Comparison of Clinical Characteristics, Plasma Cytokine Signature, Cytokine Gene Polymorphisms and Outcome Between EBV Positive and Negative Hodgkin Lymphoma: a Study of the Groupe Des Lymphomes De l'Adulte (GELA)
Authors: Ghesquieres Herve , Casasnovas Olivier , Marion Fournier , Pauline Brice , Richard Delarue , Franck Morschhauser , Catherine Sebban , Vincent Ribrag , Isabelle Gaillard , Pierre Feugier , Aspasia Stamatoullas , Fermé Christophe , Salles Gilles Andre 
Published: October 2019

Abstract
Abstract 3884

Background:
Hodgkin Lymphoma (HL) has a remarkable pathogenesis with rare neoplastic cells surrounded by numerous reactive cells that interact with cytokines, chemokines and soluble receptors. EBV is found in about 40% of HL. Recent clinical series showed that prognostic between EBV-positive and negative could be different especially in patients older than 50 years old, with a worse prognosis for patients with EBV-positive tumors (Diepstra et al. JCO 2009). Gene expression profile analysis of HL tumors are also in favor of different pathogenesis between EBV-positive and negative tumors. In this context, we assessed whether plasma cytokine pattern and cytokine gene polymorphisms could be different regarding EBV status and compared the clinical characteristics and outcome of patients according to EBV status in a series of 242 HL patients.

Patients and Methods:
the GELA conducted between 1998 and 2002, a prospective study to assess the prognostic role at diagnosis of plasma levels of TNFA, its soluble receptors TNF-R1, TNF-R2, and IL-10, IL-6, IL-1B, IL-1Ra, sCD30 (Casasnovas et al. JCO 2007). This study was also designed to investigate the role of polymorphisms (SNP) in cytokine genes of IL10 (Four SNPs), TNFA, IL6, IL1B, IL1RN, INFG, CCL17 and IL12. EBV status of classical HL samples could be obtained retrospectively for 242 patients.

Results:
EBV status was obtained according to the immunohistochemistry detection of latent membrane protein-1 (LMP-1) in 186 patients (77%), to EBER in situ hybridation results in 48 patients (20%) or others techniques in the 8 remaining patients (3%). EBV status was considered as positive and negative for 53 (21%) and 189 (79%) patients, respectively. Comparison of clinical characteristics between EBV-negative and positive HL showed some differences in term of sex-ratio and histological subtypes with a higher proportion of male in EBV-positive cohort (81% vs. 54%, P < .01) and less nodular sclerosis subtypes (74% vs. 85% P = .05). Erythrocyte sedimentation rate and white-cell count were more frequently increased in EBV-negative population but the distribution of prognostic categories according to the Hasenclever score was not different between the two cohorts. The TNFA and TNF-R2 plasma levels were significantly higher for EBV-positive compared to EBV-negative HL (P = .03) but no difference was observed for others cytokines (TNF-R1, IL-10, IL-6, IL-1Ra, sCD30). For the eleven studied SNPs, no difference in term of genotype distribution was observed between EBV-positive and negative tumors. The 6-year overall survival (OS) (91% vs. 88% P = .3) and progression free survival (PFS) (81% vs. 79% P = .3) were not statistically different between the EBV-negative and positive cohorts. Analysis of outcome by age groups, showed a non-significant trend for a worse 6-year OS (72.1% vs. 58.3% P = .14) and 6-year PFS (57.2% vs. 48% P = .42) for EBV-positive HL after 50 years old with a similar proportion of EBV-positive and negative HL tumors before and after 50 years old.

Conclusions:
In this study, we confirm difference of histological subtype distribution between EBV-positive and negative HL. A difference of plasma levels of TNFA and TNF-R2 was observed suggesting a different inflammatory profile between EBV-positive and negative EBV HL but genotype distribution of germline cytokine gene polymorphisms was not different. In this cohort of HL with a global favorable outcome, a trend for a worse prognosis became apparent for older patients with EBV-positive HL.

Disclosures:
Salles: Roche: Consultancy, Honoraria.