Treatment Regimens with Bypassing Agents in Patients with Hemophilia A and Inhibitors: A Survey from the Italian Association of Hemophilia Centers (AICE)

Antonio Coppola; Massimo Franchini; Giancarlo Castaman; Elena Santagostino; Cristina Santoro; Rita Carlotta Santoro; Massimo Morfini; Giovanni Di Minno; Angiola Rocino; on behalf of the AICE ad hoc Working Group

doi:10.1055/s-0038-1648230

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2018; 44(06): 551-560
DOI: 10.1055/s-0038-1648230

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Treatment Regimens with Bypassing Agents in Patients with Hemophilia A and Inhibitors: A Survey from the Italian Association of Hemophilia Centers (AICE)

Authors

Antonio Coppola

¹Hemophilia and Congenital Bleeding Disorders Hub Center, University Hospital of Parma, Parma, Italy
Massimo Franchini

²Department of Transfusion Medicine and Hematology, Carlo Poma Hospital, Mantova, Italy
Giancarlo Castaman

³Center for Bleeding Disorders, Careggi University Hospital, Florence, Italy
Elena Santagostino

⁴Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, IRCCS Ca' Granda Foundation, Maggiore Hospital Policlinico, Milan, Italy
Cristina Santoro

⁵Hematology Unit, Department of Cellular Biotechnology and Hematology, Sapienza University of Rome, Rome, Italy
Rita Carlotta Santoro

⁶Hemophilia and Thrombosis Center, Pugliese Ciaccio Hospital, Catanzaro, Italy
Massimo Morfini

⁷Past President of the Italian Association of Hemophilia Centers (AICE), Italy
Giovanni Di Minno

⁸Regional Reference Center for Coagulation Disorders, Federico II University Hospital, Naples, Italy
Angiola Rocino

⁹Hemophilia and Thrombosis Center, Hematology Unit, Ascalesi Hospital, Naples, Italy

on behalf of the AICE ad hoc Working Group

Abstract

The development of neutralizing antibodies (inhibitors) against infused factor VIII currently represents the main complication of replacement therapy in patients with severe hemophilia A. Inhibitors, indeed, particularly high-titer inhibitors (>5 BU/mL), greatly complicate the management of bleeding, exposing patients to an increased morbidity and mortality risk, thus representing a significant burden for physicians of Hemophilia Treatment Centers (HTCs). Although bypassing agents (i.e., activated prothrombin complex concentrate [APCC] and recombinant activated factor VII [rFVIIa]) are available for the treatment and prevention of bleeding in inhibitor patients, their efficacy, safety, and cost–benefit outcomes are poorly known in the long term and should be further improved. In the frame of the update of recommendations for the management of inhibitor patients by the Italian Association of Hemophilia Centers (AICE), to collect more information on real-life therapeutic approaches with bypassing agents in this setting, a survey was conducted among the Directors of the Italian HTCs. From questionnaires returned by 55% of them, data on the use of rFVIIa and APCC in children, adolescent, and adult patients with hemophilia A and inhibitors were obtained and are summarized in this article, including information about the implementation of prophylaxis with both bypassing agents, the adopted regimens, and reasons for starting, adjusting, and interrupting such a therapeutic approach.

Keywords

hemophilia A - inhibitors - prophylaxis - bypassing agents - activated prothrombin complex concentrate - recombinant activated factor VII

