Prognostic Relevance of Neutrophil to Lymphocyte Ratio (NLR) and Lymphocyte to Monocyte Ratio (LMR) in Newly Diagnosed Advanced-Stage Hodgkin Lymphoma Patients Treated up-Front with a PET-2 Risk Adapted Protocol
Authors: Romano Alessandra , Di Raimondo Francesco , Pavoni Chiara , Tarella Corrado , Viviani Simonetta , Rossi Andrea , Patti Caterina , Picardi Marco , Cantonetti Maria , La Nasa Giorgio , Trentin Livio , Bolis Silvia , Zoli Valerio , Gavarotti Paolo , Corradini Paolo , Cimminiello Michele , Schiavotto Corrado , Parvis Guido Eugenio , Zanotti Roberta , Gini Guido , Ferreri Andres J M , Viero Piera , Biggi Alberto , Gianni Alessandro M. , Gallamini Andrea , Rambaldi Alessandro 
Published: October 2019

Abstract
Background: Hodgkin Lymphoma (HL) is characterized by an inflammatory background and it has been demonstratedthat the reactive myeloid cells may exert an immune suppressive effect that favors progression of disease. The easily measurable NLR, the ratio between absolute neutrophils counts (ANC) and absolute lymphocyte count (ALC) and LMR, the ratio between ALC and absolute monocyte count (AMC) have been reported to reflect both the systemic inflammation and the myeloid associated immune suppression. We previously identified NLR, and to a lesser extend LMR, at baseline, as predictor of progression free survival (PFS) in HL patients.
Objectives: To validate NLR>6 and LMR≤2 as predictor of clinical outcome at diagnosis in the context of a prospective clinical trial of newly diagnosed advanced stage (aa) HL patients treated upfront with a PET-2 risk-adapted strategy.
Methods: According to HD 0607 trial (Gallamini, JCO 2018), 782 advanced-stage HL patients were treated with 2 ABVD courses and a PET-2 performed afterwards. PET-2 positive (PET-2+) patients (N=149) were randomized to either BEACOPP escalated (Be) plus BEACOPP baseline (Bb) (4+4 courses) or Be+Bb (4+4) and Rituximab. PET-2 negative (PET-2-) patients were treated with 4 additional ABVD and, upon CR achievement, randomized to either consolidation radiotherapy on the sites of initial bulky disease or no further treatment. PET scans were centrally reviewed by an expert panel by Blinded Independent Central Review.
Results:
Median NLR at baseline was 5.7 (IQ range 3.8-8.3). NLR was higher in younger patients (<45 years, p=0.0005), in females (p=0.0027) and in patients with B symptoms (p<0.0001), bulky disease (>7 cm, p<0.0001) and high IPS (p<0.0001). LMR was lower in males (p=0.01) and in patients with B symptoms (p<0.0001), bulky disease (p<0.0001) and high IPS (≥3, p<0.0001). Neither NLR nor LMR values were associated with Ann Arbor stage. Higher NLR (p=0.0001 and p=0.0003) and lower LMR (p=0.01, and p=0.02) were respectively associated with a PET-2+ (DS score 4 and 5) and failure to achieve long-term disease control. Receiving operator curve (ROC) confirmed 6 as the cut-off of NLR to predict clinical outcome with 59% (95% C.I. 51-68) sensitivity and 57% (95% C.I. 53-61) specificity (AUC 0.59). Negative predictive value of LMR, with cutoff of 2, was 79% with 40% (95% C.I. 31-48) sensitivity and 50% (95% C.I. 46-54) specificity (AUC 0.56). NLR was >6 in 88/149 (59%) PET-2+ and in 269/628 (43%) PET-2- patients. By univariate and multivariate analysis, bulky disease, IPS≥3, NLR>6 were strong independent predictors of early PET-2 response after ABVD (table I). Only PET-2 positivity (p<0.0001) and IPS≥3 (p=0.0001) were independent predictors of PFS by multivariate analysis.
Focusing on PET-2 negative patients, we found that patients with NLR>6 had an inferior 3-years PFS compared to patients with NLR ≤6 (84% versus 89%, p=0.003), while there was no stastical difference based on LMR status.
Conclusion: At diagnosis, the presence of bulky disease, IPS score ≥3 and NLR>6 are independent predictors of early ABVD response (PET-2 positivity) and this information should be considered when selecting the initial treatment for aaHL patients.

Disclosures
Di Raimondo: Celgene: Honoraria; Takeda: Honoraria, Research Funding. Trentin:Janssen: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Gilead: Research Funding. Gallamini:Takeda: Consultancy, Speakers Bureau. Rambaldi:Amgen Inc.: Consultancy; Celgene: Consultancy; Roche: Consultancy; Italfarmaco: Consultancy; Omeros: Consultancy; Pfizer: Consultancy; Novartis: Consultancy.