47 Hemoglobin Drop is an Early Predictor of Erythropoietin Supplementation in VHL Syndrome Patients Under Belzutifan Treatment - First Report From The Real-Life BELIEVE-VHL Trial

Vollständiger Abstract

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Abstract Background Von Hippel–Lindau syndrome (VHL) results from pathogenic germline variants in the VHL gene, predisposing individuals to retinal angiomas (RA), CNS hemangioblastomas (HB), renal cell carcinoma (RCC), pancreatic neuroendocrine tumors (PanNET), pheochromocytoma (PHEO), among others. The HIF-2A inhibitor belzutifan has shown robust activity in VHL-associated tumors. To evaluate its real-world effectiveness and toxicity profile, the BELIEVE-VHL prospective trial was approved by our institutional ethics committee (ClinicalTrials.gov ID: NCT07167329). Methods Fifty-eight patients (pts) with active single or multiple solid VHL-related tumors were enrolled between October 2023 and November 2025. Erythropoietin (EPO) plasma levels and hemoglobin (HB) were measured at baseline and monthly for six months. We examined whether early changes in EPO or HB levels predicted the need for subcutaneous EPO supplementation. Results Among the 45 pts who completed six months of treatment (mean age 36 years), 95.5% developed anemia of any grade. Grade 1 anemia and half of grade 2 cases were well tolerated in 30 pts (Group 1). Conversely, 15 pts (33.3%; Group 2) developed symptomatic grade 2 anemia (n = 12) or grade 3 anemia (n = 1; HB < 9 g/dL), requiring weekly EPO supplementation, typically initiated between months 2 and 4 of treatment. Mean baseline EPO levels significantly decreased during treatment in all pts, irrespective of age or sex, but were not predictive of EPO supplementation. In contrast, early hematologic changes were highly informative: the drop in HB after 1 month was significantly greater in Group 2. A decline of ≥ 1.15 g/dL in HB or ≥ 3.63% in hematocrit (HT) at month 1 significantly predicted the need for EPO supplementation, with AUCs of 0.886 (95%CI 0.781–0.991) and 0.900 (95%CI 0.804–0.996), respectively; sensitivity 83.3% and specificity 90.0%. Conclusions Preliminary BELIEVE-VHL trial results confirm that grade 2 anemia, fatigue, and headache are the most frequent adverse effects of belzutifan in routine clinical practice. Early declines in HB or HT during the first month of therapy reliably predicted which patients would require EPO supplementation, whereas plasma EPO levels did not. No treatment interruptions, dose reductions, or transfusions were needed. Weekly EPO 4,000 IU SC effectively corrected anemia in all cases but did not improve fatigue. Patients requiring EPO remained dependent on supplementation, and the long-term impact of sustained EPO use on belzutifan efficacy remains unknown. Overall, HB and HT—rather than EPO—are the most useful early markers for anticipating clinically significant anemia requiring intervention.