This study investigates a fixed-duration regimen of zanubrutinib, bendamustine, and obinutuzumab (ZBG) in the treatment of treatment-naïve patients with advanced-stage follicular lymphoma.

Patients will receive combination therapy with zanubrutinib, bendamustine, and obinutuzumab over 6 cycles, with each cycle lasting 28 days. The specific dosing schedule is as follows: Bendamustine 70 mg/m²: administered intravenously on Days 2-3 of Cycle 1, and on Days 1-2 of Cycles 2-6. Obinutuzumab 1000 mg: administered intravenously on Days 1, 8, and 15 of Cycle 1, and on Day 1 of Cycles 2-6 (every 28-day cycle). Zanubrutinib 160 mg orally twice daily (bid), continuously throughout Cycles 1-6.

Treatment is discontinued after 6 cycles, with no subsequent maintenance therapy.

Primary endpoint is 2-year PFS. Secondary endpoints include: CR rate after 6 cycles, ORR after 3 and 6 cycles MRD-negative rate after 3 and 6 cycles, OS, safety and tolerability.

Inclusion Criteria:

1. Voluntary participation with signed informed consent;
2. Age ≥18 years and ≤75 years, regardless of gender;
3. Life expectancy ≥3 months;
4. ECOG performance status 0-2; patients with ECOG 3 may be enrolled only if their decline in performance status is disease-related and the investigator judges they may benefit from treatment;
5. Histologically confirmed diagnosis of grade I, II, or IIIa follicular lymphoma (FL), treatment-naïve, stage III-IV disease, and meeting treatment criteria (GELF criteria);
6. Measurable and/or evaluable lymphoma lesions;
7. Adequate bone marrow reserve: absolute neutrophil count (ANC) >1.0×10⁹/L or platelets >75×10⁹/L, unless cytopenia is deemed related to bone marrow infiltration by lymphoma and the investigator believes it may recover;
8. Liver function: AST (SGOT), ALT (SGPT) ≤2.5×ULN (without liver involvement) or ≤5×ULN (with liver involvement); total bilirubin (TBIL) ≤ULN; serum creatinine (CRE) ≤1.5×ULN;
9. Creatinine clearance ≥30 mL/min (calculated by Cockcroft-Gault formula);
10. Ability to comply with study visit schedules and other protocol requirements;
11. All patients of childbearing potential must agree to use effective contraception during the study and for 24 months after treatment cessation; women of childbearing potential must have a negative urine pregnancy test before treatment initiation.

Exclusion Criteria:

1. Grade IIIb FL or transformed FL;

2. Received lymphoma-directed therapy within 2 weeks prior to enrollment;

3. Any severe medical condition, including but not limited to:

   • Poorly controlled hypertension (defined as failure to achieve control despite lifestyle modifications and treatment with at least 3 maximally tolerated antihypertensive drugs [including diuretics] for ≥4 weeks, or requiring ≥4 antihypertensive drugs for adequate control);
   • Uncontrolled congestive heart failure (NYHA class 3 [moderate] or 4 [severe]) within 6 months prior to screening;
   • Left ventricular ejection fraction (LVEF) <50%;
   • Symptomatic coronary artery disease (e.g., chest pain, palpitations, fatigue) or requiring medication;
   • Severe bradycardia (heart rate <40 bpm), hypotension, dizziness, or syncope; patients with arrhythmia history require cardiac evaluation;
   • Active bacterial, viral, fungal, or other infections (except for nail fungal infections) or major infections within 2 weeks before the first dose of study drug;
   • Moderate to severe liver disease (Child-Pugh B or C);
   • Active bleeding within 2 months before screening or clinically significant bleeding tendency per investigator judgment;
   • Pulmonary conditions impairing function (e.g., pulmonary fibrosis, drug-induced pneumonitis) deemed intolerable by the investigator;
   • Any psychiatric or cognitive impairment that may compromise understanding of informed consent, protocol compliance, or study adherence;

4. Known active hepatitis C virus (HCV) infection; other acquired/congenital immunodeficiency disorders, including HIV infection;

5. Central nervous system (CNS) involvement by lymphoma;

6. Diagnosis or treatment for malignancies other than lymphoma, except:

   • Malignancies treated with curative intent and no evidence of disease for ≥5 years before enrollment;
   • Adequately treated basal cell carcinoma (excluding melanoma) with no evidence of disease;
   • Adequately treated cervical carcinoma in situ with no evidence of disease;

7. Hypersensitivity to any study drug;

8. Pregnant or breastfeeding women;

9. History of stroke or intracranial hemorrhage within 6 months before enrollment;

10. Requiring anticoagulation with warfarin or equivalent vitamin K antagonists;

11. Requiring chronic use of strong CYP3A inhibitors;

12. Administration of live attenuated vaccines within 4 weeks before study entry.