Abstract
Diffuse large B-cell lymphoma (DLBCL) is the most frequent histological subtype of non-Hodgkin lymphoma and the paradigm for the management of aggressive lymphoma. An excisional or incisional lymph node biopsy evaluated by an experienced hematopathologist is recommended to establish the diagnosis. Twenty years following its introduction, the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard first-line treatment. No modification of this scheme (increased chemotherapy dose intensity, new monoclonal antibodies, or the addition of immunomodulators or anti-target agents) has significantly improved the clinical outcomes, whereas therapy for recurrence or progression is evolving rapidly. The introduction of chimeric antigen receptor T cells, polatuzumab vedotin, tafasitamab, and cluster of differentiation (CD)20/CD3 bispecific antibodies is changing the natural history of patients with relapsed DLBCL and will challenge R-CHOP as the benchmark for newly diagnosed patients. These updated guidelines (2025) summarize current evidence and available therapies for the medical management of DLBCL.