Zanubrutinib, Obinutuzumab Combined With Lenalidomide (ZGR) for the Treatment of Untreated Follicular Lymphoma

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.