Full Text

References

References
1 Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev 2013; 27 (04) 179-184
2 Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A. ; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost 2014; 12 (11) 1935-1939
3 Peyvandi F, Garagiola I, Young G. The past and future of haemophilia: diagnosis, treatments, and its complications. Lancet 2016; 388 (10040): 187-197
4 Roosendaal G, Lafeber FP. Pathogenesis of haemophilic arthropathy. Haemophilia 2006; 12 (Suppl. 03) 117-121
5 Berntorp E, Shapiro AD. Modern haemophilia care. Lancet 2012; 379 (9824): 1447-1456
6 Srivastava A, Brewer AK, Mauser-Bunschoten EP. , et al; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia 2013; 19 (01) e1-e47
7 Manco-Johnson MJ, Abshire TC, Shapiro AD. , et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357 (06) 535-544
8 Gringeri A, Lundin B, von Mackensen S, Mantovani L, Mannucci PM. ; ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost 2011; 9 (04) 700-710
9 Franchini M, Mannucci PM. Inhibitors of propagation of coagulation (factors VIII, IX and XI): a review of current therapeutic practice. Br J Clin Pharmacol 2011; 72 (04) 553-562
10 Rocino A, Franchini M, Coppola A. Treatment and prevention of bleeds in patients with inhibitors to factor VIII/IX. J Clin Med 2017; 6 (04) E46
11 Franchini M, Coppola A, Tagliaferri A, Lippi G. FEIBA versus NovoSeven in hemophilia patients with inhibitors. Semin Thromb Hemost 2013; 39 (07) 772-778
12 Coppola A, Santoro C, Tagliaferri A, Franchini M, DI Minno G. Understanding inhibitor development in haemophilia A: towards clinical prediction and prevention strategies. Haemophilia 2010; 16 (Suppl. 01) 13-19
13 Dekoven M, Wisniewski T, Petrilla A. , et al. Health-related quality of life in haemophilia patients with inhibitors and their caregivers. Haemophilia 2013; 19 (02) 287-293
14 Lindvall K, von Mackensen S, Elmståhl S. , et al. Increased burden on caregivers of having a child with haemophilia complicated by inhibitors. Pediatr Blood Cancer 2014; 61 (04) 706-711
15 Abbonizio F, Giampaolo A, Coppola A, Arcieri R, Hassan HJ. ; Italian Association of Haemophilia Centres. Therapeutic management and costs of severe haemophilia A patients with inhibitors in Italy. Haemophilia 2014; 20 (04) e243-e250
16 Santagostino E, Mancuso ME, Rocino A, Mancuso G, Scaraggi F, Mannucci PM. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. J Thromb Haemost 2006; 4 (02) 367-371
17 Kavakli K, Makris M, Zulfikar B, Erhardtsen E, Abrams ZS, Kenet G. ; NovoSeven trial (F7HAEM-1510) investigators. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor VII in patients with haemophilia and inhibitors. A multi-centre, randomised, double-blind, cross-over trial. Thromb Haemost 2006; 95 (04) 600-605
18 Leissinger C, Gringeri A, Antmen B. , et al. Anti-inhibitor coagulant complex prophylaxis in hemophilia with inhibitors. N Engl J Med 2011; 365 (18) 1684-1692
19 Antunes SV, Tangada S, Stasyshyn O. , et al. Randomized comparison of prophylaxis and on-demand regimens with FEIBA NF in the treatment of haemophilia A and B with inhibitors. Haemophilia 2014; 20 (01) 65-72
20 Konkle BA, Ebbesen LS, Erhardtsen E. , et al. Randomized, prospective clinical trial of recombinant factor VIIa for secondary prophylaxis in hemophilia patients with inhibitors. J Thromb Haemost 2007; 5 (09) 1904-1913
21 Collins PW, Chalmers E, Hart DP. , et al; UK Haemophilia Centre Doctors. Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition). Br J Haematol 2013; 160 (02) 153-170
22 National Hemophilia Foundation. MASAC Recommendation on Administration of Inhibitor Bypassing Agents in the Home for Patients with Hemophilia and Inhibitors. June 4, 2015. https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendation-on-Administration-of-Inhibitor-Bypassing-Agents-in-the-Home-for-Patients-with-Hemophilia-and-Inhibitors . Accessed November 26, 2017
23 Australian Hemophilia Centers Directors' Organization (AHCDO). Guidelines for the treatment of inhibitors in hemophilia A and B. November 2010. http://www.ahcdo.org.au/documents/item/16 . Accessed November 26, 2017
24 Gringeri A, Mannucci PM. ; Italian Association of Haemophilia Centres. Italian guidelines for the diagnosis and treatment of patients with haemophilia and inhibitors. Haemophilia 2005; 11 (06) 611-619
