Optimizing Treatment for Relapsed/Refractory Classic Hodgkin Lymphoma in the Era of Immunotherapy

Abstract

Most patients with classic Hodgkin lymphoma (cHL) are cured with combination chemotherapy, but approximately 10-20% will relapse, and another 5-10% will have primary refractory disease. The treatment landscape of relapsed/refractory (R/R) cHL has evolved significantly over the past decade following the approval of brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate, and the PD-1 inhibitors nivolumab and pembrolizumab. These agents have significantly expanded options for salvage therapy prior to autologous hematopoietic cell transplantation (AHCT), post-transplant maintenance, and treatment of relapse after AHCT, which have led to improved survival in the modern era. In this review, we highlight our approach to the management of R/R cHL in 2023 with a focus on choosing first salvage therapy, post-transplant maintenance, and treatment of relapse after AHCT. We also discuss the management of older adults and transplant-ineligible patients, who require a separate approach. Finally, we review novel immunotherapy approaches in clinical trials, including combinations of PD-1 inhibitors with other immune-activating agents as well as novel antibody-drug conjugates, bispecific antibodies, and cellular immunotherapies. Ongoing studies assessing biomarkers of response to immunotherapy and dynamic biomarkers such as circulating tumor DNA may further inform treatment decisions and enable a more personalized approach in the future.

Keywords: Hodgkin lymphoma; PD-1 inhibitor; autologous hematopoietic cell transplantation; brentuximab vedotin; checkpoint inhibitor; nivolumab; pembrolizumab; relapsed/refractory.

Figure 1

Suggested management algorithms for relapsed/refractory classic Hodgkin lymphoma.

Figure 2

HRS cell interaction with the tumor microenvironment and novel targets for immunotherapy in the classic Hodgkin lymphoma illustration highlight the complex interplay between HRS cells and various immune cells in the tumor microenvironment. 9p24.1 Amplification and EBV infection in HRS cells lead to overexpression of PD-1 ligands, contributing to immune evasion. Frequent B2M mutations lead to loss of MHC class I expression and impaired antigen presentation to T cells. HRS cells produce cytokines and chemokines that recruit other immune cells and maintain an immunosuppressive microenvironment. Exhausted CD4 + T cells are abundant in the tumor microenvironment and express other checkpoint molecules, including CTLA-4, LAG-3, TIM-3, and TIGIT, which may prevent an effective immune response. CD47 expressed by HRS cells may impair phagocytosis through interaction with its ligand SIRPα on tumor-associated macrophages. The purple boxes show novel immunotherapies, and the red lines indicate their biological targets.