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

backgroundVon 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.

methodsBetween 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.

resultsIn 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.

conclusionsOral 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 registrationnot applicable. CLINICAL TRIAL NUMBER: Not applicable.