Jacobson, Caron A.

Background: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are known safety concerns following chimeric antigen receptor (CAR) T-cell therapy. Axi-cel, a CAR T-cell therapy approved in the US for adults with R/R LBCL after ≥ 1 line of prior therapy (2L+), has been administered in the outpatient setting, where a common cause for post-infusion hospital admissions were CAR T-cell-related toxicities (Furqan et al., 2024). Due to reimbursement policies in the US, patients at higher risk for safety events requiring inpatient care within 3 days of infusion may not be ideal candidates for outpatient care. We sought to identify what pre-infusion characteristics may put patients more at risk for developing early CRS and ICANS after axi-cel. Methods : Patients receiving axi-cel for R/R LBCL 2L+ between 01/2021−10/2023 registered in the Center for International Blood and Marrow Transplant Research (CIBMTR) observational database were potentially eligible for analysis. Patients with prior non-transplant cellular therapy or missing data for analysis were excluded. Primary endpoints were onset of early CRS and early ICANS, defined as an any grade event within 3 calendar days of axi-cel infusion (date of infusion is defined as Day 0 and onset of CRS/ICANS before the end of Day 3 is an early event). Early Grade ≥ 2 and early Grade ≥ 3 CRS and ICANS (onset of CRS/ICANS before the end of Day 3 and maximum Grade ≥ 2 and ≥ 3 per ASTCT Criteria) were also evaluated. Patient demographics, ECOG PS, comorbidities, disease characteristics at diagnosis and prior to infusion, line of therapy (LoT), lab assessments prior to infusion, and infusion-related attributes were evaluated by univariate screening and multivariable regression for development of early CRS or early ICANS. Results: A total of888 patients from 105 centers were included in the analysis. Median age was 63 years (45% ≥ 65 years) and 66% were male. At LBCL diagnosis, 22% of patients had a histological transformation. Prior to infusion, 5% of patients had ECOG PS ≥ 2 and 70% had at least 1 clinically significant comorbidity. Half (50%) of patients received axi-cel with 1 prior LoT (2L) and 10% of patients underwent a prior autologous hematopoietic cell transplant. Median time from leukapheresis to infusion was 30 days (interquartile range [IQR] 27−34). Bridging therapy of any type was administered in 59%, and systemic bridging therapy in 48%, of patients and 14% of patients were intended to be treated in the outpatient setting. Thirty percent of patients had chemo-sensitive disease prior to infusion. Median follow-up post-infusion was 12.3 months (range 3−38). Median time to onset of CRS was 4 days (IQR 2−6) and 84% of patients experienced CRS at any time. Early any grade (Grade ≥ 3) CRS was observed in 47% (3%) of patients. In the multivariate analysis of early any grade CRS, only prior LoT (≥ 2 vs 1) was associated with lower risk (OR 0.71; 95% CI 0.55−0.94), but this association was not seen in the analyses of early Grade ≥ 2 nor early Grade ≥ 3 CRS. Notably, 47% and 52% of patients with ≥ 2 vs 1 prior LoT, respectively, only experienced early Grade 1 CRS (defined as fever only). In the analysis of early Grade ≥ 3 CRS, only ECOG PS 0−1 was associated with lower risk vs patients with ECOG PS ≥ 2 (OR 0.17; 95% CI 0.06−0.48). Median time to onset of ICANS was 7 days (IQR 5−9) and 47% of patients experienced ICANS at any time. Early any grade (Grade ≥ 3) ICANS occurred in 9% (5%) of patients. After multivariate adjustment, age < 65 vs ≥ 65 (OR 0.38 [95% CI 0.23−0.62]) and 1 vs ≥ 2 prior LoT (OR 0.58 [95% CI 0.36−0.95]) were associated with lower risk of early any grade ICANS. Age < 65 vs ≥ 65 was also associated with lower risk of early Grade ≥ 3 ICANS (OR 0.31 [95% CI 0.15−0.61]), as was ECOG PS 0−1 vs ECOG PS ≥ 2 (OR 0.30 [95% CI 0.11−0.83]). Comorbidities were evaluated and no significant associations with early CRS nor early ICANS were found. Conclusions: This analysis of readily available clinical variables in a real-world contemporary cohort of patients treated with axi-cel demonstrates that younger patients and patients with better ECOG PS have lower risk of early CRS and early ICANS. Axi-cel in 2L setting, vs 3L+, is associated with lower risk of early any grade ICANS and comparable early Grade ≥ 2 CRS, but a higher risk of early fever. These results further enable a more informed decision of patient selection for physicians, which is critical for the success of outpatient administration.

