Real-world outcomes with CAR T-cell therapy for secondary central nervous system lymphoma are similar between patients with active versus historical involvement

Abstract Background: Secondary central nervous system large B-cell lymphoma (sCNSL) carriers a poor prognosis and is often refractory to standard chemoimmunotherapy. Autologous anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of relapsed and/or refractory large B-cell lymphoma (LBCL) but active CNSL was excluded from pivotal trials, leading to a paucity of data in this cohort. Real-world retrospective studies have suggested these patients can achieve durable responses from anti-CD19 CAR-T therapy however questions remain regarding the outcomes in particular cohorts, especially those with active sCNSL at the time of CAR-T treatment. Methods: Data was collected retrospectively at six centres that participate in the Australian CAR-T Real-World Consortium. We included all patients who underwent apheresis for commercially available autologous anti-CD19 CAR-T therapy between 1st January 2020 and 31st March 2025 and had radiological or pathological evidence of secondary CNS involvement by LBCL at any time prior to CAR-T infusion. Active sCNSL was defined as those with radiological, histological or cerebrospinal fluid cytological evidence of CNSL at apheresis or prior to lymphodepletion. Active systemic lymphoma was defined as PET-avid extra-CNS disease. Due to low patient numbers no statistical tests were performed. Results: 62 patients with a history of and/or active sCNSL underwent apheresis with intent to receive CAR-T; 50 axicabtagene ciloleucel (axi-cel) and 12 tisagenlecleucel (tisa-cel). Median age was 63.5 years (range 28 to 85) and 63% male. 59% had diffuse large B cell lymphoma, 18% high grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements and 15% transformed follicular lymphoma. Median prior lines of therapy were 2 (range 1-4), 26% had an autologous stem cell transplant and 66% were refractory to their most recent therapy. 32 patients (52%) had active systemic and sCNSL, 8 (13%) had active sCNSL alone, and 22 (35%) had active systemic lymphoma alone (with a history of sCNSL). Distribution of sCNSL included 52% leptomeningeal, 32% intraparenchymal and 16% both. 63% of patients received systemic bridging alone, 10% radiotherapy alone and 23% both modalities. The most frequent systemic bridging was chemotherapy (47%), polatuzumab vedotin (11%) and Bruton tyrosine kinase inhibitor (11%). 44% of patients experienced disease progression at any site following bridging therapy. Seven patients did not proceed to infusion, six due to progressive disease and one due to patient choice. 55 patients (89%) proceeded to CAR-T infusion; 44 (88%) axi-cel, 11 (92%) tisa-cel. Median follow up was 11.2 months. The rate of any cytokine release syndrome (CRS) was 85% (9% grade (G) 3-4); axi-cel 89% (7% G3-4); tisa-cel 73% (9% G3-4). The rate of any immune effector cell associated neurotoxicity syndrome (ICANS) was 62% (32% G3-5); axi-cel 64% (32% G3-4); tisa-cel 55% (27% G3-5). There was 1 death due to ICANS in a patient who received tisa-cel. Overall response rate (ORR) and complete response rates (CRR) for the entire cohort were 82% and 60% respectively. The 12-month progression free (PFS) survival for patients infused with tisa-cel was 27%, and 25% in all patients undergoing apheresis (intention to treat, ITT). 12-month PFS for axi-cel was 30% (infused) and 27% (ITT). The 12-month overall survival for infused patients was 35% (tisa-cel 27%; axi-cel 40%). The 12-month PFS in patients with active systemic and sCNSL at the time of CAR-T infusion was 24%, active sCNSL alone 64% and active systemic lymphoma alone 28%. The 12-month PFS for patients with only leptomeningeal disease was 22%, intraparenchymal disease 40%, and both 42%.Conclusions: Patients with sCNSL achieved remission with CAR-T therapy at rates comparable to published data for systemic lymphoma. The CRS and ICANS rates in those receiving axi-cel in this cohort are similar to those seen in prospective trials, consistent with other published real-world series. In the small number of patients receiving tisa-cel, ICANS rates were higher than previously published. PFS appeared similar between those with active sCNSL compared to historic CNS involvement. Active sCNSL alone had favourable PFS compared with concurrent systemic and sCNSL. Larger patient numbers and longer follow-up is required to confirm these findings.