Objective:

To retrospectively evaluate the clinical and radiographic response to off-label belzutifan therapy in patients with sporadic central nervous system (CNS) hemangioblastomas not associated with von Hippel-Lindau disease (VHL).

Background:

Approximately 25% of all CNS hemangioblastomas occur in the setting of autosomal dominant tumor suppressor syndrome von Hippel-Lindau disease. Belzutifan (Welireg, Merck) is an HIF2𝛼 inhibitor that has been approved by the Food and Drug Administration (FDA) for treatment of VHL-associated hemangioblastomas. However, no FDA-approved systemic therapies currently exist for the majority of hemangioblastomas, which are sporadic and not associated with VHL disease. Tumorigenesis of both sporadic and VHL-associated hemangioblastomas is driven by dysregulation of the same hypoxia-inducible factor (HIF) pathway regulated by the VHL protein, but it remains unknown if belzutifan therapy would have a similar efficacy with off-label use in sporadic hemangioblastomas.

Design/Methods:

We present three cases from a single tertiary care center, highlighting the off-label use of belzutifan in sporadic CNS hemangioblastoma with confirmation of negative germline testing for VHL.  

Results:

Initiation of belzutifan led to radiographic improvement of hemangioblastoma and clinical improvement in the functional status of the patients in all three cases. This includes one case of isolated intramedullary thoracic spinal cord hemangioblastoma, one case with hemangioblastomas in the lumbar spine and cerebellum, and a third case with isolated hemangioblastoma of the cervicomedullary junction. Belzutifan was overall well-tolerated, with anemia noted in all three patients but without hypoxia or the indication for dose-reduction except in one patient who required a one-week break in belzutifan therapy after hemoglobin nadir of 9.7 g/dL; therapy was resumed after hemoglobin increased to >10 g/dL. 

Conclusions:

These cases suggest that belzutifan may offer therapeutic benefit in sporadic CNS hemangioblastomas and support the need for prospective studies evaluating its safety and efficacy beyond VHL-associated disease.