Emerging treatment strategies for newly diagnosed diffuse large B-cell lymphoma

Despite recent progress in improving patient survival, the outcomes in approximately 40% of patients with diffuse large B-cell lymphoma (DLBCL) remain poor. For many years, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the standard first-line treatment for DLBCL; however, pola-R-CHP (polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone) has recently emerged as a new treatment option. In parallel, novel molecularly targeted therapies that target signaling pathways, cellular antigens, and epigenetic regulators associated with high-risk DLBCL are in development. Treatment strategies tailored to the cell of origin or to specific molecular subtypes are also being explored using subtype-specific targeted agents. In addition, agents that have demonstrated efficacy in patients with relapsed or refractory DLBCL—such as the anti-CD19 antibody tafasitamab and immunomodulatory drugs such as golcadomide—are currently under investigation for use in newly diagnosed patients. Immunotherapies, including anti-CD19-chimeric antigen receptor-T therapy and CD20×CD3 bispecific antibodies (BsAbs), have significantly improved outcomes in patients with relapsed or refractory disease and are now under evaluation as early-line therapies. BsAbs can enable more flexible treatment strategies, including combination regimens with cytotoxic or chemotherapy-free approaches. This review summarizes recent advances and ongoing trials that are investigating novel therapeutic strategies for newly diagnosed DLBCL that may soon be incorporated into clinical practice.