Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. BCL-2 protein overexpression is observed in 65–85% of follicular lymphoma (FL) patients. Components of the B-cell receptor (BCR) signaling pathway, such as Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3K), are frequently activated in FL, justifying the development and clinical application of kinase inhibitors for FL treatment. The combination of zanubrutinib and obinutuzumab demonstrated superior overall response rate (ORR) versus obinutuzumab alone. This study aims to assess the feasibility and efficacy of zanubrutinib combined with venetoclax and rituximab (R) in patients with previously untreated FL.

Methods: This is a single-center, open-label, single-arm phase II clinical trial enrolling 30 patients aged ≥18 years with previously untreated FL. The treatment regimen is as follows: All patients received 3 cycles of zanubrutinib and Rituximab (ZR). Patients achieving a complete response (CR) after these 3 cycles continued ZR alone for an additional 6 cycles. Patients not achieving CR received venetoclax added to ZR for 6 cycles. The primary endpoint was complete response rate (CRR) . Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.

Results: As of the follow-up date (July 26, 2025), 4 patients have been enrolled. All 4 patients had advanced-stage disease. Bone marrow involvement was observed in 50.0% (2/4) of patients, and Ki-67 index ≥30% was present in 50.0% (2/4) of the cohort. Three patients have completed treatment. Among these 3 patients, the CRR at the end of treatment (EOT) was 100% (3/3). 1 patient achieved CR upon first response assessment after 3 cycles., while 3/4 patients achieved a partial response (PR). 3 patients achieved CR after 6 cycles. The median PFS has not been reached. The regimen's overall safety profile has been favorable, with most adverse events being grade 1 or 2 . No incidents of atrial fibrillation or tumor lysis syndrome (TLS) have been observed so far.Conclusion: Initial findings suggest that the combination of zanubrutinib, venetoclax, and rituximab induces deep responses and favorable tolerability in previously untreated FL patients . Analyses involving larger patient cohorts and longer follow-up durations are warranted to confirm these preliminary results.

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2025
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