Primary Objective: To compare the complete response rate (CR rate) after induction treatment between the ZR2 regimen and the R2 regimen.<br/><br/>Secondary Objectives: To compare the objective response rate (ORR) after induction treatment, progression-free survival (PFS), progression of disease within 24 months (POD24) rate, duration of response (DOR), overall survival (OS), treatment-related adverse events (AEs), and patient quality of life between the two groups.<br/><br/>Exploratory Objectives: To compare the histological .transformation (HT) rate at disease progression, minimal residual disease (MRD) negativity rate, changes in tumor microenvironment (TME) biomarkers, and the relationship between genetic biomarkers and efficacy/prognosis between the two groups; to further reveal the unique pattern of systemic immune status remodeling by the ZR2 regimen and identify potential efficacy-predictive biomarkers.

Study Nature Interventional study Study Design Prospective, randomized controlled, exploratory, multicenter clinical study Sample Size 100 cases Principal Investigator Professor Zhou Keshu Sponsor The Affiliated Cancer Hospital of Zhengzhou University Treatment Regimens (4 weeks per cycle) ZR2 Group<br/>- Induction Treatment (6 cycles): Zebutinib 160mg bid starting from C1D1; Rituximab 375mg/m² on Day 1; Lenalidomide 20mg qd on Days 1-21.<br/>- Maintenance Treatment: Rituximab 375mg/m² on Day 1 (once every 8 weeks for 2 years); Lenalidomide ;ZR2 Group<br/>- Induction Treatment (6 cycles): Zebutinib 160mg bid starting from C1D1; Rituximab 375mg/m² on Day 1; Lenalidomide 20mg qd on Days 1-21.<br/>- Maintenance Treatment: Rituximab 375mg/m² on Day 1 (once every 8 weeks for 2 years); Lenalidomide 10mg qd on Days 1-21 (once every 4 weeks for 12 times).<br/><br/>R2 Group<br/>- Induction Treatment (6 cycles): Rituximab 375mg/m² on Day 1; Lenalidomide 20mg qd on Days 1-21.<br/>- Maintenance Treatment: Rituximab 375mg/m² on Day 1 (once every 8 weeks for 2 years); Lenalidomide 10mg qd on Days 1-21 (once every 4 weeks for 12 times).<br/><br/>Note: Patients who achieve PR during the first 6 cycles of induction treatment may receive an additional 3 to 6 cycles of lenalidomide 20mg until CR is achieved; thereafter, during maintenance treatment, lenalidomide 10mg PO qd is administered on Days 1-21 (once every 4 weeks for 12 times).

Study Endpoints:Primary Endpoint: CR rate after induction treatment (assessed by the 2014 Lugano Classification for Non-Hodgkin Lymphomas).<br/><br/>Secondary Endpoints: ORR after induction treatment; PFS; POD24 rate; OS; DOR; treatment-related AEs; patient quality of life.<br/><br/>Exploratory Endpoints: HT rate at disease progression; MRD negativity rate; changes in TME biomarkers; relationship between genetic biomarkers and efficacy/prognosis.

Follow-up Schedule:All patients will be followed up for 2 years after completing treatment, once every 3 months.

Inclusion Criteria:

1. Voluntarily participate in the clinical study; fully understand and comprehend this study and sign the Informed Consent Form (ICF); willing to follow and capable of completing all study steps;

2. According to the 5th edition of the WHO classification of hematological and lymphoid tumors, diagnosed as CD20+ classic FL (grade 1-3a FL) by histology, and no previous anti-FL treatment has been received;

3. Age ≥ 18 years;

4. Judged by the investigator, the subject must urgently need to receive systemic treatment, based on meeting at least one GELF criterion;

5. At least one measurable lesion [longest diameter (LDi) ≥ 15mm, lymph node lesion LDi ≥ 10mm, evaluated according to the 2014 Lugano efficacy criteria];

6. The subject has at least one measurable target lesion:

   i. PET/CT scan shows positive PET lesion, or ii. CT scan or MRI shows > 1 measurable lymph node lesion (long axis > 1.5 cm) or > 1 measurable extranodal lesion (long axis > 1.0 cm);

7. ECOG performance status is 0-2;

8. Expected survival period > 3 months;

9. Adequate organ function and bone marrow function, without severe heart, lung, liver, kidney and immune deficiencies (no blood transfusion, granulocyte colony-stimulating factor or other medical support drugs within 7 days before starting this study): hemoglobin (HB) ≥ 60 g/L; absolute neutrophil count (ANC) ≥ 5×109/L; platelets (PLT) ≥ 50×109/L; aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) ≤ 5×ULN; total bilirubin (TBIL) ≤ 1.5×ULN; creatinine clearance rate (Ccr) ≥ 40 ml/min (estimated by Cockcroft-Gault formula); left ventricular ejection fraction (LVEF) ≥ lower limit of normal value.

10. Patients with reproductive potential must agree to use effective contraceptive measures (dual methods, such as condom + oral contraceptive), and avoid pregnancy or make their partners pregnant during the treatment period and within 12 months after the last administration.

Exclusion Criteria:

1. The subject has a history of systemic anti-leukemia treatment for FL (including any curative radiotherapy for the purpose of cure);
2. The subject has a history of aggressive B-cell lymphoma or has currently undergone histological transformation to DLBCL;
3. FL 3b;
4. The subject had suspected or confirmed primary CNS tumor at screening or had evidence of known CNS involvement;
5. The subject has a history of severe allergic reaction or immediate severe allergic reaction to any component or excipient of zanubrutinib, lenalidomide, or rituximab;
6. Has other tumors that affect the study medication or interfere with the results;
7. Received live vaccine within 28 days before treatment;
8. Has reproductive capacity and is unwilling to use effective contraceptive measures;
9. Pregnant or lactating women;
10. Known human immunodeficiency virus (HIV) infection, or any serological status indicating active hepatitis B or hepatitis C virus infection: 1) HBV DNA positive. Positive for hepatitis B surface antigen (HBsAg) or serologically positive for hepatitis B core antibody (HBcAb), if HBV DNA is undetectable and is willing to undergo monthly HBV reactivation monitoring, then can be enrolled. 2) HCV antibody positive. For patients with HCV antibody, if HCV RNA is undetectable, then can be enrolled;
11. Severe coagulation disorders and severe damage to organs such as heart, brain, lungs, liver, and kidneys;
12. Had a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within the past 12 months; has any life-threatening disease, medical condition, or organ system dysfunction that the subject considers may affect the safety of the subject or cause study risks.