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Intravenous Bevacizumab for Refractory Hereditary Hemorrhagic Telangiectasia–Related Epistaxis and Gastrointestinal Bleeding

Published:January 24, 2018DOI:https://doi.org/10.1016/j.mayocp.2017.11.013

      Abstract

      Objective

      To present a multiyear clinical experience with intravenous bevacizumab for the management of severe gastrointestinal bleeding and/or epistaxis in patients with hereditary hemorrhagic telangiectasia (HHT).

      Patients and Methods

      All patients treated with intravenous bevacizumab for severe hereditary hemorrhagic telangiectasia–related bleeding from June 1, 2013, through January 31, 2017, were included in this report. Severity of epistaxis (determined using the Epistaxis Severity Score questionnaire); hemoglobin, iron, and ferritin levels; and quality of life data were collected serially in all patients.

      Results

      Intravenous bevacizumab was administered to 34 patients using a standardized treatment protocol. Anemia was primarily related to severe epistaxis (n=15, 44%), severe gastrointestinal bleeding (n=4, 12%), or both (n=15, 44%), with a median baseline hemoglobin level of 9.1 g/dL (range, 8.3-10.5 gm/dL; to convert to mmol/L, multiply by 0.62). Red blood cell (RBC) transfusions had been administered to 28 patients (82%). Of these, 16 patients (47%) were RBC transfusion dependent and had received a median of 75 RBC transfusions (range, 4->500 RBC units) before bevacizumab initiation. The median length of follow-up was 17.6 months from the beginning of bevacizumab treatment (range, 3-42.5 months). There was a significant reduction in epistaxis severity scores (P<.001) and RBC transfusion requirements (P=.007) after completion of the initial bevacizumab treatment cycle. New-onset or worsened hypertension was noted in 4 patients, with 1 patient experiencing hypertensive urgency with a temporary decline in renal function.

      Conclusion

      Intravenous bevacizumab is an effective treatment option for patients with severe anemia related to epistaxis and/or gastrointestinal bleeding. Further studies are needed to establish a dose-response relationship as well as clinical, genetic, and biomarker predictors of response.

      Abbreviations and Acronyms:

      AVM (arteriovenous malformation), E-QOL (epistaxis-related quality of life), ESS (Epistaxis Severity Score), GI (gastrointestinal), HHT (hereditary hemorrhagic telangiectasia), HTN (hypertension), IV (intravenous), QOL (quality of life), RBC (red blood cell), VEGF (vascular endothelial growth factor)
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      References

