e19013 Background: CD19 chimeric antigen receptor (CAR) T-cell therapy has improved outcomes for relapsed or refractory large B-cell lymphoma (LBCL). While infusion-era responses appear comparable across biologic subgroups, outcomes following CAR T-cell failure remain poor. The impact of high-grade cytogenetic biology on responsiveness to subsequent therapy after CAR T-cell failure has not been quantified. Methods: We performed a systematic review and meta-analysis of multicenter cohorts reporting outcomes of adult patients with LBCL who relapsed or progressed after CD19 CAR T-cell therapy and received salvage treatment. Searches were conducted in PubMed/MEDLINE and Google Scholar with reference screening from January 2015 through November 30, 2025. Eligible studies reported comparative salvage outcomes stratified by biologic risk, defined as high-grade B-cell lymphoma with double- or triple-hit cytogenetics or double-hit lymphoma versus biologically standard-risk LBCL. The primary endpoint was complete remission (CR) to first salvage therapy following CAR T-cell failure. Risk ratios were pooled using inverse-variance fixed-effect models with continuity correction. Results: Approximately 70 studies were identified through database searching and screened for eligibility. Six studies were reviewed in full text, of which two large multicenter cohorts met inclusion criteria and were included in quantitative synthesis (total N = 282). Median age across cohorts was approximately 60 years, and 51 patients (18%) had biologically high-risk disease. In the Dodero cohort, CR to salvage therapy after CAR T-cell failure occurred in approximately 16% of patients with high-grade B-cell lymphoma compared with 37% of biologically standard-risk LBCL. In the Karmali cohort, patients with double-hit lymphoma achieved no complete remissions (0%) to first subsequent therapy after CAR T-cell failure, compared with approximately 19% among non-double-hit disease. Pooled analysis demonstrated a 62% relative reduction in likelihood of achieving CR among biologically high-risk patients compared with standard-risk LBCL (pooled RR 0.38, 95% CI 0.17-0.85), with no observed heterogeneity (I² = 0%). Conclusions: Biologically high-risk LBCL is associated with marked salvage refractoriness following CD19 CAR T-cell therapy failure, despite similar infusion-era outcomes. These findings suggest that adverse lymphoma biology, temporarily masked during CAR-T response, reasserts itself at relapse and identifies a population with limited responsiveness to conventional salvage approaches. Risk-adapted post-CAR T strategies and early clinical trial enrollment should be prioritized for patients with high-grade disease.
Burke et al. (Thu,) studied this question.