Background: Zamto-cel is an investigational autologous tandem CD20-CD19-directed non-cryopreserved CAR-T cell product administered as a fresh formulation to patients (pts) with relapsed/refractory Diffuse Large B Cell Lymphoma (r/r DLBCL) in the DALY II USA clinical trial (NCT04792489), a multicenter, open label, single-arm Phase 2 study. Here, we report efficacy and safety outcomes as part of a pre-planned interim analysis of 59 evaluable patients and 69 patients in the safety population. Methods: Eligible adults had r/r DLBCL after at least 2 prior lines of treatment including anti-CD20 monoclonal antibody and anthracycline-containing regimen and measurable disease per Lugano 2014 classification. Zamto-cel was manufactured utilizing CliniMACS Prodigy® (Miltenyi Biotec), a closed, automated system with a 14-day vein-to-vein time and administered as a fresh formulation. Lymphodepletion chemotherapy was initiated during the manufacturing process (either cyclophosphamide/ fludarabine or bendamustine) prior to receiving a single dose of zamto-cel at a dose of 2.5x106 CAR T cells/kg on Day 0. The primary endpoint was overall response rate (ORR) defined as best overall response (BOR) of either complete response (CR) or partial response (PR). Secondary endpoints included complete response rate (CRR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and CD19 and CD20 antigen expression at relapse. Results: As of March 29th, 2024, 69 pts received zamto-cel of which 59 were evaluable having received a fresh, conforming product and completed a minimum of 3 months follow-up. Median age was 63 years (range 25-85), 39 (66%) were male. Sixteen pts (27%) received 3 or more lines of prior treatment. The majority of pts (53%) had elevated LDH at study entry, and 49% had ≥ 2 extranodal lesions, indicative of a study population with advanced disease. No pts received any bridging therapy, in the week after apheresis and before lymphodepletion. Only 7 pts (12%) received bendamustine as lymphodepleting regimen. Successful manufacturing of a fresh, in specification product occurred in 91.3% out of 69 treated pts. Four patients received a cryopreserved formulation to permit time for comorbid condition management. The mean viability of the final product was 96.0% with 29.4 % transduction efficacy. No patient died or withdrew during the manufacturing process. The ORR in the evaluable patient population (n=59) as assessed by an Independent Radiology Committee (IRC) was 72.9% (95% CI, 59.7-83.6), with a CRR of 49.2% (95% CI,35.9-62.5). The 6 month and 12 month-PFS was 55% (95%CI, 41-67) and 42% (95%CI, 28-56), respectively; 12 month-OS was 72% (95%CI, 57-83). The median DOR was 11.4 months. All 69 treated pts were assessed for safety outcomes. Treatment-emergent adverse events (TEAEs) were mostly of grade 1-2, the majority of grade ≥ 3 were hematological. Thirty-two pts (46.4%) experienced cytokine release syndrome (CRS), all grade 1-2. Immune effector cell-associated neurotoxicity syndrome (ICANS) was reported in 12 pts (17.4%), grade 1-2 (9 pts; 13.1%); grade 3 (3 pts; 4.3%). One patient experienced immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), which resolved after 2 days. Biopsies at progression were available in 24 pts. CD19-negative relapse (defined as H Score <100) was seen in 2 pts, CD20-negative relapse was observed in 3 pts. Only one patient experienced loss of both antigens compared to pre-treatment status, demonstrating that most lymphomas maintain target antigen expression at relapse after treatment with zamto-cel. Conclusion: This pre-planned interim analysis represents the first pivotal trial of a tandem CD20-CD19 directed non-cryopreserved CAR-T cell product for patients with third-line r/r DLBCL. The trial plans to enroll 100 evaluable patients and the final data will be presented upon study completion. Among the 59 evaluable patients at the interim analysis, there is encouraging activity and a favorable safety profile in DLBCL patients treated with zamto-cel. Unlike currently registered CAR-T cell products, zamto-cel is administered as a fresh product with a short vein-to-vein time of 14 days with lymphodepletion initiated during the manufacturing process. With a manufacturing success rate of 91% we have demonstrated the feasibility of this process among high-risk patients with r/r DLBCL.

