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.

Amsterdam UMC University Amsterdam The Netherlands

Assistance Publique Hôpitaux de Paris Hôpital Cochin Université Paris Paris France

Biostatistics Assistance Publique Hôpitaux de Paris Hôpital Necker Enfants Malades Paris France

Candiolo Cancer Institute FPO IRCCS Turin Italy

Charles University Prague Czech Republic

Department of Hematology and INSERM U1245 Centre Henri Becquerel Rouen France

Department of Medicine 3 LMU Munich Germany

Department of Radiation Oncology University Hospital Muenster Münster Germany

Hemato oncologie Assistance Publique Hôpitaux de Paris Hôpital Saint Louis Paris France

Hematology and Oncology University Hospital Münster Münster Germany

Hematology Department Instituto Portugues de Oncologia Lisbon Portugal

Hospital Clinic y Provincial de Barcelona Barcelona Spain

Institut Carnot Calym Paris France

Lymphoma Coalition Mississauga ON Canada

Maria Skłodowska Curie National Research Institute of Oncology Warszawa Poland

Medical Oncology Department Southampton General Hospital University Hospital Southampton NHS Trust Southampton United Kingdom

School of Medicine University of Nottingham Nottingham United Kingdom

The Christie NHS Foundation Trust Manchester NIHR Biomedical Research Centre University of Manchester Manchester United Kingdom

Universitair Medische Centra Amsterdam Amsterdam The Netherlands

Université Paris Cité Paris France

University Hospital Centre Zagreb and School of Medicine University of Zagreb Zagreb Croatia

University of Helsinki and Helsinki University Hospital Helsinki Finland

University of Wuerzburg Würzburg Germany

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