Frontline Therapy in Diffuse Large B‐Cell Lymphoma: Evolving Standards, Biological Insights, and Future Directions

Diffuse large B-cell lymphoma (DLBCL) remains the most common aggressive lymphoma, representing a biologically heterogeneous disease with diverse clinical behaviors. For more than two decades, R-CHOP has been the cornerstone of frontline treatment, curing approximately two-thirds of patients. Despite this success, a substantial subset—particularly those with high-risk biology, double-hit genetics, activated B-cell-like (ABC) subtype, or adverse clinical features—still experience relapse or refractory disease. Recent advances in lymphoma biology, immunotherapy, and targeted therapy have stimulated intense interest in improving frontline outcomes. Strategies include optimizing cytotoxic backbone regimens, incorporating antibody–drug conjugates (ADCs), immunomodulatory agents (IMiDs), bispecific antibodies, and exploring the feasibility of frontline CAR-T cell therapy. This review provides a comprehensive and discursive synthesis of the biological rationale, clinical evidence, trial results, and practical considerations shaping contemporary frontline treatment. We highlight the emerging role of molecular subtyping, the tumor microenvironment, and high-risk biomarkers, while discussing ongoing challenges and opportunities in integrating novel modalities into standard practice. Although R-CHOP remains the universal backbone, the therapeutic landscape is entering a transformative era, with polatuzumab-based regimens, bispecific combinations, and precision-guided approaches positioned to redefine frontline care for selected subgroups.