Richter transformation: emerging immunologic strategies beyond chemoimmunotherapy

Richter transformation (RT) is an aggressive lymphoma that arises in patients with chronic lymphocytic leukemia (CLL), most commonly diffuse large B-cell lymphoma (DLBCL-RT). Outcomes remain poor with conventional chemoimmunotherapy, reflecting the role of increased genomic instability and impaired DNA repair in the pathogenesis of RT.. Targeted therapies used in CLL (BTK or BCL2 inhibition) have shown efficacy in RT; however, durable disease control remains elusive, highlighting the need for immunological approaches. This review discusses the clinical evidence supporting immunologic approaches in RT, focusing on allogeneic stem cell transplantation, chimeric antigen T-cell (CAR T-cell) therapy, bispecific T-cell directing antibodies, and checkpoint inhibition. Allogeneic stem cell transplantation can provide long-term remission in selected patients; however, there are considerable barriers, such as the requirement for adequate patient fitness and pre-transplant disease control. Post-approval observational studies have provided evidence of the efficacy and safety of CAR T-cell therapy, as well as the risk of immunologic toxicity. Early phase studies on bispecific antibodies and checkpoint inhibition have demonstrated disease activity, and multiple studies on combination strategies are ongoing. Future priorities include optimizing disease control prior to immunologic therapy, testing novel combination approaches and conducting correlative studies to optimize future therapeutic strategies.