Abstract Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) large B-cell lymphoma (LBCL). Despite extensive data supporting its use, outcomes stratified by race and ethnicity groups are limited. Here, we report clinical outcomes with axi-cel in patients with R/R LBCL by race and ethnicity in both real-world and clinical trial settings. In the real-world setting, 1290 patients who received axi-cel between 2017 and 2020 were identified from the Center for International Blood and Marrow Transplant Research database; 106 and 169 patients were included from the ZUMA-1 and ZUMA-7 trials, respectively. Overall survival was consistent across race/ethnicity groups. However, non-Hispanic (NH) Black patients had lower overall response rate (OR, 0.37; 95% CI, 0.22-0.63) and lower complete response rate (OR, 0.57; 95% CI, 0.33-0.97) than NH White patients. NH Black patients also had a shorter progression-free survival vs NH White (HR, 1.41; 95% CI, 1.04-1.90) and NH Asian patients (HR, 1.67; 95% CI, 1.08-2.59). NH Asian patients had a longer duration of response than NH White (HR, 0.56; 95% CI, 0.33-0.94) and Hispanic patients (HR, 0.54; 95% CI, 0.30-0.97). There was no difference in cytokine release syndrome by race/ethnicity; however, higher rates of any-grade immune effector cell–associated neurotoxicity syndrome were observed in NH White patients than in other patients. These results provide important context when treating patients with R/R LBCL with CAR T-cell therapy across different racial and ethnic groups. ZUMA-1 and ZUMA-7 (ClinicalTrials.gov identifiers: #NCT02348216 and #NCT03391466, respectively) are registered on ClinicalTrials.gov.

AbstractAxicabtagene ciloleucel (axi‐cel) in trials has demonstrated favorable efficacy compared with historical controls after ≥2 lines of therapy for the treatment of relapsed or refractory (R/R) large B cell lymphoma (LBCL). Herein, we compared the real‐world effectiveness of axi‐cel with efficacy and effectiveness of chemoimmunotherapy (CIT) in patients aged ≥65 years and patients with Eastern Cooperative Oncology Group performance status (ECOG PS) of 2. A total of 1146 patients treated with commercial axi‐cel for R/R LBCL with ≥2 lines of prior therapy were included from the Center for International Blood and Marrow Transplantation Research prospective observational study, and 469 patients treated with CIT for R/R LBCL after ≥2 lines of prior therapy were included from SCHOLAR‐1 (an international, multicohort, retrospective study). After propensity score matching, at a median follow‐up of 24 months for patients receiving axi‐cel and 60 months for patients receiving CIT, 12‐month overall survival rates were 62% and 28%, respectively (hazard ratio, 0.30 [95% CI, 0.24–0.37]). Objective response rate (ORR) was 76% (complete response [CR] rate 58%) in patients receiving axi‐cel versus 28% (CR rate 16%) for those receiving CIT. A 57% difference in ORR (55% difference in CR rate) favoring axi‐cel over CIT was observed among patients aged ≥65 years. Increased magnitude of benefit in response rates for axi‐cel versus CIT was also observed among patients with ECOG PS = 2. These findings further support the broader use of axi‐cel in older patients and patients with ECOG PS = 2 with R/R LBCL.

Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after 1 prior therapy as a result of ZUMA-7 (NCT. In ZUMA-1 (NCT02348216), the pivotal study which initially led to the approval of axi-cel in the 3L+ setting, the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019) and at 5 years follow up an OS rate of 42.6%, 5 years durable response and 5 years disease specific survival at 51% ( Neelapu et al. Blood 2023). T cell-related biology (Immunosign 21; Immunoscore®IC) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel ( Scholler et al., 2022). Increased density of activated PD-1+LAG-3+/−TIM-3−CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post-axi-cel. This expanded analysis characterized the impact of axi-cel treatment on the TME immune contexture and examined associations between immune cell subsets and relapse. Methods: Baseline and post-infusion tumor biopsy samples were analyzed by multiplex immunohistochemistry ( Brightplex®). Four panels were developed and applied to assess T cell infiltration (CD3 CD8 FOXP3 TIM3 PD1 LAG3 TOX), regulatory T cell subtyping (CD3 CD8 GATA3 TBET RORg BCL6), T cell activation & exhaustion (CD3 CD8 TIM3 LAG3 PD1 GZMB KI67), macrophage (CD68 CD64 CD163 CD204 CD206 PDL1) and MDSC (CD3 CD11B CD68 CD14 CD15 LOX1 S100A9) subsets. Transcriptomic analysis was performed using nCounter® Pan Cancer panel. The association between T cell subtypes and macrophages cell subset density, and probability to relapse was evaluated. T test values were based on Brightplex analysis. Results: 34 tumor biopsies (16 at baseline, 18 post-infusion) from 26 pts were analyzed including 11 relapsed (6 CR/5 PR) and 15 durable response (15 CR). The baseline and post-infusion TME comprised all major macrophages, MDSC and T cell subsets, with diverse distribution across samples analyzed. Low proinflammatory M1 macrophage density was observed at baseline and post-infusion across patients. In relapsed patients, baseline tumors were enriched with a significantly higher proportion of protumoral M2 macrophage (p<0.0001). A shift of M1-M2 polarization was observed between baseline and post-infusion (Baseline 33%M1M2 / 65%M2, post infusion 76%M1M2 / 21%M2, p<0,0001) across the cohort. In contrast, in relapsed patients, M-MDSC cell density was significantly increased post treatment (p=0.0420). In addition, Innate lymphocyte cells subtype 2 (ILC2) cell density, previously described to be positively correlated with improved overall survival in CRC ( Huang et al. 2021 Cancers), was significantly decreased in relapsed patients post infusion (p=0.019).Post-infusion, durable response was associated with a significant increase in pan-Macrophages (p=0.0360) and cytotoxic T cell subset densities: CD8 naïve T cells (p=0.016); Activated Cytotoxic T cell (GZMB+)(p=0.0203); PD1+TIM3+LAG3- cytotoxic T cell (p=0.0117); CD8 regulatory T cell (FOXP3+)(p=0.012). Regarding T helper lineage, ongoing response was associated with a significant increase of: CD4 naïve T cells (p=0.021); T helper Th2 (p=0.020); cytotoxic T lymphocyte TC2 and TC1/TC2 cell densities (respectively p=0.0052 and 0.011).Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusion: These results suggest that baseline proportions of protumor M2 macrophages may predict disease relapse after axi-cel treatment. Following infusion, relapse is also associated with spatial enrichment of M-MDSC, whereas durable response is related to increases in T cell subpopulation densities inclusive of cytotoxic T cells, T helper, TC1/TC2 ratios and innate T-subpopulations. These findings suggest that axi-cel treatment drastically impacts tumor immune mobilization, infiltration and contexture, which correlates with long term response.

