{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:30:18Z","timestamp":1786113018091,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: The treatment paradigm for relapsed\/refractory (R\/R) large B-cell lymphoma (LBCL) has undergone significant change with the advent of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies and CD20 \u00d7 CD3 bispecific antibodies (BsAbs). Although both approaches have shown high response rates in single-arm studies, the absence of prospective randomized head-to-head comparisons has resulted in true clinical equipoise. Methods: A narrative synthesis was conducted, incorporating pivotal and updated phase 2 and 3 trial data, real-world evidence, and published meta-analyses. Results: In the second-line setting, CAR-T therapy demonstrates superior event-free survival, progression-free survival, and overall survival compared to standard-of-care chemo-transplant regimens. In the third-line setting, a pooled meta-analysis indicates significantly higher complete response rates for CAR-T compared with BsAbs, as well as superior 12-month progression-free survival. BsAbs provide immediate availability, greater accessibility, more favorable neurotoxicity profiles, and are feasible for frail or elderly patients. Real-world data show that BsAb complete response rates are consistently lower than those observed in clinical trials, whereas CAR-T real-world effectiveness closely aligns with pivotal trial outcomes. Emerging phase 3 data on fixed-duration and monotherapy bispecific regimens suggest that a genuine, if less mature, curative fraction may also be achievable among BsAb-treated complete responders. Conclusions: CAR-T therapy remains the standard of care for fit, eligible patients with R\/R LBCL in second- and third-line settings with curative intent, providing superior depth and durability of response and a growing potential for long-term cure. BsAbs constitute a critical therapeutic alternative for patients ineligible for CAR-T, those with rapidly progressive disease, frail or elderly individuals, and as bridging strategies. A patient-centered, scenario-specific clinical decision framework is recommended.<\/jats:p>","DOI":"10.3390\/cancers18152513","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T16:48:08Z","timestamp":1785948488000},"page":"2513","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Great Debate: CAR-T-Cell Therapy Versus Bispecific Antibodies in B-Cell Lymphoma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3987-419X","authenticated-orcid":false,"given":"Massimo","family":"Martino","sequence":"first","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violetta","family":"Marafioti","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3982-4141","authenticated-orcid":false,"given":"Martina","family":"Pitea","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4739-349X","authenticated-orcid":false,"given":"Gaetana","family":"Porto","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgia","family":"Policastro","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo Antonio","family":"Canale","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Naso","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Alati","sequence":"additional","affiliation":[{"name":"Hematology and Stem Cell Transplantation and Cellular Therapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano \u201cBianchi-Melacrino-Morelli\u201d, 89133 Reggio Calabria, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1053\/j.seminhematol.2023.11.004","article-title":"Epidemiology and etiology of diffuse large B-cell lymphoma","volume":"60","author":"Wang","year":"2023","journal-title":"Semin Hematol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1080\/10428194.2021.1975188","article-title":"Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: Population-level projections for 2020-2025","volume":"63","author":"Kanas","year":"2022","journal-title":"Leuk. 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