Pazopanib for severe bleeding and transfusion-dependent anemia in hereditary hemorrhagic telangiectasia

Joseph G Parambil, James R Gossage, Keith R McCrae, Troy D Woodard, K V Narayanan Menon, Kasi L Timmerman, Douglas P Pederson, Dennis L Sprecher, Hanny Al-Samkari, Joseph G Parambil, James R Gossage, Keith R McCrae, Troy D Woodard, K V Narayanan Menon, Kasi L Timmerman, Douglas P Pederson, Dennis L Sprecher, Hanny Al-Samkari

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is a rare angiogenic disorder causing chronic gastrointestinal bleeding, epistaxis, and severe anemia. Pazopanib is an oral multi-kinase angiogenesis inhibitor with promise to treat bleeding in HHT. We analyzed outcomes of HHT patients with the most severe bleeding causing RBC transfusion dependence treated on a predefined institutional pazopanib treatment pathway (with data collected retrospectively). The primary endpoint was achievement of transfusion independence. Secondary endpoints included hemoglobin, epistaxis severity score, RBC transfusion and iron infusion requirements, number of local hemostatic procedures, ferritin and transferrin saturation, compared using paired and repeated measures mean tests. Thirteen transfusion-dependent HHT patients received pazopanib [median (range) dose 150 (25-300) mg daily)] for a median of 22 months. All patients achieved transfusion independence. Compared with pretreatment, pazopanib increased mean hemoglobin by 4.8 (95% CI, 3.6-5.9) g/dL (7.8 vs. 12.7 g/dL, P < 0.0001) and decreased mean epistaxis severity score by 4.77 (3.11-6.44) points (7.20 vs. 2.43 points, P < 0.0001) after 12 months of treatment. Compared with 3 months of pretreatment, RBC transfusions decreased by 93% (median of 16.0 vs. 0.0 units, P < 0.0001) and elemental iron infusion decreased by 92% (median of 4500 vs. 0 mg, P = 0.005) during the first 3 months of treatment; improvements were maintained over time. Pazopanib was well-tolerated: hypertension, lymphocytopenia, and fatigue were the most common TEAEs. In conclusion, pazopanib was safe and effective to manage severe bleeding in HHT, liberating all patients from transfusion dependence and normalizing hematologic parameters at doses lower than used to treat malignancies. These findings require confirmation in a randomized trial.

Keywords: Anemia; Angiogenesis; Bleeding; Epistaxis; Gastrointestinal bleeding; HHT; Hereditary hemorrhagic telangiectasia; Iron deficiency; Osler-Weber-Rendu; Pazopanib.

Conflict of interest statement

Al-Samkari: consultancy (Agios, Dova, Argenx, Rigel, Sobi, Novartis), Research Funding to Institution (Agios, Dova, Amgen). All other authors have nothing to disclose.

© 2021. The Author(s), under exclusive licence to Springer Nature B.V.

Figures

Fig. 1
Fig. 1
Predefined pazopanib treatment pathway. Patients had required in-person clinic visits at least every 3 months and either telephone or in-person visits monthly (for drug titration and TEAE assessment). RBC red blood cell, CBC complete blood count, TSH thyroid-stimulating hormone, ESS epistaxis severity score, ECG electrocardiogram, TEAE treatment-emergent adverse event
Fig. 2
Fig. 2
Flow diagram describing patient inclusion and exclusion in study analysis
Fig. 3
Fig. 3
Box-and-whisker plots (box represents median and interquartile range and tails represent minimum and maximum) showing effect of pazopanib on hematologic parameters and epistaxis severity. A Hemoglobin, B Epistaxis severity score, C RBC transfusion, D Iron infusion, E Serum ferritin, F Transferrin saturation. Mo months, PreTx pretreatment, On Tx on-treatment
Fig. 4
Fig. 4
Swimmer plot detailing timeline of red cell transfusion and iron infusion events for each patient during the 24 months prior to pazopanib initiation and 36 weeks following its initiation

