Background

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment scheme of relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL). However, patients with central nervous system (CNS) relapse after CAR-T treatment encounter poorer prognosis and higher mortality. While currently, there are limited studies in this area. We here conducted a multi-center, retrospective study on adult patients with R/R NHL receiving CD19-targeted CAR-T cell therapy, and evaluated the incidence and prognosis of CNS relapse, which, to our knowledge, is the first large-scale research in the world on CNS relapse in patients with R/R NHL after CAR-T therapy.

Methods

This study enrolled patients with R/R NLH in the Bone Marrow Transplantation Center (Hangzhou, China), Department of Hematology and 0ncology, international Cancer Center (Shenzhen, China) and Queen Mary Hospital (Hong Kong, China) between April 2017 and September 2024. CRS and ICANS were graded by ASTCT consensus criteria. CNS relapse was evaluated by magnetic resonance imaging (MRI), lumbar puncture for analysis of cell count, cytology and flow cytometry, and brain biopsy, according to standard clinical protocols.

Results

A total of 134 patients were included in this analysis, in which 124 (92.5%) pts were DLBCL, 3pts were MCL, 3 pts were FL, 2 pts were LBL, 1 pt was Burkitt lymphoma and 1 pt was not classified. The medium age was 62 (range, 22 to 83) years, and 75 (55.9%) pts were male. The clinical characteristics of all 134 patients at baseline and after CAR-T cell therapy are summarized. The medium follow-up period was 11.3 (range, 0.5 to 64.6) months. The medium infusion dose of CAR-T cells was 2.2 (range 0.6-10.7) 10^6/kg. Overall, 59 (44.0%) pts achieved complete remission (CR), 42 (31.3%) pts achieved partial remission (PR). The cytokine release syndrome (CRS) was mild (grade 1 or 2) in most patients (120, 89.6%). Fourteen pts underwent CRS with grade 3, which was manageable and controlled eventually. Unfortunately, 76 (56.7%) pts relapsed after CAR-T treatment and had significantly poorer prognosis compared to patients without relapse. Among them, 17 (22.4%) pts possessed isolated CNS relapse confirmed by MRI, cerebrospinal cytology or brain biopsy, all of whom were heavily pre-treated with prior multiple lines of chemotherapy. Only 7 of 17 (41.2%) pts with isolated CNS relapse achieved CR. The median time to CNS relapse from CAR-T cell infusion was 3.1 (range, 1.0 to 25.8) months. The medium OS, PFS, relapse-free survival (RFS) in patients with CNS relapse was 10.7 [95%CI 4.1-17.2], 3.1 [95%CI 1.0-5.1] and 3.1 [95%CI 1.0-5.1] months, respectively, which was much shorter than those in patients without relapse (medium OS, PFS and RFS were not reached, P<0.0001), while showing no significant difference compared to the systemic only recurrence group (OS, 10.3 months [95%CI 7.8-12.8], P=0.317; PFS, 3.0 months [95%CI 2.9-3.2], P=0.410; RFS, 5.1 months [95%CI 2.1-8.2], P=0.694).

Conclusion

In conclusion, in this first large-scale, multi-center, retrospective study on adult patients with R/R NHL receiving CD19-targeted CAR-T cell therapy, CNS relapse in patients with R/R NHL after CAR-T cell therapy indicates significantly poorer prognosis than those without relapse, but showing no difference compared to those with systemic relapse only. Further investigation is necessary to better define the risk factors in patients who might potentially developed CNS relapse after CAR-T treatment and be worth additional effective prophylaxis. In the future, CAR-T cells with dual-targeting, knocked-out of immune inhibitory receptors, secreting tumor microenvironment-remodeling factors, or combined with HSCT might increase efficacy and prevent CNS relapse.

Acknowledgements

The study was supported by clinical trials (ChiCTR1800015575; NCT03118180; NCT04532281; NCT04532268; NCT04213469), and we sincerely thank all patients in participation.

Disclosures No relevant conflicts of interest to declare.

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2025
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