Large B-cell lymphoma (LBCL) accounts for about one-third of adult lymphoma cases. Diagnosis requires specialized hematopathology laboratories, with immunophenotypic analysis essential for confirming B-cell lineage and identifying variants. MYC and BCL2 rearrangements indicate a poor prognosis. Staging and prognosis rely on positron emission tomography computed tomography (PET-CT). The International Prognostic Index (IPI) aids risk stratification. PET-CT is critical for assessing treatment response and guiding strategies. First-line management for LBCL can be informed by interim PET to assess chemosensitivity, with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or polatuzumab vedotin rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) for advanced stages depending on IPI scores. Primary mediastinal B-cell lymphoma (PMBCL) management favors R-CHOP given every 14 days (R-CHOP14) or dose-adjusted etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab (DA-EPOCH-R) without radiotherapy in complete responders. Elderly patients, unfit or not (≥80 years or <80 with poor fitness), need geriatric assessment to guide therapy, often R-miniCHOP or non-anthracycline regimens. Frail patients should have adapted treatments. Prephase corticosteroids improve performance status, and supportive treatment should be optimized. The value of central nervous system (CNS) prophylaxis remains uncertain. CNS-IPI scores and specific anatomical sites help identify high-risk patients; magnetic resonance imaging (MRI) and colony-stimulating factor (CSF) analysis are recommended. Approximately 30%-40% of patients with LBCL experience relapsed or refractory disease after 1L treatment. Treatment strategies vary based on the timing of relapse (<1 year or ≥1 year). For those refractory or relapsing within <1 year and fit for therapy, chimeric antigen receptor T (CART) are the gold standard in 2L. CART in CART-naïve patients and bispecific antibodies appear to be the best approach in 3L. Follow-up includes clinical examination for 2 years and management for long-term side effects, such as cardiotoxicity, osteoporosis, immune dysfunction, neurocognitive impairment, endocrine dysfunction, fatigue, neuropathy, and mental distress.

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