Background: Brexu-cel is a CAR T therapy approved for adult patients (pts) with R/R MCL. In a 3-year follow-up of ZUMA-2 (Wang et al., 2022), ORR was 91% (CR 68%). Median DOR, PFS and OS were 28.2, 25.8 and 46.6 mo respectively. Here, we describe real-world outcomes of brexu-cel by receipt of prior BTK inhibitor (BTKi), bendamustine, autoHCT, and 1-2 vs ≥ 3 prior lines of therapy. Methods: From 07/2020-08/2022, 397 pts receiving brexu-cel for R/R MCL from 79 US centers were registered in the CIBMTR observational database. In this analysis, 272 were included (median follow-up 6.6 mo; range 0.3-16.5), excluding pts with prior non-HCT cellular therapy (n = 7), missing data on prior treatment, or no follow-up. Descriptive analyses were used for all outcomes. Results: Median age was 65.8 years (range 34.1-84.9); pts were mostly male (78%). Prior to infusion, 7% had ECOG PS ≥ 2; 76% had clinically significant comorbidities; 4% had extranodal CNS involvement. At diagnosis, Ki-67 ≥ 30%, Ki-67 ≥ 50% and TP53/17p deletion were seen in 69% (n = 111/160), 44% (n = 70/160) and 19% (n = 29/153) of pts respectively. Pts had a median of 4 lines of prior therapy (range 1-12; 6% as 2L). Prior to leukapheresis, 87% were BTKi-exposed; 54% received bendamustine; 31% were autoHCT recipients. Median time from leukapheresis to infusion was 28 d (IQR 26-34 d), during which 18% received bridging therapy. ORR for all was 89% (CR 78%). At 6 mo, cumulative incidence of relapse/PD was 21%; DOR, PFS and OS were 76%, 73% and 83% respectively. Grade ≥ 3 (ASTCT consensus) CRS and ICANS occurred in 9% and 27% of pts (88% and 62% for any grade). Most CRS (94%) and ICANS (79%) resolved within 3 weeks. Prolonged cytopenia by 30 d occurred in 23% pts. NRM at 100 d and 180 d were 3% and 6% respectively, mainly due to infections. ORR for BTKi-naïve (n = 36) vs -exposed (n = 233) pts was 85% (CR 79%; 6-mo DOR 84%) vs 89% (CR 77%; 6-mo DOR 74%); for pts with (n = 145) vs without (n = 124) prior bendamustine was 88% (CR 75%; 6-mo DOR 75%) vs 89% (CR 80%; 6-mo DOR 77%); for pts with (n = 83) vs without (n = 188) prior autoHCT was 90% (CR 82%; 6-mo DOR 83%) vs 88% (CR 76%; 6-mo DOR 72%). Higher CR rates were seen in pts with brexu-cel as 2/3L (n = 56) vs 4L+ (n = 213) (91% vs 74%; ORR 92% vs 88%; 6-mo DOR 77% vs 75%). Similar safety profiles were seen regardless of prior BTKi or autoHCT. Pts with prior bendamustine had fewer Grade ≥ 3 ICANS (19% vs 36%) but more prolonged cytopenia (29% vs 16%) vs pts without. Conclusions: These early findings suggest that real-world outcomes of brexu-cel are consistent regardless of prior BTKi, bendamustine, or autoHCT. Use of brexu-cel in earlier lines may help achieve a higher CR rate. Further studies with longer follow-up are warranted to contextualize response rates in relation to long-term clinical benefits of brexu-cel. Updated data with longer follow-up will be reported at the time of presentation. SK and NA contributed equally.