Zanubrutinib-based regimen as the salvage or bridging treatment of CART therapy in relapsed or refractory, non-germinal center B-cell–like diffuse large B-cell lymphoma: a retrospective multicenter cohort study

Background: Relapsed or refractory (R/R) non-germinal center B-cell-like (non-GCB) diffuse large B-cell lymphoma (DLBCL) shows poor clinical outcomes. Bruton tyrosine kinase (BTK) inhibitors have established therapeutic activity by targeting B-cell receptor signaling, with promising results in treating DLBCL. The monotherapy of zanubrutinib, a selective BTK inhibitor, or second-line salvage chemotherapy has shown limited efficacy in patients with R/R DLBCL. Thus, the present study evaluated the efficacy and safety of zanubrutinib-combined therapy in heavily treated patients with non-GCB DLBCL. Methods: This retrospective study consists of 27 heavily treated patients with non-GCB DLBCL who received zanubrutinib-combined therapy between January 2021 and February 2024 in Shanghai Tongji Hospital and Zhejiang Second Affiliated Hospital. Efficacy outcomes included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS), whereas safety outcomes included incidence of adverse events. Results: Of all the 27 enrolled patients' baseline,24 patients (88.9%) showed a high IPI score (≥3), 23 patients (85.2%) had a high proliferation score (Ki 67≥80%) and 20 patients (74.1%) were heavily treated with ≥3 lines of previous treatments. The ORR in all patients was 74.1% (95%CI, 53.7%-88.9%), the partial response (PR) was 66.7% (95%CI, 46.0%-83.5%). With a median follow-up of 36.6 months, the median PFS was 10.6 months (95%CI 7.3-14) and median OS was 19.6 months (95%CI 12.3-not reached). The grade ≥3 hematologic toxicities included neutropenia (85.1%, 23/27) and thrombocytopenia (37%, 10/27). The grade ≥3 nonhematologic AEs were hypokalemia (11.1%, 3/27) and pulmonary infection (11.1%, 3/27). No treatment-related deaths occurred. Subgroups stratified by gender, age, and presence/absence of extranodal lesions all maintained an ORR of over 70%. The efficacy of the combined therapy seemed to be not affected by most baseline characteristics and was associated with high response even in high-risk subgroups. Of all the evaluated 27 patients, 2 patients got complete response (CR) received autologous stem cell transplantation and lenalidomide maintenance therapy respectively. 19 patients got no CR were bridged to CD19 chimeric antigen receptor (CAR)-T cell therapy, while the other 6 patients received additional salvage chemotherapy. In the CAR-T cohort, the ORR was 89.5% (95%CI: 67.0%~98.2%) and CR was 57.9% (95%CI: 34.5%~78.9%), the median PFS was 14 months (95% CI: 5.2-37.9) and median OS was 27.7 months (95% CI: 10.1- not reached). The CAR-T group was associated with improved overall survival relative to the non-CAR-T group (HR = 0.21, 95% CI: 0.05-0.79, P = 0.02). In the landmark analysis, the survival probability of CART group was 80% at 12 months post-landmark, the non-CAR-T group exhibited an earlier initial drop with survival decreasing to 57.1% at 12 months. Conclusion: Zanubrutinib-combined therapy was effective and safe for the treatment of heavily treated patients with non-GCB DLBCL. It offers a promising treatment option and serving as an effective bridge to CAR-T therapy, with manageable toxicity. Future prospective studies with larger cohorts are needed to validate these findings.