Real-world effectiveness and safety outcomes by age, comorbidities, and frailty among relapsed or refractory (R/R) Mantle Cell Lymphoma (MCL) patients treated with brexucabtagene autoleucel (brexu-cel)

Abstract Introduction: Brexu-cel is a CAR T-cell therapy approved in the US for adults with R/R MCL and has demonstrated durable responses and manageable safety after long-term follow up in the ZUMA-2 trial (Wang et al. JCO 2022). Early real-world (RW) data from CIBMTR was similar to those from trials and when stratified by prior bendamustine use, hematopoietic stem cell transplant, Bruton's tyrosine kinase inhibitors-naïve status (Kambhampati et al. JCO 2023; ASCO abstract), and in those with high-risk disease (Kambhampati et al. Blood 2023; ASH abstract). However, long-term RW data remain limited, particularly for patient (pt) subgroups often excluded from clinical trials. This study aimed to describe RW outcomes of brexu-cel in R/R MCL, stratified by age, performance status, and comorbidities. Methods Adult pts with R/R MCL who received commercial brexu-cel between 07/2020–12/2022 in the US were identified in the CIBMTR® registry; pts without consent or who had prior CAR T-cell therapy were excluded. Descriptive analyses were done among all pts and by age at infusion (<65 vs ≥65 yr), Karnofsky performance score (KPS), and presence of hepatic, cardiovascular (CV), or moderate to severe pulmonary comorbidities. Multivariable (MV) logistic and Cox regression were used to adjust for confounders. Results In total, 476 pts from 83 centers were included with a data cut-off of January 2025. Median age at infusion was 67 yr (range, 34-85; ≥65 yr, 61%), and 83% were non-Hispanic White. Pts had KPS of ≤70% (21%), 80% (37%), or 90-100% (42%); 5% had ECOG PS ≥2, and 76% had at least one clinically significant comorbidity (hepatic, 10%; CV, 23%; pulmonary, 22%). At a median follow-up of 25.0 months (95% CI, 24.7-26.0), objective response rate (ORR) was 91% (complete response [CR] rate, 83%). The 2-yr (95% CI) DOR, PFS, and OS were 55% (49-60), 51% (46-56), and 62% (58-67) respectively. Grade ≥3 cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 11% and 30% of pts (any grade, 89% and 61%), respectively. Prolonged cytopenias by day 30 occurred in 25% (14% with neutropenia and 19% with thrombocytopenia) and 45% had clinically significant infections by 1-yr. Second primary malignancies occurred in 68 (14%), including 4 (0.8%) cases with therapy-related myeloid neoplasms. The leading causes of death were primary disease (105; 56%), bacterial infection (16; 8%), and COVID (16; 8%). Cumulative incidence of non-relapse mortality at 2-yr was 11%. Effectiveness and safety outcomes were generally comparable among age and comorbidity subgroups. However, by KPS (≤70%, 80%, and 90-100%, respectively): the ORR (89%; 91%; 92%) and CR (77%; 81%; 88%) increased with higher KPS. Similarly, the 2-yr DOR (45%; 52%; 61%), PFS (42%; 46%; 59%), and OS (46%; 57%; 74%) were better at higher KPS. MV analysis showed that pts with KPS ≤70% and 80% respectively had worse effectiveness outcomes [OR/HR (95% CI)]: CR [0.47 (0.23-0.94) and 0.57 (0.31 – 1.05)]; DOR [1.83 (1.22 – 2.74) and 1.66 (1.16 – 2.39)]; PFS [1.73 (1.21-2.47) and 1.62 (1.18-2.23)]; and OS [2.41 (1.63 -3.58) and 1.69 (1.17-2.44)] compared to those with KPS 90-100%. The Grade ≥3 CRS and ≥3 ICANS for KPS (≤70%, 80%, and 90-100%) were (16%; 13%; 6%) and (26%; 32%; 24%) respectively while prolonged neutropenia (26%; 12%; 11%) and prolonged thrombocytopenia (33%; 17%; 14%) were less common at higher KPS. By age (<65 vs ≥65 respectively), the rates of any-grade CRS were 94% vs 85% while for any-grade ICANS they were 56% vs 65%. On MV analysis, pts with KPS ≤70% and 80% respectively had higher odds of grade ≥3 CRS [2.98 (1.24-7.15) and 2.91 (1.30-6.51)], prolonged neutropenia [2.66 (1.31-5.42) and 1.10 (0.55-2.21)], and prolonged thrombocytopenia [2.52 (1.28-4.95) and 1.16 (0.61-2.19)] compared to the 90-100% group. Compared to pts aged <65 yr, those ≥65 yr had lower odds of any-grade CRS [0.34 (0.16 – 0.73)] but higher for any-grade ICANS [1.67 (1.07 – 2.62)]. Summary/Conclusion In this long-term RW study of brexu-cel for R/R MCL, we found durable responses and comparable effectiveness and safety outcomes similar to the ZUMA-2 trial. Outcomes were generally consistent irrespective of hepatic, CV, and pulmonary comorbidities, demonstrating evidence for the use of brexu-cel in these subgroups. The findings reinforce the relevance of KPS in prognostication and suggest that age and comorbidity alone should not preclude brexu-cel use in R/R MCL.