An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study

Hereditary hemorrhagic telangiectasia (HHT, Osler-Weber-Rendu disease) is a rare multisystem vascular disorder that causes chronic gastrointestinal bleeding, epistaxis, and severe anemia. Bevacizumab, an anti-vascular endothelial growth factor antibody, may be effective to treat bleeding in HHT. This international, multicenter, retrospective study evaluated the use of systemic bevacizumab to treat HHTassociated bleeding and anemia at 12 HHT treatment centers. Hemoglobin, Epistaxis Severity Score (ESS), red cell units transfused, and intravenous iron infusions before and after treatment were evaluated using paired means testing and mixed-effects linear models. Bevacizumab was given to 238 HHT patients for a median of 12 (range, 1-96) months. Compared with pretreatment, bevacizumab increased mean hemoglobin by 3.2 g/dL (95% confidence interval: 2.9-3.5 g/dL); i.e., from a mean hemoglobin of 8.6 (8.5-8.8) g/dL to 11.8 (11.5-12.1) g/dL; P<0.0001) and decreased the ESS by 3.4 (3.2-3.7) points (mean ESS 6.8 [6.6-7.1] versus 3.4 [3.2-3.7]; P<0.0001) during the first year of treatment. Compared with 6 months before treatment, the number of red blood cell units transfused decreased by 82% (median of 6.0 [interquartile range, 0.0-13.0] units versus 0 [0.0-1.0] units; P<0.0001) and iron infusions decreased by 70% (median of 6.0 [1.0-18.0] infusions versus 1.0 [0.0-4.0] infusions, P<0.0001) during the first 6 months of bevacizumab treatment. Outcomes were similar regardless of the underlying pathogenic mutation. Following initial induction infusions, continuous/scheduled bevacizumab maintenance achieved higher hemoglobin and lower ESS than intermittent/as-needed maintenance but with more drug exposure. Bevacizumab was well tolerated: hypertension, fatigue, and proteinuria were the most common adverse events. Venous thromboembolism occurred in 2% of patients. In conclusion, systemic bevacizumab was safe and effective for managing chronic bleeding and anemia in HHT.

[1]  V. Iyer,et al.  An international survey to evaluate systemic bevacizumab for chronic bleeding in hereditary haemorrhagic telangiectasia , 2020, Haemophilia : the official journal of the World Federation of Hemophilia.

[2]  V. Iyer,et al.  Systemic bevacizumab for high-output cardiac failure in hereditary hemorrhagic telangiectasia: an international survey of HHT centers , 2019, Orphanet Journal of Rare Diseases.

[3]  E. Decullier,et al.  Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial , 2019, Scientific Reports.

[4]  C. Shovlin,et al.  Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia , 2019, Orphanet Journal of Rare Diseases.

[5]  H. Al‐Samkari.  Systemic Bevacizumab for Hereditary Hemorrhagic Telangiectasia: Considerations from Observational Studies , 2019, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[6]  H. Al‐Samkari,et al.  Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia , 2018, Journal of internal medicine.

[7]  Troy D Woodard,et al.  Pazopanib effective for bevacizumab‐unresponsive epistaxis in hereditary hemorrhagic telangiectasia , 2018, The Laryngoscope.

[8]  C. Bai,et al.  Medical Treatment for Epistaxis in Hereditary Hemorrhagic Telangiectasia: A Meta-analysis , 2018, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[9]  C. Hughes,et al.  Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia , 2018, Angiogenesis.

[10]  H. Al‐Samkari,et al.  Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist’s perspective , 2018, Haematologica.

[11]  M. Karafin,et al.  Re-treatment versus extended treatment strategy of systemic bevacizumab in hereditary hemorrhagic telangiectasia: which is better? , 2018, Annals of Hematology.

[12]  P. Kamath,et al.  Impact of Age on Outcomes in Hospitalized Patients with Hereditary Hemorrhagic Telangiectasia , 2018, Advances in hematology.

[13]  D. Schroeder,et al.  Intravenous Bevacizumab for Refractory Hereditary Hemorrhagic Telangiectasia–Related Epistaxis and Gastrointestinal Bleeding , 2018, Mayo Clinic proceedings.

[14]  J. Harlé,et al.  Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): A retrospective study of 46 patients , 2017, PloS one.

[15]  M. Lawton,et al.  Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia , 2017, American journal of hematology.

