Outcomes of Salvage Therapy after Early-Line CD19 Chimeric Antigen Receptor T-Cell Failure in Large B-Cell Lymphoma.

The approval of CD19 chimeric antigen receptor T-cell (CAR-T) therapy in the second-line (2L) setting for large B-cell lymphoma (LBCL) has reshaped treatment sequencing and the population at risk for post-CAR-T relapse; however, management after failure of early-line CAR-T therapy remains informed largely by later-line cohorts. We conducted an international, multicenter retrospective study of adults with LBCL treated with 2L or third-line (3L) CAR-T therapy to evaluate clinical characteristics, salvage strategies, and outcomes following relapse or progression. Among 545 patients, the 1-year cumulative incidence of relapse or progression after CAR-T was 40%. Of 235 patients who relapsed or progressed, 193 received salvage therapy, with an overall response rate (ORR) of 47%. One-year event-free survival (EFS) and overall survival (OS) after salvage were 18% and 44%, respectively. Outcomes were comparable after 2L and 3L CAR-T therapy, with no independent association between CAR-T line and EFS or OS in multivariable analyses. Relapse within 3 months of CAR-T infusion was strongly associated with inferior response and survival. Post-CAR-T salvage therapy consisted of heterogeneous regimens, most commonly polatuzumab-bendamustine-rituximab and CD20 × CD3 bispecific antibody monotherapy. Response rates and short-term survival varied across approaches, with bispecific antibody monotherapy having the highest ORR (65%) and favorable 1-year outcomes (OS 56%; EFS 43%). In this contemporary multicenter cohort, salvage therapy after CAR-T failure achieved objective but often short-lived responses, with outcomes driven by relapse timing after CAR-T infusion rather than the line of prior CAR-T therapy, supporting individualized treatment selection in this high-risk setting.