The ZR2-Minichop Study: Zanubrutinib, Lenalidomide, Rituximab, Cyclophosphamide, Vincristine, Epirubicin, and Prednisone in Elderly Patients with Previously Untreated Diffuse Large B-Cell Lymphoma
Authors: Sun Jianai , Xu Yi , Wang Huafeng , Zheng Xiaolong , Yu Wenjuan , Zhou De , Yang Chunmei , Zhou Xinping , Mao Liping , Meng Haitao , You Liangshun , Yang Min , Tong Hongyan , Jin Jie , Xie Wanzhuo 
Published: December 2024

Background: DLBCL is a common subtype of NHL, with approximately 70% of cases occurring in the elderly population, who often have poor tolerability to standard chemotherapy regimens, leading to suboptimal outcomes. This study aims to evaluate the efficacy and safety of the ZR2-miniCHOP regimen (zanubrutinib, lenalidomide, rituximab, cyclophosphamide, vincristine, epirubicin, and prednisone) in elderly patients newly diagnosed with DLBCL. Methods: This multicenter, single-arm, phase II clinical trial commenced June 2021 in China. Eligible patients were newly diagnosed with DLBCL, aged 65 to 80 with an Eastern Cooperative Oncology Group (ECOG) performance status above 2, or over 80 years with an ECOG status of 0-4. The treatment protocol consisted of a 2-cycle induction with zanubrutinib 160 mg twice daily on days 1-28, lenalidomide 25 mg daily on days 1-10, and rituximab 375 mg/m² (ZR2) on day 1. Patients not achieving complete remission (CR) received 4-6 cycles of reduced-dose CHOP: cyclophosphamide 400 mg/m², vincristine 1.4 mg/m², epirubicin 35 mg/m² on day 2, and prednisone 45 mg/m² on days 2-6. Treatment efficacy was assessed by PET-CT after 6 cycles, with long-term outcomes monitored for 2 years. Additionally, genetic profiling was performed to assess the impact of specific mutations on treatment outcomes. Results: From June 2021 to September 2023, 50 patients were enrolled. Baseline characteristics: median age 78 years (range 65-90, with 42% aged 80 or older). The revised international prognostic index identified 73.5% as high risk, and 48.8% were double expresson of MYC and BCL2 protein. The ORR after 2 cycles of ZR2 was 91.49%, with a CR rate of 29.79%. At the end of the regimen, the ORR was 95.00%, and the CR rate was 90.00%.With a median follow-up of 22.73 months, the 2-year PFS was 77.81 % (95% CI 65.93 - 91.84), and the 2-year OS was 83.57% (95% CI 73.12 - 95.52). The most common adverse events observed were neutropenia and febrile neutropenia. During the initial ZR2 cycles, 36% of patients experienced grade 3-4 neutropenia and 12% had febrile neutropenia. After adding the miniCHOP regimen, these incidences increased to 80% and 10%, respectively, with infections managed by medication and no impact on subsequent treatments.There was one new case of atrial fibrillation, managed with rivaroxaban anticoagulation therapy, with no adjustments to the treatment regimen. No treatment-related deaths were recorded. Despite 44.9% of patients having high-risk CNS-IPI scores, no central nervous system relapses occurred during the follow-up period. Genetic profiling revealed the following mutation frequencies by LymphGen subtype: BN2: 17.07%, EZB: 2.44%, MCD: 14.63%, N1: 4.88%, ST2: 12.20%, TP53 disruption: 4.88%, Unclassified: 31.71%, and BN2/MCD composite: 4.88%. Conclusion:The ZR2-miniCHOP regimen demonstrates promising efficacy and manageable safety in elderly patients with newly diagnosed DLBCL. The ZR2 induction therapy improves the overall tolerability of the regimen, reducing tumor burden, and the subsequent combination with reduced-dose chemotherapy significantly enhances response rates. Overall, the safety profile is acceptable, with potential CNS protection observed. Further investigation and consideration in clinical practice are warranted.