Palabras clave
Hemofilia A – Emicizumab – Inhibidor
Cómo citar
Arbesú, G. (2019). Emicizumab: nuevo tratamiento para personas con hemofilia A con y sin inhibidor. Revista Hematología, 23(3), 81–90. Recuperado a partir de https://www.revistahematologia.com.ar/index.php/Revista/article/view/219
Resumen
La hemofilia A es una enfermedad hemorrágica hereditaria por deficiencia de FVIII. En su forma severa (FVIII<1%) los sangrados deben prevenirse o tratarse con FVIII endovenoso.
La complicación más frecuente (30%) del tratamiento sustitutivo con factor VIII es el desarrollo de anticuerpos neutralizantes que dificultan su tratamiento.
Durante años este grupo de pacientes con inhibidores han controlado las hemorragias con la administración de agentes baipaseantes (rFVIIa o aPCC). La inmunotolerancia es la actual recomendación para erradicar el inhibidor en todos los pacientes.
Emicizumab es un anticuerpo biespecífico que mimetiza el FVIIIa, de uso subcutáneo, modifica el
fenotipo de los pacientes y ha demostrado ser útil como profilaxis en pacientes con y sin inhibidor.
Su cómoda administración, farmacocinética estable, baja inmunogenicidad y efectiva prevención del sangrado le dan un lugar muy importante para el presente y futuro del tratamiento de las personas con hemofilia A.
Debido a efectos adversos observados en su asociación con aPCC en los estudios clínicos, se recomiendan diferentes dosis y esquemas de aPCC. El uso de emicizumab debe ser monitoreado en centros de tratamiento de hemofilia.
Citas
BIBLIOGRAFIA
1 Srivastava A, Brewer AK, Mauser-Bunschoten EPy col. Guidelines for the management of hemophilia. Haemophilia. 2012;19(1):e1–47
2 Manco-Johnson M. Comparing prophylaxis with episodic treatment in haemophilia A: implications for clinical practice. Haemophilia. 2007;13(Suppl 2):4–9.
3 Peyvandi F, Garagiola I Product type and other environmental risk factors for inhibitor development in severe hemophilia A Res Pract Thromb Haemost. 2018;2:220–227
4 Young J, Grabell J, Mahlangu J y col. Relationship between quality of life and coagulation factor level in hemophilia carriers: preliminary results. J Thromb Haemost. 2015;13:590
5 Morfini M, Haya S, Tagariello G y col. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia. 2007;13(5):606–12.
6- Rodriguez-Merchan EC, Valentino LA. Emicizumab: Review of the literature and critical appraisal. Haemophilia, 2019 jan: 25(1): 11-20
7. Astermark J, Donfield SM, DiMichele DM, y col FENOC Study Group. A randomized
comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA
NovoSeven Comparative (FENOC) Study. Blood. 2007;109(2):546-551.
8 DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002;87:52-7.
9 - Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia. Blood 2014;124:3365-72.
10 KitazawaT, Shima M. Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity.Int J Hematol 2018 Oct 22. 2345-9
11 – Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs 2017; 9:182-212
12 - Sedykh SE, Prinz VV, Buneva VN y col Biespecific antibodies: design, therapy, perspctives. Drugs Des Devel Ther 2018;12:195-208
13 - Mahlangu JN. Biespecific Antibody Emicizumab for Haemophilia A: Breakthrough for patients with inhibitors. BioDrugs. 2018 Dec;32(6):561-570
14 Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017; 130: 2463-8.
15 Blair H. Emicizumab: A review in Haemophilia A. Drugs. Drugs. 2019 Oct;79 (15): 1697-1707
16 Muto A, Yoshihashi K, Takeda M, y col. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost 2014; 12: 206-13.
17 Uchida N, Sambe T, Yoneyama K, y col. A first-inhuman phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016; 127: 1633-41
18 Shima M, Hanabusa H, Taki M, y col. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med 2016; 374: 2044-53
19 -Franchini M, Marano G, Pati I y col. Emicizumab for the treatment of haemophilia A: a narrative review. Blood Transfus. 2019 May;17(3):223-228
20 - Pipe SW, Shima M, Jimenez- Juste V y col. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study Lancet Haematol 2019 Jun;6(6):e295-e305
21 Ragni MV The effect of emicizumab on haemophilia outcomes. Lavcet Haematol 2019 Jun:6 (6):e286-e287
22 Adamkewicz JI, Chen DC1 Paz-Priel y col Effects and Interferences of Emicizumab, a Humanised Bispecific Antibody Mimicking Activated Factor VIII Cofactor Function, on Coagulation Assays Thromb Haemost 2019; 119(07): 1084-1093
23 Nogami K, Soeda T, Matsumoto T, y col. Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies. J Thromb Haemost 2018; 16: 1383-90
24 Brophy DF, Martin EJ, Kuhn J. Use of global assays to monitor emicizumab prophylactic therapy in patients with haemophilia A with inhibitors. Haemophilia. 2019;00:1–3
25 Langer AL, Etra A, Aledort L. Evaluating the safety of emicizumab in patients with hemophilia A. Expert Opin Drug Saf 2018; 17: 1233-7
26 Barg AA, Avishai E, Budnik I y col Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors—a single-center cohort Pediatr Blood Cancer. 2019 Nov;66 (11)
27 Collins PW, Liesner R, Makris M, y col. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee. Haemophilia 2018; 24: 344-7
28 National Hemophilia Foudation - MASAC Document #255
29 Levy GG, Asikanius E, Seremetis S y col. Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program J Thromb Haemost. 2019 Sep;17(9):1470-1477
30 Shima M, Nogami K, Nagami S y col. A multicentre, open‐label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without Inhibitors Haemophilia. 2019;00:1–9
31 Pierce G Safety and efficacy of emicizumab and other novel agents in newborns and infants. Haemophilia Haemophilia. 2019;00:1–2.
32 Patel AM, Corman SL, Sidonio RF y col. Economic impact model of delayed inhibitor development in patients with hemophilia A receiving emicizumab for the prevention of bleeding eventsJ Med Econ. 2019 Oct 7:1-10
33 Batsuli G, Zimowski KL, Sidonio RF Jr y col Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia. 2019 Sep;25(5):789-796
34 Carcao M, Escuriola-Ettingshausen C, Young G y col; Future of Immunotolerance Treatment Group The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab Haemophilia. 2019 Jul;25(4):676-684
35 Santagostino E, Young G, Carcao M. y col
Inhibitors: A Need for Eradication? Acta Haematol. 2019;141(3):151-155
36 Santagostino E, Oldenburg J, Kruse-Jarres R y col. Surgical Experience from Four Phase III Studies (HAVEN 1-4) of Emicizumab in Persons with Haemophilia A (PwHA) with or without FVIII Inhibitors ISTH Academy. Jul 9, 2019; 273889; OC 60.1 Topic: Hemophilia – Clinical
37 Susen S, Gruel Y, Négrier C y col. Management of bleeding and invasive procedures in haemophilia A patients with inhibitor treated with emicizumab (Hemlibra®): Proposals from the French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia, in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) Haemophilia. 2019 Sep;25(5):731-737
38 Paz-Priel I, Chang T, Schmitt C y col. Immunogenicity of Emicizumab in People with Hemophilia A (PwHA): Results from the HAVEN 1-4 Studies. Blood (2018) 132 (Supplement 1): 633
39 Young G How I treat children with haemophilia and inhibitors Br J Haematol. 2019 Aug;186(3):400-408
40 Makris M, Iorio A, Lenting PJ. Emicizumab and thrombosis: The story so far J Thromb Haemost. 2019 Aug;17(8):1269-1272
1 Srivastava A, Brewer AK, Mauser-Bunschoten EPy col. Guidelines for the management of hemophilia. Haemophilia. 2012;19(1):e1–47
2 Manco-Johnson M. Comparing prophylaxis with episodic treatment in haemophilia A: implications for clinical practice. Haemophilia. 2007;13(Suppl 2):4–9.
3 Peyvandi F, Garagiola I Product type and other environmental risk factors for inhibitor development in severe hemophilia A Res Pract Thromb Haemost. 2018;2:220–227
4 Young J, Grabell J, Mahlangu J y col. Relationship between quality of life and coagulation factor level in hemophilia carriers: preliminary results. J Thromb Haemost. 2015;13:590
5 Morfini M, Haya S, Tagariello G y col. European study on orthopaedic status of haemophilia patients with inhibitors. Haemophilia. 2007;13(5):606–12.
6- Rodriguez-Merchan EC, Valentino LA. Emicizumab: Review of the literature and critical appraisal. Haemophilia, 2019 jan: 25(1): 11-20
7. Astermark J, Donfield SM, DiMichele DM, y col FENOC Study Group. A randomized
comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA
NovoSeven Comparative (FENOC) Study. Blood. 2007;109(2):546-551.
8 DiMichele DM, Kroner BL. The North American Immune Tolerance Registry: practices, outcomes, outcome predictors. Thromb Haemost 2002;87:52-7.
9 - Kempton CL, Meeks SL. Toward optimal therapy for inhibitors in hemophilia. Blood 2014;124:3365-72.
10 KitazawaT, Shima M. Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity.Int J Hematol 2018 Oct 22. 2345-9
11 – Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs 2017; 9:182-212
12 - Sedykh SE, Prinz VV, Buneva VN y col Biespecific antibodies: design, therapy, perspctives. Drugs Des Devel Ther 2018;12:195-208
13 - Mahlangu JN. Biespecific Antibody Emicizumab for Haemophilia A: Breakthrough for patients with inhibitors. BioDrugs. 2018 Dec;32(6):561-570
14 Lenting PJ, Denis CV, Christophe OD. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII? Blood 2017; 130: 2463-8.
15 Blair H. Emicizumab: A review in Haemophilia A. Drugs. Drugs. 2019 Oct;79 (15): 1697-1707
16 Muto A, Yoshihashi K, Takeda M, y col. Anti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementation. J Thromb Haemost 2014; 12: 206-13.
17 Uchida N, Sambe T, Yoneyama K, y col. A first-inhuman phase 1 study of ACE910, a novel factor VIII-mimetic bispecific antibody, in healthy subjects. Blood 2016; 127: 1633-41
18 Shima M, Hanabusa H, Taki M, y col. Factor VIII-mimetic function of humanized bispecific antibody in hemophilia A. N Engl J Med 2016; 374: 2044-53
19 -Franchini M, Marano G, Pati I y col. Emicizumab for the treatment of haemophilia A: a narrative review. Blood Transfus. 2019 May;17(3):223-228
20 - Pipe SW, Shima M, Jimenez- Juste V y col. Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study Lancet Haematol 2019 Jun;6(6):e295-e305
21 Ragni MV The effect of emicizumab on haemophilia outcomes. Lavcet Haematol 2019 Jun:6 (6):e286-e287
22 Adamkewicz JI, Chen DC1 Paz-Priel y col Effects and Interferences of Emicizumab, a Humanised Bispecific Antibody Mimicking Activated Factor VIII Cofactor Function, on Coagulation Assays Thromb Haemost 2019; 119(07): 1084-1093
23 Nogami K, Soeda T, Matsumoto T, y col. Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies. J Thromb Haemost 2018; 16: 1383-90
24 Brophy DF, Martin EJ, Kuhn J. Use of global assays to monitor emicizumab prophylactic therapy in patients with haemophilia A with inhibitors. Haemophilia. 2019;00:1–3
25 Langer AL, Etra A, Aledort L. Evaluating the safety of emicizumab in patients with hemophilia A. Expert Opin Drug Saf 2018; 17: 1233-7
26 Barg AA, Avishai E, Budnik I y col Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors—a single-center cohort Pediatr Blood Cancer. 2019 Nov;66 (11)
27 Collins PW, Liesner R, Makris M, y col. Treatment of bleeding episodes in haemophilia A complicated by a factor VIII inhibitor in patients receiving Emicizumab. Interim guidance from UKHCDO Inhibitor Working Party and Executive Committee. Haemophilia 2018; 24: 344-7
28 National Hemophilia Foudation - MASAC Document #255
29 Levy GG, Asikanius E, Seremetis S y col. Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program J Thromb Haemost. 2019 Sep;17(9):1470-1477
30 Shima M, Nogami K, Nagami S y col. A multicentre, open‐label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without Inhibitors Haemophilia. 2019;00:1–9
31 Pierce G Safety and efficacy of emicizumab and other novel agents in newborns and infants. Haemophilia Haemophilia. 2019;00:1–2.
32 Patel AM, Corman SL, Sidonio RF y col. Economic impact model of delayed inhibitor development in patients with hemophilia A receiving emicizumab for the prevention of bleeding eventsJ Med Econ. 2019 Oct 7:1-10
33 Batsuli G, Zimowski KL, Sidonio RF Jr y col Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis. Haemophilia. 2019 Sep;25(5):789-796
34 Carcao M, Escuriola-Ettingshausen C, Young G y col; Future of Immunotolerance Treatment Group The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab Haemophilia. 2019 Jul;25(4):676-684
35 Santagostino E, Young G, Carcao M. y col
Inhibitors: A Need for Eradication? Acta Haematol. 2019;141(3):151-155
36 Santagostino E, Oldenburg J, Kruse-Jarres R y col. Surgical Experience from Four Phase III Studies (HAVEN 1-4) of Emicizumab in Persons with Haemophilia A (PwHA) with or without FVIII Inhibitors ISTH Academy. Jul 9, 2019; 273889; OC 60.1 Topic: Hemophilia – Clinical
37 Susen S, Gruel Y, Négrier C y col. Management of bleeding and invasive procedures in haemophilia A patients with inhibitor treated with emicizumab (Hemlibra®): Proposals from the French network on inherited bleeding disorders (MHEMO), the French Reference Centre on Haemophilia, in collaboration with the French Working Group on Perioperative Haemostasis (GIHP) Haemophilia. 2019 Sep;25(5):731-737
38 Paz-Priel I, Chang T, Schmitt C y col. Immunogenicity of Emicizumab in People with Hemophilia A (PwHA): Results from the HAVEN 1-4 Studies. Blood (2018) 132 (Supplement 1): 633
39 Young G How I treat children with haemophilia and inhibitors Br J Haematol. 2019 Aug;186(3):400-408
40 Makris M, Iorio A, Lenting PJ. Emicizumab and thrombosis: The story so far J Thromb Haemost. 2019 Aug;17(8):1269-1272
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