Management of patients with hemophilia A on emicizumab prophylactic treatment: Recommendation from Russian Experts
T. A. Andreeva,
P. A. Zharkov,
N. I. Zozulya,
V. Yu. Zorenko,
V. N. Konstantinova,
V. V. Lebedev,
A. N. Mamaev,
I. V. Markova,
V. Yu. Petrov,
T. Yu. Polyanskaya,
E. E. Schiller https://doi.org/10.35754/0234-5730-2022-67-2-267-280
Abstract
Introduction. In 2018 emicizumab was approved in Russia for prophylactic treatment in patients with hemophilia A (HA) with inhibitors and in 2019 for patients with severe HA without inhibitors. A significant amount of data has been accumulated from clinical trials and real-world data, which allow us to resolve most of the questions that hematologists may have when to prescribe emicizumab.
Aim — to provide information on the management of patients on emicizumab.
Results. The recommendations accumulated the currently available information and world experience in the management of patients receiving emicizumab in order to facilitate decision-making when prescribing and using emicizumab. Information on the use of emicizumab in patients with HA with FVIII inhibitors and severe HA without FVIII inhibitors is presented. Possible complications and measures for their prevention and treatment are presented.
About the Authors
T. A. Andreeva
City Polyclinic No 37, City Center for the Treatment of Patients with Hemophilia of St. Petersburg
Russian Federation
Russian Federation
Tatiana A. Andreeva, Cand. Sci. (Med.), Hematologist, Head of the City Center for the Treatment of Patients with Hemophilia of St. Petersburg
191186, Saint Petersburg
P. A. Zharkov
Dmitriy Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology
Russian Federation
Russian Federation
Pavel A. Zharkov, Dr. Sci. (Med.), Hematologist of the Consultative Department, Pediatrician of the Short-Term Treatment Inpatient Department
117997, Moscow
N. I. Zozulya
National Medical Research Center for Hematology
Russian Federation
Russian Federation
Nadezhda I. Zozulya, Dr. Sci. (Med.), Head of the Department of Hemostasis Disorders
125167, Moscow
V. Yu. Zorenko
National Medical Research Center for Hematology
Russian Federation
Russian Federation
Vladimir Yu. Zorenko, Dr. Sci. (Med.), Head of the Department of Traumatology and Orthopedics
125167, Moscow
V. N. Konstantinova
City Polyclinic No 37, City Center for the Treatment of Patients with Hemophilia of St. Petersburg
Russian Federation
Russian Federation
Valeriia N. Konstantinova, Cand. Sci. (Med.), Hematologist
191186, Saint Petersburg
V. V. Lebedev
Children's Regional Clinical Hospital
Russian Federation
Russian Federation
Vladimir V. Lebedev, Cand. Sci. (Med.), Head of the Children’s Regional Oncohematological Center, Chief Pediatric Oncohematologist of the Ministry of Health of the Krasnodar Region
350007, Krasnodar
A. N. Mamaev
Altai Division of the National Research Center for Hematology
Russian Federation
Russian Federation
Andrey N. Mamaev, Dr. Sci. (Med.), Senior Researcher
656050, Barnaul
I. V. Markova
Raisa Gorbacheva Memorial Research Institute for Pediatric Oncology, Hematology and Transplantation
Russian Federation
Russian Federation
Inna V. Markova, Cand. Sci. (Med.), Deputy Director
1999022, Saint Petersburg
V. Yu. Petrov
Morozovskaya Children's City Clinical Hospital of the Moscow Health Department
Russian Federation
Russian Federation
Victor Y. Petrov, Dr. Sci. (Med.), Hematologist of the Hematology Department
119049, Moscow
T. Yu. Polyanskaya
National Medical Research Center for Hematology
Russian Federation
Russian Federation
Tatyana Yu. Polyanskaya, Cand. Sci. (Med.), Senior Researcher of the Department of Traumatology and Orthopedics
125167, Moscow
E. E. Schiller
Odintsovo Region Hospital
Russian Federation
Russian Federation
Ekaterina E. Schiller, Chief Hematologist of Moscow Region, Head of Children Hematology Department
143003, Odintsovo
References
1. MASAC Document 258 — Recommendation on the Use and Management of Emicizumab-kxwh (Hemlibra®) for Hemophilia A with and without Inhibitors. URL: https://www.hemophilia.org/healthcare-professionals/guidelines-on-care/masac-documents/masac-document-258-recommendation-on-the-use-and-management-of-emicizumab-kxwh-hemlibrar-for-hemophilia-a-with-and-without-inhibitors
