This is a prospective, open-label, single-arm, single-center, Phase II clinical study designed to evaluate the efficacy and safety of zanubrutinib, rituximab, and lenalidomide (ZR²) in combination with tislelizumab in patients with relapsed/refractory follicular lymphoma who have relapsed or are refractory after ≥1 prior systemic therapy.

After successful screening, enrolled patients will receive 6 treatment cycles (21 days per cycle). Disease response will be assessed by CT/PET-CT during treatment and after completion of induction. Patients who achieve CR/PR/SD will proceed to the maintenance phase; patients who do not achieve at least SD (i.e., fail to reach CR/PR/SD) during induction will discontinue the study. Patients with CR/PR/SD after induction will receive maintenance therapy with zanubrutinib plus tislelizumab until disease progression, unacceptable toxicity, or completion of 1 year of maintenance.

Efficacy and safety assessments will be performed per protocol. Tumor response will be assessed by site investigators according to the 2014 Lugano criteria, including determination of response status, date of response, and date of progression/relapse.

Inclusion Criteria:

• Eligible participants must meet all of the following criteria:

Provide written informed consent. Age ≥18 years . Histologically confirmed relapsed/refractory follicular lymphoma (R/R FL) . Received at least two prior lines of systemic therapy , including anti-CD20 monoclonal antibody therapy.

ECOG performance status 0-1 . Measurable disease , with longest diameter >1.5 cm . Estimated life expectancy (per investigator assessment) ≥18 weeks . Adverse events from prior anticancer therapy must have resolved to ≤ grade 1 (except alopecia and anorexia).

Adequate hepatic function:

Total bilirubin ≤1.5 × ULN ; for patients with documented Gilbert syndrome: total bilirubin ≤3 × ULN with predominantly indirect hyperbilirubinemia.

AST and ALT ≤3 × ULN .

Adequate hematologic function:

ANC ≥1.5 × 10⁹/L (≥1,500/µL) Platelets ≥75,000/µL , with no platelet transfusion within 14 days prior to first dosing on Cycle 1 Day 1 Hemoglobin ≥10.0 g/dL (6.2 mmol/L), with no blood transfusion within 21 days prior to first dosing on Cycle 1 Day 1 Adequate renal function: serum creatinine ≤1.5 × ULN , or creatinine clearance ≥50 mL/min calculated by the Cockcroft-Gault formula (see Appendix 14), for patients in whom serum creatinine may not adequately reflect renal function per investigator judgment.

For women of childbearing potential: negative serum pregnancy test within 7 days before study treatment; postmenopausal women (non-treatment-related amenorrhea ≥12 months) or surgically sterile women (no ovaries and/or uterus) are exempt. Women of childbearing potential must agree to abstinence (avoid heterosexual intercourse) or to use effective contraception.

For men: agree to abstinence (avoid heterosexual intercourse) or to use effective contraception.

Exclusion Criteria:

• Participants meeting any of the following will be excluded:

  1. Unable to comply with protocol-required hospitalization and restrictions.

  2. Active infection or latent tuberculosis infection.

  3. History of severe hypersensitivity to drugs of the same class.

  4. Current central nervous system involvement.

  5. Pregnant or breastfeeding women.

  6. Uncontrolled comorbidities (e.g., cardiac disease, immune disorders); myocardial infarction, unstable arrhythmia, or unstable angina within the past 6 months.

  7. Illicit drug use or alcohol abuse within 12 months prior to screening, per investigator judgment.

  8. Any other disease, metabolic disorder, physical examination finding, or clinical laboratory abnormality that reasonably suggests a contraindication to the investigational products.

  9. The investigator should review vaccination status of potential participants and, prior to study initiation, follow local disease control and prevention guidelines for adult immunization with non-live vaccines aimed at preventing infectious diseases.

  10. Any psychiatric or cognitive disorder that may limit understanding/execution of informed consent or protocol compliance.

  11. Pregnant or breastfeeding women, or women/men (or male partners) planning pregnancy during the study period.

  12. Any other condition deemed by the investigator to make the participant unsuitable for the trial.

      • Cases to Be Excluded From Statistical Analysis (per protocol)

Participants already enrolled who meet any of the following will be treated as excluded cases in statistical analyses:

Post-enrollment discovery of non-fulfillment of eligibility criteria. Prior exposure to zanubrutinib or other BTK inhibitors. Intolerable toxicity after taking zanubrutinib or other BTK inhibitors. Received fewer than two consecutive administrations after enrollment such that objective efficacy cannot be assessed (adverse events may still be assessable).

Protocol violations. Prior hematopoietic stem cell transplantation.