Efficacy and safety of zanubrutinib combined with chimeric antigen receptor T-cell therapy targeting CD19 in refractory or relapsed diffuse large B cell lymphoma: A retrospective analysis

Abstract

Background: While chimeric antigen receptor T-cell (CAR T) therapy has shown promise in treating B-cell non-Hodgkin lymphoma, its efficacy is variable in patients with poor initial responses. This study investigates the efficacy and safety of zanubrutinib combined with CAR T therapy targeting CD19 in refractory/relapsed diffuse large B cell lymphoma (DLBCL).

Methods: We conducted a retrospective study of 17 patients with R/R DLBCL who received zanubrutinib combined with anti-CD19 CAR T-cell therapy. We assessed overall survival (OS) and progression-free survival (PFS) and conducted subgroup analyses. We also monitored CAR T-cell expansion by quantifying vector copy numbers (VCN). Safety and tolerability were assessed by documenting adverse events, including cytokine release syndrome and neurotoxicity.

Results: The median follow-up was 30 months (range, 4-36). The overall response rate(ORR) was 88.2 %, with 70.5 % achieving complete remission. At 24 months, the estimated PFS was 59 % (95 %CI, 40-88 %), and the OS was 71 % (95 %CI, 52-90 %). At 36 months, the estimated OS was 65 % (95 %CI, 46-92 %). Patients with non-elevated lactate dehydrogenase(LDH) levels showed a higher PFS probability (100 %) compared to those with elevated LDH (42 %, 95 %CI: 21 %-81 %) (log-rank, p = 0.071). The area under the receiver-operating characteristic (ROC) curve for peak CAR T-cell expansion was 0.773, suggesting an optimal cutoff at day 13 for enhancing survival (sensitivity 66.7 %, specificity 90.9 %; p = 0.07). Early peak expansion (before day 13) correlated with better PFS and OS (log-rank, p = 0.0018 and p = 0.0053, respectively). The total VCN AUC was 0.636, with a cutoff of 12,690 significantly predicting survival (sensitivity 83.3 %, specificity 72.7 %; p = 0.366). Kaplan-Meier analysis indicated statistically significant differences in OS for patients with VCN below 12,690 (log-rank, p = 0.017) in comparison to those exceeding 12,690, though trends in PFS did not reach statistical significance (log-rank, p = 0.12). Safety profiles indicated manageable cytokine release syndrome, with no severe neurotoxicity reported.

Conclusions: Zanubrutinib combined with CAR T-cell therapy offers an effective treatment option for patients with R/R DLBCL, enhancing response rates and survival. Detailed analysis of CAR T-cell expansion provides insight into the dynamics of cellular responses, underscoring the potential for tailored therapeutic approaches based on biological markers.

Keywords: CAR T-cell; Chimeric antigen receptors; Efficacy and safety; Refractory/relapsed diffuse large B cell lymphoma; Zanubrutinib.