2. Instruction for use of Emicizumab. URL: https://www.rlsnet.ru/tn_index_id_96727.htm#farmakokinetika (In Russian).
3. Yoneyama K., Schmitt C., Kotani N., et al. A pharmacometric approach to substitute for a conventional dose-finding study in rare diseases: Example of phase III dose selection for emicizumab in hemophilia A. Clin Pharmacokinet. 2018; 57(9): 1123–34. DOI: 10.1007/s40262-017-0616-3.
4. Ito S. Pharmacokinetics 101. Paediatr Child Health. 2011;16(9):535-6. DOI: 10.1093/pch/16.9.535.
5. Klinge J., Auberger K., Auerswald G., et al. Prevalence and outcome of intracranial haemorrhage in haemophiliacs — a survey of the paediatric group of the German Society of Thrombosis and Haemostasis (GTH). Eur J Pediatr. 1999; 158(Suppl 3): S162–5. DOI: 10.1007/pl00014346.
6. Revel-Vilk S., Golomb M.R., Achonu C., et al. Effect of intracranial bleeds on the health and quality of life of boys with hemophilia. J Pediatr. 2004; 144(4): 490–5. DOI: 10.1016/j.jpeds.2003.12.016.
7. Garcia J., Zia А. Real‐world case series and summary of current literature of infants and toddlers with severe hemophilia A with inhibitor on prophylaxis with emicizumab. Pediatr Blood Cancer. 2021; 68(5): e28942. DOI: 10.1002/pbc.28942.
8. Bush K.A., Lucas T.L., Haley K.M., et al. Initiation of emicizumab prophylaxis in an infant with haemophilia A and subdural haemorrhage. Haemophilia. 2020; 26(6): e353–5. DOI: 10.1111/hae.14133.
9. Barg A.A., Livnat T., Budnik I., et al. Emicizumab treatment and monitoring in a paediatric cohort: Real world data. Br J Haematol. 2020; 191(2): 282–90. DOI: 10.1111/bjh.16964.
10. A study to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of subcutaneous emicizumab in participants from birth to 12 months of age with hemophilia A without inhibitors (HAVEN 7). URL: https://www.clinicaltrials.gov/ct2/show/NCT04431726?term=emicizumab&draw=3&rank=6
11. Kitazawa T., Igawa T., Sampei Z., et al. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med. 2012; 18(10): 1570–4. DOI: 10.1038/nm.2942.
12. Kitazawa T., Esaki K., Tachibana T., et al. Factor VIIIa-mimetic cofactor activity of a bispecific antibody to factors IX/IXa and X/Xa, emicizumab, depends on its ability to bridge the antigens. Thromb Haemost. 2017; 117(7): 1348–57. DOI: 10.1160/TH17-01-0030.
13. Hartmann R., Feenstra T., Valentino L., et al. In vitro studies show synergistic effects of a procoagulant bispecific antibody and bypassing agents. J Thromb Haemost. 2018; 16 (8): 1580–91. DOI: 10.1111/jt;h.14203.
14. Lenting P.J., Denis C.V., Christophe O.D. Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: How does it actually compare to factor VIII? Blood. 2017; 130(23): 2463–8. DOI: 10.1182/blood-2017-08-801662.
15. Bravo M.I., Raventós A., Pérez A., et al. Plasma-derived FVIII/VWF combined with emicizumab in hemophilia A plasma with and without inhibitor has a non-additive effect on in vitro thrombin generation. Oral Abstract OC 53.3. Paper presented at: The ISTH Congress, Melbourne, Australia, July 6–10, 2019.
16. Mahlangu J., Oldenburg J., Paz-Priel I., et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med. 2018; 379(9): 811–22. DOI: 10.1056/NEJMoa1803550.
17. Oldenburg J., Mahlangu J.N., Kim B., et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med. 2017; 377(09): 809–18. DOI: 10.1056/NEJMoa1703068.