        • Longacre A.V.
        • Gross C.P.
        • Gallitelli M.
        • Henderson K.J.
        • White Jr., R.I.
        • Proctor D.D.
        Diagnosis and management of gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia.
        Am J Gastroenterol. 2003; 98: 59-65
        • Brinjikji W.
        • Wood C.P.
        • Lanzino G.
        • et al.
        High rates of bleeding complications among hospitalized patients with hereditary hemorrhagic telangiectasia in the United States.
        Ann Am Thorac Soc. 2016; 13: 1505-1511
        • Kazazi-Hyseni F.
        • Beijnen J.H.
        • Schellens J.H.
        Bevacizumab.
        Oncologist. 2010; 15: 819-825
        • Sadick H.
        • Naim R.
        • Sadick M.
        • Hörmann K.
        • Riedel F.
        Plasma level and tissue expression of angiogenic factors in patients with hereditary hemorrhagic telangiectasia.
        Int J Mol Med. 2005; 15: 591-596
        • Sadick H.
        • Riedel F.
        • Naim R.
        • et al.
        Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression.
        Haematologica. 2005; 90: 818-828
        • Dupuis-Girod S.
        • Ginon I.
        • Saurin J.C.
        • et al.
        Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output.
        JAMA. 2012; 307: 948-955
        • Fleagle J.M.
        • Bobba R.K.
        • Kardinal C.G.
        • Freter C.E.
        Iron deficiency anemia related to hereditary hemorrhagic telangiectasia: response to treatment with bevacizumab.
        Am J Med Sci. 2012; 343: 249-251
        • Lupu A.
        • Stefanescu C.
        • Treton X.
        • Attar A.
        • Corcos O.
        • Bouhnik Y.
        Bevacizumab as rescue treatment for severe recurrent gastrointestinal bleeding in hereditary hemorrhagic telangiectasia.
        J Clin Gastroenterol. 2013; 47: 256-257
        • Faughnan M.E.
        • Palda V.A.
        • Garcia-Tsao G.
        • et al.
        HHT Foundation International - Guidelines Working Group. International guidelines for the diagnosis and management of hereditary haemorrhagic telangiectasia.
        J Med Genet. 2011; 48: 73-87
        • Yin L.X.
        • Reh D.D.
        • Hoag J.B.
        • et al.
        The minimal important difference of the Epistaxis Severity Score in hereditary hemorrhagic telangiectasia.
        Laryngoscope. 2016; 126: 1029-1032
        • Hoag J.B.
        • Terry P.
        • Mitchell S.
        • Reh D.
        • Merlo C.A.
        An Epistaxis Severity Score for hereditary hemorrhagic telangiectasia.
        Laryngoscope. 2010; 120: 838-843
        • Thompson A.B.
        • Ross D.A.
        • Berard P.
        • Figueroa-Bodine J.
        • Livada N.
        • Richer S.L.
        Very low dose bevacizumab for the treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia.
        Allergy Rhinol (Providence). 2014; 5: 91-95
        • Geisthoff U.W.
        • Fiorella M.L.
        • Fiorella R.
        Treatment of recurrent epistaxis in HHT.
        Curr Pharm Des. 2006; 12: 1237-1242
        • Lund V.J.
        • Howard D.J.
        A treatment algorithm for the management of epistaxis in hereditary hemorrhagic telangiectasia.
        Am J Rhinol. 1999; 13: 319-322
        • Saba H.I.
        • Morelli G.A.
        • Logrono L.A.
        Brief report: treatment of bleeding in hereditary hemorrhagic telangiectasia with aminocaproic acid.
        N Engl J Med. 1994; 330: 1789-1790
        • Haq A.U.
        • Glass J.
        • Netchvolodoff C.V.
        • Bowen L.M.
        Hereditary hemorrhagic telangiectasia and danazol.
        Ann Intern Med. 1988; 109: 171
        • Fernandez-L A.
        • Garrido-Martin E.M.
        • Sanz-Rodriguez F.
        • et al.
        Therapeutic action of tranexamic acid in hereditary haemorrhagic telangiectasia (HHT): regulation of ALK-1/endoglin pathway in endothelial cells.
        Thromb Haemost. 2007; 97: 254-262
