This study systematically summarizes the latest advances in targeted therapy for first-line treatment of PCNSL, providing critical evidence-based support for the design of clinical trials and personalized treatment strategies in PCNSL.
Literature Overview
The article titled 'Advances in first-line treatment for primary central nervous system lymphoma: highlights from the 2025 ASH annual meeting,' published in the Journal of Hematology & Oncology, systematically explores the efficacy and safety of targeted agents—including BTK inhibitors, immunomodulatory drugs, nuclear export inhibitors, and PD-1 antibodies—in newly diagnosed PCNSL patients. By integrating clinical data presented at the 2025 ASCO annual meeting, the study reveals significant advantages of combining traditional chemotherapy with targeted therapies. Further analysis suggests this approach may replace or optimize existing high-dose chemotherapy regimens, improving complete response rates and long-term survival. Notably, the study highlights the therapeutic challenges faced by elderly or transplant-ineligible patients, offering direction for future research.Background Knowledge
Primary central nervous system lymphoma (PCNSL) is a highly aggressive form of non-Hodgkin lymphoma that has long relied on high-dose methotrexate (HD-MTX)-based chemotherapy. However, traditional regimens achieve complete response rates of only about 50%, with significant toxicity and poor tolerability, especially among elderly patients, representing an unmet clinical need. In recent years, deeper understanding of the BCR signaling pathway and tumor microenvironment has revealed the potential of targeting key nodes such as BTK, IMiDs, XPO1, and PD-1. Yet, challenges remain regarding the optimal timing, combination strategies, and long-term safety of integrating these agents into first-line therapy. This review focuses on synthesizing key clinical studies presented at the 2025 ASH meeting, comparing efficacy and toxicity profiles across different targeted combinations to provide direct evidence for optimizing future treatment pathways. Of particular interest are the blood-brain barrier penetration and improved safety profiles of next-generation BTK inhibitors, as well as the feasibility of 'chemotherapy-free' strategies.
Research Methods and Experiments
The authors conducted a literature review and data integration, analyzing results from multiple Phase II clinical trials and real-world studies on first-line PCNSL treatment presented at the 2025 ASH annual meeting. The study evaluated various regimens combining targeted agents with chemotherapy or immunotherapy, including BTK inhibitors (ibrutinib, zanubrutinib, orelabrutinib) combined with rituximab and HD-MTX, or with immunomodulatory agents (lenalidomide, pomalidomide). Key evidence comes from clinical trial data summarized in Table 1; for example, the ZANA study showed that the zanubrutinib-based regimen achieved a complete response rate of 89.7% and a 2-year progression-free survival rate of 82.8%, significantly outperforming traditional regimens. The MSZ study was the first to demonstrate that selinexor effectively penetrates the blood-brain barrier and acts synergistically with BTK inhibitors, achieving a remarkable 95.2% complete response rate. These outcomes were quantitatively supported by metrics such as overall response rate (ORR), complete response rate (CR), progression-free survival (PFS), and overall survival (OS).Key Conclusions and Perspectives
Research Significance and Prospects
This study provides robust evidence for a paradigm shift in PCNSL treatment, demonstrating that targeted therapies are moving from salvage settings into first-line combination regimens. For drug development, next-generation BTK inhibitors and 'chemotherapy-free' regimens represent highly promising directions. In clinical practice, management pathways for agent-specific toxicities—such as BTKi-associated bleeding—must be established. Furthermore, future research should explore biomarker-driven personalized approaches, such as selecting optimal targeted combinations based on MYD88 or CD79B mutation status.
Conclusion
This literature digest comprehensively summarizes the latest advances in first-line targeted therapy for PCNSL presented at the 2025 ASH meeting, marking a profound shift in the field from traditional chemotherapy toward precision-targeted combination therapies. By integrating findings from multiple clinical studies involving BTK inhibitors, immunomodulatory agents, XPO1 inhibitors, and PD-1 antibodies, the review confirms the significant advantages of these regimens in improving complete response rates and extending survival, particularly highlighting the dual improvements in efficacy and safety offered by next-generation BTK inhibitors. These developments not only provide clinicians with better treatment options but also offer new hope for elderly patients or those unable to tolerate intensive chemotherapy. From bench to bedside, these findings underscore the critical role of disease-specific animal models—such as CD79B-mutant mice—in validating the efficacy of targeted combinations. In the future, molecular subtype-based personalized treatment strategies are expected to become the cornerstone of PCNSL care, driving toward the goal of long-term remission or even cure. This work lays a solid foundation for the design of large-scale Phase III trials and real-world implementation.
