Follicular lymphoma (FL) remains an incurable indolent B-cell lymphoma for many patients, and although rituximab-based chemoimmunotherapy can achieve high initial response rates, a substantial proportion of patients experience early progression, including POD24, which is associated with poor long-term outcomes. This underscores the need for more effective and better-tolerated frontline treatment strategies, particularly chemotherapy-free approaches. The present study is based on a strong biologic rationale that simultaneously targets two key pathogenic mechanisms in FL: aberrant B-cell receptor signaling and impaired apoptosis driven by BCL2 overexpression. Zanubrutinib, a next-generation BTK inhibitor, has shown clinical activity with a favorable safety profile in FL, while sonrotoclax, a potent and highly selective next-generation BCL2 inhibitor, has demonstrated promising preclinical and early clinical activity. In combination with rituximab, this chemotherapy-free triplet regimen may produce deeper and more durable remissions while maintaining manageable toxicity, and therefore has the potential to expand frontline treatment options and improve outcomes for patients with previously untreated FL.

Inclusion Criteria:

1. Willing to participate in the clinical study and signed informed consent.
2. Age ≥18 years, no gender restrictions.
3. Pathologically diagnosed with follicular lymphoma (Grade 1, 2, or 3a) and previously untreated.
4. Has at least one measurable or assessable lesion.
5. Ann-Arbor stage III or IV, or stage II with bulky disease.
6. Meets at least one GELF criterion.
7. Eastern Cooperative Oncology Group (ECOG) performance status score ≤2.
8. Adequate major organ function.

Exclusion Criteria:

1. Known active central nervous system lymphoma or leptomeningeal disease.
2. Evidence of follicular lymphoma with transformation to diffuse large B-cell lymphoma.
3. Prior history of other malignancies other than follicular lymphoma (except for those with disease-free survival ≥5 years and assessed by the investigator as having low risk of recurrence).
4. History of allergy to the investigational drug, similar drugs, or excipients.
5. Known history of human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS).
6. Active systemic infection requiring intravenous antibiotic therapy or hospitalization (occurring within 4 weeks prior to screening).
7. Confirmed progressive multifocal leukoencephalopathy (PML), positive for human T-lymphotropic virus type 1 (HTLV-1), or suspected active/latent tuberculosis.
8. Pregnant or breastfeeding women, and women of childbearing potential who are unwilling to use contraception.
9. Patients with significant dysfunction of vital organs.
10. Receipt of any moderate or strong CYP3A4 inhibitors or strong CYP3A4 inducers within 14 days (or 5 half-lives, whichever is longer) prior to the first dose of sotoclax.
11. Use of strong cytochrome P450 (CYP) 3A4 inhibitors within 7 days prior to the first dose of zanubrutinib, or requirement for continuous use of strong CYP3A inhibitors/inducers.
12. Receipt of concurrent therapy for the study disease outside of this clinical study (including the screening period).
13. Autoimmune anemia and/or thrombocytopenia that does not respond adequately to corticosteroids or other standard treatments.
14. Receipt of medications known to prolong the QT/QTc interval.
15. Vaccination with a live vaccine within ≤35 days prior to the first dose of study drug.
16. Major surgery within 4 weeks prior to the first dose of study drug.
17. Unwillingness or inability to complete all assessments and procedures required by the study.