Bridging to CD19 CAR T-cell therapy for LBCL: An analysis of 1,154 patients by the EBMT lymphoma working party and the gocart coalition

Abstract Background CD19-directed CAR T-cell therapy (CART) is the standard of care for relapsed/refractory large B-cell lymphoma (R/R LBCL). Because patients (pts) with LBCL frequently progress between leukapheresis and lymphodepletion, they often undergo bridging therapy (BT). To date, data on the efficacy and optimal choice of BT are sparse. Methods We analyzed 1,154 LBCL pts treated with CART ( [axi-cel] or tisagenlecleucel [tisa-cel]) across 38 EBMT centers between 2018 and 2023. Use of BT, type of BT, and response to BT were analyzed. BT was grouped as high-dose (HDT) or low-dose therapy (LDT), with HDT comprising intravenous standard salvage regimens and LDT featuring oral or low-intensity non-standard therapies. Combination regimens containing polatuzumab vedotin and rituximab with or without bendamustine were grouped under Pola-(B)R. Radiotherapy (RT) was analyzed as a separate category. Results Median age at CART was 62.1 years (range 19–88.9), 38.9% of pts were female. Diagnoses included DLBCL NOS (91.8%), PMBCL (5.5%), and other (2.7%). At diagnosis, stage III–IV disease was found in 76.2%, bulky disease in 32.8%, elevated LDH (LDH>N) in 69.6%, ECOG ≥1 in 60.9%. Most pts (86.4%) had stable/progressive disease at apheresis. The median number of lines of therapy prior to BT was 2 (range 1–11, IQR 2-3). CART was administered as third-line or later in 94.4% of pts. BT was given to 911 (79.1%) pts. In 873 pts BT was categorized: 26.3% received Pola-(B)R, 42.1% had HDT, 16.7% LDT, and 14.8% RT. At CART, 32.6% of pts were in CR/PR, 47.1% showed LDH>N, 59.2% ECOG ≥1, 14.9% bulky disease; 76.9% had stage III/IV. Axi-cel was used in 57.5%, tisa-cel in 40.8%. Pts with BT were younger (median 61.5 vs. 64.3 yrs, p=.001), had received less autoHCT (22.7% vs. 32.8%, p=.001) and less previous RT (19.8% vs. 28.1%, p=.007). At CART, pts showed higher CR/PR rates (36% vs. 19.9%, p<.001) and more frequently had LDH>N (49.3% vs. 38.1%, p=.005), ECOG ≥1 (62% vs. 48.9%, p<.001), and bulky disease (17.1% vs. 6.7%, p<.001). At a median follow-up of 36 months, OS was 47.5% and PFS 37.1% for all pts. CRS occurred in 85.5% (9.1% grade 3-5), ICANS in 33.5% (32.4% grade 3-5), incidence of grade 3-4 infections at 36 months was 22.4%. Interestingly, BT was associated with worse OS (44.7% vs. 58.6%, p<.001) and PFS (34.7% vs. 46.1%, p=.002), mostly reflecting the higher RI (52.7% vs. 45.4%, p=.028). These associations remained significant in multivariate analysis adjusted for transformed DLBCL, age, sex, prior autoHCT, number of prior treatment lines, disease status at CART, LDH>N, ECOG, CART product. Absence of BT was associated with improved OS (HR 0.58, p<.001), PFS (HR 0.64, p<.001), and lower relapse incidence (HR 0.66, p<.001). While NRM was not significantly different in univariate analysis (12.6% vs. 8.6%), absence of BT was associated with reduced NRM in the multivariate analysis (HR 0.50, p=.018). We also explored whether response and outcomes varied by type of BT. Among patients not in CR at apheresis, 13.8% bridged with Pola-(B)R, 7.8% with HDT, 9.3% with LDT, and 8.2% with RT had achieved CR at lymphodepletion. In multivariate analysis of patients with BT, no BT modality was associated with significantly improved survival. Established prognostic factors, including LDH>N (HR 1.72, p<.001), ECOG ≥1 (HR 1.41, p=.004), active disease at lymphodepletion (HR 1.81, p<.001), and ≥3 prior lines of therapy (HR 1.27, p=.02) were significantly associated with inferior PFS. Conclusion In this large cohort of pts, BT vs. no BT before CART resulted in significantly worse OS, PFS, and higher RI, also after adjustment for key prognostic factors. No specific BT modality showed superior OS or PFS in multivariate analysis restricted to BT pts. Our results do not support the notion that in comparable pts any BT investigated is superior to others; in particular, more aggressive BT did not improve outcomes after CART. These findings indicate that pts in need of BT present with more aggressive disease, the negative prognostic impact of which cannot be overcome by BT of any type. BT should be used carefully, aiming for disease control without inducing unnecessary toxicity.