Introduction: Historically, older patients (pts) with relapsed/refractory large B-cell lymphoma (R/R LBCL) were often deemed ineligible for curative-intent autologous stem cell transplant (ASCT) due to age and concern for increased toxicity related to comorbidities. We previously demonstrated in the pivotal ZUMA-7 study that older pts with R/R LBCL can safely receive axicabtagene ciloleucel (axi-cel) as second-line (2L) therapy with improved event-free survival (EFS), response rate, and quality of life compared with standard of care (SOC) based on results from the primary EFS analysis (Westin, et al. Clin Cancer Res. 2023). At a median follow-up of 47.2 months (mo), results from the ZUMA-7 primary overall survival (OS) analysis demonstrated superior OS in the intention-to-treat (ITT) analysis (hazard ratio [HR], 0.73; 95% CI, 0.54-0.98; stratified two-sided log-rank P=0.03; Westin, et al. N Engl J Med. 2023; NCT03391466). We now report updated efficacy and safety results from the primary OS analysis among ZUMA-7 pts aged ≥65 years (y) and ≥70 y. Methods: Eligible pts were randomized 1:1 to axi-cel or SOC (2-3 cycles of platinum-based chemoimmunotherapy; responding pts proceeded to high-dose chemotherapy with ASCT). The primary OS analysis occurred 5 y after the first pt was randomized (01/25/2018) per protocol. Other endpoints included progression-free survival (PFS) per investigator assessment and safety. A planned subgroup analysis of pts aged ≥65 y was conducted in addition to an analysis for those ≥70 y. Multivariate analyses were performed to examine treatment efficacy with axi-cel compared with SOC after adjusting for multiple covariates, including sex, disease type, molecular subgroup, lactate dehydrogenase (LDH), tumor burden, and age; strata for these analyses included second-line age-adjusted International Prognostic Index (aaIPI), and relapsed vs refractory disease. Exploratory analyses were conducted to determine the association between OS and axi-cel product characteristics for pts aged ≥65 y. Results: A total of 109 pts were included in the analysis (axi-cel: 51 were ≥65 y, 26 of whom were ≥70 y, maximum age was 80 y; SOC: 58 were ≥65 y, 27 of whom were ≥70 y, maximum age was 81 y). Compared with SOC pts at baseline, more axi-cel pts had high-risk features, including aaIPI 2-3, elevated LDH, and high-grade B-cell lymphoma. At a median follow-up of 46.6 mo, OS was prolonged in the axicel vs SOC arm in pts aged ≥65 y (HR, 0.691; 95% CI, 0.401-1.190) and for those ≥70 y (HR, 0.330; 95% CI, 0.135-0.809). Similar results were observed using the piecewise Cox regression model. The median OS for axi-cel and SOC pts was 43.5 mo (95% CI, 20.9-not estimable [NE]) and 19.6 mo (95% CI, 12.3-NE), respectively, among those aged ≥65 y, and 24.7 mo (95% CI, 12.8-NE) and 11.2 mo (95% CI, 6.1-NE), respectively, among those aged ≥70 y. In the SOC arm, 57% and 52% of pts received subsequent cellular immunotherapy off protocol in pts aged ≥65 y and ≥70 y, respectively. Multivariate analyses demonstrated an even greater OS benefit with axi-cel over SOC when adjusting for differences in baseline characteristics in pts aged ≥65 y (HR, 0.526; 95% CI, 0.266-1.041) and in pts aged ≥70 y (HR, 0.184; 95% CI, 0.045-0.755). PFS assessed by investigator confirmed benefit of axi-cel over SOC in pts aged ≥65 y (HR, 0.406; 95% CI, 0.230-0.715) and in pts aged ≥70 y (HR, 0.206; 95% CI, 0.078-0.547). The median PFS for axi-cel and SOC pts was 28.7 mo (95% CI, 5.1-NE) and 5.0 mo (95% CI, 2.8-7.2), respectively, for those aged ≥65 y, and 11.4 mo (95% CI, 4.1-NE) and 2.7 mo (95% CI, 1.7-5.0), respectively, for those aged ≥70 y. No new treatment-related deaths occurred since the primary EFS analysis. There were no manufacturing failures for any pt who underwent leukapheresis. Similar associations between product characteristics and outcomes were observed among the elderly and overall populations, including improved OS associated with a greater (>median) proportion of juvenile or stem memory T-cell phenotype cells (CCR7+CD45RA+ T cells) in the axi-cel product among pts aged ≥65 y (HR, 0.369; 95% CI, 0.138-0.984). Conclusion: Axi-cel as 2L therapy prolonged survival over SOC in pts aged ≥65 y, including in pts aged ≥70 y. These findings confirm that age alone should not be a barrier for consideration of CAR T-cell therapy, supporting the use of axi-cel as a curative-intent 2L therapeutic option for older pts with R/R LBCL.

