The incidence of indolent B-cell lymphomas, particularly follicular lymphoma (FL) and marginal zone lymphoma (MZL), continues to rise. Frontline therapy represents the critical window to improve long-term outcomes in patients with high-risk prognostic factors. Combinations of BTK inhibitors with anti-CD20 monoclonal antibodies have demonstrated encouraging efficacy in both treatment-naïve and relapsed/refractory FL and MZL. However, this precise combination strategy in high-risk patients is not fully understood.

To assess the effects of zanubrutinib-based regimens on high-risk FL/MZL patients, we performed a retrospective analysis. All treatment-naïve high-risk FL/MZL patients received zanubrutinib combined with anti-CD20 monoclonal antibody-based regimens as first-line therapy from January 2022 through March 2025. High-risk features were defined as bulky disease ≥7cm, high Ki67 index (≥60% in FL,≥40% in MZL), extranodal involvement, and intermediate-to-high risk FLIPI or MZL-IPI scores. A total of 15 patients were enrolled, with a median age of 60 years (range 30-80), including 6 patients aged ≥65 years (40%). Ten patients had FL disease, and 7 were male, with the male-to-female ratio of 1:1.14. High-risk characteristics included bulky disease (n=2), high Ki67 index (n=8), extranodal involvement (n=9), and FLIPI/MZL-IPI score ≥2 (n=12). Advanced-stage disease was present in 11 patients. Four patients harbored 2 high-risk factors, while 6 patients had ≥3 high-risk factors. All patients completed a minimum of 6 treatment cycles (median 7, range 6–8), and 8 FL patients received maintenance therapy with zanubrutinib plus rituximab or obinutuzumab. Following 4 cycles, the objective response rate (ORR) reached 86.7% (13/15), with a complete response (CR) rate of 33.3% (5/15). After 6 cycles, the ORR reached 93.3% (14/15), with a CR rate of 80% (12/15). With a median follow-up of 18 months (range 4-41 months), no deaths or disease progression events were observed.

Further subgroup analyses demonstrated that patients with Ki67 >40% achieved superior CR rates compared with those with Ki67 ≤40% (100% vs 57.1%). Patients with extranodal involvement showed higher CR rates than those without (88.9% vs 66.7%). Notably, patients harboring ≥3 high-risk factors achieved higher CR rates than those with 1-2 factors (100% vs 66.7%). Both patients with bulky disease achieved partial responses only, suggesting bulky disease may represent an independent adverse prognostic factor. The most frequent adverse event was hematologic toxicity (86.7%). The grade ≥3 hematologic toxicity occurred in 20% of patients, and no grade 4 event was reported. Pneumonia was documented in 1 patient, while no cardiac toxicities or treatment-related deaths occurred.

Our findings suggested that zanubrutinib combined with anti-CD20 monoclonal antibody-based regimens demonstrates exceptional efficacy (CR 80% in our study, 27% in the GALLIUM study) as first-line therapy for high-risk FL/MZL patients, substantially outperforming conventional treatment approaches. The regimen also exhibits a favorable safety profile with manageable toxicities. This combination may represent a compelling therapeutic option for patients with indolent lymphomas harboring high-risk features.

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2025
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