Safety and efficacy of brexucabtagene autoleucel in elderly patients with relapsed or refractory Mantle Cell Lymphoma: A retrospective, multicenter, international study

Abstract Purpose: Mantle cell lymphoma (MCL) predominantly affects older adults, who may be ineligible for intensive therapies. Limited data exist regarding the safety and efficacy of CD19 CAR-T therapy for treating relapsed or refractory (R/R) MCL specifically in older patients (pts). This represents a significant knowledge gap in this vulnerable subset of pts. We sought to determine the safety and efficacy of brexucabtagene autoleucel (brexu-cel) in older [≥70 years (yrs) at CAR-T infusion] pts with R/R MCL. Methods: We conducted a multicenter, international retrospective study across 6 institutions among pts with R/R MCL receiving brexu-cel 2020-2025. Treatment may have occurred as standard-of-care or in a clinical trial. We used univariable and multivariable Cox proportional hazards models to assess predictors of PFS and OS, from CAR-T infusion, including interaction terms for age and key covariates (primary refractory disease, receipt of bridging therapy, performance status, and elevated LDH pre-lymphodepletion). Our primary endpoints were PFS and OS. Competing risk analyses for relapse/progression and non-relapse mortality (NRM) were performed using Gray's test. Results: 74 pts were identified with a median age at CAR-T infusion of 68 yrs; 43% (N = 32) were ≥70. In this subset, the median age was 76 yrs (range, 70-83). Key MCL clinical/disease characteristics (e.g., Ki67, TP53 mutation, bridging therapy, blastoid/pleomorphic, LDH, performance status) were balanced between age groups, except for a more unfavorable pre-apheresis MIPI score distribution in ≥70 pts (MIPI-high: 79% vs. 54%, P = 0.033) and a higher frequency of patients with disease progressing on a BTK inhibitor pre-CAR-T in the ≥70 group (93% vs. 68%, P = 0.013). The proportion of pts experiencing CRS and ICANS were similar between cohorts: CRS (any grade) in 87% of pts ≥70 yrs vs. 92% of pts <70; CRS grade ≥3 in 22% vs. 21% (P > 0.9). ICANS (any grade) occurred in 56% of pts ≥70 vs. 62% <70; grade ≥3 ICANS in 29% vs. 25% (P = 0.7). In the ≥70 cohort, no significant predictors of CRS/ICANS (any grade or grade >1) were identified in univariable or multivariable analysis. The rate of infection within 100 days of infusion (31% ≥70 vs. 34% <70, P = 0.8) was similar. ICU admission occurred less frequently in pts ≥70 (16% vs. 36%, P = 0.054) and median time from infusion to hospital discharge was equivalent (14 days). Finally, the 12-month (mo) incidence of NRM was similar between groups (10% ≥70 vs. 17% <70, P = 0.9). The overall response rate (ORR) among all pts was 92% without difference between age groups: ORR 93% ≥70 vs. 92% <70 (P = 0.2); CR rates were 87% and 74%, respectively. With a median follow-up of 21.7 mos. (IQR 12.2–30.8), the 12-mo. PFS rate was 66% for all pts – 58% (95% CI 43-80) for pts ≥70 and 73% (95% CI 60-89) for pts <70 (P = 0.26). The 12-mo. OS rate was 74% for all pts: 80% (95% CI 67-96) for pts ≥ 70 and 69% (95% CI 55-87) for pts <70 (P = 0.54). Age was not associated with inferior PFS (adjusted HR 1.03, 95% CI 0.99-1.08, P = 0.11) nor OS (adjusted HR 1.04, 95% CI 1.00-1.09, P = 0.054) in multivariable models. The 1-year cumulative incidence of relapse did not differ significantly between groups (23% ≥70 vs. 13% <70, P = 0.2). Conclusions: In this international multicenter study, the largest to date addressing this question, we have characterized the efficacy and safety of brexu-cel specifically in older pts with R/R MCL. No significant differences in ORR, PFS, or OS were observed between pts aged ≥70 and <70 yrs at time of brexu-cel infusion although differences in 12-mo. PFS rates were observed that were not statistically significant. Additionally, the rates of overall/higher-grade CRS and ICANS were comparable between groups. Our data suggest that in selected fit elderly pts, brexu-cel may be safely offered as a therapeutic option for treating R/R MCL given similar results in our two cohorts for safety/efficacy. Our data address a critical knowledge gap in the field that can inform shared decision-making in clinical practice, weighing the use of brexu-cel vs. other therapeutic options. Of note, NRM, affecting ≥10% of pts in each age cohort, remains a substantial challenge and warrants further evaluation for mitigation strategies. One potential limitation of our cohort is selection bias wherein only highly fit older patients were selected to receive brexu-cel.