Exploring the effect and mechanism of zanubrutinib, lenalidomide and temozolomide in the treatment of primary central nervous system lymphoma

Abstract Background and Objective Primary central nervous system lymphoma (PCNSL) is a rare, highly aggressive non-Hodgkin lymphoma confined to the central nervous system (CNS). It is characterized by poor overall prognosis, high relapse rate, and limited therapeutic options. Due to the existence of the blood-brain barrier (BBB), many systemic chemotherapeutic agents fail to achieve sufficient drug concentrations within brain lesions. At present, there remains no universally accepted standard first-line chemotherapy regimen for PCNSL, which highlights an urgent need to explore novel, BBB-penetrable combinatorial treatment strategies to improve anti-tumor efficacy. Methods In this study, we established an innovative triple-drug regimen consisting of zanubrutinib, lenalidomide, and temozolomide (Zan + Len + Tmz), all of which possess favorable blood-brain barrier permeability. A series of in vitro cellular assays and in vivo xenograft mouse models of PCNSL were applied to evaluate the anti-lymphoma effects and underlying molecular mechanisms of this combination therapy. Results Concurrent administration of the three agents exerted potent synergistic anti-proliferative effects on PCNSL cells, induced obvious cell cycle arrest, and significantly elevated cellular apoptosis rate. Mechanistically, the triple combination effectively suppressed the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Moreover, the therapeutic benefit of this regimen was further verified in a PCNSL xenograft mouse model. Conclusion Collectively, these findings demonstrate that the triple combination of zanubrutinib, lenalidomide and temozolomide represents a promising and effective therapeutic strategy for PCNSL, which warrants further translational investigation.