25 Astermark J, Rocino A, Von Depka M. , et al; EHTSB. Current use of by-passing agents in Europe in the management of acute bleeds in patients with haemophilia and inhibitors. Haemophilia 2007; 13 (01) 38-45
26 López-Fernández MF, Altisent Roca C, Álvarez-Román MT. , et al. Spanish Consensus Guidelines on prophylaxis with bypassing agents in patients with haemophilia and inhibitors. Thromb Haemost 2016; 115 (05) 872-895
27 Brown SA, Barnes C, Curtin J. , et al; Hematology working group. How we use recombinant activated factor VII in patients with haemophilia A or B complicated by inhibitors. Working group of hematology experts from Australia and New Zealand, Melbourne, April 2011. Intern Med J 2012; 42 (11) 1243-1250
28 Ewing N, Escuriola-Ettingshausen C, Kreuz W. Prophylaxis with FEIBA in paediatric patients with haemophilia A and inhibitors. Haemophilia 2015; 21 (03) 358-364
29 Franchini M, Coppola A, Rocino A. , et al; Italian Association of Haemophilia Centers AICE Working Group. Perceived challenges and attitudes to regimen and product selection from Italian haemophilia treaters: the 2013 AICE survey. Haemophilia 2014; 20 (02) e128-e135
30 Astermark J, Donfield SM, DiMichele DM. , et al; FENOC Study Group. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study. Blood 2007; 109 (02) 546-551
31 Young G, Shafer FE, Rojas P, Seremetis S. Single 270 microg kg(-1)-dose rFVIIa vs. standard 90 microg kg(-1)-dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison. Haemophilia 2008; 14 (02) 287-294
32 Abbonizio F, Giampaolo A, Arcieri R, Hassan HJ. . e Associazione Italiana Centri Emofilia (AICE). Registro Nazionale Coagulopatie Congenite. Rapporto 2015. Roma: Istituto Superiore di Sanità; 2017. (Rapporti ISTISAN 17/14). http://old.iss.it/publ/?lang=1&id=3060&tipo=5
33 Rocino A, Coppola A, Franchini M. , et al; Italian Association of Haemophilia Centres (AICE) Working Party. Principles of treatment and update of recommendations for the management of haemophilia and congenital bleeding disorders in Italy. Blood Transfus 2014; 12 (04) 575-598
34 Coppola A, Di Minno MN, Santagostino E. Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence-based approaches. Br J Haematol 2010; 150 (05) 515-528
35 Šalek SZ, Auerswald G, Benson G. , et al. Beyond stopping the bleed: short-term episodic prophylaxis with recombinant activated factor FVII in haemophilia patients with inhibitors. Blood Transfus 2017; 15 (01) 77-84
36 Tagliaferri A, Feola G, Molinari AC. , et al; POTTER Study Group. Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study. Thromb Haemost 2015; 114 (01) 35-45
37 Morfini M, Auerswald G, Kobelt RA. , et al. Prophylactic treatment of haemophilia patients with inhibitors: clinical experience with recombinant factor VIIa in European Haemophilia Centres. Haemophilia 2007; 13 (05) 502-507
38 Rocino A, Cortesi PA, Scalone L, Mantovani LG, Crea R, Gringeri A. ; European Haemophilia Therapy Strategy Board (EHTSB); European Haemophilia Therapy Strategy Board EHTSB. Immune tolerance induction in haemophilia A patients and inhibitors: effectiveness and cost-analysis in an European cohort (the ITER study). Haemophilia 2016; 22 (01) 96-102
39 Earnshaw SR, Graham CN, McDade CL, Spears JB, Kessler CM. Factor VIII alloantibody inhibitors: cost analysis of immune tolerance induction vs. prophylaxis and on-demand with bypass treatment. Haemophilia 2015; 21 (03) 310-319
40 Hoots WK, Ebbesen LS, Konkle BA. , et al; Novoseven (F7HAEM-1505) Investigators. Secondary prophylaxis with recombinant activated factor VII improves health-related quality of life of haemophilia patients with inhibitors. Haemophilia 2008; 14 (03) 466-475
41 Gringeri A, Leissinger C, Cortesi PA. , et al. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia 2013; 19 (05) 736-743
42 Gringeri A, Fischer K, Karafoulidou A, Klamroth R, López-Fernández MF, Mancuso E. ; European Haemophilia Treatment Standardisation Board (EHTSB). Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors. Haemophilia 2011; 17 (04) 630-635
43 Mannucci PM, Mancuso ME, Santagostino E, Franchini M. Innovative pharmacological therapies for the hemophilias not based on deficient factor replacement. Semin Thromb Hemost 2016; 42 (05) 526-532
44 Oldenburg J, Mahlangu JN, Kim B. , et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377 (09) 809-818