LAUSR

Simple Summary Leptomeningeal disease in melanoma (LMM) patients is characterized by aggressiveness and dismal outcomes. Clinical studies and case reports demonstrate the potential of immune and targeted therapies (especially in combinatorial or multi-modal settings) in improving survival for some patients; however, LMM still progresses rapidly in most patients regardless of treatment. Several recent studies have characterized the melanoma microenvironment within the CSF compartment and improved the basic understanding of the biology of LMM. Additional laboratory and clinical studies are necessary to substantiate the relevance of different therapies and their impact on melanoma within the leptomeningeal microenvironment. Abstract Leptomeningeal disease (LMD) is a devastating complication caused by seeding malignant cells to the cerebrospinal fluid (CSF) and the leptomeningeal membrane. LMD is diagnosed in 5–15% of patients with systemic malignancy. Management of LMD is challenging due to the biological and metabolic tumor microenvironment of LMD being largely unknown. Patients with LMD can present with a wide variety of signs and/or symptoms that could be multifocal and include headache, nausea, vomiting, diplopia, and weakness, among others. The median survival time for patients with LMD is measured in weeks and up to 3–6 months with aggressive management, and death usually occurs due to progressive neurologic dysfunction. In melanoma, LMD is associated with a suppressive immune microenvironment characterized by a high number of apoptotic and exhausted CD4+ T-cells, myeloid-derived suppressor cells, and a low number of CD8+ T-cells. Proteomics analysis revealed enrichment of complement cascade, which may disrupt the blood–CSF barrier. Clinical management of melanoma LMD consists primarily of radiation therapy, BRAF/MEK inhibitors as targeted therapy, and immunotherapy with anti-PD-1, anti-CTLA-4, and anti-LAG-3 immune checkpoint inhibitors. This review summarizes the biology and anatomic features of melanoma LMD, as well as the current therapeutic approaches.