CAR T‐Cell Therapy in Patients With Primary Central Nervous System Lymphoma: A LOC Network Study

Despite significant advances in recent years, the prognosis of relapsed or refractory primary central nervous system lymphoma (PCNSL) remains poor, with a median overall survival (OS) of around 6 months 1. Although high-dose chemotherapy with autologous stem cell transplantation (ASCT) can induce durable responses, only a minority of patients with relapsed PCNSL are eligible for this approach 1. While anti-CD19 chimeric antigen receptor T-cell therapy has demonstrated efficacy in relapsed systemic lymphomas 2-4, PCNSL was historically excluded because of concerns regarding immune effector cell–associated neurotoxicity syndrome (ICANS) in brain-injured patients 5. In recent years, however, several cohorts have reported an acceptable safety profile and encouraging efficacy in PCNSL 6-12 (Table S1). Nevertheless, these studies were limited by small sample sizes (≤ 25 patients) and relatively short follow-up. The aim of the present study was to report a larger cohort of patients with relapsed PCNSL treated with CAR T-cells, with longer follow-up. Since January 2020, anti-CD19 CAR T-cell therapy has been available in France for patients with relapsed PCNSL after at least two and subsequently one prior lines of chemotherapy. Adult patients treated with commercial CAR T-cells for relapsed PCNSL were retrospectively identified from the LOC database, the database of the French national expert network for PCNSL. Response was assessed according to IPCG criteria 13. Cytokine release syndrome (CRS) and neurotoxicity were graded according to the 2019 guidelines of the American Society for Transplantation and Cellular Therapy (ASTCT) 14. Progression-free survival (PFS) was defined as the time from CAR T-cell infusion to disease progression or death from any cause. Relapse-free survival (RFS) was defined as the time from infusion to disease progression. OS was defined as the time from infusion to death from any cause. Survival functions were estimated using the Kaplan–Meier method. Comparisons between groups were performed using log-rank tests and a multivariate Cox model. Patients treated with lisocabtagene maraleucel (liso-cel) were excluded from multivariate analyses because of the small sample size. To account for unbalanced covariates, propensity scores were estimated using random forests trained on all baseline variables. The propensity scores were used to perform an inverse probability weighted (IPW) version of the log-rank tests mentioned above. All statistical analyses were performed using R software. The LOC database was approved by the Institutional Ethical Committee of the coordinating center and by the French “Commission Nationale de l'Informatique et des Libertés” (CNIL). All patients gave written informed consent. This study was conducted in accordance with the Declaration of Helsinki. Between December 2019 and July 2025, 78 patients with PCNSL from 18 centers of the LOC network were treated with anti-CD19 CAR T-cells (Table 1). Twenty-five of these patients were previously reported in earlier publications 6, 15. The median age was 66 years (range, 31–83). The median number of prior treatment lines before bridging therapy was 2 (range, 1–6), and 33 patients (43%) had previously undergone ASCT. At pre-bridging evaluation, 65 patients (83%) had a cerebral intraparenchymal lesion, and 17 (22%) had cerebrospinal fluid dissemination. Seventy-six patients (97%) received bridging therapy. At the time of infusion, the median Eastern Cooperative Oncology Group (ECOG) performance status was 1 (range, 0–4). Thirteen patients (17%) were in complete response (CR), 48 (62%) in partial response (PR), four (5%) had stable disease, and 13 (17%) had progressive disease. Eleven patients were treated with two or more bridging therapies to obtain a CR or PR before CAR T-cell infusion (Table S2). Forty-six patients (59%) were treated with axicabtagene ciloleucel (axi-cel), 24 (31%) with tisagenlecleucel (tisa-cel), and 8 (10%) with liso-cel. There was no significant difference between patients treated with axi-cel and those treated with tisa-cel, except for the year of infusion (Table S3). CRS occurred in 73 