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Pivotal Phase III trials, ZUMA-7 and TRANSFORM, have established second-line CD19-directed CAR T-cell therapies (axi-cel and liso-cel) as standard of care for primary refractory or early-relapsing disease, displaying superior survival outcomes compared with salvage chemoimmunotherapy followed by autologous hematopoietic stem cells transplantation (auto-HSCT) which is now limited to late relapses. However, clinical management of R\/R LBCL becomes highly complex in peculiar settings, especially in case of multiple relapses even after CAR T-cell therapy, as described in our clinical case of secondary central nervous system disease relapse. Allogeneic HSCT remains a niche consolidative strategy exclusively for fit patients lacking other therapeutic options. Moving forward, novel bioengineering approaches, including dual-targeting, memory-enriched and \u201carmored\u201d CARs, aim to overcome current resistance mechanisms and redefine future clinical practice.<\/jats:p>","DOI":"10.3389\/fonc.2026.1924365","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T12:52:46Z","timestamp":1789390366000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating new and \u201cold\u201d cellular therapies in the evolving landscape of relapsed or refractory large B-cell lymphoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Enrico","family":"Amaducci","sequence":"first","affiliation":[{"name":"Division of Hematology, Transplant and Cell Therapy Unit, Department of Molecular Biotechnology and Health Sciences, University of Torino","place":["Turin, 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