Association of Epstein-Barr Virus with Advanced Stage and Survival Outcomes in Classic Hodgkin's Lymphoma
Authors: Al Hadidi Samer , Nair Ranjit , Steiner Raphael E , Ahmed Sairah , Strati Paolo , Parmar Simrit , Iyer Swami P. , Gunther Jillian R. , Pinnix Chelsea C. , Dabaja Bouthaina S. , Nieto Yago , Samaniego Felipe , Cuglievan Branko , Jain Preetesh , Fang Penny , Miranda Roberto N. , Medeiros Jeffrey , Feng Lei , Chuang Hubert , Wang Michael , Lee Hun Ju 
Published: February 2021

Introduction
Classic Hodgkin's lymphoma (cHL) is a highly curable lymphoid malignancy. Epstein-Barr virus (EBV) is associated with cHL, with a variable rate of detection in Hodgkin and Reed-Sternberg (HRS) cells among different histologic types and geographic areas.Although most adults worldwide are EBV seropositive, only a minority of patients infected with EBV will develop cHL. EBV is thought to be one of the causative agents for the development of cHL with an important pathobiology role. The goal of this study was to compare the presentation and the outcomes of patients with EBV+ HRS cells at the time of initial diagnosis of cHL.
Methods
This single-center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Pathology was confirmed and analyzed for positivity of EBV (EBV +ve) in all patients by immunohistochemical (IHC) staining for by Epstein-Barr virus-encoded small RNA (EBER) with available paraffin blocks. The primary aims were to assess overall survival (OS), progression-free survival (PFS) and frequency of advanced disease. Descriptive statistics for categorical and continues variables were analyzed. Kaplan-Meier method was used for time-to-event analysis, including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses.
Results
Between 2016 and 2020, 644 patients met the inclusion criteria. Three hundred and fifty six patients (55%) had enough/available tissue to undergo testing for EBV at the time of initial diagnosis. The median age at diagnosis was 36 years with 51.4% males. Eighty-eight patients had positive EBV (25%) at diagnosis. The median age of +ve EBV was 37 years (Range: 18-83 years) compared to 33 years (Range: 18-85 years) for patients with -ve EBV. Mixed cellularity histology was more frequent in patients with +ve EBV when compared to the whole group of patients (32% vs. 7%; p-value: 0.03). Human immunodeficiency virus (HIV) was positive in a minority of the patients (8 patients out of 498 patients with available results) (1.6%) however 50% of the patients with HIV had +ve EBV at the time of diagnosis. Baseline demographics are summarized in Table 1. EBV was associated with the initial stage (stage II 38% in EBV +ve vs. 53% in EBV -ve, stage III 25% in EBV +ve vs. 14% in EBV -ve, stage IV 24% in EBV +ve vs. 31% in EBV -ve; p-value 0.0001). Most of the patients were treated with doxorubicin, bleomycin, vinblastine and decarbazine (ABVD) based therapy (77%). Other therapies included brentuximab vedotin (BV) (13%) and checkpoint inhibitors (CPIs) (6%). Median follow up was 1.97 years (range: 0.047- 44.09 years). PFS rate difference at 5 years was not statistically significant (64% in EBV +ve vs. 52% in EBV -ve; p-value 0.14). OS rate at 5 years was significantly lower in patients with +ve EBV (89% vs. 98%, p-value: 0.0014). OS rates at 10 years were similar (89% in EBV +ve vs. 88% in EBV -ve).
Conclusions
EBV at the time of diagnosis was associated with lower prevalence of localized cHL and inferior survival rates at 5 years of follow up (9% lower OS rate at 5 years). Implementation of different frontline therapy treatment algorithms specific to EBV +ve patients may help in improving the survival outcomes. Further research is needed to understand the biological significance of +ve EBV in cHL to help in developing novel agents targeting EBV positive cHL population with the ultimate goal of improving outcome.

Disclosures
Parmar: Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Iyer:Rhizen: Research Funding; CRISPR: Research Funding; Seattle Genetics, Inc.: Research Funding; Merck: Research Funding; Legend Biotech: Consultancy; Daiichi Sankyo: Consultancy; Trillium: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Spectrum: Research Funding. Nieto:Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support. Chuang:Sage-Evidence=Based Medicine & Practice: Consultancy. Wang:Beijing Medical Award Foundation: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Nobel Insights: Consultancy; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; Lu Daopei Medical Group: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Juno: Consultancy, Research Funding; OncLive: Honoraria; Guidepoint Global: Consultancy. Lee:Celgene: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy.