Abstract
Purpose
Belzutifan is a selective inhibitor of hypoxia-inducible factor 2 alpha (HIF-2a) that has emerged as a targeted therapy option for Von Hippel–Lindau (VHL) syndrome-associated tumors with recent FDA approval. There is limited real-world evidence regarding safety and efficacy in CNS hemangioblastoma. Our objective was to report on our clinical experience with belzutifan in adult patients with VHL-associated CNS hemangioblastoma.
Methods
We retrospectively reviewed our institutional experience of belzutifan in adult patients (> 18 years of age at time of therapy) with VHL and craniospinal CNS hemangioblastomas not amenable to surgical resection. The period for study review was October 2021 to March 2023.
Results
4 patients (all female) with a median age of 36 years at time of belzutifan initiation were included. Median duration of therapy at last follow-up was 11 months (6–17 months). All patients had radiographic response to therapy after a median of 3 months (2–5 months), with maximal response to therapy after a median of 8 months (3–17 months). Therapy was well tolerated, with the most common adverse effect being anemia. No patients had treatment pauses or dose adjustments due to belzutifan-related toxicity. No patients experienced hypoxia.
Conclusion
We showed that belzutifan is safe and well-tolerated with strong disease response for CNS hemangioblastoma in adults with VHL, supporting continued use of belzutifan in this patient population. Future studies should assess duration of treatment, effects of cessation after long-term use, and markers of therapeutic response.
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References
Chittiboina P, Lonser RR (2015) Von Hippel-Lindau disease. Handb Clin Neurol 132:139–156. https://doi.org/10.1016/B978-0-444-62702-5.00010-X
von Hippel E (1904) Über eine sehr seltene Erkrankung der Netzhant. Klinische Beobachtungen, von Graefes Arch, Ophth
Yoda RA, Cimino PJ (2022) Neuropathologic features of central nervous system hemangioblastoma. J Pathol Transl Med 56:115–125. https://doi.org/10.4132/jptm.2022.04.13
Yin X, Duan H, Yi Z, Li C, Lu R, Li L (2020) Incidence, prognostic factors and survival for Hemangioblastoma of the Central Nervous System: analysis based on the Surveillance, Epidemiology, and end results database. Front Oncol 10:570103. https://doi.org/10.3389/fonc.2020.570103
Glasker S, Bender BU, Apel TW, Natt E, van Velthoven V, Scheremet R, Zentner J, Neumann HP (1999) The impact of molecular genetic analysis of the VHL gene in patients with haemangioblastomas of the central nervous system. J Neurol Neurosurg Psychiatry 67:758–762. https://doi.org/10.1136/jnnp.67.6.758
Conway JE, Chou D, Clatterbuck RE, Brem H, Long DM, Rigamonti D (2001) Hemangioblastomas of the central nervous system in von Hippel-Lindau syndrome and sporadic disease. Neurosurgery 48:55–63
Lonser RR, Butman JA, Huntoon K, Asthagiri AR, Wu T, Bakhtian KD, Chew EY, Zhuang Z, Linehan WM, Oldfield EH (2014) Prospective natural history study of central nervous system hemangioblastomas in von Hippel-Lindau disease. J Neurosurg 120:1055–1062
Couch V, Lindor NM, Karnes PS, Michels VV (2000) von Hippel-Lindau disease. Mayo Clin Proc 75:265–272. https://doi.org/10.4065/75.3.265
Ben-Skowronek I, Kozaczuk S (2015) Von Hippel-Lindau Syndrome. Horm Res Paediatr 84:145–152. https://doi.org/10.1159/000431323
Takami H, Graffeo CS, Perry A, Brown DA, Meyer FB, Burns TC, Parney IF (2022) Presentation, imaging, patterns of care, growth, and outcome in sporadic and von Hippel-Lindau-associated central nervous system hemangioblastomas. J Neurooncol 159:221–231. https://doi.org/10.1007/s11060-022-04021-8
Koh E-S, Nichol A, Millar B-A, Ménard C, Pond G, Laperriere NJ (2007) Role of fractionated external beam radiotherapy in hemangioblastoma of the central nervous system. Int J Radiation Oncology* Biology* Phys 69:1521–1526
Pan J, Jabarkheel R, Huang Y, Ho A, Chang SD (2018) Stereotactic radiosurgery for central nervous system hemangioblastoma: systematic review and meta-analysis. J Neurooncol 137:11–22
Jonasch E, McCutcheon IE, Gombos DS, Ahrar K, Perrier ND, Liu D, Robichaux CC, Villarreal MF, Weldon JA, Woodson AH (2018) Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial. Lancet Oncol 19:1351–1359
Migliorini D, Haller S, Merkler D, Pugliesi-Rinaldi A, Koka A, Schaller K, Leemann B, Dietrich P-Y (2015) Recurrent multiple CNS hemangioblastomas with VHL disease treated with pazopanib: a case report and literature review. CNS Oncol 4:387–392
Taylor DG, Ilyas A, Mehta GU, Chen C-J, Schiff D, Oldfield EH, Asthagiri AR (2018) Variable response of CNS hemangioblastomas to Pazopanib in a single patient with von Hippel-Lindau disease: Case report. J Clin Neurosci 50:154–156
Omar AI (2012) Bevacizumab for the treatment of surgically unresectable cervical cord hemangioblastoma: a case report. J Med Case Rep 6:1–4
Riklin C, Seystahl K, Hofer S, Happold C, Winterhalder R, Weller M (2012) Antiangiogenic treatment for multiple CNS hemangioblastomas. Oncol Res Treat 35:443–445
Nguyen TH, Pham T, Strickland T, Brewer D, Belirgen M, Al-Rahawan MM (2018) Von Hippel-Lindau with early onset of hemangioblastoma and multiple drop-metastases like spinal lesions: a case report. Medicine 97
Yaghobi Joybari A, Azadeh P (2017) Von Hippel-Lindau Disease with Multi-Organ involvement: a Case Report and 8-Year clinical Course with Follow-Up. Am J Case Rep 18:1220–1224. https://doi.org/10.12659/ajcr.907356
Gläsker S, Vergauwen E, Koch CA, Kutikov A, Vortmeyer AO (2020) Von Hippel-Lindau Disease: current Challenges and Future prospects. Onco Targets Ther 13:5669–5690. https://doi.org/10.2147/ott.S190753
Fallah J, Weinstock C, Mehta GU, Brave MH, Pierce WF, Pazdur R, Nair A, Suzman DL, Amiri-Kordestani L (2023) FDA approval Summary: Belzutifan for VHL Disease Tumors—Response. Clin Cancer Res 29:685–685
Zhang Y, Nguyen CC, Zhang NT, Fink NS, John JD, Venkatesh OG, Roe JD, Hoffman SC, Lesniak MS, Wolinsky JP, Horbinski C, Szymaniak BM, Buerki RA, Sosman JA, Shenoy NK, Lukas RV (2022) Neurological applications of Belzutifan in von Hippel Lindau Disease. Neuro Oncol. https://doi.org/10.1093/neuonc/noac234
Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, Bloomquist EW, Charlab R, Hamed SS, Miller CP (2022) FDA approval summary: belzutifan for von Hippel-Lindau disease–associated tumors. Clin Cancer Res 28:4843–4848
Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, Oudard S, Else T, Maranchie JK, Welsh SJ, Thamake S, Park EK, Perini RF, Linehan WM, Srinivasan R, Investigators MK (2021) Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease. N Engl J Med 385:2036–2046. https://doi.org/10.1056/NEJMoa2103425
Mor V, Laliberte L, Morris JN, Wiemann M (1984) The Karnofsky performance status scale: an examination of its reliability and validity in a research setting. Cancer 53:2002–2007
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Dhawan A, Peereboom DM, Stevens GH (2022) First clinical experience with belzutifan in von Hippel–Lindau disease associated CNS hemangioblastoma. CNS Oncol 11:CNS91
Fairbanks AM, Hoyek S, Patel NA (2022) Systemic treatment reduces Von-Hippel-Lindau-Associated Retinal Capillary Hemangioblastoma. Ophthalmology. https://doi.org/10.1016/j.ophtha.2022.07.007
Grimes JM, Gershkovich A, Bogomolny D, Marr BP (2022) Two cases of von Hippel-Lindau syndrome-associated retinal hemangioblastoma treated with belzutifan. Retin Cases Brief Rep. https://doi.org/10.1097/icb.0000000000001376
Iliopoulos O, Rapalino O, Barker FG, Coumans J-V, Jones P, Bear L, Konstantakou E, Orr C, Mahar M, Nahed B (2023) Belzutifan treatment of Von Hippel-Lindau (VHL) related central nervous system (CNS) hemangioblastomas (HBs): a single institution experience. American Society of Clinical Oncology
Saeed Z, Tasleem A, Asthagiri A, Schiff D, Jo J (2023) Fatal intracranial hemorrhage with Belzutifan in von Hippel-Lindau Disease–Associated Hemangioblastoma: a Case Report. JCO Precision Oncology 7:e2300066
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH (2003) von Hippel-Lindau disease. Lancet 361:2059–2067. https://doi.org/10.1016/S0140-6736(03)13643-4
van Leeuwaarde RS, Ahmad S, Links TP, Giles RH (1993) Von Hippel-Lindau Syndrome. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A (eds) GeneReviews(®). University of Washington, Seattle Copyright © 1993–2023, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved., Seattle (WA)
Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427. https://doi.org/10.1038/35017054
Choueiri TK, Kaelin WG Jr (2020) Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat Med 26:1519–1530. https://doi.org/10.1038/s41591-020-1093-z
Chen W, Hill H, Christie A, Kim MS, Holloman E, Pavia-Jimenez A, Homayoun F, Ma Y, Patel N, Yell P, Hao G, Yousuf Q, Joyce A, Pedrosa I, Geiger H, Zhang H, Chang J, Gardner KH, Bruick RK, Reeves C, Hwang TH, Courtney K, Frenkel E, Sun X, Zojwalla N, Wong T, Rizzi JP, Wallace EM, Josey JA, Xie Y, Xie XJ, Kapur P, McKay RM, Brugarolas J (2016) Targeting renal cell carcinoma with a HIF-2 antagonist. Nature 539:112–117. https://doi.org/10.1038/nature19796
Cho H, Du X, Rizzi JP, Liberzon E, Chakraborty AA, Gao W, Carvo I, Signoretti S, Bruick RK, Josey JA, Wallace EM, Kaelin WG (2016) On-target efficacy of a HIF-2alpha antagonist in preclinical kidney cancer models. Nature 539:107–111. https://doi.org/10.1038/nature19795
Courtney KD, Infante JR, Lam ET, Figlin RA, Rini BI, Brugarolas J, Zojwalla NJ, Lowe AM, Wang K, Wallace EM, Josey JA, Choueiri TK (2018) Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible Factor-2alpha antagonist in patients with previously treated Advanced Clear Cell Renal Cell Carcinoma. J Clin Oncol 36:867–874. https://doi.org/10.1200/JCO.2017.74.2627
Choueiri TK, Bauer TM, Papadopoulos KP, Plimack ER, Merchan JR, McDermott DF, Michaelson MD, Appleman LJ, Thamake S, Perini RF, Zojwalla NJ, Jonasch E (2021) Inhibition of hypoxia-inducible factor-2alpha in renal cell carcinoma with belzutifan: a phase 1 trial and biomarker analysis. Nat Med 27:802–805. https://doi.org/10.1038/s41591-021-01324-7
Courtney KD, Ma Y, Diaz de Leon A, Christie A, Xie Z, Woolford L, Singla N, Joyce A, Hill H, Madhuranthakam AJ, Yuan Q, Xi Y, Zhang Y, Chang J, Fatunde O, Arriaga Y, Frankel AE, Kalva S, Zhang S, McKenzie T, Reig Torras O, Figlin RA, Rini BI, McKay RM, Kapur P, Wang T, Pedrosa I, Brugarolas J (2020) HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a first-in-class HIF-2 inhibitor, in patients with Clear Cell Renal Cell Carcinoma. Clin Cancer Res 26:793–803. https://doi.org/10.1158/1078-0432.CCR-19-1459
Wen PY, Chang SM, Van den Bent MJ, Vogelbaum MA, Macdonald DR, Lee EQ (2017) Response Assessment in Neuro-Oncology clinical trials. J Clin Oncol 35:2439–2449. https://doi.org/10.1200/jco.2017.72.7511
Rankin EB, Biju MP, Liu Q, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH (2007) Hypoxia-inducible factor–2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Investig 117:1068–1077
Lee YT, Tan YJ, Oon CE (2018) Molecular targeted therapy: treating cancer with specificity. Eur J Pharmacol 834:188–196
Lin L, Cai J, Jiang C (2017) Recent advances in targeted therapy for glioma. Curr Med Chem 24:1365–1381
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BN: design and conception, data collection, interpretation of results, writing the first draft; MW, JW: data collection, interpretation of results, critical review and editing of manuscript for intellectual content; JU, PP: interpretation of results, critical review and editing of manuscript for intellectual content; US: design and conception, interpretation of results, critical review and editing of manuscript for intellectual content.
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Neth, B.J., Webb, M.J., White, J. et al. Belzutifan in adults with VHL-associated central nervous system hemangioblastoma: a single-center experience. J Neurooncol 164, 239–247 (2023). https://doi.org/10.1007/s11060-023-04395-3
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DOI: https://doi.org/10.1007/s11060-023-04395-3