Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia

Marie E Faughnan,S Paul Oh,Pamela Berry,James R Gossage,Justin P Mcwilliams,Jill Donaldson,Joseph G Parambil,Raj Kasthuri,Dennis L Sprecher,Murali M Chakinala,Gitanjali Paul,Christopher C W Hughes,Nicholas Vozoris

doi:10.1007/s10456-018-9646-1

Abstract

Pazopanib (Votrient) is an orally administered tyrosine kinase inhibitor that blocks VEGF receptors potentially serving as anti-angiogenic treatment for hereditary hemorrhagic telangiectasia (HHT). We report a prospective, multi-center, open-label, dose-escalating study [50 mg, 100 mg, 200 mg, and 400 mg], designed as a proof-of-concept study to demonstrate efficacy of pazopanib on HHT-related bleeding, and to measure safety. Patients, recruited at 5 HHT Centers, required ≥ 2 Curacao criteria AND [anemia OR severe epistaxis with iron deficiency]. Co-primary outcomes, hemoglobin (Hgb) and epistaxis severity, were measured during and after treatment, and compared to baseline. Safety monitoring occurred every 1.5 weeks. Seven patients were treated with 50 mg pazopanib daily. Six/seven showed at least 50% decrease in epistaxis duration relative to baseline at some point during study; 3 showed at least 50% decrease in duration during Weeks 11 and 12. Six patients showed a decrease in ESS of > 0.71 (MID) relative to baseline at some point during study; 3/6 showed a sustained improvement. Four patients showed > 2 gm improvement in Hgb relative to baseline at one or more points during study. Health-related QOL scores improved on all SF-36 domains at Week 6 and/or Week 12, except general health (unchanged). There were 19 adverse events (AE) including one severe AE (elevated LFTs, withdrawn from dosing at 43 days); with no serious AE. In conclusion, we observed an improvement in Hgb and/or epistaxis in all treated patients. This occurred at a dose much lower than typically used for oncologic indications, with no serious AE. Further studies of pazopanib efficacy are warranted.

Highlights

Hereditary hemorrhagic telangiectasia (HHT) is a common genetic disorder affecting between 1 in 5000 to 1 in 10,000 [1] and is characterized by the development of vascular malformations (VMs) and bleeding
We report here the first human trial of pazopanib for treatment of HHT-related bleeding
This was observed at a dose much lower than typically used for oncologic indications, with no serious adverse events

Summary

Introduction

Hereditary hemorrhagic telangiectasia (HHT) is a common genetic disorder affecting between 1 in 5000 to 1 in 10,000 [1] and is characterized by the development of vascular malformations (VMs) and bleeding. Causative mutations in one of several genes, most commonly endoglin (ENG) or activin receptor-like kinase 1 (ACVRL1) and less commonly SMAD4, lead to the characteristic HHT lesions—large vessel arteriovenous malformations (AVMs) and/or small vessel telangiectases [2,3,4]. Telangiectases develop in the gastric and small intestinal mucosa and lead to chronic gastrointestinal (GI) bleeding, typically in adults [5]. Serum and plasma levels of vascular endothelial growth factor (VEGF) are increased in HHT patients [17], and adult-onset AVMs in the brain and skin have been shown to require angiogenic stimulators such as VEGF in addition to ACVRL1 or ENGdeficiency [18, 19]. The requirement for parenteral administration, uncertainty over effective dosing, limited durability of effect necessitating repetitive doses, and potential serious side effects have limited the use of bevacizumab [10, 23, 25]

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