The neutrophil/lymphocyte (N/L) ratio at diagnosis has been shown to be a prognostic factor for survival in solid tumors. The N/L ratio at diagnosis as a prognostic factor for non-Hodgkin lymphoma (NHL) has not been studied. Thus, we studied N/L ratio at diagnosis as a prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL) treated with R-CHOP. From 2000 until 2007, 255 consecutive DLBCL patients, originally diagnosed, treated with R-CHOP, and followed at Mayo Clinic, Rochester, were included in this study. With a median follow-up of 4.0 years (range: 0.3–9.0 years), patients with an N/L ratio <3.5 at diagnosis experienced a superior overall survival (OS) and progression-free survival (PFS) compared with those patient with an N/L ratio ≥3.5 at diagnosis. The median OS was not reached versus 6.8 years, P < 0.0001; and the median PFS was not reached versus 3.3 years, P < 0.0001, respectively. Multivariate analysis showed N/L ratio to be an independent prognostic factor for OS and PFS. This study suggests that baseline N/L ratio at diagnosis is a simple, inexpensive, standardized prognostic factor to assess clinical outcomes in DLBCL patients treated with R-CHOP. Absolute lymphocyte count (ALC), as a surrogate marker of host immunity, has been reported to a prognostic factor for survival in patients with diffuse large B-cell lymphoma (DLBCL) at diagnosis [1-4], or after first relapse [5]. In solid tumor, baseline neutrophil count, as a surrogate marker of inflammation, has been associated with survival [6-8]. Furthermore, the neutrophil/lymphocyte (N/L) ratio at diagnosis in solid tumors has been reported to be a prognostic factor for clinical outcomes [9-13]. The rationale for the N/L ratio is to compare the inflammatory response (i.e., neutrophils) produced by cancer to the host immunity (i.e., lymphocytes). Thus we set out to investigate if N/L ratio at diagnosis is a predictor of survival in DLBCL patients treated with rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone (R-CHOP). The median age at the time of diagnosis for this cohort of 255 DLBCL patients was 64 years (range: 20–92). The distribution of additional baseline characteristics for the cohort are presented at on line Supporting Information Table I. The median follow-up on living patients (N = 170) in this cohort was 59.1 months (range: 13.9–107.8). Fifty-eight patients died due to lymphoma recurrence and 27 patients due to non-lymphoma related causes. As continuous variable N/L ratio at diagnosis was predictor for OS and PFS by univariate and multivariate analysis (on line Supporting Information Tables II and III). Using the cutoff for N/L ratio ≥3.5 at diagnosis, patients with an N/L ratio <3.5 at diagnosis experienced superior OS compared with patients with an N/L ratio ≥3.5 at diagnosis (see Fig. 1). The median OS was not reached versus 6.8 years and the OS 5-year rates were 87% versus 56%, respectively, P < 0.0001. In similar fashion, superior PFS was observed in patients with an N/L ratio <3.5 at diagnosis compared with patients with an N/L ratio ≥3.5 at diagnosis (see Fig. 2). The median PFS was not reached versus 3.3 years and the PFS 5-year rates were 72% versus 45%, respectively, P < 0.0001. Overall survival (OS) on N/L ratio. Patients with an N/L ratio <3.5 experienced superior OS compared with patients with an N/L ratio ≥3.5. The median OS was not reached versus 6.8 years and the OS 5-year rates were 87% versus 56%, respectively, P < 0.0001. Progression-free survival (PFS) based on N/L ratio. Patients with an N/L ratio <3.5 experienced superior PFS compared with patients with an N/L ratio ≥3.5. The median PFS was not reached versus 3.3 years and the PFS 5-year rates were 72% versus 45%, respectively, P < 0.0001. To evaluate the relevance of N/L ratio ≥3.5 at diagnosis in DLBCL patients, patients were divided into patients with an N/L ratio ≥3.5 versus <3.5 at diagnosis. Patients with an N/L ratio <3.5 at diagnosis presented with higher levels of LDH, neutrophilia, lymphopenia, poor performance status, and high International Prognostic Index (IPI) score. Stage was borderline statistically significant. Extranodal disease, number of cycles of R-CHOP, post-chemotherapy radiation therapy, and the reasons for post-chemotherapy radiation therapy was similar in both groups (on line Supporting Information Table IV). Patients with an N/L ratio <3.5 at diagnosis were associated with prognostic factors related to inflammation (i.e., neutrophilia and B-symptoms) and tumor burden (i.e., LDH). Thus, in an attempt to understand