Biology of classical Hodgkin lymphoma: implications for prognosis and novel therapies

Hodgkin lymphoma is considered a prime example of treatment success, with cure rates exceeding 80% using modern combined modality therapies. However, especially in adolescents and young adults, treatment-related toxicity and long-term morbidity still represent persistent challenges. Moreover, outcomes in patients with relapsed or refractory disease remain unfavorable in the era of high-dose chemotherapy and stem-cell transplantation. Hence, there is a high demand for novel and innovative alternative treatment approaches. In recent years, many new therapeutic agents have emerged from preclinical and clinical studies that target molecular hallmarks of Hodgkin lymphoma, including the aberrant phenotype of the tumor cells, deregulated oncogenic pathways, and immune escape. The antibody-drug conjugate brentuximab vedotin and immune checkpoint inhibitors have already shown great success in patients with relapsed/refractory disease, leading to US Food and Drug Administration approval and new trials testing these agents in various clinical settings. The expanding knowledge and understanding of Hodgkin lymphoma biology and disease progression, as well as the development of robust tools for biomarker-driven risk stratification and therapeutic decision making, continue to be fundamentally important for the success of these and other novel agents. We anticipate that the availability and clinical implementation of novel molecular assays will be instrumental in an era of rapid shifts in the treatment landscape of this disease. Here, we review the current knowledge of Hodgkin lymphoma pathobiology, highlighting the related development of novel treatment strategies and prognostic models that hold the promise to continually challenge and change the current standard of care in classical Hodgkin lymphoma.