Abstract Background: While the putative cell of origin (COO) (GCB vs non-GCB) impacts prognosis and treatment responses in LBCL as well as with autoHCT (Iqbal et al. CLML 2022), the impact of COO on CAR-T outcomes remains elusive. Additionally, while survival following axi-cel therapy (CAR-T in second line) was prolonged compared to SOC for both COO subtypes, the studies were not designed to detect differences in outcomes based on COO (Locke et al. NEJM 2022). Methods: We retrospectively examined the impact of COO in patients with LBCL receiving commercial CD19+CAR-T between 2019-2024, stratified by lines of therapy (LOT; 2L vs 3L+). Axicabtagene ciloleucel (axi-cel) and lisocabtagene maraleucel (liso-cel) were included in 2L and axi-cel, liso-cel and tisagenlecleucel (tisa-cel) in third line and beyond (3L+) setting. COO stratification was based on Hans algorithm and response to CAR-T per Lugano PET/CT criteria. Progression free survival (PFS) was the primary endpoint. Results: Of 344 patients, 59% (n=203) patients had GCB and 41% (n=141) had non-GCB subtype. Axi-cel accounted for 79. 1% (n=272) CAR-T, liso-cel 17. 2% (n=59), and tisa-cel 3. 8% (n=13) ; and 75% (n=257) patients received CAR-T in 3L+ vs 25% (n=87) in 2L. Median interval between diagnosis and CAR-T was 16. 6 months, 48% (n=165) had HCT-CI33, 59. 9% (n=172) elevated LDH, 9. 5% (n=25) bulky disease (10cm), 15. 7% (n=54) ECOG32, and 45. 5% (n=154) IPI33. Of 132 patients who died, primary cause of death was disease progression in 69. 5% patients, infections (11. 5%), secondary malignancy (6. 1%), ICANS (3. 1%), and CRS (0. 8%). Median PFS in GCB was 13. 8 vs 6. 7 months in non-GCB cohort. In multivariate analysis adjusted for LOT, HCT-CI, prior overall response rate (ORR), and ECOG, PFS was significantly superior in GCB vs non-GCB arm (HR, 1. 40; p=0. 028). Median OS in GCB arm was 24. 1 vs 18. 3 months in non-GCB. In multivariate analysis adjusted for LOT, prior ORR, and ECOG, OS was significantly superior in GCB arm vs non-GCB (HR, 1. 46; p=0. 032). While there was no significant difference in median PFS (p=0. 49) and OS (p=0. 82) between 2 COO arms with CAR-T in 2L, median PFS (13. 5 vs 6. 2 months; p=0. 0176) and OS (28. 6 vs 14 months; p=0. 028) were significantly superior in GCB arm with CAR-T in 3L+ vs non-GCB. There were no significant differences in PFS or OS at 1, 2, and 3 years between the 2 COO subtypes in 2L, whereas these were superior in GCB arm, when CAR-T was given in 3L+. In multivariate analysis, CAR-T in 2L vs 3L+ was associated with superior PFS (HR, 1. 65; p=0. 013), however, there was no significant difference in OS (HR, 1. 23; p=0. 366). Conclusion: These results demonstrate that GCB subtype have a superior PFS (HR 1. 4) and OS (HR 1. 5) compared to non-GCB from CD19+CAR-T. Additionally, GCB subtype derive a significant survival benefit when CAR-T is given in 3L+ setting. Consistent with existing literature, CAR-T in earlier lines (2L vs 3L+) confers a PFS advantage (HR 1. 65). Citation Format: Muhammad Bilal Abid. Impact of putative cell of origin on CD19+CAR-T outcomes in patients with large B-cell lymphoma abstract. In: Proceedings of the Fifth AACR International Meeting on Advances in Malignant Lymphoma: From Discovery to Clinical Impact; 2026 Jun 24-27; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2026;7 (3Suppl): Abstract nr A013.
Muhammad Bilal Abid (Wed,) studied this question.