Novel Agents and Immunotherapies for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System: Innovating for Impact in a Disease With Unmet Needs

Abstract

Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL), also known as primary CNS lymphoma (PCNSL), is a highly aggressive extranodal non-Hodgkin lymphoma (NHL) confined to the CNS. Systemic methotrexate-based chemoimmunotherapy regimens, followed by consolidative autologous stem cell transplantation (ASCT), are the standard treatment for newly diagnosed PCNSL. Many patients, however, are too medically frail and present with multiple comorbidities, rendering them unsuitable for ASCT, and a significant number still experience disease relapse. There is no universally accepted treatment for relapsed disease, particularly for patients who are unable to tolerate chemotherapy, and participation in clinical trials is encouraged. This underscores a substantial treatment gap for patients presenting with PCNSL, especially those who are elderly or medically unfit for intensive therapy. In this context, there is an urgent need to investigate novel agents and immunotherapies as alternatives that may offer improved tolerability and efficacy profiles. Emerging therapies could play a pivotal role in expanding the therapeutic landscape and addressing the limitations inherent in current treatments. This review examines the oncogenesis of PCNSL, highlighting its reliance on chronic active B-cell receptor (BCR) and nuclear factor-kappa B (NF-κB) signaling pathways, mechanisms of immune evasion, and characteristics of its immunosuppressive tumor microenvironment (TME), which have facilitated the exploration of methotrexate-free targeted therapies for PCNSL.