each two groups.

Categorical variables were expressed as number and percentage and analyzed with the Chi-square test.

Survival function was estimated by Kaplan–Meier analysis for neutrophil-lymphocyte (NL) ratio and LM ratio.

P < 0.05 was considered to indicate a statistically significant difference.


  Results Top


Demographic and clinical characteristics data

Mean age of the patients was 53.54 ± 14.95 years (range 24–84 years). Females represented about 60% of the patients with male-female ratio were 1:1.53. More than 60% of patients had no specific comorbidity, while 18.75%, 6.25%, and 12.5% of them had hypertension, diabetes mellitus, or both, respectively. Slightly less than half of the patients (45.83%) had extranodal involvement. Head and neck mass was the most common mode of presentation accounting for 47.92% of the patients followed by intraabdominal mass (29.17%). B-Symptoms were reported in exactly two-third of the patients [Table 1].
Table 1: Demographic and clinical characteristics of the patients (n=48)

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According to staging, 29.17% of the patients were within early stages of the disease, while the other 70.83% were within the advanced stages. Patients were almost evenly distributed between different categories of IPI score. The vast majority of patients (83.33%) had received the standard chemotherapy, while only 16.67% were treated with adjusted therapy.

White blood cells parameters

Most of these indices were found to be nonnormally distributed, and therefore they were expressed as median and range in addition to mean + standard deviation. Median total WBC count was 8.7 × 109/L, while median absolute neutrophil and lymphocyte were 5.65 × 109/L, 1.78 × 109/L, respectively. Median N/L ratio was 3.39, [Table 2].
Table 2: White blood cells parameters

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Neutrophil/lymphocyte ratio as predictor for Progression

ROC curve was used to determine the cut-off values of each N/L ratio. For N/L ratio, the cut-off value was 4.41. The sensitivity and specificity of the test were 63% and 68% respectively.

KaplanMeier survival curve was constructed to find out the prognostic value of NL ratio in free-progression survival. Median PFS for patients with N/L ratio ≤4.41 was 12.15 month (95% confidence interval [CI] = 10.56–13.75), while that for patients with N/L ratio >4.41 was 9.86 months (95% CI = 7.32–12.4), with no significant difference P value (Tarone-Ware) = 0.238, P value (Breslow) = 0.222 [Figure 1].
Figure 1: Progression free survival according to neutrophil-lymphocyte ratio

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Furthermore, Cox regression analysis was used to define the relation of demographic and clinical characteristics as well as WBC parameters with the prediction of PFS. Out of these parameters, two were found to be significantly affecting PFS which are the presence of comorbidities, extranodal involvement, (P value 0.021, 0,028, respectively) [Table 3]. Diabetes mellitus seems to significantly increase the hazard of progression (P = 0.021). Likewise, the presence of extranodal involvement will increase such hazard (hazard ratio [HR] = 3.71, 95% = 1.16–11.93, P = 0.028).
Table 3: Univariate Cox regression analysis of progression-free survival in relation to patient characteristics

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Neutrophil/lymphocyte ratio as predictor for advanced stages

According to KaplanMeier curve [Figure 2], mean time till progression for patients with N/L ratio ≤4.41 was 11 months (95% CI 9.94–12.06), while it was 9 months (95% CI = 4.19–13.81) for those with NL ratio >4.41, with no significant difference, P value (Tarone-Ware) = 0.343, P value (Breslow) = 0.296.
Figure 2: Meantime till progression according to the neutrophil-lymphocyte ratio

Click here to view


In cox regression analysis both extra-nodal involvement (HR = 2.23, 95% CI = 1.06–4.67, P = 0.033) and high IPI-score (HR = 10.18, 95% CI = 2.0–34.6, P < 0.001) were found to significantly increase the risk for advanced stage development, but N/L ratio, had a significant effect.


  Discussion Top


It is observed that the cut-off values of N/L ratio 4.41; However the cut-off values appeared to be different in different studies, Ho et al. 2015[14] used the same cut-off value for N/L ratio (4.35) unlike Wang J et al. 2017[2] different N/L ratio value (2.81). This difference in the cut-of values between the studies was due to the difference in the method that had been used for measuring these values whether including band stage or not.

