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

SIMPLE SUMMARY: Classic Hodgkin lymphoma (cHL) has a high cure rate with chemotherapy, but 10–30% of patients experience relapse or refractory (R/R) disease, depending on stage and risk factors. Treatment for R/R cHL differs between young, fit patients who are eligible for high-dose chemotherapy and autologous stem cell transplants and older adults who are not eligible for intensive therapies. Over the past decade, management of R/R cHL has evolved significantly following the approval of three highly active novel agents: brentuximab vedotin, nivolumab, and pembrolizumab, leading to improved cure rates and overall survival. In this review, we discuss our approach to the treatment of first relapse, maintenance therapy after transplant, relapse after transplant, and management of older adults and frail patients. Finally, we highlight emerging immunotherapies in clinical trials that hold great promise for the future. 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.