Background: Axicabtagene ciloleucel (axi-cel), an autologous chimeric antigen receptor (CAR) T-cell therapy, achieved an overall response rate (ORR) of 94% and a complete response (CR) rate of 79% in patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two or more prior lines of therapy in the ZUMA-5 trial ( Jacobson et al. Lancet Oncol. 2022). Since its FDA approval in March 2021, there has been little evidence on comparative effectiveness (CE) studies of axi-cel vs standard-of-care (SoC), except ones using ZUMA-5 and historical SCHOLAR-5 data (eg, Ghione et al. Blood. 2022). This study was aimed to address this evidence gap in CE of axi-cel vs SoC used to treat r/r FL in real-world settings. Methods: The two data sources in this study were patients who received commercial axi-cel between March 2021 and May 2023 from the CIBMTR and patients who received historical SoC (eg, chemotherapy, anti-CD20 mAb + chemotherapy, immunomodulatory imide drugs) between July 2014 and December 2020 from SCHOLAR-5, which served as an external control of ZUMA-5 trial. The index date was defined as the initiation date of either the infusion for axi-cel patients or the last eligible systemic therapy for SoC patients. Patients were included if they were age ≥ 18, had documented r/r FL with histological grade 1, 2 or 3a, and received at least 2 prior lines of therapy at the index. Patients were excluded if they had transformed diffused large B-cell lymphoma, central nervous system involvement, prior receipt of CAR T or other non-CAR T cellular therapies or allogeneic stem cell transplant, or no post-index information on outcomes. Four effectiveness outcomes were ORR, CR rate, progression-free survival (PFS), and overall survival (OS). Imbalance in observed prognostic risk factors between the two was adjusted via a propensity score analysis using the standard mortality ratio weighting (SMRW). The primary analyses included weighted univariable analysis and multivariable logistic (ORR and CR rate) or Cox (PFS and OS) regressions that were adjusted for the covariates after the SMRW. A sub-analysis of patients age ≥ 65 was conducted using the same methods as the primary analyses. Results: The unweighted study cohort included 376 patients, in which 256 (68%) received axi-cel . Thepatients who received axi-cel were more likely to be younger (median age 61 for axi-cel vs 67 for SoC), have grade 3a FL (37% vs 12%), received 3 or more prior lines of therapy (83% vs 58%), or remained refractory to the last prior therapy (79% vs 73%) vs those who received SoC. The imbalance in the observed prognostic risk factors was mitigated via the SMRW. The weighted univariable analysis, in which the sample size by treatment reflected the SMRW, is shown in Table 1. In patients of all ages, ORR was 92% in axi-cel vs 67% in SoC, and CR rate was 84% vs 37%. Because of varying follow-up lengths by treatment (median 7 months for axi-cel and 37 months for SoC), survival outcomes were reported at month 6, at which time PFS rate was 88% in axi-cel vs 64% in SoC and OS rate was 97% vs 85%. The corresponding proportions for patients age ≥ 65 were similar to those reported for patients of all ages. In the weighted multivariable regressions, axi-cel was associated with statistically significantly better outcomes by all 4 effectiveness measures vs SoC (Table 1). Specifically, in patients of all ages, the odds ratios for axi-cel were 4.93 (95% CI, 2.35−10.34) for ORR and 16.72 (95% CI, 7.03−39.73) for CR rate, and the hazard ratios for axi-cel were 0.41 (95% CI, 0.22−0.77) for PFS and 0.15 (95% CI, 0.06−0.34) for OS. Similar to the patients of all ages in the primary analyses, patients age ≥ 65 in the sub-analysis also demonstrated improved outcomes associated with axi-cel (Figure 1). Conclusions: This study showed that patients with r/r FL after two or more prior lines of therapy treated with axi-cel experienced better outcomes compared with patients treated with SoC, and that older patients also benefited significantly from axi-cel. These findings suggest that axi-cel addresses an important unmet medical need in patients with r/r FL. Future research should include longer follow-up data on outcomes of axi-cel and CE of axi-cel vs other contemporary SoC therapies.

