Relapsed or Refractory Diffuse Large B-Cell Lymphoma: "Dazed and Confused"

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Approximately 30% to 40% of patients will develop relapsed/refractory (R/R) DLBCL, leading to significant morbidity and mortality. Salvage chemoimmunotherapy followed by high-dose chemotherapy and autologous stem cell rescue (HDT-ASCR) is the standard of care for chemosensitive and transplant-eligible R/R DLBCL. In patients who are ineligible for HDT-ASCR or who fail HDT-ASCR, treatment is mostly with palliative intent. However, the recent advances with chimeric antigen receptor T-cell (CAR-T) therapy and several FDA-approved targeted agents are changing the current landscape of R/R DLBCL management. There is no one-size-fits-all approach, and guidance regarding optimal sequencing of subsequent therapies is an unmet need. This review highlights the approved CAR-T constructs, including their efficacy, adverse effects, and real-world data; bridging therapy to CAR-T; the role of emerging targeted agents, including bispecific antibodies; and the timing of these targeted agents in relation to CAR-T therapy. Providing individualized treatment with thoughtful sequencing of available agents is essential until future prospective randomized clinical trials provide more insights.