Outcomes of CAR T-cell therapy in high-grade B-cell lymphomas compared to DLBCL: a weighted comparison analysis.

High-grade B-cell lymphomas (HGBL, including double-hit/triple-hit [HGBL-DH/TH], and HGBL not otherwise specified) have a poor prognosis upon failure of first-line therapy. Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for third-line aggressive large B-cell lymphomas (LBCL) resulted in long-term remission in ≤40% of patients. This study evaluated factors that can predict outcomes in HGBL compared to diffuse LBCL (DLBCL). We assessed the predictive value of the subtype (HGBL vs DLBCL) using weighted log-rank tests and weighted Cox models, and overall survival (OS) following CAR T-cell therapy failure. The prospective study cohort comprised 432 patients (HGBL, n = 78; DLBCL, n = 354), median follow-up of 22.8 months for HGBL and 18 months for DLBCL. Interestingly, there was no statistically significant difference in progression-free survival and OS between patients with HGBL-DH/TH lymphomas vs other high-grade histotypes. CAR T-cell therapy expansion in HGBL did not correlate with response. Before weighting, a significant difference in OS was observed between HGBL vs DLBCL (24-month OS: 37% vs 49%, P = .0036). After weighting, the difference in 2-year OS remained significant (37% vs 44%, P = .0343), and it was related to inferior survival following CAR T-cell therapy failure. The 2-year nonrelapse mortality and incidence of secondary malignancies were similar in patients with HGBL and DLBCL (11% vs 11%, P = .830; 6.4% vs 11.4%, P = .844). Among patients in whom CAR T-cell therapy failed, the 1-year OS after failure was significantly higher in transformed than de novo DLBCL and HGBL (59% vs 32% vs 11%, <0.0004). Earlier use of CAR T-cell therapy may improve the outcome of HGBL. This trial was registered at www.clinicaltrials.gov as #NCT06339255.