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

Abstract

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.

Validation of the RHL30 digital gene expression assay as a prognostic biomarker for relapsed Hodgkin lymphoma

“…The overall role of clinical, radiological and molecular risk factors for cHL continues to evolve and the changing treatment landscape will likely influence the value of previously established biomarkers 10 . For example, the question arises whether brentuximab vedotin maintenance, found to improve progression‐free survival post‐ASCT in the Aethera trial, 11,12 or novel salvage regimens 13,14 obviate the need for prognostic biomarkers.…”

Novel therapeutic agents for relapsed classical Hodgkin lymphoma

“…In conclusion, the future for patients with HL is bright (Table ). The main challenge continues to be the identification of predictive biomarkers, which will require well‐designed clinical trials with prospectively collected bio‐specimens in order to optimise patient selection (Younes et al , ; Mottok & Steidl, ). In addition, we propose the adoption of adaptive ‘pick a winner’ trial designs with early clinical endpoints to help establish the best treatment or treatment‐combination at pre‐defined time points given the plethora of new therapies.…”

The Immunosuppressive Microenvironment of Classic Hodgkin Lymphoma and Therapeutic Approaches to Counter It

“…Histologically, a low number of malignant cells, collectively termed Hodgkin and Reed-Sternberg (HRS) cells characterize cHL. HRS cells include small, mononucleated Hodgkin cells and large, binucleated or [16]. Several lines of evidence suggest that HRS cells need the TME to survive.…”