Neutrophil - Lymphocyte Ratio (NLR) at Diagnosis Is an Independent Prognostic Factor in Patients with Nodular Sclerosis Hodgkin Lymphoma: Results of a Large Multicenter Study Involving 990 Patients

Background

There is an increasing amount of  data showing that tumor microenvironment, host immunity and  inflammatory  responses play an important role in determining the clinical course and outcome in patients with malignant lymphoma. Several investigators have considered  the absolute monocyte count (AMC) as a surrogate biomarker of tumor associated macrophages within the tumor microenvironment, the absolute lymphocyte count (ALC) as an important  biomarker of tumor infiltrating lymphocytes, reflecting  host immunity status , and the absolute neutrophil count (ANC) as indicative of  the systemic  inflammatory response to malignancy . All the above  parameters have been suggested as significant  prognostic factors in Hodgkin lymphoma (HL). The aim of the present retrospective study was to verify in whether neutrophil : lymphocyte ratio (NLR) can be utilized as  an independent prognostic factor in a large cohort of patients  with  nodular sclerosis (NS) subtype HL .

Patients and Methods

This retrospective analysis included data from 1017 patients diagnosed with NS HL according to the WHO criteria. We reviewed the clinical and laboratory data of consecutive “therapy-naïve” patients, treated in different centers in Italy  and in Israel between 1993–2012, after approval by local institutional review boards.

Patients had received different  combination chemotherapy regimens : doxorubicin, bleomycin, vinblastine and darcarbacine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/epidoxirubicin, bleomycin, and vinblastine (EBV)/lomustine (CCNU), doxorubicin, and vindesine (CAD), Vinblastine, bleomycin,  and methotrexate (VBM), bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) and Stanford V.

The cut-off for NLR was determined from the analysis of the log (HR) as a function of NLR, using  Cox cubic spline regression. The importance of the covariate was examined  using the bootstrap inclusion frequency (BIF) with log-likelihood ratio test, (cut-off of 0.05), over 1000 resample of hierarchical Cox PH model, where NLR was added to IPI.

Progression free survival (PFS) and overall survival (OS) were determined by Kaplan-Meier estimates and risk groups compared using the log-rank test .We also performed Cox proportional hazard analysis. The effect size of risk was reported as a hazard ratio (HR) with the associated 95% confidence interval (CI95).

Results

Of the  1017 patients, 990 (97%) had data on both IPS and NLR. Median age was 31 years (range 17-69) and 49% were males.  The 5-yr PFS and OS after  median follow-up of 85 months (range 1-244 months) were 81% (95CI 78-84) and 91% (95CI 89-93), respectively, for all patients. The log(HR) for PFS and OS varied  linearly for the  function of NLR and the cut-off was selected at 6 for both outcomes. Patients with NLR >6 had a worse PFS and OS  compared to NLR ≤6 (84% vs 75% and 92% vs 88% at 5-years, respectively). Figure 1). For  PFS the HR for patients with NLR>6 was 1.65 (CI95 1.25-2.18, p<0.001), while for  OS the HR was 1.82 (CI95 1.25-2.65, p=0.002). When adjusted in Cox PH regression by IPS score, NLR >6 maintained it's prognostic value  in both PFS (HR 1.49, CI95  1.12-1.98, p=0.006; with a BIF of 76%) and OS (HR  1.56, CI95  1.06-2.29, p=0.023; with a BIF of 64%).  This was also evident  in continuous form for NLR both s in PFS (HR adjusted by IPS 1.02, CI95 1.01-1.04, p=0.010)  and OS (HR adjusted by IPS 1.02, CI95 1.01-1.05, p=0.039).

Conclusion.

Although the majority of  patients with HL can be cured, about 1/3 of those  with advanced stage disease relapse  or progress after first line therapy. Several approaches have been employed to recognize high risk patients , including gene expression profiling and positron emission tomography. However these procedures are expensive and not always easy to perform and interpret. In conclusion ,despite  it is retrospective nature  , our study shows  that  NLR can reliably identify  high risk patients at the time of diagnosis .This easily obtainable simple prognostic parameter  could well be utilized to improve the discriminating power  of the IPS score in patients with NS HL .

Figure 1:

PFS and OS by NLR < 6 or NLR ≥ 6