Tislelizumab combined with zanubrutinib and high-dose methotrexate in newly diagnosed primary central nervous system DLBCL: A phase 2 study

Abstract

Abstract Background: Primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL) is a rare subtype of non-Hodgkin lymphoma with poor prognosis and significant treatment-related side effects. Currently, some new drugs have shown good therapeutic effects in patients with PCNSL-DLBCL. Aims: To enhance the prognosis of patients with PCNS-DLBCL and minimize treatment-related adverse effects, we initiated a phase 2 clinical trial utilizing a TZM regimen, which integrated tislelizumab, zanubrutinib, and methotrexate, for the management of PCNS-DLBCL (ChiCTR2300071346). This study aimed to assess the efficacy and safety profile of the TZM regimen in patients with PCNS-DLBCL. Methods: Newly diagnosed PCNS-DLBCL patients aged 18-90 years were enrolled from five centers in China between May 2022 and May 2025. Clinical information, objective response rates, survival times, and adverse events were collected for all patients. Results: Thirty-eight patients with newly diagnosed PCNSL-DLBCL were enrolled, with a median age of 65.5 years (42-82 years) at diagnosis. The ratio of male to female was 1.7:1. Based on the IELSG risk score, 42.1% (16/38) of the patients were assigned to the low-risk group and 64.0% (22/38) patients were allocated to the intermediate-risk group. The white blood cell count, hemoglobin level, and platelet count of all patients with PCNSL-DLBCL were almost normal when enrolled in this study. Regarding the levels of lactic dehydrogenase (LDH) and β2 microglobulin (β2-MG), the majority of patients had normal results, and only five and three patients had abnormal results, respectively. Based on the Hans algorithm, 89.5% (34/38) of patients belonged to the non-GCB group. A total of 39.5% (15/38) of patients were diagnosed with double-expression lymphoma. The mutation rate of the TP53 gene was observed to be 36.1% (13/36). Furthermore, 54.3% (19/35) of patients demonstrated PD-L1 immunostaining in ≥20% of tumor cells. MYD88L265P gene mutation was detected in 86.8% (33/38) patients. As of May 2025, four patients died of treatment-related toxicity. A cohort of 37 patients underwent a minimum of two cycles of chemotherapy, yielding an overall response rate (ORR) of 97.1% (34/35) and a complete response rate (CRR) of 8.6% (3/35) after two cycles of chemotherapy. Remarkably, the ORR following six cycles of chemotherapy achieved 100% (28/28), with a CRR of 85.7% (27/28). The median follow-up duration was 16 (range, 2–24) months. The median overall survival (OS) and progression-free survival (PFS) were not determined. At the 18-month interval, both estimatedOS and PFS rates for the TZM regimen were documented at 86.8%. After two years, the estimated OS rate persisted at 86.8%, whereas the estimated PFS rate decreased to 73.4%. The most prevalent adverse reaction associated with the TZM regimen was non-hematological toxicity. These included three instances of MTX-related renal injury, two cases of severe infection, one case of severe gastrointestinal mucosal injury, one instance of chemotherapy-related capillary cell leakage syndrome, and one case of tislelizumab-related rash and liver injury. Hematological toxicity was limited to two cases of grade 1-2 granulocytopenia in this study. Conclusion: The TZM regimen markedly enhanced the survival prognosis of patients with PCNS-DLBCL and demonstrated favorable treatment safety.