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.
None
Unable to comply with protocol-required hospitalization and restrictions.
Active infection or latent tuberculosis infection.
History of severe hypersensitivity to drugs of the same class.
Current central nervous system involvement.
Single group
tislelizumab + zanubrutinib + rituximab + lenalidomide
DrugPatients with FL will receive a PD-1 + ZR² regimen (tislelizumab + zanubrutinib + rituximab + lenalidomide) for 6 cycles (3 weeks per cycle). Induction Phase (Cycles 1-6; 21 days per cycle) Zanubrutinib (Z): 160 mg orally twice daily (BID). Rituximab (R): 375 mg administered intravenously on Day 1 of cycles 1-6; additionally administered on Day 1 of cycles 2-8/12 per protocol (21-day cycles). Lenalidomide: 20 mg orally once daily on cycles 1-6. Tislelizumab: 200 mg intravenous infusion on Day 1 every 3 weeks. After 6 cycles of the four-drug combination, response will be assessed by CT/PET-CT. Patients achieving CR/PR/SD will proceed to maintenance; those not achieving at least SD will discontinue the study. Maintenance Phase Patients achieving CR/PR/SD during induction will receive: Zanubrutinib: 160 mg orally BID; and Tislelizumab: 200 mg IV on Day 1 every 3 weeks until disease progression, unacceptable toxicity, or completion of 1 year of maintenance.
Complete response rate (CRR)
The proportion of evaluable participants who achieve complete response (CR) following 6 cycles of induction therapy. CR is defined in accordance with the 2014 Lugano Classification for Lymphoma: this requires the complete disappearance of all measurable/evaluable lymphoma lesions, resolution of all disease-related clinical symptoms, and normalization of imaging findings (e.g., no residual measurable disease on CT/MRI, and no metabolically active disease on FDG-PET/CT). The analysis population is restricted to participants who complete at least 4 cycles of induction therapy and have available post-treatment efficacy assessment data.
Objective response rate (ORR)
The proportion of evaluable participants who achieve objective response (defined as complete response \[CR\] or partial response \[PR\]) following 6 cycles of induction therapy. Response assessment adheres to the 2014 Lugano Classification for Lymphoma: PR requires a ≥50% reduction in the sum of the longest diameters of measurable lesions, with no new lesions or progression of existing non-measurable disease. The analysis population includes participants who complete at least 4 induction cycles and have available post-treatment efficacy evaluation data.
2-Year Progression-Free Survival (PFS)
The duration from randomization to the first occurrence of disease progression (per the 2014 Lugano Classification) or death from any cause. PFS will be estimated using the Kaplan-Meier method, and between-arm comparisons will be conducted via the log-rank test. Participants without progression or death at the end of follow-up will be censored at their last documented disease-evaluation date.
2-Year Overall Survival (OS)
The duration from randomization to death from any cause. OS will be estimated using the Kaplan-Meier method, with between-arm comparisons performed using the log-rank test. Participants who remain alive at the 2-year follow-up endpoint will be censored at their last confirmed survival date.
Incidence of Treatment-Related Adverse Events (TRAE)
The proportion of participants experiencing any treatment-related adverse event, graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 5.0. This includes the incidence of grade 3-4 TRAEs and serious adverse events (SAEs; defined as events that are life-threatening, require hospitalization, result in persistent disability, or are fatal).
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