[16]  S. Kundu,et al.  Pomalidomide in Hereditary Hemorrhagic Telangiectasia: Interim Results of a Phase I Study , 2016 .

[17]  D. Kallmes,et al.  High Rates of Bleeding Complications among Hospitalized Patients with Hereditary Hemorrhagic Telangiectasia in the United States. , 2016, Annals of the American Thoracic Society.

[18]  C. Merlo,et al.  Effect of Topical Intranasal Therapy on Epistaxis Frequency in Patients With Hereditary Hemorrhagic Telangiectasia: A Randomized Clinical Trial. , 2016, JAMA.

[19]  B. Gilbert-Dussardier,et al.  Effect of Bevacizumab Nasal Spray on Epistaxis Duration in Hereditary Hemorrhagic Telangectasia: A Randomized Clinical Trial. , 2016, JAMA.

[20]  K. Friedman,et al.  Effect of systemic bevacizumab in severe hereditary hemorrhagic telangiectasia associated with bleeding , 2016, American journal of hematology.

[21]  C. Merlo,et al.  The minimal important difference of the epistaxis severity score in hereditary hemorrhagic telangiectasia , 2016, The Laryngoscope.

[22]  R. Hubbard,et al.  Complications and mortality in hereditary hemorrhagic telangiectasia , 2015, Neurology.

[23]  F. Gueyffier,et al.  Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross‐over controlled trial in a rare disease , 2014, Journal of thrombosis and haemostasis : JTH.

[24]  P. Plinkert,et al.  Treatment of epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid - a double-blind placebo-controlled cross-over phase IIIB study. , 2014, Thrombosis research.

[25]  J. Saurin,et al.  Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. , 2012, JAMA.

[26]  N. Choong,et al.  Long-term therapy with bevacizumab in hereditary hemorrhagic telangiectasia. , 2011, The New England journal of medicine.

[27]  C. Shovlin.  Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. , 2010, Blood reviews.

[28]  C. Merlo,et al.  An epistaxis severity score for hereditary hemorrhagic telangiectasia , 2010, The Laryngoscope.

[29]  J. Holter,et al.  Bevacizumab in hereditary hemorrhagic telangiectasia. , 2009, The New England journal of medicine.

[30]  S. Oosting,et al.  More on bevacizumab in hereditary hemorrhagic telangiectasia. , 2009, The New England journal of medicine.

[31]  P. Vase.  Estrogen treatment of hereditary hemorrhagic telangiectasia. A double-blind controlled clinical trial. , 2009, Acta medica Scandinavica.

[32]  P. Zanen,et al.  Genotype–phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia , 2008, American journal of medical genetics. Part A.

[33]  Huiman Barnhart,et al.  Correction of anemia with epoetin alfa in chronic kidney disease. , 2006, The New England journal of medicine.

[34]  N. Pece-Barbara,et al.  Reduced endothelial secretion and plasma levels of transforming growth factor-beta1 in patients with hereditary hemorrhagic telangiectasia type 1. , 2005, Cardiovascular research.

[35]  P. Rosenfeld,et al.  Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. , 2005, Ophthalmology.

[36]  A. Pisani,et al.  Evidence of small-bowel involvement in hereditary hemorrhagic telangiectasia: a capsule-endoscopic study. , 2004, Endoscopy.

[37]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[38]  S. Kaneko,et al.  Hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease) , 2003, The Lancet.

[39]  F. D. d'Ovidio,et al.  Vascular Endothelial Growth Factor Serum Levels Are Elevated in Patients with Hereditary Hemorrhagic Telangiectasia , 2003, Acta Haematologica.

[40]  D. Bonneau,et al.  Visceral manifestations in hereditary haemorrhagic telangiectasia type 2 , 2003, Journal of medical genetics.

[41]  A. Kjeldsen,et al.  [Hereditary hemorrhagic telangiectasia. A population-based study on prevalence and mortality among Danish HHT patients]. , 2000, Ugeskrift for laeger.

[42]  Robert I. White,et al.  The natural history of epistaxis in hereditary hemorrhagic telangiectasia , 1991, The Laryngoscope.

[43]  H. Kwaan,et al.  Fibrinolytic activity in lesions of hereditary hemorrhagic telangiectasia. , 1973, Archives of dermatology.

[44]  T. Morishima,et al.  [Fibrinolytic activity in cutaneous lesions of hereditary hemorrhagic telangiectasia]. , 1985, Nihon Hifuka Gakkai zasshi. The Japanese journal of dermatology.