Zanubrutinib combined with anti-CD19 CAR-T cell therapy in relapsed and refractory B-cell lymphoma

Abstract Background The response rate and long-term survival of anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory (r/r) B-cell lymphoma need to be further improved in recent years. B-cell receptor (BCR) signaling pathway plays an indispensable role in the pathogenesis of B cell malignancies. Bruton's tyrosine kinase inhibitors (BTKi) was shown in preclinical study and small scale clinical researches to potentially enhance the efficacy of anti-CD19 CAR-T cell therapy for lymphoma. Aims In this single arm, multi-center pilot study (NCT05744037), we aimed to observe the efficacy and safety of zanubrutinib combined with anti-CD19 CAR-T cell therapy in r/r B-cell lymphoma patients. Methods Patients received a lymphodepletion regimen comprising fludarabine and cyclophosphamide, followed by infusion of autologous anti-CD19 CAR-T cells. All patients received zanubrutinib (160 mg bid) simultaneously, which was maintained for a maximum of 2 years after CAR-T cell infusion. The primary endpoint was overall response rate (ORR), while key secondary endpoints were progression-free survival (PFS), overall survival (OS) and safety. Results We enrolled 10 patients in the preliminary study, with 5 achieving CR and 3 achieving PR, resulting in a CR rate of 50% and an ORR of 80% (8/10). The 1-year OS and PFS rates of patients were 87.5% (95% CI, 38.7%–98.1%) and 78.8% (95% CI, 38.1%–94.3%), respectively. In terms of safety, zanubrutinib combined with anti-CD19 CAR-T strategy is well tolerated, the most frequent toxicities were hematologic adverse events (AEs), with a 70% incidence rate of grade 3 hematologic AEs. Three patients (30%) developed cytokine release syndrome, all of which were grade 1. No instances of immune effector cell-associated neurotoxicity syndrome (ICANS) were observed. All patients had no cardiac events . Conclusion In this single arm clinical trial, zanubrutinib combined with anti-CD19 CAR-T cell therapy demonstrates notable efficacy and good tolerability in r/r B-cell lymphoma patients. A confirmation trial based on larger population is needed in the future.