how N/L ratio affects survival in DLBCL, we studied the relationships between N/L ratio and prognostic factors associated with inflammation/tumor burden. We identified a higher N/L ratio with higher IPI scores: IPI score of 0 (median N/L ratio = 2.5; IPI score of 1 (median N/L ratio = 2.9); IPI score of 2 (median N/L ratio = 4.4); IPI score of 3 (median N/L ratio = 4.5); IPI score of 4 (median N/L ratio = 4.6); and IPI score of 6 (median N/L ratio = 6.1) (P < 0.002). Higher N/L ratio was also associated with B-symptoms (P < 0.003), Stage III/IV (P < 0.002), and with higher LDH (rs = 0.4, P < 0.0001). LDH released into the circulation is due to tissue breakdown. In lymphomas, LDH production has been mainly attributed to tumor burden. However, the association between N/L ratio and LDH in DLBCL argues that another source of LDH production in DLBCL could be due to another tissue breakdown rather than lymphoma produced by the inflammatory reaction produced by the tumor. To assess this hypothesis, we studied factors associated with LDH in DLBCL. Univariate logistic regression model identified the following factors associated with LDH: age (P < 0.04); B-symptoms (P < 0.0003); extranodal disease (P < 0.001); stage (P < 0.0001); and N/L ratio (P < 0.0001). In themultivariate logistic regression model, only N/L ratio (P < 0.03) and stage (P < 0.0001) remained significantly associated with LDH. The current risk factors used to assess prognosis in DLBCL patients treated with standard therapy are identified prior to treatment, such as gene expression profiling [14, 15] and the IPI [16]. A limitation of the DLBCL cell of origin gene expression profiling or the IPI is that neither of these prognostic models take into consideration the role of the host immunity (i.e., ALC) and the inflammatory environment produced by the tumor (i.e., neutrophil count). Therefore we set up to investigate if the N/L ratio at diagnosis, a biomarker comparing tumor inflammation and host immunity, affects survival in DLBCL patients. Our study shows that DLBCL patients with an N/L ratio ≥3.5 at diagnosis were associated with worst clinical outcomes compared with patients with a low N/L ratio <3.5. N/L ratio at diagnosis was identified to be an independent prognostic indicator for survival. N/L ratio at diagnosis was associated with prognostic factors of tumor burden such stage and LDH, as well as biomarkers of inflammation such as B-symptoms (fever, and night sweats). LDH production in lymphoma has been attributed to the tumor burden. However, we identified a positive correlation between N/L ratio at diagnosis and LDH. In addition, N/L ratio at diagnosis was an independent predictive factor besides stage for LDH production. Blatt et al. [17] reported no correlation between the intracellular lymphoma LDH isoenzymes and the serum LDH isoenzymes. From the clinical standpoint, the sensitivity of LDH post treatment to detect lymphoma relapse has been reported to be only 45% [18]. These findings suggests that other sources of tissue breakdown (i.e., the reason for release of LDH into the circulation) such as the inflammatory environment produced by the tumor besides tumor burden could be an important factor for the LDH production in lymphomas. The association of poor clinical outcomes with a high N/L ratio could be the result of tumor-associated events that in turn produce inflammatory mediators of immune suppression manifesting as a decrease in host immunity (i.e., ALC). Key inflammatory transcription factors NF-kB, HIF-1α and STAT-3 have been associated with cancer development [19]. Besides antibody-dependent cell cytotoxicity and direct apoptosis against lymphoma cells, another possible mechanism of action of rituximab is to target the inflammatory component of the tumor by causing neutropenia [20] and direct inhibition of NF-kB [21] and STAT-3 [22]. Infiltrating tumor-associated macrophages (TAM) has been associated with poor prognosis in lymphomas as well as solid tumors. M2 macrophages has been associated with polarizing the host immunity from a Th1 to a Th2, leading to host immunity suppression [19]. However, despite these associations, a mechanistic explanation for the association between N/L ratio at diagnosis and clinical outcomes in DLBCL can only be addressed in an appropriately designed prospective clinical trial where relevant analyses of both systemic immunity and tumor phenotype can be studied. Nevertheless, based on the presented data, the association between N/L ratio at diagnosis and DLBCL survival seems clinically