Rituximab, lenalidomide, and zanubrutinib (ZR2) with sequential CAR-T cell as first-line therapy for high-risk large B cell lymphoma

Abstract Background High-risk large B-cell lymphoma (LBCL) demonstrates poor response rates and prognosis with standard chemotherapy, which ​​requires​​ more effective first-line therapies in disease management. Although chimeric antigen receptor T-cell (CAR-T) therapy shows significant efficacy in relapsed/refractory LBCL, its first-line application remains limited by chemotherapy-induced T-cell impairment and poor tolerance to pre-CAR-T chemotherapy. Targeted therapy combinations achieved substantial efficacy and safety as first-line treatment for LBCL through non-cytotoxic mechanisms. Here, we report sequential targeted therapy combination (rituximab, lenalidomide, and zanubrutinib) followed by CAR-T as first-line treatment for high-risk LBCL. Methods This investigator-initiated, single-center, single-arm phase II clinical trial evaluated rituximab, lenalidomide, and zanubrutinib (ZR2) with sequential CAR-T cells as first-line therapy in patients with newly diagnosed high-risk LBCL. Patients with high-risk LBCL underwent 2 cycles of ZR2 regimen. After leukapheresis and lymphodepletion, these patients received sequential CD19 CAR-T cell infusion. The primary endpoint was complete response (CR) rate following CD19 CAR-T cell therapy. The secondary endpoints were survival and safety profile. Results 34 patients were enrolled and received ZR2 regimen. Among 30 patients completed ZR2 therapy, 26.7% (n=8) achieved CR, 70% (n=21) achieved partial response (PR).1 patient had progressive disease and withdrew from the study. Eventually, 28 patients completed CAR-T therapy and accepted efficacy assessment. No death due to adverse events was found. Adverse events included grade 1 cytokine release syndrome occurred in 35.7% of patients (n=10), cytopenia grade 3-4 in 100% (n=28). No neurotoxicity was found. All adverse events were reversible. 96.4% of patients (n=27) achieved CR after CAR-T therapy. 3.6% of patients (n=1) achieved PR. At a median follow-up of 18.4months (range 2.0-50.8), 24 patients remained in remission and 4 patients relapsed. The 3-year overall survival rate and progression-free survival rate were 90.9% and 80.9%, respectively. Conclusion The ZR2 regimen sequential with CD19 CAR-T therapy has enabled an almost chemotherapy-free first-line treatment for newly diagnosed high-risk LBCL. This treatment is characterized by high CR rate, acceptable toxicity and great survival outcomes. This establishes the potential for developing CAR-T therapy as first-line therapy for LBCL.