From breakthroughs to blueprints: evolving evidence and future directions in relapsed and refractory large B-cell lymphoma

Abstract

Abstract The therapeutic landscape for relapsed or refractory large B-cell lymphoma (R/R LBCL) has undergone rapid and profound change, driven by cellular therapies, bispecific antibodies, and next-generation antibody-drug conjugates (ADCs). These advances have redefined historical standards while exposing persistent gaps in trial design, biological insight, and therapeutic sequencing. Recent randomized studies show that ADC- and bispecific-anchored regimens can outperform legacy chemotherapy comparators, yet interpretation is hindered by geographic heterogeneity, selective enrollment, and a proliferation of trials lacking contemporary control arms. Next-generation approaches, including bispecific-ADC combinations, dual-target chimeric antigen receptor T-cell therapy (CAR-T) constructs, and strategies explicitly designed to circumvent antigen escape, are poised to challenge long-standing therapeutic hierarchies and may broaden curative potential to patients who are ineligible for, or relapse after, CAR-T. The field now stands at an inflection point at which therapeutic innovation is advancing faster than the evidence infrastructure required to guide practice. Delivering durable, equitable benefit will require control arms aligned with current CAR-T standards, harmonized eligibility criteria, prospective molecular profiling, and adaptive trial platforms capable of evolving with the standard of care. As ADCs and bispecifics move earlier in treatment and diffuse into community practice, the central challenge is no longer the development of active therapies alone, but the creation of biologically rational, accessible, and interpretable pathways that make tolerable, curative treatments a realistic and universal goal for all patients with R/R LBCL.