Introduction: Axi-cel utilization expanded after demonstration of superior event-free survival in patients (pts) with early relapsed or primary refractory LBCL (Locke, et al. NEJM. 2022) and was reinforced by improved overall survival (OS) among these pts (Westin, et al. NEJM. 2023). Despite increased demand, limited data exist on the impact of bridging therapies (BT) on pt outcomes. Thus, BT use between leukapheresis and lymphodepletion (LD) is largely at the discretion of treating physicians. Here, we assessed the impact of BT on effectiveness and safety outcomes after axi-cel. Methods: Pts receiving axi-cel for 3L+ LBCL in the US between 2017-2020 were prospectively collected through the CIBMTR registry in a post-authorization safety study; data up to May 2023 were included. Effectiveness outcomes were overall response rate (ORR), complete response (CR) rate, duration of response (DOR), progression-free survival (PFS), and OS. Safety outcomes were cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) per ASTCT grading, non-relapse mortality (NRM), and other key adverse events. Propensity score-based inverse probability of treatment weighting (IPTW) was used in logistic and Cox regressions to account for potential confounding in BT use. For pts who had BT, effects of BT types and responses on outcomes were evaluated using conventional logistic and Cox regressions. Results: Of 1497 pts registered, 1307 had BT data available and were included (median follow-up, 36 mo). Overall, 430 pts (33%) received BT (median time from leukapheresis to LD, 23 days [IQR, 21-28]). Systemic therapy was used in 403 pts (31%), including 305 (23%) with chemotherapy (CT)-based BT (19% treated with CT + anti-CD20 monoclonal antibody [mAb; mainly rituximab] and 4% with CT only), and 98 (7%) with non-CT systemic therapy (Table). Radiotherapy (± systemic therapy) was used in 44 pts (3%). Pts with ≥3 lines of prior therapy (odds ratio [OR], 10.67 [95% CI, 7.17−15.87]) or mild hepatic impairment prior to infusion (OR, 1.64 [1.06−2.55]) were more likely to receive BT, while those with histologic transformation (OR, 0.69 [0.51−0.92]) or longer time from diagnosis to leukapheresis were less likely to receive BT. ORRs to axi-cel were 70% and 79% (CR rates 51% and 64%) for pts with or without BT, respectively. Unadjusted DOR, PFS, and OS at 3 years were 40%, 28%, and 37%, respectively, in pts with BT vs 49%, 39%, and 49%, respectively, in those without BT. After multivariate adjustment, no statistical significance was found between BT and any effectiveness outcome. Adjusted hazard ratios (HRs) for BT were 1.13 (95% CI, 0.94-1.36) for PFS and 1.11 (95% CI, 0.92-1.34) for OS, respectively (Figure). Most safety endpoints were consistent regardless of BT. Grade ≥3 CRS and ICANS occurred in 12% and 30% of pts, respectively, who received BT vs 10% and 24% of pts who did not. Use of BT was associated with more frequent prolonged neutropenia (OR, 2.24 [1.44-3.50]) and thrombocytopenia (OR, 2.33 [1.67-3.24]), but not associated with a higher rate of infections or NRM (Table). Among pts receiving BT, 74 (17%) had a CR or partial response to BT. Of them, median PFS and median OS post infusion were 12.7 mo (3.8-not estimable [NE]) and 48.7 mo (18.6-NE), respectively. Response to BT was associated with increased CR rate (OR, 2.00 [1.07-3.75]), PFS (HR, 0.69 [0.49-0.99]), and OS (HR, 0.59 [0.40-0.88]) and decreased any-grade ICANS (OR, 0.51 [0.29-0.92]). When different BT strategies were considered, effectiveness and most safety outcomes for CT + anti-CD20 mAb vs non-CT treatment were comparable without significant difference. CT + anti-CD20 mAb was associated with improved ORR (OR, 1.90 [1.00-3.60]), PFS (HR, 0.69 [0.49-0.98]), and OS (HR, 0.66 [0.46-0.95]) but increased any-grade CRS (OR, 2.16 [1.02-4.57]) vs CT only. CT use was associated with an increased risk of prolonged thrombocytopenia (41% vs 24% for pts receiving non-CT treatment; OR, 2.37 [1.39-4.02]). No significant association was found between use of radiotherapy as BT and any outcome. Conclusion: These US real-world findings suggest that the addition of BT prior to axi-cel is associated with more frequent prolonged cytopenias but does not impact effectiveness or other critical safety outcomes. Response to BT may prognosticate more favorable outcomes after axi-cel infusion. Further study is warranted to identify the optimal bridging regimen.