Fixed-Duration Zanubrutinib, Bendamustine, and Obinutuzumab (ZBG) in Treatment-Naïve Advanced Stage Follicular Lymphoma

Inclusion criteria

• Voluntary participation with signed informed consent;
• Age ≥18 years and ≤75 years, regardless of gender;
• Life expectancy ≥3 months;
• 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;
• Histologically confirmed diagnosis of grade I, II, or IIIa follicular lymphoma (FL), treatment-naïve, stage III-IV disease, and meeting treatment criteria (GELF criteria);
• Measurable and/or evaluable lymphoma lesions;
• 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;
• 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;
• Creatinine clearance ≥30 mL/min (calculated by Cockcroft-Gault formula);
• Ability to comply with study visit schedules and other protocol requirements;
• 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

• Grade IIIb FL or transformed FL;
• Received lymphoma-directed therapy within 2 weeks prior to enrollment;
• 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;
• Known active hepatitis C virus (HCV) infection; other acquired/congenital immunodeficiency disorders, including HIV infection;
• Central nervous system (CNS) involvement by lymphoma;
• 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;
• Hypersensitivity to any study drug;
• Pregnant or breastfeeding women;
• History of stroke or intracranial hemorrhage within 6 months before enrollment;
• Requiring anticoagulation with warfarin or equivalent vitamin K antagonists;
• Requiring chronic use of strong CYP3A inhibitors;
• Administration of live attenuated vaccines within 4 weeks before study entry.