Novel Therapies and Approaches to Relapsed/Refractory HL Beyond Chemotherapy

Abstract

Although Hodgkin lymphoma (HL) is highly curable with first-line therapy, relapses occur in approximately 10–20% of patients with early stage disease and 30–40% of patients with advanced stage disease. The standard approach for relapsed or refractory disease is salvage therapy, followed by consolidation with high dose therapy and autologous stem cell transplant (ASCT). Patients who achieve a complete response to salvage therapy prior to ASCT have better outcomes, thus recent studies have focused on incorporating newer agents in this setting. Major challenges in the management of relapsed patients remain how to choose and sequence the many salvage therapies that are currently available and how to best incorporate novel agents in the current treatment paradigms. In this article, we will summarize the most recent advances in the management of patients with recurrent HL and will mainly focus on the role of new agents approved and under investigation. Aside from brentuximab vedotin and checkpoint inhibitors, other novel agents and therapies are showing promising early results. However, at least with some of the newest targeted strategies, it is important to recognize that we are facing new challenges in terms of toxicities, which require very close monitoring and education of both the patient and treating physician.

Molecular Pathogenesis of Hodgkin Lymphoma: Past, Present, Future

“…Results have been very encouraging with responses generally correlating with the intensity of PD-L1 expression and amplification of the chromosome arm 9p24.1 [ 96 ]. The advent of PD-L1 inhibitors has been one of the recent great success stories of therapeutics in oncology [ 102 , 103 , 104 ].…”

“…Other immune checkpoints at play and contributing to T-cell exhaustion are CTLA-4, TIM3, 2B4, LAG-3, CD160, BTLA, and CD112R/TIGIT [ 96 , 103 , 104 ]. CTLA-4 inhibitors and chimeric antigen receptor (CAR) T cell therapies are being studied in relapsed/refractory cHL with encouraging early results, but severe adverse effects, mainly immune-related toxicities are a major issue [ 103 , 104 ].…”

“…A detailed immunopathologic diagnosis, including the lymph node architecture, percentages of infiltrating CD4+ and CD8+ lymphocytes, tumor-associated macrophages, and eosinophils, belongs to an optimal work up. This interactive (interdisciplinary) diagnostic approach between hemato-pathologists, nuclear medicine specialists, and treating hematologists/oncologists, has drastically increased the predictability of long-term survival of this particular B-cell lymphoma [ 103 , 104 ]. The next decade will teach us if cHL will be the first aggressive B-cell lymphoma with a cure rate near to 100%.…”

“…Even in the area of new immune-mediated therapies refractory/relapsing cHL remains a major issue [ 104 , 105 ]. The 5-year survival rate for cHL is currently around 87% [ 105 ].…”

“… Hodgkin (H) and Reed-Sternberg (RS)-cells (especially LMP1+) express a high number of PD-L1 & PD-L2 molecules at their surface thereby paralysing normal CD8+ cytotoxicity and CD4+ cytokine secretion. MoAbs directed against PD-1, expressed on CD4+ and CD8+ lymphocytes, block PD-1 signaling thereby restoring CD8+ cytotoxic activity and CD4+ antigen recognition and effector function, when docking at the MHC class-I (CD8+) or MHC class II receptor (CD4+) at the surface of H- and RS-cells [ 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 ]. …”