This study is planned to prospectively evaluates the efficacy and safety of the zanubrutinib, obinutuzumab, and lenalidomide (ZGR) combination regimen in treatment-naïve follicular lymphoma (FL) patients in a Chinese population.

Regarding chemotherapy-free first-line treatment regimens, current targeted therapies primarily focus on lenalidomide combined with anti-CD20 antibodies. Chemotherapy-free regimens such as rituximab plus lenalidomide (R²) or obinutuzumab plus lenalidomide (O-Len) have been recommended for clinical use. Encouraged by the promising efficacy of dual-targeted therapies, the potential of triple-combination therapy-comprising a BTK inhibitor (BTKi), an anti-CD20 monoclonal antibody, and lenalidomide-has garnered increasing attention in untreated hematologic malignancies. Most existing studies have concentrated on BTKi combined with rituximab and lenalidomide (e.g., ibrutinib + R²).

Given current clinical needs and available evidence, this study aims to explore a novel chemotherapy-free triple regimen: zanubrutinib combined with obinutuzumab and lenalidomide (ZGR) in treatment-naïve follicular lymphoma (FL) patients. This combination is expected to provide a new treatment paradigm for untreated FL, offering high antitumor efficacy while minimizing toxicity, thereby improving patients' quality of life.

Inclusion Criteria:

• Gender: No restrictions; age ≥18 years.
• Diagnosis: Histologically confirmed CD20-positive follicular lymphoma (FL), Grade 1, 2, or 3A, per 2016 WHO classification. All patients must provide sufficient archived or fresh tumor tissue samples for immunohistochemical (IHC) analysis.
• Disease Stage & Treatment Need:
• Stage III or IV disease, or Stage II with bulky disease, meeting at least one of the following criteria:
• a) Bulky disease: Lymph node or extranodal (excluding spleen) mass with maximum diameter ≥7 cm.
• b) Local symptoms or organ dysfunction due to progressive lymphadenopathy or extranodal tumor mass.
• c) B symptoms (fever, night sweats, or unintentional weight loss >10% of body weight within ≤6 months).
• d) Symptomatic extranodal involvement (e.g., pleural/peritoneal effusion).
• e) Cytopenias due to bone marrow infiltration (hemoglobin <10 g/dL, absolute neutrophil count [ANC] <1.0×10⁹/L, platelets <100×10⁹/L).
• f) Involvement of ≥3 lymph nodes, each ≥3 cm in diameter.
• g) Symptomatic splenomegaly.
• Prior Therapy: No prior systemic therapy for FL.
• ECOG Performance Status: ≤2.
• Measurable Disease: At least one measurable lesion (>2 cm in longest diameter by CT/MRI).
• Life Expectancy: ≥6 months.
• Adequate Organ Function:
• a) ANC ≥1.0×10⁹/L (without growth factor support).
• b) Platelets ≥50×10⁹/L (untransfused within 7 days).
• c) Total bilirubin (TBIL) ≤1.5×ULN.
• d) ALT/AST ≤3×ULN.
• e) Creatinine clearance ≥30 mL/min (calculated by modified Cockcroft-Gault formula).
• Contraception: Men and women of childbearing potential must agree to use highly effective contraception during the study and for 4 weeks after treatment discontinuation.
• Informed Consent: Patients must voluntarily participate and sign informed consent forms (ICF).

Exclusion Criteria:

• Patients meeting any of the following criteria will be excluded from this study:
• Histologic evidence of central nervous system (CNS) lymphoma, leptomeningeal lymphoma, or transformation to high-grade lymphoma (e.g., diffuse large B-cell lymphoma, DLBCL).
• Grade 3B follicular lymphoma (FL) or transformed FL.
• Ann Arbor Stage I FL.
• Prior history of malignancy, unless the patient has been disease-free for ≥5 years and the treating physician deems the risk of recurrence low (exceptions: non-melanoma skin cancer, cured localized prostate cancer, carcinoma in situ of the cervix, or squamous intraepithelial lesions on PAP smear).
• Use of any investigational drugs, antibiotics, or participation in another interventional clinical trial within 4 weeks prior to enrollment.
• Major surgery (excluding lymph node biopsy) within 14 days before enrollment or anticipated need for major surgery during the study.
• Prior treatment with zanubrutinib, obinutuzumab, or lenalidomide.
• Immunodeficiency or autoimmune disease history, or chronic systemic steroid therapy (>10 mg/day prednisone equivalent) or immunosuppressive therapy within 7 days before enrollment.
• Severe hepatic dysfunction (including severe jaundice, hepatic encephalopathy, refractory ascites, or hepatorenal syndrome), cachexia, or multi-organ failure with renal impairment.
• Clinically significant cardiovascular abnormalities:
• NYHA Class III/IV heart failure
• Myocardial infarction within 6 months before enrollment, Malignant arrhythmias (including QTc ≥480 ms), Uncontrolled hypertension (Systolic blood pressure (SBP) ≥150 mmHg and diastolic blood pressure (DBP) ≥100 mmHg), Unstable angina.

Active infections:

• HIV, active hepatitis B/C infection (HBV DNA ≥2000 IU/mL or HCV RNA detectable)
• Uncontrolled systemic infections.
• Bleeding disorders or coagulation abnormalities, or thrombotic events within 3 months.
• Severe hypersensitivity to the active ingredients or excipients of the study drugs.
• Pregnancy, lactation, or unwillingness to use effective contraception in women of childbearing potential.
• Other conditions deemed unsuitable by the investigator.