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.

Primary diffuse large B-cell lymphoma of the central nervous system (CNS-DLBCL), the most prevalent subtype of primary CNS lymphoma (PCNSL), is a highly aggressive extranodal non-Hodgkin lymphoma (NHL) that arises in the brain, spinal cord, leptomeninges, and orbits. Systemic methotrexate-based chemoimmunotherapy regimens, followed by consolidative autologous stem cell transplantation (ASCT), are the standard treatments for newly diagnosed PCNSL. A considerable number of patients with PCNSL, however, are medically frail and possess multiple comorbidities, which render them unsuitable for these intensive treatments. Furthermore, a substantial proportion of those who undergo treatment still face the challenge of disease recurrence. There is no universally accepted treatment for relapsed disease, particularly for patients who are unable to tolerate systemic chemotherapy, and participation in clinical trials is encouraged. There is a notable treatment gap in PCNSL, underscoring an urgent need to investigate novel agents and immunotherapies that could potentially offer superior 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 this disease.