Checkpoint inhibition therapy as possible frontline therapy for Hodgkin lymphoma

Classic Hodgkin lymphoma (cHL) is a unique lymphoid malignancy with an immunosuppressed tumor microenvironment. Increased PD-L1 expression on the malignant Hodgkin Reed Sternberg (HRS) cells due to genetic amplification at chromosome 9p24.1 is likely one of the primary mechanisms for this unique biology. For this reason, immune checkpoint inhibitors targeting PD-1/PD-L1 interaction have proven to be uniquely successful in relapsed/refractory cHL. While the response rates are in the 70–80% range and are often durable, most patients still relapse. Combination strategies with conventional chemotherapy, novel drugs such as antibody–drug conjugates (ADCs), and other immune therapies are ongoing. Many unanswered questions about checkpoint inhibitors remain, such as defining the best modality for evaluation of response, confirming a strategy of modifying therapy based on the response, validating response endpoints specific to immune therapies and, identifying predictive biomarkers for response. As we evaluate the use of checkpoint inhibitors in the frontline setting for cHL, we need a critical approach to evaluate the benefits and challenges that ensue.