Here it is found that N/L ratio had no significant association with PFS with the cut off ratio of (4.41) P value 0.238, although it is observed that patients with N/L ratio ≤4.41 had mean PFS slightly higher than those with ratio >4.41 (12.15 month (95% CI = 10.56–13.75), 9.86 months (95% CI = 7.32–12.4, respectively), which is in concordance with the Azuma et al. 2019 who also didn't find any statistical association with both OS and PFS.[15] On the other hand Wang et al. 2017 designed a meta-analysis and concluded that higher N/L ratio is correlated with poor OS as well as worse PFS.[6] The differences in calculation the cut-off values may be an explanation for this inconsistence of finding based on number of patients enrolled.

Lymphocytes have a crucial role in innate cellular immunity and are important in destroying the residual malignant cells. It is widely believed that the tumor-infiltrating lymphocytes (TILs) are associated with the better clinical outcomes in cancer. Hence, N/L ratio might be a good index that reflects balance between inflammation and immunoreaction in cancer. However, lymphoma is a cancer of lymphocytes where host innate immunity has been destroyed, and TIL number might be decreased in lymphoma patients. Thus, it might be difficult for NL ratio to reflect the outcome of lymphoid malignancies.[16],[17]

Lymphocytes are the basic components of the immune system; they can induce cytotoxic cell death and produce cytokines in the cancer cells. Lymphocytopenia adversely affects the antitumor immune response of the host, which in turn promotes the tumor expansion and leads to a poor patient prognosis.[9]

In the present study, there is no significant statistical relationship between advanced stage of presentation with the NL ratio at cut-off values 4.41. On the other hand, a study from Porrata et al. concluded that stage was borderline statistically significant with NL ratio at a cut-off value (3.5),[18] unlike Jing Wang et al. 2017 concluded that a higher NL ratio group had advanced disease stages (P = 0.009).[6] The small number of patients and the cut-off value difference might be the reasons behind that.


  Conclusion Top


The NL ratio higher than the cut-off value 4.41 has a significant association with higher IPI score, but not with the disease progression, but without significant association with the advanced stage presentation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Smith SD, Press OW. Diffuse large B cell lymphoma and related diseases. In: Kaushansky K, Lichtman MA, Prchal JT, Levi MM, Press OW, Burns LJ, et al., editors. Williams Hematology. 9th ed. New York: McGraw-Hill; 2016. p. 1625-37.  Back to cited text no. 1
    
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Wang J, Gao K, Lei W, Dong L, Xuan Q, Feng M, et al. Lymphocyte-to-monocyte ratio is associated with prognosis of diffuse large B-cell lymphoma: Correlation with CD163 positive M2 type tumor-associated macrophages, not PD-1 positive tumor-infiltrating lymphocytes. Oncotarget 2017;8:5414-25.  Back to cited text no. 2
    
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Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-90.  Back to cited text no. 4
    
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Ho C-L, Lu C-S, Chen J-H, Chen Y-G, Huang T-C, Wu Y-Y. Neutrophil/Lymphocyte Ratio, Lymphocyte/Monocyte Ratio, and Absolute Lymphocyte Count/Absolute Monocyte Count Prognostic Score in Diffuse Large B-Cell Lymphoma: Useful Prognostic Tools in the Rituximab Era. Medicine (Baltimore) 2015; 94(24):e993. Available from: https://doi.org/10.1097/MD.0000000000000993.  Back to cited text no. 14
    
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Azuma Y, Nakaya A, Fujita S, Satake A, Nakanishi T, Tsubokura Y, et al. Neutrophil-to-lymphocyte ratio (NLR) fails to predict outcome of diffuse large B cell lymphoma. Leuk Res Rep 2019;12:100173. https://doi.org/10.1016/j.lrr.2019.100173.  Back to cited text no. 15
    
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Sun HL, Pan YQ, He BS, Nie ZL, Lin K, Peng HX, et al. Prognostic performance of lymphocyte-to-monocyte ratio in diffuse large B-cell lymphoma: An updated meta-analysis of eleven reports. Onco Targets Ther 2016;9:3017-23.  Back to cited text no. 16
    
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