A Multicenter Study on Front-Line Treatment of Diffuse Large B-Cell Lymphoma with Zanubrutinib Combination Therapy

Background Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma. The traditional treatment regimen, RCHOP, achieves a complete response (CR) rate of 75% and a 10-year overall survival (OS) rate of 43.5%. However, 30-40% of patients experience relapse with a very poor prognosis. To improve cure rates of frontline treatments, experts worldwide are striving to make advancements. The LymphGen algorithm has categorized DLBCL into seven subtypes, each with potential targeted therapies. The Guidance-01 study, which incorporated genotyping and targeted agents for newly diagnosed, intermediate to high-risk DLBCL, demonstrated that RCHOP+X was superior to RCHOP alone, with CR rate（CRR）of 88% vs. 66% (P=0.003), overall response rate (ORR) of 92% vs. 73% (P=0.005), two-year progression-free survival (PFS) rate of 88% vs. 63% (P<0.001), and two-year OS rate of 94% vs. 77% (P=0.001). Objectives To retrospectively analyze the efficacy and safety of combination therapy with zanubrutinib in the front-line treatment of diffuse large B-cell lymphoma across multiple centers. Methods Patient information was collected from August 2020 to October 2023 for those newly diagnosed with DLBCL who received zanubrutinib first-line combination regimens. Data were gathered from four hospitals: Shenzhen People's Hospital, Peking University Shenzhen Hospital, The Seventh Affiliated Hospital of Sun Yat-sen University, and The Second People's Hospital of Shenzhen. The combination therapy primarily involved RCHOP, and for patients with CNS involvement, the main approach was R+HD-MTX. CRR, ORR, PFS, and OS were analyzed, and adverse effects were documented. Results A total of 38 patients were enrolled, comprising 23 (60.5%) females and 15 (39.5%) males. The median age was 65 years (range: 29-86), with 36 (94.7%) patients in Ann Arbor stage III-IV. Among them, 9 (23.7%) had CNS involvement, 13 (34.2%) had more than one extranodal involvement, 37 (97.4%) were at medium to high risk, and 32 (84.2%) were non-GCB subtype. Genetic testing was conducted on 25 patients, revealing 12 (48.0%) cases of the MCD gene (MYD88mut/CD79Bmut) subtype. The CRR was 92.1% (95% CI: [83.5%, 100%]), and the ORR was 94.7% (95% CI: [87.6%, 100%]). The two-year PFS rate was 86.0% (95% CI: [75.0%, 97.0%]), and the two-year OS rate was 97.1% (95% CI: [91.8%, 100%]) . The median duration of remission was 430.5 days (range, 0-1228). Subgroup analysis indicated no significant difference in two-year PFS and OS between patients with more than one extranodal involvement and those without, nor between patients with CNS involvement and those without. Genetic grouping showed that the MCD group (the BTK inhibitor-sensitive group) had a better two-year PFS rate compared to other groups (100% vs. 67.7%, P=0.034). Adverse Effects: Hematological adverse effects included granulocytopenia (grade 3/4, n=9, 23.7%), anemia, and thrombocytopenia (grade 3/4, n=1, 2.6%). Non-hematological adverse effects included infections (grade 3/4, n=9, 23.7%), coronary heart disease (grade 3/4, n=2, 5.3%), bleeding (grade 3/4, n=1, 2.6%), and vomiting. There were no treatment-related deaths in this study. Conclusions The first-line treatment of DLBCL with zanubrutinib combined regimens show good efficacy, particularly for the MCD subtype, and is associated with fewer adverse effects. This approach merits further exploration.