Optimizing the Role of Checkpoint Inhibitors in the Management of Hodgkin Lymphoma

Immune checkpoint inhibitors have transformed the therapeutic landscape of classic Hodgkin lymphoma (cHL), leading to significant improvement in patient outcomes in the modern era. This review provides an overview of the established and evolving roles of PD-1 inhibitors in the management of cHL. We highlight the pivotal trials of nivolumab and pembrolizumab in relapsed/refractory cHL and discuss subsequent studies combining these agents with chemotherapy in the second-line setting, which have led to improved cure rates following autologous stem cell transplant (ASCT). In the frontline setting, the SWOG S1826 trial established nivolumab in combination with doxorubicin, vinblastine, and dacarbazine (AVD) as the new standard of care for advanced-stage cHL in North America, improving progression-free survival and tolerability compared with brentuximab vedotin with AVD. In early-stage cHL, PD-1 inhibitors are being explored as part of treatment strategies to omit bleomycin and/or radiotherapy. PD-1 inhibitor-based regimens have also become a new standard for older adults with cHL, leading to improved overall survival in this population with historically poorer outcomes compared with younger patients. We address the challenging scenario of managing patients with disease relapse after PD-1 inhibitor therapy, including novel combination strategies aimed at restoring sensitivity to checkpoint blockade. Finally, we highlight emerging directions in the field, including efforts to develop predictive biomarkers and to incorporate circulating tumor DNA-based strategies to monitor response and personalize therapy, with the potential to abbreviate chemotherapy or omit ASCT in a subset of patients. As PD-1 inhibitors are increasingly incorporated across treatment regimens for cHL, ongoing studies aim to refine patient selection, identify those most likely to benefit from therapy escalation or de-escalation, and optimize therapeutic combinations to maximize cure rates, tolerability, and survivorship.