useful in judging survival risk for DLBCL patients treated with R-CHOP. This study identifies a worldwide, standardized; low cost risk factor to assess clinical outcomes in DLBCL patients treated with R-CHOP. To our knowledge, this study is the first to identify N/L ratio as a prognostic factor for survival in DLBCL patients treated with R-CHOP. Thus, our study suggests that the N/L ratio can be used as a simple, inexpensive tool to assess survival outcomes in DLBCL treated with immunochemotherapy. To participate in this study, patients were required to have the diagnosis of de novo DLBCL, be treated with R-CHOP with or without consolidation radiation therapy at the discretion of the attending physician, and be followed at Mayo Clinic Rochester. Patients with primary DLBCL central nervous system (CNS) lymphoma, transformed NHL, post-solid organ transplant lymphoproliferative disorder, or positive human immunodeficiency virus were excluded from the study. From December 20, 2000 until December 27, 2007, 255 consecutive DLBCL patients were qualified for the study. Data from DLBCL patients were collected prospectively and entered into a computerized database. No patients were lost to follow-up. All patients gave written, informed consent allowing the use of their medical records for medical research. Approval for the retrospective review of these records was obtained from the Mayo Clinic Institutional Review Board and was in accordance with US federal regulations and the Declaration of Helsinki. The primary endpoint of the study was to assess if baseline N/L ratio at diagnosis predicts survival in DLBCL patients treated with R-CHOP. The ALC and the neutrophil count were obtained from the complete blood cell count [23] at diagnosis. Risk factors tested in the study included B symptoms (Fevers >38°C; drenching sweats; and weight loss >10% of normal body weight), baseline N/L ratio, IPI index [16]; [Age ≥ 60, extranodal sites ≥2, LDH (abnormal versus normal levels), performance status ≥2, and stage (I/II versus III/IV)], and postchemotherapy consolidation radiation. All patients received rituximab 375 mg m−2; cyclophosphamide 750 mg m−2; doxorubicin 50 mg m−2; vincristine 1.4 mg m−2; and prednisone 100 mg m−2 × 5 days, every 21 days. Response criteria were based on criteria from the Lymphoma International Workshop [24]. Overall survival (OS) was defined as the time from diagnosis to death as a result of any causes or last follow-up. Progression-free survival (PFS) was defined as the time from diagnosis to disease progression, death as a result of any causes, or last follow-up. OS and PFS times were analyzed using the method described by Kaplan and Meier [25]. Differences between survival curves were tested for statistical significance using the two-tailed log-rank test. The Cox proportional hazards model [26] was used to assess N/L ratio at diagnosis as a prognostic factor for OS and PFS times as well as to adjust for other known prognostic factors. The cutoff of N/L ratio ≥3.5 at diagnosis was supported by the data because it yielded the greatest differential in survival at N/L ratio ≥3.5 at diagnosis based on χ2 values analyzed at different cut-points between the 25th and 75th quartiles (2.4–6.3) from log-rank tests (χ2 = 15.6 for OS and χ2 = 18.7 for PFS). χ2-tests were used to determine relationships between categorical variables. The Wilcoxon/Kruskal-Wallis rank tests were used to determine associations between continuous variables and categories, and Spearman correlation coefficients were used to evaluate associations for continuous variables. Logistic regression models were also used to assess associations between prognostic variables. All P values represented were two-sided, and statistical significance was declared at P < 0.05. LFP had the original idea for the study, designed the study, analyzed and interpreted data, did statistical analysis, and wrote the manuscript. KR collected the data and wrote the manuscript. TH, DJI, INM, wrote the manuscript. SNM designed the study, analyzed and interpreted data, and wrote manuscript. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Luis F. Porrata*, Kay Ristow*, Thomas Habermann*, David J. Inwards*, Ivana N. Micallef*, Svetomir N. Markovic*, * Division of Hematology/Department of Medicine, Mayo College of Medicine, Rochester, Minnesota.
No takes yet. Share an insight, caveat, or question.
Porrata et al. (2010) studied this question.
Synapse has enriched 4 closely related papers on similar clinical questions. Consider them for comparative context: