Background: The CD19-targeted chimeric antigen receptor T (CAR-T) cell therapy has achieved significant efficacy in the treatment of B-cell lymphoma. However, during the manufacturing of CAR-T cells, there is a time interval of about 2-8 weeks between leukapheresis and lymphodepletion. Approximately 7-11% of patients experience disease progression and/or death during the wait for CAR-T infusion, especially those with highly invasive tumors, high tumor burden, and tumors compressing important organs. Bridging therapy defined as the pre-treatment from leukapheresis to lymphodepletion before CAR-T cell infusion, aims to prevent rapid disease progression, reduce tumor burden, and ensure that patients can safely infuse CAR-T cells. However, there is currently no unified standard for bridging therapies and suitable selection; whether patients can benefit from bridging therapy needs to be further confirmed.

Methods: From June 2017 to September 2024, 88 patients with relapsed/refractory B-cell non-Hodgkin lymphoma who were intended to receive CAR-T therapy in the Zhujiang Hospital of Southern Medical University, were retrospectively analyzed; there are 11 (12.5%) patients could not receive CAR-T infusion due to disease progression or infection during the process. Among the 77 patients who received CAR-T infusion, 40 (52.0%) patients received bridging therapy, including chemotherapy (n=13, 32.5%), targeted therapy (n=14, 35%), radiotherapy (n=7, 17.5%), and immunotherapy (n=6, 15.0%), and the other 37 (48.0%) patients did not receive bridging therapy. Our study revealed the baseline characteristics and survival analysis of patients between the bridging group and the non-bridging group.

Results: The baseline characteristics of patients who received bridging therapy had higher IPI score of 3-5 (92.5% vs 78.4%, P<0.001) and more extranodal sites ≥ 2 (87.5% vs 56.8%, P=0.004), with higher levels of lactate dehydrogenase [median: 221.0 (138.3-2179.7) U/L vs median: 189.0 (80.3-603.7) U/L, P<0.001]. In the 3-month efficacy evaluation after CAR-T infusion, the complete response rate (CRR) and objective response rate (ORR) in the bridging group were 30.0% and 48.6%, while the CRR and ORR in the non-bridging group were 40.0% and 64.9%.

The last follow-up date was June 22, 2025, with a median follow-up time of 921.0 days. The median progression-free survival (PFS) of the bridging group was 104.5 days, and the median PFS of the non-bridging group was 505.0 days. The median overall survival (OS) of the bridging and non-bridging groups was not reached. The 2-year PFS and OS rates of the bridging group were 37.5% and 70.4%, while the 2-year PFS and OS rates of the non-bridging group were 45.6% and 73.9%. After multivariate Cox regression analysis correcting for confounding characteristics, the two groups had no significant statistical difference in PFS and OS (P>0.05).

In safety, the risk of cytokine release syndrome (CRS) (75.0% vs 32.4%, P<0.001) and grade 4 hematological toxicity (85.0% vs 35.1%, P<0.001) in the bridging group was significantly higher than the non-bridging group, although there was no statistical difference in risk of ICANS. The interval time in the bridging group was significantly longer than the non-bridging group (40 days vs 20 days, P=0.026), and most patients were still in progressive disease or stable disease after bridging therapy (60.0%, 24/40), although lactate dehydrogenase levels generally decreased after bridging therapy [after median: 221.0 (138.3-2179.0) U/L vs before median: 307.0 (144.4-3470.0) U/L, P=0.005].

Conclusions: In our retrospective study, the bridging group had higher tumor burden and more factors related to poor prognosis and risk of adverse events. For those patients, the bridging therapies in our study have limited effectiveness in improving the long-term survival of CAR-T cell therapy. There is the possibility that bridging therapy may have toxic side effects and the drug washout period, which may delay the timing of CAR-T cell infusion. It's necessary to select the hypotoxic drug as much as possible in the bridging process and explore more effective bridging therapies or strategies that can shorten the preparation time during CAR-T cell manufacturing. Besides, for patients with stable conditions, it is recommended to infuse CAR-T cells as soon as possible, and bridging therapy should be used only for patients in emergent disease with rapidly progressing or high-risk factors.

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2025
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