18. Dargaud Y., Lienhart A., Janbain M., et al. Use of thrombin generation assay to personalize treatment of breakthrough bleeds in a patient with hemophilia and inhibitors receiving prophylaxis with emicizumab. Haematologica. 2018; 103(4): e181–3. DOI: 10.3324/haematol.2017.185330.
19. Furukawa S., Nogami K., Matsumoto T., et al. Pre-analysis for hemostatic effect of bypassing agents in hemophilia A patients with inhibitors under the emicizumab prophylaxis by global assays. Blood. 2018; 132(Suppl 1): 3793. DOI: 10.1182/blood-2018-99-114355.
20. Levy G.G., Asikanius E., Kuebler P., et al. Safety analysis of rFVII a with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program. J Thromb Haemost. 2019; 17(9): 1470–7. DOI: 10.1111/jth.14491.
21. Srivastava A., Santagostino E., Dougall A., et al. Guidelines for the management of hemophilia. Haemophilia. 2020; 26(Suppl 6): 1–158. DOI: 10.1111/hae.14046.
22. Pipe S.W., Shima M., Lehle M., et al. 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; 6(6): e295–305. DOI: 10.1016/S2352-3026(19)30054-7.
23. Young G., Liesner R., Chang TY., et al. A multicentre, open-label, phase 3 study of emicizumab prophylaxis in children with haemophilia A with inhibitors. Blood. 2019; 134(24): 2127–38. DOI: 10.1182/blood.2019001869.
24. Adamkewicz J.I., Chen D.C., Paz-Priel I. Effects and interferences of emicizumab, a humanised bispecific antibody mimicking activated factor VIII cofactor function, on coagulation assays. Thromb Haemost. 2019; 119(7): 1084–93. DOI: 10.1055/s-0039-1688687.
25. Müller J., Pekrul I., Pötzsch B., et al. Laboratory monitoring in emicizumabtreated persons with hemophilia A. Thromb Haemost. 2019; 119(9): 1384–93. DOI: 10.1055/s-0039-1692427.
26. Young G., Liesner R., Sidonio R.F., et al. Emicizumab prophylaxis provides fl exible and effective bleed control in children with hemophilia A with inhibitors: Results from the HAVEN 2 study. Blood. 2018; 132(Suppl 1): 632. DOI: 10.1182/blood-2018-99-118153.
27. Callaghan M.U., Negrier C., Paz-Priel I., et al. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1–4 studies. Blood. 2021; 137(16): 2231–42. DOI: 10.1182/blood.2020009217.
28. Windyga J., Chojnowski K., Klukowska A., et al. Emicizumab (Hemlibra®) in hemophilia A patients with inhibitors against factor VIII — guidelines of the Group for Haemostasis of the Polish Society of Haematology and Transfusion Medicine. J Transf Med. 2020; 13(3): 165–75. DOI: 10.5603/JTM.2020.0006.
29. Williams L.A., Drwiega J.C., Cao W., et al. Acquired autoimmune thrombotic thrombocytopenic purpura in a case of severe haemophilia A. Haemophilia. 2016; 22(6): e565–7. DOI: 10.1111/hae.13091.
30. URL: www.emicizumabinfo.com
31. Sood S.L., Cheng D., Ragni M., et al. A cross-sectional analysis of cardiovascular disease in the hemophilia population. Blood Adv. 2018; 2(11): 1325–33. DOI: 10.1182/bloodadvances.2018018226.
32. Zimmermann R., Staritz P., Huth-Kühne A. Challenges in treating elderly patients with haemophilia: A focus on cardiology. Thromb Res. 2014; 134(Suppl 1): S48–52. DOI: 10.1016/j.thromres.2013.10.023.
33. Clinical Guidelines, Haemophilia. 2018: 26-27. URL: http://www.consultant.ru/document/cons_doc_LAW_327537/ (In Russian).
Review
For citations:
Andreeva T.A., Zharkov P.A., Zozulya N.I., Zorenko V.Yu., Konstantinova V.N., Lebedev V.V., Mamaev A.N., Markova I.V., Petrov V.Yu., Polyanskaya T.Yu., Schiller E.E. Management of patients with hemophilia A on emicizumab prophylactic treatment: Recommendation from Russian Experts. Russian journal of hematology and transfusiology. 2022;67(2):267-280. (In Russ.) https://doi.org/10.35754/0234-5730-2022-67-2-267-280
Views:
3552
Email this article 
