Fatal intracranial haemorrhage shortly after belzutifan initiation in von Hippel-Lindau (VHL) disease-associated haemangioblastoma

Abstract

Background: Belzutifan, a selective hypoxia-inducible factor-2α inhibitor, is approved for von Hippel-Lindau (VHL) disease-associated tumours and is Food and Drug Administration-approved for the management of advanced sporadic clear-cell renal-cell carcinoma. While belzutifan has demonstrated efficacy across VHL-related lesions, real-world safety data remain limited.

Patients and methods: We report a fatal intracranial haemorrhage occurring within 72 h of belzutifan initiation in a patient with VHL-associated central nervous system haemangioblastomas (CNS-HBs).

Results: This represents the third post-marketing case of early haemorrhage involving CNS or spinal haemangioblastomas, following previously reported spinal and cerebellar bleeds. Although CNS-HBs are highly vascular, spontaneous haemorrhage is exceedingly rare. The clustering of haemorrhagic events in these cases, within days of treatment initiation, suggests a rare but potentially serious adverse event not currently listed on regulatory labels.

Conclusions: This case highlights the importance of pharmacovigilance as belzutifan use expands into broader real-world populations, particularly in rare disease settings where trial cohorts are small and long-term safety data are limited.

Keywords: VHL disease; belzutifan; haemangioblastoma; haemorrhage.

Figure 1

Pre-treatment MRI showing bilateral cerebellar haemangioblastomas. Axial T2-weighted (A) and coronal T1-weighted images after gadolinium intravenous contrast administration (B) through the posterior fossa demonstrating bilateral cerebellar subpial haemangioblastomas, larger on the left of heterogenous intermediate to high T2-weighted signal (∗) with associated high T2-weighted signal peripheral cystic component (A, arrow). Solid areas enhance avidly following gadolinium administration due to the vascular nature of the tumours and serpiginous internal vascular flow voids are visible (B, arrow).

Figure 2

CT brain before and after intracerebral haemorrhage. Axial non-enhanced CT brain before the intraparenchymal haemorrhage (A) demonstrates the solid component of the right posterior fossa haemangioblastoma as isoattenuating to adjacent cerebellar parenchyma and the cystic component (arrow) as hypoattenuating. A CT at the time of the intracranial bleed (B) shows the tumour replaced by hyperdense acute haematoma which extends into the cystic component (+) and subarachnoid space layering between cerebellar folia (arrow). CT, computed tomography.