patients (94%) (grade ≥ 3: 5%), while neurotoxicity occurred in 50 patients (64%) (grade ≥ 3: 27%). There was a significantly higher rate of neurotoxicity in patients treated with axi-cel compared with those treated with tisa-cel (76% vs. 54%, p = 0.04, Figure S1), which persisted after adjustment (p = 0.035). However, the rate of severe neurotoxicity did not differ between the two groups (32% vs. 25%, p = 0.51). There were five toxicity-related deaths (7%), including three cases of septic shock, one mucormycosis, and one prolonged neurotoxicity. The median follow-up was 20.0 months (maximum 60 months). The best response after CAR T-cell infusion was CR in 47 patients (60%) and PR in 16 (21%). Relapses occurred in 34 patients (44%). Among the 29 patients who remained relapse-free at 12 months, only three experienced a subsequent relapse, whereas no relapse was observed beyond 24 months among the 14 patients still relapse-free at that time. The estimated 1-year and 2-year RFS rates were 55% (95% CI, 44%–68%) and 48% (95% CI, 37%–63%), respectively (Figure 1A). The estimated 1-year and 2-year PFS rates were 49% (95% CI, 39%–62%) and 43% (95% CI, 33%–57%), respectively (Figure 1B). One-year and two-year OS rates were 68% (95% CI, 57%–80%) and 53% (95% CI, 41%–68%), respectively (Figure 1C). Median RFS was significantly longer in patients who were in response after bridging therapy compared with non-responders (HR = 2.4, 95% CI 1.2–4.8, p = 0.01; adjusted HR = 2.6, 95% CI 1.1–5.9, adjusted p = 0.02) (Figure 1D and Figure S2). In addition, patients treated with axi-cel had significantly improved RFS compared with those treated with tisa-cel (HR = 2.9, 95% CI 1.4–5.9, p = 0.004; adjusted HR = 3.9, 95% CI 1.3–7.9, adjusted p = 0.003) (Figure 1E and Figure S2). This association remained statistically significant after inverse probability of treatment weighting based on a propensity score model, with an IPW-adjusted hazard ratio of 3.2 (95% CI 1.3–7.6, p = 0.009). Prior ASCT was also associated with improved RFS in the multivariable analysis (adjusted HR = 0.33, 95% CI 0.12–0.93, p = 0.036). Interestingly, no significant difference was observed between patients who received a single bridging therapy and those who received multiple therapies (HR = 0.8, 95% CI 0.3–2.7, p = 0.7; adjusted HR = 0.8, 95% CI 0.2–2.9, adjusted p = 0.7). We identified eight patients with bulky disease at the time of CAR T-cell infusion (defined as diameter > 2 cm). RFS was particularly poor in this subgroup (median, 2.9 months 95% CI 2.1–NR). To our knowledge, this is the largest reported cohort to date of relapsed PCNSL patients treated with CAR T-cells. Despite the advanced age and heavily pretreated status of the population, the 2-year PFS rate exceeded 40%, which represents an important outcome in this population. Moreover, only three relapses were observed among patients who remained relapse-free beyond 12 months, suggesting the possibility of a cure in those achieving durable responses in this cohort with follow-up durations reaching up to 60 months. Our findings support the trend previously observed by Choquet et al., who reported that patients achieving CR or PR after bridging therapy experienced significantly longer RFS compared with non-responders 6. Patients with bulky disease at the time of CAR T-cell infusion had a particularly unfavorable prognosis. On the other hand, the strategy of multiple bridging therapies to achieve an objective response before CAR T-cells appears effective, with a 1-year RFS of 70%. Although these are preliminary data from a small number of patients, we can suggest not infusing CAR T-cells in cases of bulky disease and instead attempting another bridging therapy. Interestingly, patients with prior ASCT showed improved outcomes, which may partly reflect selection of fitter patients initially eligible for this intensive treatment. Concerns have repeatedly been raised regarding a potentially increased risk of neurotoxicity with CAR T-cell therapy in PCNSL. In our cohort, the incidence of neurotoxicity reached 64%, including 27% grade ≥ 3, which is slightly higher than that reported in most other series. However, it remains acceptable given the severity of the disease and close to rates