Classical Hodgkin’s Lymphoma: Pathogenesis and Future Treatment Directions

Abstract

Classical Hodgkin Lymphoma is a germinal center B cell malignancy. Over the past 40 years, through greater understanding of disease pathogenesis, advancements in treatment have lead to greater than 80% long-term survival rates after standard first line therapy. Currently, first-line management of the disease varies, most commonly involving the use of a standard chemotherapy regime (i.e. ABVD or BEACOPP), with or without the use of additional chemotherapies or involved-field radiation therapy. Treatment selection is influenced by disease staging at diagnosis and the need to maintain therapeutic efficacy, whilst minimising the risk of late and potentially fatal therapy-associated side effects. Consequently, higher than acceptable drug-associated toxicities and patient relapse represent the future challenges of this disease. Novel therapies, targeting the aberrant signalling pathways and phenotypic features of the malignant cell pool, and its associatedinflammatory infiltrate, are the future direction of disease management. Currently, combination therapies targeting the PI3K/Akt/mTOR pathway and transcription modulation have shown the greatest clinical efficacy in improving survival outcomes in previously heavily treated cHL patients, with minimal side effects. Whilst these therapies do not yet achieve the clinical efficacy of first line therapies, preliminary stage I and II trials havedemonstrated a reduction in drug associated toxicities and side effects relative to existing treatments for relapse. This paper will investigate current understanding of the pathogenesis of cHL, and how this has shaped the targets of novel therapies for the disease.