Integrating new and “old” cellular therapies in the evolving landscape of relapsed or refractory large B-cell lymphoma

The therapeutic algorithm for relapsed or refractory large B-cell lymphoma (R/R LBCL) is rapidly evolving. 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 “armored” CARs, aim to overcome current resistance mechanisms and redefine future clinical practice.