Update on Novel Therapeutics for Primary CNS Lymphoma

SIMPLE SUMMARY: Primary central nervous system lymphoma is a rare and aggressive form of non-Hodgkin lymphoma. While it is highly responsive to first-line chemo and radiation treatments, rates of relapse are high, demonstrating the need for improved therapeutic strategies. Recent advancements in the understanding of the pathophysiology of this disease have led to the identification of new potential treatment targets and the development of novel agents. This review aims to discuss different targeted strategies and review some of the data supporting these approaches, and discusses recently completed and ongoing clinical trials using these novel agents. ABSTRACT: Primary central nervous system lymphoma (PCNSL) is a rare lymphoma isolated to the central nervous system or vitreoretinal space. Standard treatment consists of cytotoxic methotrexate-based chemotherapy, with or without radiation. Despite high rates of response, relapse is common, highlighting the need for novel therapeutic approaches. Recent advances in the understanding of PCNSL have elucidated mechanisms of pathogenesis and resistance including activation of the B-cell receptor and mammalian target of rapamycin pathways. Novel treatment strategies such as the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib, phosphatidylinositol-3 kinase (PI3K) inhibitors, and immunomodulatory drugs are promising. Increasingly, evidence suggests immune evasion plays a role in PCNSL pathogenesis and several immunotherapeutic strategies including checkpoint inhibition and targeted chimeric antigen receptor T (CAR-T) cells are under investigation. This review provides a discussion on the challenges in development of targeted therapeutic strategies, an update on recent treatment advances, and offers a look toward ongoing clinical studies.