Primary Central Nervous System Lymphoma: Evolving Biologic Insights and Recent Therapeutic Advances.

Primary central nervous system lymphoma (PCNSL) is a rare and clinically aggressive disease entity associated with poor survival. Though high-dose methotrexate-based immunochemotherapy approaches are effective at inducing responses, few patients experience long-term durable remissions. Recently, novel insights into the biology of this unique disease have been elucidated and have paved the way for the investigation of rational approaches such as Bruton tyrosine kinase inhibition and immunomodulation. Although these strategies can induce high response rates in PCNSL, remissions are short lived, with median progression-free survivals in the range of 6 months or less. Moving forward, understanding the mechanisms of treatment resistance with these and other novel agents is key to developing optimal combinatorial strategies. New approaches such as immune checkpoint inhibition and chimeric antigen receptor T-cell therapy are under investigation for PCNSL and thus far demonstrate activity in anecdotal clinical experiences. Future trials should focus on investigating novel rational combinations designed to optimally target the biology of PCNSL and simultaneously investigate mechanisms of resistance leading to treatment failure.