Impact of Tumour Epstein-Barr Virus Status on Clinical Outcome in Patients with Classical Hodgkin Lymphoma (cHL): A Review of the Literature and Analysis of a Clinical Trial Cohort of Children with cHL

Simple Summary The Epstein-Barr virus (EBV) contributes to different forms of human cancer, including a subset of classical Hodgkin lymphoma (cHL), a B-cell lymphoma with unusual histological features. Although the pathogenesis of EBV-associated cHL remains to be elucidated, biological investigations point to an important aetiological role for the virus in the development of this tumour. This is even more relevant now considering the potential opportunities that exist to treat EBV-associated disorders, for example, with immunotherapeutics or small molecule inhibitors targeting viral proteins. For this reason, we believe it is now timely to review the association between EBV and cHL and in particular to re-evaluate the impact of EBV status on clinical outcomes in cHL patients. Herein, we also report the impact of EBV on clinical outcomes in a cohort of children and adolescents with cHL. In this study, we have re-evaluated how EBV status influences clinical outcome. To accomplish this, we performed a literature review of all studies that have reported the effect of EBV status on patient outcome and also explored the effect of EBV positivity on outcome in a clinical trial of children with cHL from the UK. Our literature review revealed that almost all studies of older adults/elderly patients have reported an adverse effect of an EBV-positive status on outcome. In younger adults with cHL, EBV-positive status was either associated with a moderate beneficial effect or no effect, and the results in children and adolescents were conflicting. Our own analysis of a series of 166 children with cHL revealed no difference in overall survival between EBV-positive and EBV-negative groups (p = 0.942, log rank test). However, EBV-positive subjects had significantly longer event-free survival (p = 0.0026). Positive latent membrane protein 1 (LMP1) status was associated with a significantly lower risk of treatment failure in a Cox regression model (HR = 0.21, p = 0.005). In models that controlled for age, gender, and stage, EBV status had a similar effect size and statistical significance. This study highlights the age-related impact of EBV status on outcome in cHL patients and suggests different pathogenic effects of EBV at different stages of life.