        • Morales-Angulo C.
        • Pérez del Molino A.
        • Zarrabeitia R.
        • Fernández A.
        • Sanz-Rodríguez F.
        • Botella L.M.
        Treatment of epistaxes in hereditary haemorrhagic telangiectasia (Rendu-Osler-Weber disease) with tranexamic acid [in Spanish].
        Acta Otorrinolaringol Esp. 2007; 58: 129-132
        • Gaillard S.
        • Dupuis-Girod S.
        • Boutitie F.
        • et al.
        Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease.
        J Thromb Haemost. 2014; 12: 1494-1502
        • Albiñana V.
        • Bernabeu-Herrero M.E.
        • Zarrabeitia R.
        • Bernabéu C.
        • Botella L.M.
        Estrogen therapy for hereditary haemorrhagic telangiectasia (HHT): effects of raloxifene, on Endoglin and ALK1 expression in endothelial cells.
        Thromb Haemost. 2010; 103: 525-534
        • Yaniv E.
        • Preis M.
        • Hadar T.
        • Shvero J.
        • Haddad M.
        Antiestrogen therapy for hereditary hemorrhagic telangiectasia: a double-blind placebo-controlled clinical trial.
        Laryngoscope. 2009; 119: 284-288
        • Yaniv E.
        • Preis M.
        • Shevro J.
        • Nageris B.
        • Hadar T.
        Anti-estrogen therapy for hereditary hemorrhagic telangiectasia—a long-term clinical trial.
        Rhinology. 2011; 49: 214-216
        • Jameson J.J.
        • Cave D.R.
        Hormonal and antihormonal therapy for epistaxis in hereditary hemorrhagic telangiectasia.
        Laryngoscope. 2004; 114: 705-709
        • Boyer H.
        • Fernandes P.
        • Le C.
        • Yueh B.
        Prospective randomized trial of sclerotherapy vs standard treatment for epistaxis due to hereditary hemorrhagic telangiectasia.
        Int Forum Allergy Rhinol. 2015; 5: 435-440
        • Boyer H.
        • Fernandes P.
        • Duran O.
        • Hunter D.
        • Goding G.
        Office-based sclerotherapy for recurrent epistaxis due to hereditary hemorrhagic telangiectasia: a pilot study.
        Int Forum Allergy Rhinol. 2011; 1: 319-323
        • Morais D.
        • Millás T.
        • Zarrabeitia R.
        • Botella L.M.
        • Almaraz A.
        Local sclerotherapy with polydocanol (Aethoxysklerol®) for the treatment of epistaxis in Rendu-Osler-Weber or hereditary hemorrhagic telangiectasia (HHT): 15 years of experience.
        Rhinology. 2012; 50: 80-86
        • Lennox P.A.
        • Harries M.
        • Lund V.J.
        • Howard D.J.
        A retrospective study of the role of the argon laser in the management of epistaxis secondary to hereditary haemorrhagic telangiectasia.
        J Laryngol Otol. 1997; 111: 34-37
        • Mahoney E.J.
        • Shapshay S.M.
        New classification of nasal vasculature patterns in hereditary hemorrhagic telangiectasia.
        Am J Rhinol. 2006; 20: 87-90
        • Karapantzos I.
        • Tsimpiris N.
        • Goulis D.G.
        • Van Hoecke H.
        • Van Cauwenberge P.
        • Danielides V.
        Management of epistaxis in hereditary hemorrhagic telangiectasia by Nd:YAG laser and quality of life assessment using the HR-QoL questionnaire.
        Eur Arch Otorhinolaryngol. 2005; 262: 830-833
        • Jørgensen G.
        • Lange B.
        • Wanscher J.H.
        • Kjeldsen A.D.
        Efficiency of laser treatment in patients with hereditary hemorrhagic telangiectasia.
        Eur Arch Otorhinolaryngol. 2011; 268: 1765-1770
        • Luk L.
        • Mace J.C.
        • Bhandarkar N.D.
        • Sautter N.B.
        Comparison of electrosurgical plasma coagulation and potassium-titanyl-phosphate laser photocoagulation for treatment of hereditary hemorrhagic telangiectasia-related epistaxis.
        Int Forum Allergy Rhinol. 2014; 4: 640-645
        • Tseng E.Y.
        • Narducci C.A.
        • Willing S.J.
        • Sillers M.J.
        Angiographic embolization for epistaxis: a review of 114 cases.