References

    1. Kritharis A, Al-Samkari H, Kuter DJ. Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist’s perspective. Haematologica. 2018 doi: 10.3324/haematol.2018.193003.
    1. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, Kjeldsen AD, Plauchu H. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome) Am J Med Genet. 2000;91(1):66–67. doi: 10.1002/(SICI)1096-8628(20000306)91:1<66::AID-AJMG12>;2-P.
    1. Parambil JG. Hereditary hemorrhagic telangiectasia. Clin Chest Med. 2016;37(3):513–521. doi: 10.1016/j.ccm.2016.04.013.
    1. Shovlin CL. Hereditary haemorrhagic telangiectasia: pathophysiology, diagnosis and treatment. Blood Rev. 2010;24(6):203–219. doi: 10.1016/j.blre.2010.07.001.
    1. Letteboer TG, Mager HJ, Snijder RJ, Lindhout D, Ploos van Amstel HK, Zanen P, Westermann KJ. Genotype-phenotype relationship for localization and age distribution of telangiectases in hereditary hemorrhagic telangiectasia. Am J Med Genet A. 2008;146A(21):2733–2739. doi: 10.1002/ajmg.a.32243.
    1. Kasthuri RS, Montifar M, Nelson J, Kim H, Lawton MT, Faughnan ME, Brain Vascular Malformation Consortium HHTIG Prevalence and predictors of anemia in hereditary hemorrhagic telangiectasia. Am J Hematol. 2017 doi: 10.1002/ajh.24832.
    1. Donaldson JW, McKeever TM, Hall IP, Hubbard RB, Fogarty AW. Complications and mortality in hereditary hemorrhagic telangiectasia: a population-based study. Neurology. 2015;84(18):1886–1893. doi: 10.1212/WNL.0000000000001538.
    1. Geisthoff UW, Heckmann K, D'Amelio R, Grunewald S, Knobber D, Falkai P, Konig J. Health-related quality of life in hereditary hemorrhagic telangiectasia. Otolaryngol Head Neck Surg. 2007;136(5):726–733. doi: 10.1016/j.otohns.2006.12.019.
    1. Merlo CA, Yin LX, Hoag JB, Mitchell SE, Reh DD. The effects of epistaxis on health-related quality of life in patients with hereditary hemorrhagic telangiectasia. Int Forum Allergy Rhinol. 2014;4(11):921–925. doi: 10.1002/alr.21374.
    1. Cirulli A, Liso A, D'Ovidio F, Mestice A, Pasculli G, Gallitelli M, Rizzi R, Specchia G, Sabba C. Vascular endothelial growth factor serum levels are elevated in patients with hereditary hemorrhagic telangiectasia. Acta Haematol. 2003;110(1):29–32. doi: 10.1159/000072411.
    1. Sadick H, Riedel F, Naim R, Goessler U, Hormann K, Hafner M, Lux A. 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(6):818–828.
    1. Al-Samkari H. Hereditary hemorrhagic telangiectasia: systemic therapies, guidelines, and an evolving standard of care. Blood. 2020 doi: 10.1182/blood.2020008739.
    1. Al-Samkari H, Albitar HA, Olitsky SE, Clancy MS, Iyer VN. Systemic bevacizumab for high-output cardiac failure in hereditary hemorrhagic telangiectasia: an international survey of HHT centers. Orphanet J Rare Dis. 2019;14(1):256. doi: 10.1186/s13023-019-1239-6.
    1. Al-Samkari H, Albitar HA, Olitsky SE, Clancy MS, Iyer VN. An international survey to evaluate systemic bevacizumab for chronic bleeding in hereditary haemorrhagic telangiectasia. Haemophilia. 2020 doi: 10.1111/hae.14034.
    1. Al-Samkari H, Kasthuri RS, Parambil JG, Albitar HA, Almodallal YA, Vazquez C, Serra MM, Dupuis-Girod S, Wilsen CB, McWilliams JP, Fountain EH, Gossage JR, Weiss CR, Latif MA, Issachar A, Mei-Zahav M, Meek ME, Conrad M, Rodriguez-Lopez J, Kuter DJ, Iyer VN. An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica. 2020 doi: 10.3324/haematol.2020.261859.
    1. Al-Samkari H, Kritharis A, Rodriguez-Lopez JM, Kuter DJ. Systemic bevacizumab for the treatment of chronic bleeding in hereditary haemorrhagic telangiectasia. J Intern Med. 2019;285(2):223–231. doi: 10.1111/joim.12832.
    1. Iyer VN, Apala DR, Pannu BS, Kotecha A, Brinjikji W, Leise MD, Kamath PS, Misra S, Begna KH, Cartin-Ceba R, DuBrock HM, Krowka MJ, O'Brien EK, Pruthi RK, Schroeder DR, Swanson KL. Intravenous bevacizumab for refractory hereditary hemorrhagic telangiectasia-related epistaxis and gastrointestinal bleeding. Mayo Clin Proc. 2018;93(2):155–166. doi: 10.1016/j.mayocp.2017.11.013.
    1. Dupuis-Girod S, Ginon I, Saurin JC, Marion D, Guillot E, Decullier E, Roux A, Carette MF, Gilbert-Dussardier B, Hatron PY, Lacombe P, Lorcerie B, Riviere S, Corre R, Giraud S, Bailly S, Paintaud G, Ternant D, Valette PJ, Plauchu H, Faure F. Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output. JAMA. 2012;307(9):948–955. doi: 10.1001/jama.2012.250.
    1. Buscarini E, Botella LM, Geisthoff U, Kjeldsen AD, Mager HJ, Pagella F, Suppressa P, Zarrabeitia R, Dupuis-Girod S, Shovlin CL, Vascern HHT. Safety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia. Orphanet J Rare Dis. 2019;14(1):28. doi: 10.1186/s13023-018-0982-4.
    1. Schutz FA, Choueiri TK, Sternberg CN. Pazopanib: clinical development of a potent anti-angiogenic drug. Crit Rev Oncol Hematol. 2011;77(3):163–171. doi: 10.1016/j.critrevonc.2010.02.012.
    1. Kim YH, Kim MJ, Choe SW, Sprecher D, Lee YJ. Selective effects of oral antiangiogenic tyrosine kinase inhibitors on an animal model of hereditary hemorrhagic telangiectasia. J Thromb Haemost. 2017;15(6):1095–1102. doi: 10.1111/jth.13683.
    1. Parambil JG, Woodard TD, Koc ON. Pazopanib effective for bevacizumab-unresponsive epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 2018;128(10):2234–2236. doi: 10.1002/lary.27129.
    1. Faughnan ME, Gossage JR, Chakinala MM, Oh SP, Kasthuri R, Hughes CCW, McWilliams JP, Parambil JG, Vozoris N, Donaldson J, Paul G, Berry P, Sprecher DL. Pazopanib may reduce bleeding in hereditary hemorrhagic telangiectasia. Angiogenesis. 2019;22(1):145–155. doi: 10.1007/s10456-018-9646-1.
    1. Gale RP, Barosi G, Barbui T, Cervantes F, Dohner K, Dupriez B, Gupta V, Harrison C, Hoffman R, Kiladjian JJ, Mesa R, Mc Mullin MF, Passamonti F, Ribrag V, Roboz G, Saglio G, Vannucchi A, Verstovsek S. What are RBC-transfusion-dependence and -independence? Leuk Res. 2011;35(1):8–11. doi: 10.1016/j.leukres.2010.07.015.
    1. Mir O, Touati N, Lia M, Litiere S, Le Cesne A, Sleijfer S, Blay JY, Leahy M, Young R, Mathijssen RHJ, Van Erp NP, Gelderblom H, Van der Graaf WT, Gronchi A. Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials. Clin Cancer Res. 2019;25(5):1479–1485. doi: 10.1158/1078-0432.CCR-18-2748.
    1. Hoag JB, Terry P, Mitchell S, Reh D, Merlo CA. An epistaxis severity score for hereditary hemorrhagic telangiectasia. Laryngoscope. 2010;120(4):838–843. doi: 10.1002/lary.20818.
    1. Yin LX, Reh DD, Hoag JB, Mitchell SE, Mathai SC, Robinson GM, Merlo CA. The minimal important difference of the epistaxis severity score in hereditary hemorrhagic telangiectasia. Laryngoscope. 2016;126(5):1029–1032. doi: 10.1002/lary.25669.
    1. Invernizzi R, Quaglia F, Klersy C, Pagella F, Ornati F, Chu F, Matti E, Spinozzi G, Plumitallo S, Grignani P, Olivieri C, Bastia R, Bellistri F, Danesino C, Benazzo M, Balduini CL. Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-centre, phase 2 study. The Lancet Haematology. 2015;2(11):e465–473. doi: 10.1016/S2352-3026(15)00195-7.
    1. Samour M, Saygin C, Abdallah R, Kundu S, McCrae KR. Pomalidomide in hereditary hemorrhagic telangiectasia: interim results of a phase I study. Blood. 2016;128(22):210. doi: 10.1182/blood.V128.22.210.210.
    1. Kroon S, Snijder RJ, Hosman AE, Vorselaars VMM, Disch FJM, Post MC, Mager JJ. Oral itraconazole for epistaxis in hereditary hemorrhagic telangiectasia: a proof of concept study. Angiogenesis. 2020 doi: 10.1007/s10456-020-09758-2.
    1. de Jel DVC, Disch FJM, Kroon S, Mager JJ, Verdam FJ. Intranasal Efudix reduces epistaxis in hereditary hemorrhagic telangiectasia. Angiogenesis. 2020;23(3):271–274. doi: 10.1007/s10456-020-09712-2.
    1. Faughnan ME, Mager JJ, Hetts SW, Palda VA, Lang-Robertson K, Buscarini E, Deslandres E, Kasthuri RS, Lausman A, Poetker D, Ratjen F, Chesnutt MS, Clancy M, Whitehead KJ, Al-Samkari H, Chakinala M, Conrad M, Cortes D, Crocione C, Darling J, de Gussem E, Derksen C, Dupuis-Girod S, Foy P, Geisthoff U, Gossage JR, Hammill A, Heimdal K, Henderson K, Iyer VN, Kjeldsen AD, Komiyama M, Korenblatt K, McDonald J, McMahon J, McWilliams J, Meek ME, Mei-Zahav M, Olitsky S, Palmer S, Pantalone R, Piccirillo JF, Plahn B, Porteous MEM, Post MC, Radovanovic I, Rochon PJ, Rodriguez-Lopez J, Sabba C, Serra M, Shovlin C, Sprecher D, White AJ, Winship I, Zarrabeitia R. Second international guidelines for the diagnosis and management of hereditary hemorrhagic telangiectasia. Ann Intern Med. 2020 doi: 10.7326/M20-1443.
    1. FDA US Votrient (pazopanib) prescribing information. Novartis

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren