Prophylaxis in children with haemophilia in an evolving treatment landscape
Maria Elisa Mancuso
Centre for Thrombosis and Haemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
Search for more papers by this authorChristoph Male
Thrombosis & Haemostasis Unit, Department of Paediatrics, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorGili Kenet
The National Haemophilia Centre, The Amalia Biron Thrombosis Research Institute, Sheba Medical Centre, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorKaan Kavakli
Department of Haematology, Ege University Faculty of Medicine, Children's Hospital, Bornova, Izmir, Turkey
Search for more papers by this authorChristoph Königs
Department of Paediatrics and Adolescent Medicine, Clinical and Molecular Haemostasis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
Search for more papers by this authorJan Blatný
Department of Paediatric Haematology and Biochemistry, University Hospital Brno and Masaryk University, Brno, Czech Republic
Search for more papers by this authorCorresponding Author
Karin Fijnvandraat
Department of Paediatric Haematology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
Correspondence
Karin Fijnvandraat, Department of Paediatric Haematology, AMC H7–266, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
Email: [email protected]
Search for more papers by this authorMaria Elisa Mancuso
Centre for Thrombosis and Haemorrhagic Diseases, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
Search for more papers by this authorChristoph Male
Thrombosis & Haemostasis Unit, Department of Paediatrics, Medical University of Vienna, Vienna, Austria
Search for more papers by this authorGili Kenet
The National Haemophilia Centre, The Amalia Biron Thrombosis Research Institute, Sheba Medical Centre, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel
Search for more papers by this authorKaan Kavakli
Department of Haematology, Ege University Faculty of Medicine, Children's Hospital, Bornova, Izmir, Turkey
Search for more papers by this authorChristoph Königs
Department of Paediatrics and Adolescent Medicine, Clinical and Molecular Haemostasis, University Hospital Frankfurt, Goethe University, Frankfurt, Germany
Search for more papers by this authorJan Blatný
Department of Paediatric Haematology and Biochemistry, University Hospital Brno and Masaryk University, Brno, Czech Republic
Search for more papers by this authorCorresponding Author
Karin Fijnvandraat
Department of Paediatric Haematology, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
Correspondence
Karin Fijnvandraat, Department of Paediatric Haematology, AMC H7–266, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
Email: [email protected]
Search for more papers by this authorAbstract
Introduction
For children with haemophilia, early initiation of prophylaxis is crucial to prevent life-threatening bleeds and maintain joint health throughout life. Options for prophylaxis have recently increased from replacement therapy with standard or extended half-life coagulation factor products to include other haemostasis products, such as the non-replacement therapy emicizumab.
Aim
To review key factors that determine the choice of prophylaxis in young children.
Methods
Key clinical questions on the implementation of prophylaxis for haemophilia in children were identified and PubMed was searched for evidence supporting guidance on the implementation of prophylaxis.
Results
The results of the literature search and the practical experience of the authors were used to build consensus on when to start prophylaxis, the pros and cons of the products available to guide the choice of product, and practical aspects of starting prophylaxis to guide the choice of regimen.
Conclusions
In this era of increasing therapeutic choices, available information about the range of treatment options must be considered when initiating prophylaxis in young children. Parents or care givers must be sufficiently informed to allow informed shared decision making. Although plentiful data and clinical experience have been gathered on prophylaxis with clotting factor replacement therapy, its use in young children brings practical challenges, such as the need for intravenous administration. In contrast, our relatively brief experience and limited data with subcutaneously administered non-replacement therapy (i.e., emicizumab) in this patient group imply that starting emicizumab prophylaxis in young children requires careful consideration, despite the more convenient route of administration.
Open Research
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.
REFERENCES
- 1Srivastava A, Santagostino E, Dougall A, et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia. 2020; 26(Suppl 6): 1-158.
- 2Mancuso ME, Mahlangu JN, Pipe SW. The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing. Lancet. 2021; 397: 630-640.
- 3Bladen M, Main E, Khair K, Hubert N, Koutoumanou E, Liesner R. The incidence, risk and functional outcomes of intracranial haemorrhage in children with inherited bleeding disorders at one haemophilia center. Haemophilia. 2016; 22: 556-563.
- 4Andersson NG, Chalmers EA, Kenet G, et al. Mode of delivery in hemophilia: vaginal delivery and Cesarean section carry similar risks for intracranial hemorrhages and other major bleeds. Haematologica. 2019; 104: 2100-2106.
- 5Davies J, Kadir RA. Mode of delivery and cranial bleeding in newborns with haemophilia: a systematic review and meta-analysis of the literature. Haemophilia. 2016; 22: 32-38.
- 6Andersson NG, Auerswald G, Barnes C, et al. Intracranial haemorrhage in children and adolescents with severe haemophilia A or B – the impact of prophylactic treatment. Br J Haematol. 2017; 179: 298-307.
- 7Chalmers EA, Alamelu J, Collins PW, et al. Intracranial haemorrhage in children with inherited bleeding disorders in the UK 2003–2015: a national cohort study. Haemophilia. 2018; 24: 641-647.
- 8Zanon E, Pasca S. Intracranial haemorrhage in children and adults with haemophilia A and B: a literature review of the last 20 years. Blood Transfus. 2019; 17: 378-384.
- 9Witmer C, Presley R, Kulkarni R, Soucie JM, Manno CS, Raffini L. Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States. Br J Haematol. 2011; 152: 211-216.
- 10World Federation of Hemophilia, World Bleeding Disorders Registry; 2019. Accessed: February 4, 2021. https://www.wfh.org/en/our-work-research-data/world-bleeding-disorders-registry?
- 11Blanchette VS, Key NS, Ljung LR, et al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 2014; 12: 1935-1939.
- 12Astermark J, Petrini P, Tengborn L, Schulman S, Ljung R, Berntorp E. Primary prophylaxis in severe haemophilia should be started at an early age but can be individualized. Br J Haematol. 1999; 105: 1109-1113.
- 13Fischer K, Collins PW, Ozelo MC, Srivastava A, Young G, Blanchette VS. When and how to start prophylaxis in boys with severe hemophilia without inhibitors: communication from the SSC of the ISTH. J Thromb Haemost. 2016; 14: 1105-1109.
- 14Warren BB, Thornhill D, Stein J, et al. Young adult outcomes of childhood prophylaxis for severe hemophilia A: results of the Joint Outcome Continuation Study. Blood Adv. 2020; 4: 2451-2459.
- 15Chalmers EA. Haemophilia and the newborn. Blood Rev. 2004; 18: 85-92.
- 16Castaman G, Fijnvandraat K. Molecular and clinical predictors of inhibitor risk and its prevention and treatment in mild hemophilia A. Blood. 2014; 124: 2333-2336.
- 17Dunn A, Young G. Plasma or recombinant products for hemophilia?. ASH Clinical News. https://www.ashclinicalnews.org/spotlight/plasma-recombinant-products-hemophilia/. Published: April 17, 2018. Accessed: December 9, 2020.
- 18Franchini M. Plasma-derived versus recombinant factor VIII concentrates for the treatment of haemophilia A: recombinant is better. Blood Transfus. 2010; 8: 292-296.
- 19Mannucci PM. Plasma-derived versus recombinant factor VIII concentrates for the treatment of haemophilia A: plasma-derived is better. Blood Transfus. 2010; 8: 288-291.
- 20Gringeri A. Factor VIII safety: plasma-derived versus recombinant products. Blood Transfus. 2011; 9: 366-370.
- 21Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl J Med. 2016; 374: 2054-2064.
- 22Gouw SC, van der Bom JG, Ljung R, et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med. 2013; 368: 231-239.
- 23Peyvandi F, Garagiola I, Boscarino M, Ryan A, Hermans C, Makris M. Real-life experience in switching to new extended half-life products at European haemophilia centres. Haemophilia. 2019; 25: 946-952.
- 24Khair K, Pollard D, Harrison C, Hook S, O'Driscoll M, Holland M. How patients view extended half-life products: impressions from real-world experience (The HOPE study). Haemophilia. 2019; 25: 814-820.
- 25Chhabra A, Fogarty PF, Tortella BJ, et al. Real-world analysis of dispensed international units of coagulation factor VIII and resultant expenditures for hemophilia A patients: a comparison between standard half-life and extended half-life products. Manag Care. 2018; 27: 39-50.
- 26Male C, Andersson NG, Rafowicz A, et al. Inhibitor incidence in an unselected cohort of previously untreated patients with severe haemophilia B: a PedNet study. Haematologica. 2021; 106.
- 27Turecek PL, Johnsen JM, Pipe SW, O'Donnell JS. iPATH study group. Haemophilia. 2020; 26: 575-583.
- 28Björkman S, Blanchette VS, Fischer K, et al. Comparative pharmacokinetics of plasma- and albumin-free recombinant factor VIII in children and adults: the influence of blood sampling schedule on observed age-related differences and implications for dose tailoring. J Thromb Haemost. 2010; 8: 730-736.
- 29Konkle BA, Shapiro AD, Quon DV, et al. BIVV001 fusion protein as factor VIII replacement therapy for hemophilia A. N Engl J Med. 2020; 383: 1018-1027.
- 30Mahdi AJ, Obaji SG, Collins PW. Role of enhanced half-life factor VIII and IX in the treatment of haemophilia. Br J Haematol. 2015; 169: 768-776.
- 31Mahlangu J, Young G, Hermans C, Blanchette V, Berntorp E, Santagostino E. Defining extended half-life rFVIII – a critical review of the evidence. Haemophilia. 2018; 24: 348-358.
- 32Pasi KJ, Fischer K, Ragni M, et al. Long-term safety and sustained efficacy for up to 5 years of treatment with recombinant factor IX Fc fusion protein in subjects with haemophilia B: results from the B-YOND extension study. Haemophilia. 2020; 26: e262-e271.
- 33Kenet G, Chambost H, Male C, et al. Long-acting recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in children. Results of a phase 3 trial. Thromb Haemost. 2016; 116: 659-668.
- 34Kenet G, Chambost H, Male C, et al. Long-term safety and efficacy of recombinant coagulation factor IX albumin fusion protein (rIX-FP) in previously treated pediatric patients with hemophilia B: results from a phase 3b extension study. Thromb Haemost. 2020; 120: 599-606.
- 35Carcao M, Zak M, Abdul Karim F, et al. Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial. J Thromb Haemost. 2016; 14: 1521-1529.
- 36Álvarez Román MT, Benítez O, Canaro MI, et al. Expert opinion paper on the treatment of hemophilia B with albutrepenonacog alfa. Expert Opin Biol Ther. 2021: 1-7. Published: online July 6.
- 37Mann DM, Stafford KA, Poon M-C, Matino D, Stafford DW. The Function of extravascular coagulation factor IX in haemostasis. Haemophilia. 2021; 27: 332-339.
- 38Collins P, Chalmers E, Chowdary P, et al. The use of enhanced half-life coagulation factor concentrates in routine clinical practice: guidance from UKHCDO. Haemophilia. 2016; 22: 487-498.
- 39Chowdary P. Anti-tissue factor pathway inhibitor (TFPI) therapy: a novel approach to the treatment of haemophilia. Int J Hematol. 2020; 111: 42-50.
- 40Young G, Liesner R, Chang T, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019; 134: 2127-2138.
- 41Shima M, Nogami K, Nagami S, et al. A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia. 2019; 25: 979-987.
- 42Barg AA, Avishai E, Budnik I, et al. Emicizumab prophylaxis among infants and toddlers with severe hemophilia A and inhibitors – a single-center cohort. Pediatr Blood Cancer. 2019; 66:e27886.
- 43Barg AA, Livnat T, Budnik I, et al. Emicizumab treatment and monitoring in a paediatric cohort: real-world data. Br J Haematol. 2020; 191: 282-290.
- 44Ebbert PT, Xavier F, Seaman CD, Ragni MV. Emicizumab prophylaxis in patients with haemophilia A with and without inhibitors. Haemophilia. 2020; 26: 41-46.
- 45McCary I, Guelcher C, Kuhn J, et al. Real-world use of emicizumab in patients with haemophilia A: bleeding outcomes and surgical procedures. Haemophilia. 2020; 26: 631-636.
- 46Mason JA, Young G. Emicizumab prophylaxis in infants with severe haemophilia A without inhibitors: illustrative real-world cases to support shared decision-making. Haemophilia. 2021.
- 47Martin AP, Burke T, Asghar S, Noone D, Pedra G, O'Hara J. Understanding minimum and ideal factor levels for participation in physical activities by people with haemophilia: an expert elicitation exercise. Haemophilia. 2020; 26: 711-717.
- 48Yu JK, Iorio A, Chelle P, Edginton AN. Pharmacokinetic implications of dosing emicizumab based on vial size: a simulation study. Haemophilia. 2021; 27: 358-365.
- 49Bukkems L, Fischer K, Kremer Hovinga I, et al. Emicizumab dosing in children and adults with hemophilia A: simulating a user-friendly and cost-efficient regimen. Thromb Haemost. 2021.
- 50Liesner RJ, Abraham A, Altisent C, et al. Simoctocog alfa (Nuwiq) in previously untreated patients with severe haemophilia A: final results of the NuProtect Study. Thromb Haemost. 2021.
- 51Blatný J, Kardos M, Miljic P, et al. Incidence of inhibitor development in PUPs with severe haemophilia A in the CEE region between 2005 and 2015. Thromb Res. 2021; 198: 196-203.
- 52Gouw SC, van den Berg HM, Fischer K, et al. Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study. Blood. 2013; 121: 4046-4055.
- 53Young G. How I treat children with haemophilia and inhibitors. Br J Haematol. 2019; 186: 400-408.
- 54Abdi A, Kloosterman FR, Eckhardt CL, et al. The factor VIII treatment history of non-severe hemophilia A. J Thromb Haemost. 2020; 18: 3203-3210.
- 55Young G. Management of children with hemophilia A: how emicizumab has changed the landscape. J Thromb Haemost. 2021.
- 56Scott MJ, Xiang H, Hart DP, et al. Treatment regimens and outcomes in severe and moderate haemophilia A in the UK: the THUNDER study. Haemophillia. 2019; 25: 205-212.
- 57Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of current prophylactic regimens. Blood. 2015; 125: 2038-2044.
- 58Ljung R. Hemophilia and prophylaxis. Pediatr Blood Cancer. 2013; 60(Suppl 1): S23-26.
- 59Feldman BM, Rivard GE, Babyn P, et al. Tailored frequency-escalated primary prophylaxis for severe haemophilia A: results of the 16-year Canadian Hemophilia Prophylaxis Study longitudinal cohort. Lancet Haematol. 2018; 5: e252-e260.
- 60Wu R, Luke KH. The benefit of low dose prophylaxis in the treatment of hemophilia: a focus on China. Expert Rev Hematol. 2017; 10: 995-1004.
Citing Literature
