Feasibility, outcomes and challenges of CAR-T cell therapy as advanced or earlier line of treatment for B-cell non-Hodgkin lymphomas: A multicenter national study Free

Chimeric antigen receptor (CAR) T-cell therapy has transformed the therapeutic landscape of refractory B-cell non-Hodgkin lymphomas (B-NHL). Moreover, moving of CAR-T cells into 2^nd line has changed the management of diffuse large B-cell lymphoma (DLBCL). However, real-world evidence (RWE) data on the efficacy and feasibility of cellular therapy are limited and highly anticipated. In this retrospective multicenter study, we describe the entire national RWE of the implementation of CAR-T cell therapy for B-NHL in Greece.

We enrolled consecutive adult B-NHL patients, who received commercial CAR-T cell therapy at 6 Greek centers, between 01/2020 and 05/2025. Examined variables included age, gender, prior lines of treatment and autologous stem cell transplantation, administration and response to bridging therapy, CAR-T product used, and vein-to-vein time. Estimated outcomes were best response to CAR-T therapy, overall and progression-free survival (OS, PFS), as well as incidence and severity of main adverse events including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS).

A total of 210 patients (female: 82, male:128) were analyzed, with a median age of 56 (range: 18-77) years. The cohort included 156 patients with DLBCL, 18 with primary mediastinal B-cell lymphoma (PMBCL), 17 with follicular lymphoma (FL) and 19 with mantle cell lymphoma (MCL). Patients had received a median of 3 prior lines of therapy (range: 1–9), 24/179 (13.4%) had undergone autologous stem cell transplantation. Among DLBCL patients, 26 received CAR-T as 2nd-line therapy (17 for primary refractory disease and 9 for early relapse). Commercial CAR-T products used were Axi-cel (n=164), Tisa-cel (n=28) and Brexu-cel (n=19). Bridging therapy prior to CAR-T infusion was administered to 155/208 (74%) patients, resulting in partial response (PR) in 21 and complete response (CR) in 25 (30%). Notably, 96/210 (45.5%) of the patients had never achieved a CR prior to CAR-T treatment. Median vein-to-vein time differed between the periods during and after the COVID-19 pandemic; 74 days (range: 31-346) versus 62 days (range: 33-257), respectively (p=0.029).

Overall response rate (ORR) to CAR-T therapy was 74%, including CR in 60.7% of cases. With a median follow-up of 12.3 (1.0-57.8) months, 1-year OS and PFS were 61.1% (95% CI: 57-72%) and 48.2% (95% CI: 41-55.5%), respectively. Grade ≥3 CRS and ICANS occurred in 12.3% and 15.2% of patients, respectively. No significant difference in OS/PFS was observed between patients treated in 2nd versus ³3rd line of therapy (p=0.214/0.818), with the limitation of very small patient number in the former group. Regarding product type, no difference in efficiency or toxicity was found between Axi-cel and Tisa-cel in DLBCL patients. Notably, the administration of bridging therapy was associated with inferior PFS (p=0.024); however, any response to bridging therapy (CR/PR) benefited this heavily pretreated population as it was correlated with superior OS (p=0.026) and PFS (p=0.035). In addition, patients achieving CR after CAR-T therapy had significantly superior OS/PFS compared to non-CR patients. One-year OS was 75.2% (95% CI: 67-84%) versus 40% (95% CI: 28-53%), respectively (HR=3.848, 95% CI: 2.43-6.10, p <0.001). Similarly, 1-year PFS was 76.1% (95% CI: 67.9-84.3%) versus 16.3% (95% CI: 6.7-25.9%), (HR=4.641, 95% CI: 3.19-6.77, p <0.001).

In multivariate analysis, any response to bridging therapy was independently related with PFS (p=0.038) and complete response after CAR-T therapy was independently associated with PFS (p <0.001) and OS (p <0.001).Conclusions: Our findings demonstrate the feasibility and efficacy of CAR-T therapy in a real-world setting, consistent with the results of pivotal clinical trials. Interestingly, in a poor-risk population, with almost half of patients never being in CR and more than 70% needing bridging therapy due to progression, high rates of OS/PFS were achieved in strong correlation with response to bridging. Furthermore, accumulation of experience in 2nd-line treatment and optimization of the procedure (e.g. by shortening vein-to-vein time and using immunotherapy as a holistic management approach) remain challenging in current clinical practice. Upgraded RWE data with enlarged patient populations and extended follow-up periods will help clarify differential outcomes and optimize patient selection.