        Laryngoscope. 1998; 108: 615-619
        • Elden L.
        • Montanera W.
        • Terbrugge K.
        • Willinsky R.
        • Lasjaunias P.
        • Charles D.
        Angiographic embolization for the treatment of epistaxis: a review of 108 cases.
        Otolaryngol Head Neck Surg. 1994; 111: 44-50
        • Ricci G.
        • Molini E.
        • Hamam M.
        • et al.
        Treatment of severe epistaxis by superselective embolization: a review of 22 cases.
        Rev Laryngol Otol Rhinol (Bord). 2004; 125: 247-251
        • Layton K.F.
        • Kallmes D.F.
        • Gray L.A.
        • Cloft H.J.
        Endovascular treatment of epistaxis in patients with hereditary hemorrhagic telangiectasia.
        AJNR Am J Neuroradiol. 2007; 28: 885-888
        • Strach K.
        • Schröck A.
        • Wilhelm K.
        • et al.
        Endovascular treatment of epistaxis: indications, management, and outcome.
        Cardiovasc Intervent Radiol. 2011; 34: 1190-1198
        • Trojanowski P.
        • Jargiello T.
        • Trojanowska A.
        • Klatka J.
        Epistaxis in patients with hereditary hemorrhagic telangiectasia treated with selective arterial embolization.
        Acta Radiol. 2011; 52: 846-849
        • Chavan A.
        • Schumann-Binarsch S.
        • Luthe L.
        • et al.
        Systemic therapy with bevacizumab in patients with hereditary hemorrhagic telangiectasia (HHT).
        Vasa. 2013; 42: 106-110
        • Fiorella M.L.
        • Ross D.
        • Henderson K.J.
        • White Jr., R.I.
        Outcome of septal dermoplasty in patients with hereditary hemorrhagic telangiectasia.
        Laryngoscope. 2005; 115: 301-305
        • Harvey R.J.
        • Kanagalingam J.
        • Lund V.J.
        The impact of septodermoplasty and potassium-titanyl-phosphate (KTP) laser therapy in the treatment of hereditary hemorrhagic telangiectasia-related epistaxis.
        Am J Rhinol. 2008; 22: 182-187
        • Levine C.G.
        • Ross D.A.
        • Henderson K.J.
        • Leder S.B.
        • White Jr., R.I.
        Long-term complications of septal dermoplasty in patients with hereditary hemorrhagic telangiectasia.
        Otolaryngol Head Neck Surg. 2008; 138: 721-724
        • Hitchings A.E.
        • Lennox P.A.
        • Lund V.J.
        • Howard D.J.
        The effect of treatment for epistaxis secondary to hereditary hemorrhagic telangiectasia.
        Am J Rhinol. 2005; 19: 75-78
        • Richer S.L.
        • Geisthoff U.W.
        • Livada N.
        • et al.
        The Young's procedure for severe epistaxis from hereditary hemorrhagic telangiectasia.
        Am J Rhinol Allergy. 2012; 26: 401-404
        • Ting J.Y.
        • Remenschneider A.
        • Holbrook E.H.
        Management of severe epistaxis after Young's procedure: a case report.
        Int Forum Allergy Rhinol. 2013; 3: 334-337
        • Oozeer N.B.
        • Bingham B.J.
        Reversal of Young's procedure in hereditary haemorrhagic telangiectasia.
        J Laryngol Otol. 2012; 126: 1169-1171
        • Whitehead K.J.
        • Sautter N.B.
        • McWilliams J.P.
        • et al.
        Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial.
        JAMA. 2016; 316: 943-951
        • Riss D.
        • Burian M.
        • Wolf A.
        • Kranebitter V.
        • Kaider A.
        • Arnoldner C.
        Intranasal submucosal bevacizumab for epistaxis in hereditary hemorrhagic telangiectasia: a double-blind, randomized, placebo-controlled trial.
        Head Neck. 2015; 37: 783-787
        • Chen IV, S.
        • Karnezis T.
        • Davidson T.M.
        Safety of intranasal bevacizumab (Avastin) treatment in patients with hereditary hemorrhagic telangiectasia-associated epistaxis.
        Laryngoscope. 2011; 121: 644-646
        • Karnezis T.T.
        • Davidson T.M.
        Treatment of hereditary hemorrhagic telangiectasia with submucosal and topical bevacizumab therapy.
