Abstract
Background
Chimeric antigen receptor (CAR) T-cell therapy has recently shown promise in treating diffuse large B-cell non-Hodgkin lymphomas with primary or secondary central nervous system (CNS) involvement. Mantle cell lymphoma with CNS involvement (MCLSNC) is a rare presentation, occurring in approximately 4% of MCL cases, mostly in a relapse setting. It is associated with a poor prognosis, with median survival ranging from 3 to 6 months, and currently lacks an established standard of care. In systemic MCL, the anti-CD19 CAR T-cell therapy brexucabtagene autoleucel has demonstrated encouraging results, achieving a complete response rate of 68%, with a median progression-free survival (PFS) of 25.8 months and a median overall survival (OS) of 46.6 months. However, clinical data on MCLSNC remain extremely limited. Here, we present clinical outcomes specific to this rare CNS-involved presentation.
Methods
We analyzed the use of anti-CD19 CAR T-cell therapy for MCLSNCs using data from the French DESCAR-T registry (NCT04328298) between 2020 and 2024. Among patients treated with CAR T-cells for relapsed or refractory MCL, 20 cases were identified with documented CNS involvement.
Results
The median age at the time of CAR T-cell therapy decision was 62.1 years (range: 46–79). At initial diagnosis of MCL, 7 out of 14 evaluable patients (50%) had blastoid variant, 3 of 7 (43%) harbored a TP53 mutation, 2 of 7 (29%) had a 17p deletion, and 6 of 12 (50%) showed circulating disease. Patients had received a median of 3 prior lines of therapy (range: 2–9), and 8 patients (40%) had undergone autologous stem cell transplantation (ASCT) prior to CAR T-cell therapy. All patients were treated with the anti-CD19 CAR T-cell therapy brexucabtagene autoleucel, following lymphodepletion with fludarabine and cyclophosphamide. Cytokine release syndrome (CRS) occurred in 15 patients (75%): 11 (73%) experienced grade 1 and 4 (27%) grade 2 CRS. Neurotoxicity was observed in 17 patients (85%), including 7 (41%) with grade 1, 6 (35%) with grade 2, 1 (6%) with grade 3, and 2 (12%) with grade 4.
At one-month post-infusion, 10 patients (50%) achieved a CR, 6 (30%) had a PR, 3 (15%) had stable disease and 1 had a progressive disease. By month 3, 12 patients (60%) were in CR, 1 remained in PR, and 2 had progressive disease (PD). At last follow-up, 11 patients (55%) remained in CR and 1 in PR.
With a median follow-up of 18.6 months (95% CI: 6.6–NA), 7 patients (35%) experienced PD following CAR T-cell, and 9 patients had died. Among those who progressed, 6 received salvage therapy. Of the 9 deaths, 6 were attributed to PD, 1 to acute treatment-related toxicity, and 2 to unknown causes. The median PFS was 10.2 months (95% CI: 5.3–NA), and the median OS was 23.3 months (95% CI: 12.2–NA).
Conclusion
Our study demonstrates the efficacy of CAR T-cell therapy in patients with MCL and CNS involvement. Compared to the ZUMA-2 study, the incidence of neurotoxicity events of any grade was slightly higher in our cohort, but with fewer grade ≥2. CAR T-cell therapy appears to be a promising treatment option for MCLSNC. However, these findings require confirmation in larger, prospective studies.