observed in trials such as ZUMA-7 8. Of note, our data did not allow us to differentiate ICANS from tumor inflammation–associated neurotoxicity syndrome, another neurologic toxicity related to CAR T-cells 16. Of note, the treatment-related mortality rate appears relatively high in our cohort 2, 3, 17. This may be explained by the particular frailty of real-life patients with PCNSL, who often have significant neurological impairment and are therefore at increased risk of sepsis. This study also provides preliminary insights into the choice of CAR T-cell products for the treatment of PCNSL. Axi-cel has previously been shown to be significantly more effective but more toxic than tisa-cel in systemic diffuse large B-cell lymphoma (DLBCL) 17. In our cohort, axi-cel use was likewise significantly associated with improved RFS compared with tisa-cel, although with a higher risk of neurotoxicity. Nevertheless, the rate of severe neurotoxicity observed with tisa-cel appeared particularly high compared with that reported in the literature 17. However, given the small sample size, these findings should be interpreted with caution. This study is also among the first series to include PCNSL patients treated with liso-cel, which has shown promising outcomes and lower rates of ICANS in systemic DLBCL 18, 19. The toxicity profile observed in our series was encouraging, as no cases of severe neurotoxicity or CRS were reported; however, efficacy outcomes are not yet mature and require additional follow-up. This series has several limitations mainly due to its retrospective design and to a relatively short median follow-up. In conclusion, this study provides encouraging evidence regarding both the efficacy and safety of CAR T-cell therapy in a larger cohort of relapsed PCNSL. Further studies are needed to better define the optimal bridging strategy and to clarify the positioning of CAR T-cells within the therapeutic landscape for this population. In particular, the role of CAR T-cells versus ASCT, both at relapse and as part of first-line therapy, remains to be determined. The authors have nothing to report. The LOC database was approved by the Institutional Ethical Committee of the coordinating center and by the French “Commission Nationale de l'Informatique et des Libertés” (CNIL). All patients gave written informed consent. This study was conducted in accordance with the Declaration of Helsinki. E.G.: Honoraria from BMS, Gilead-Kite, Novartis, AbbVie, Pfizer, Servier, and Janssen; research support from Novartis, Sanofi, GlaxoSmithKline, Takeda, and BeiGene. J.P.: Honoraria and consultancy from Kite-Gilead, AbbVie, Janssen, Pierre Fabre, and Incyte. B.G.: Honoraria from Kite-Gilead. M.B.: Honoraria from Novartis and BMS. R.H.: Honoraria from Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, Incyte, Janssen, MSD, Takeda, Amgen, Abbvie, and Roche; and is a member on an entity's Board of Directors or advisory committees of Kite/Gilead, Novartis, Bristol-Myers Squibb/Celgene, Tessa Therapeutics, Abbvie and Roche. S.C.: Honoraria from AstraZeneca, Takeda, Pierre Fabre, Nocatris, Lilly, Johnson and Johnson, Abbvie, Beone, Gilead-Kite. C.H.: Honoraria from Kite/Gilead, BMS Celgene, Serb Pharmaceuticals. The data supporting the findings of this study are not publicly available due to patient confidentiality but are available from the corresponding author upon reasonable request and with appropriate ethical approval. Figure S1A: Incidence and severity of CAR T-cell-associated toxicities according to CAR T-cell product Figure S1B: Adjusted risk ratios for CAR T-cell–associated toxicities (tisa-cel vs. axi-cel) Figure S2A: Prognostic factors in terms of relapse-free survival after CAR T-cell therapy (Univariate log rank analysis). Figure S2B: Prognostic factors in terms of relapse-free survival after CAR T-cell therapy (Multivariable Cox regression analysis) Table S1: Published studies reporting CAR T-cell therapy in patients with primary central nervous system lymphoma. Table S2: Detailed bridging therapies before CAR T-cell infusion for patients who received multiple bridging strategies (n = 11) Table S3: Baseline characteristics by CAR T-cell product Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.