        Laryngoscope. 2012; 122: 495-497
        • Rohrmeier C.
        • Sachs H.G.
        • Kuehnel T.S.
        A retrospective analysis of low dose, intranasal injected bevacizumab (Avastin) in hereditary haemorrhagic telangiectasia.
        Eur Arch Otorhinolaryngol. 2012; 269: 531-536
        • Dheyauldeen S.
        • Østertun Geirdal A.
        • Osnes T.
        • Vartdal L.S.
        • Dollner R.
        Bevacizumab in hereditary hemorrhagic telangiectasia-associated epistaxis: effectiveness of an injection protocol based on the vascular anatomy of the nose.
        Laryngoscope. 2012; 122: 1210-1214
        • Alam M.A.
        • Sami S.
        • Babu S.
        Successful treatment of bleeding gastro-intestinal angiodysplasia in hereditary haemorrhagic telangiectasia with thalidomide.
        BMJ Case Rep. 2011; : 2011
        • Wang X.Y.
        • Chen Y.
        • Du Q.
        Successful treatment of thalidomide for recurrent bleeding due to gastric angiodysplasia in hereditary hemorrhagic telangiectasia.
        Eur Rev Med Pharmacol Sci. 2013; 17: 1114-1116
        • Ou G.
        • Galorport C.
        • Enns R.
        Bevacizumab and gastrointestinal bleeding in hereditary hemorrhagic telangiectasia.
        World J Gastrointest Surg. 2016; 8: 792-795
        • Epperla N.
        • Hocking W.
        Blessing for the bleeder: bevacizumab in hereditary hemorrhagic telangiectasia.
        Clin Med Res. 2015; 13: 32-35
        • Kochanowski J.
        • Sobieszczańska M.
        • Tubek S.
        • Żurek M.
        • Pawełczak J.
        Successful therapy with bevacizumab in a case of hereditary hemorrhagic telangiectasia.
        Hum Vaccin Immunother. 2015; 11: 680-681
        • Geirdal A.Ø.
        • Dheyauldeen S.
        • Bachmann-Harildstad G.
        • Heimdal K.
        Quality of life in patients with hereditary hemorrhagic telangiectasia in Norway: a population based study.
        Am J Med Genet A. 2012; 158A: 1269-1278
        • Pasculli G.
        • Resta F.
        • Guastamacchia E.
        • Di Gennaro L.
        • Suppressa P.
        • Sabbà C.
        Health-related quality of life in a rare disease: hereditary hemorrhagic telangiectasia (HHT) or Rendu-Osler-Weber disease.
        Qual Life Res. 2004; 13: 1715-1723
        • Merlo C.A.
        • Yin L.X.
        • Hoag J.B.
        • Mitchell S.E.
        • Reh D.D.
        The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia.
        Int Forum Allergy Rhinol. 2014; 4: 921-925
        • van Heeckeren W.J.
        • Ortiz J.
        • Cooney M.M.
        • Remick S.C.
        Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker?.
        J Clin Oncol. 2007; 25: 2993-2995
        • Hood J.D.
        • Meininger C.J.
        • Ziche M.
        • Granger H.J.
        VEGF upregulates ecNOS message, protein, and NO production in human endothelial cells.
        Am J Physiol. 1998; 274: H1054-H1058
        • Horowitz J.R.
        • Rivard A.
        • van der Zee R.
        • et al.
        Vascular endothelial growth factor/vascular permeability factor produces nitric oxide-dependent hypotension. Evidence for a maintenance role in quiescent adult endothelium.
        Arterioscler Thromb Vasc Biol. 1997; 17: 2793-2800

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      • Correction
        Mayo Clinic ProceedingsVol. 93Issue 3
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          In the Original Article entitled, “Intravenous Bevacizumab for Refractory Hereditary Hemorrhagic Telangiectasia–Related Epistaxis and Gastrointestinal Bleeding” published in the February 2018 issue of Mayo Clinic Proceedings (Mayo Clin Proc. 2018;93(2):155-166), an error is present in Table 4. In the Variable for All patients (N=34), Any transfusion, n (%), under Before bevacizumab treatment at 6 mo, the value should be 16 (47).
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