Fixed-duration zanubrutinib plus bendamustine and obinutuzumab for newly diagnosed advanced follicular lymphoma

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.