Oral belzutifan treatment in von hippel-lindau-associated retinal hemangioblastoma: a promising approach.

BACKGROUND: Von Hippel-Lindau (VHL)-associated retinal hemangioblastomas (RHs) may cause vision-threatening exudation and hemorrhage. Conventional local therapies may be limited in advanced, recurrent, or anatomically high-risk lesions. This study evaluated ocular outcomes and observed tolerability during oral belzutifan treatment in a real-world cohort. METHODS: Between January 2023 and June 2025, this retrospective observational study included five consecutive patients with genetically confirmed VHL, contributing seven eyes; each eye had at least one RH that progressed despite prior conventional local therapy. Patients received oral belzutifan 120 mg once daily. Median on-treatment follow-up (FU) was 43 weeks (IQR, 27-50); median documented cumulative belzutifan exposure was 43 weeks (range, 27-50). Data were available through January 2026. Tumor regression was quantified as the relative change in projected pixel area from baseline to last on-treatment FU. The largest baseline lesion per fundus-imaged eye was predefined for the primary analysis; all fundus-imaged lesions were assessed exploratorily. Fourteen fundus-imaged RHs were included in the projected-pixel-area analyses, and one MRI-assessed RH was reported separately. Three retinal specialists independently performed lesion measurements and exploratory overall ocular response (OOR) grading as separate assessments. Readers were masked to one another's assessments; quantitative lesion measurements were additionally masked to patient information, treatment course, and image chronology. Safety was monitored within an interdisciplinary clinical framework. RESULTS: In the predefined primary descriptive analysis of the largest baseline lesion per fundus-imaged eye (six eyes from four patients), all six index lesions regressed (median projected-pixel-area reduction, 58.3%; IQR, 17.2-64.7%). All four lesions in the patient-level sensitivity analysis regressed (median, 59.6%; range, 14.5-64.8%). Across all 14 fundus-imaged lesions, median regression was 57.2% (IQR, 28.5-66.9%), and 11/14 lesions (78.6%) showed > 20% regression. All three readers classified all six evaluable eyes as improved. Exudative retinal detachment resolved in three of four affected eyes. Drug-related adverse events were mostly mild to moderate and manageable. CONCLUSIONS: Oral belzutifan was associated with RH regression and improved exudative disease activity in this selected real-world cohort. These findings support systemic HIF-2α inhibition as a potential adjunctive therapeutic option for selected patients with progressive or anatomically high-risk ocular VHL disease. Prospective validation is required. TRIAL REGISTRATION: not applicable. CLINICAL TRIAL NUMBER: Not applicable.