CNSC-82. Therapeutic Response to Belzutifan in Two Cases of Sporadic Disseminated Central Nervous System Hemangioblastomatosis

Central nervous system (CNS) hemangioblastomas are benign, highly vascular tumors that most commonly arise in the posterior fossa or the spinal cord. CNS hemangioblastomas can be sporadic (in 75% of the cases) or associated with von Hippel-Lindau (VHL) disease, the latter driven by germline mutations in the VHL gene. Somatic VHL mutations are identified in up to 50% of sporadic cases. Alteration of the VHL gene function leads to the dysregulation and accumulation of hypoxia-inducible factor (HIF) – alpha, which in turn activates downstream genes, including vascular endothelial growth factor, that promote tumorigenesis. Belzutifan, a HIF-2 alpha inhibitor, downregulates hypoxia-driven pathways and is approved by the Food and Drug Administration for VHL-associated CNS hemangioblastomas. While surgery and/or radiation are the mainstay of treatment for sporadic, isolated CNS hemangioblastomas, there are limited options in cases of disseminated disease. We describe two cases of sporadic disseminated CNS hemangioblastomatosis with clinical and radiographic response to belzutifan. The first patient is a 61-year-old woman with a remote history of a resected posterior fossa hemangioblastoma who presented decades later with dural-based suprasellar disease compressing the optic chiasm and extensive leptomeningeal disease in the cerebellum and spine. Genetic testing for VHL pathogenic variants was negative, though possible mosaicism was suspected. She achieved a durable complete response on belzutifan 80 mg daily (reduced from 120 mg due to anemia), with no evidence of recurrence at three years. The second patient is a 54-year-old woman who developed diffuse dural and leptomeningeal spinal involvement six years after resection of a right cerebellar hemangioblastoma. Systemic staging was negative. She began belzutifan 120 mg daily and experienced symptomatic improvement at two months. These cases suggest that belzutifan may offer a promising noninvasive therapeutic option for patients with sporadic CNS hemangioblastomas, especially in disseminated cases where conventional therapies are limited.