2026 Update on the Management of Diffuse Large B-Cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL in the Western Hemisphere. It comprises a heterogenous group of lymphomas, with different biology and clinical prognoses. R-CHP remains the backbone of therapy, and frontline therapeutic options in fit patients are pola-R-CHP and R-CHOP, whereas elderly or frail/unfit patients may be treated with R-mini-CHOP or palliation. Frontline trials aim to improve outcomes for patients with high-risk disease utilizing R-CHOP + novel agents, CAR-T, and bispecific antibodies. Trials in the elderly/unfit population are minimizing and omitting chemotherapy. Risk-adapted approaches targeting cell of origin (COO) and utilizing interim PET imaging or ctDNA to guide therapy escalation or deescalation remain under investigation. Second line therapy curative-intent approaches include CAR-T or autologous stem cell transplantation, depending upon timing of disease progression after first-line therapy. In the relapsed/refractory setting, there has been a rapid growth in the therapeutic armamentarium, including bispecific antibody combinations with chemotherapy, bispecific antibodies with antibody-drug conjugates, and brentuximab vedotin + lenalidomide + rituximab. Multiple novel trials are further advancing the field away from chemotherapy including targeted therapy-antibody combinations, new bispecific antibodies and bispecific antibody combinations, immunomodulatory agents, and cellular therapy. In this review, we summarize recent data and discuss ongoing efforts to improve the management of DLBCL.