Abstract
BACKGROUND: Von Hippel-Lindau (VHL) disease is a hereditary tumor predisposition syndrome characterized by benign and malignant tumors affecting multiple organ systems. Standard treatment primarily involves surgical resection and tumor ablation, which can lead to progressive organ dysfunction. Belzutifan, an oral hypoxia-inducible factor-2 alpha (HIF-2α) inhibitor, has emerged as a novel therapeutic option for VHL-associated tumors. However, data on its efficacy and safety outside of clinical trials remain limited. This study evaluates the outcomes of off-label belzutifan treatment in patients with advanced VHL-related organ manifestations, where standard therapeutic options were limited or contraindicated. RESULTS: A retrospective analysis was conducted on eight patients with genetically or clinically confirmed VHL disease treated with belzutifan at a specialized VHL center in Germany. The median treatment duration was 16.4 months (range: 3.6-26 months). Disease stabilization was achieved in all patients, with a partial response observed in three cases. Tumor progression was noted in two patients, involving the emergence of new lesions, but no progression occurred in the primary target lesions, prompting treatment initiation. Belzutifan demonstrated tumor control across multiple organ systems, reducing the need for surgical interventions. The most common adverse event was anemia, occurring in all patients, with three requiring erythropoiesis-stimulating agents or dose reductions. Mild leukocytopenia and transient liver enzyme elevations were observed but did not require treatment modifications. Other adverse effects included infections, which were managed with temporary treatment interruptions. CONCLUSIONS: Belzutifan represents a promising treatment option for VHL disease, particularly in patients for whom surgery carries significant risks. The therapy demonstrated effective tumor control and delayed disease progression in most cases. However, anemia remains a key side effect requiring close monitoring and management. Larger, long-term studies are needed to further assess the efficacy and safety of belzutifan in VHL patients and to refine treatment strategies.