Feature: The Blood Stops Here: Management of Pediatric Hemophilia in 2022
Alexis Kuhn, PharmD, BCOP
Pediatric Oncology Pharmacist- Ambulatory Service,
Assistant Professor of Pharmacy
Mayo Clinic College of Medicine, Mayo Clinic
The therapeutic landscape in the field of hematology/oncology pharmacy has drastically evolved over the past decade, with mainstream emergence of precision medicine and immunotherapies changing the paradigm of how we treat certain cancers.1 So too has the paradigm shifted in the management of persons with hemophilia; where once we could only offer short-acting clotting factor concentrates (“factors”), we can now offer non-factor therapeutics, and extended half-life factors, and we stand on the cusp of gene therapy.2
Babies with hemophilia born today have therapeutic options available to them that their uncles and grandfathers never even dreamed about. Herein we will review the management of hemophilia in pediatric patients and highlight several promising avenues that the next decade could bring.
Congenital hemophilia is an X-linked bleeding disorder arising from genetic mutations that result in inadequate production of clotting factor.3 When the F8 gene, which is responsible for factor VIII (FVIII) production, is implicated, the clinical syndrome is termed hemophilia A; when F9, responsible for factor IX (FIX) production, is implicated, hemophilia B is the result.4 An estimated 1.25 million individuals worldwide are expected to have hemophilia, with 80-85% of those having hemophilia A.5 Given that the F8 and F9 genes are located on the X chromosome, hemophilia predominantly affects males who inherit the gene from their carrier mothers.
Both hemophilia A and B are classified by severity, which is determined by baseline factor activity level: a level of <1% indicates severe disease, 1-5% moderate disease, and 6-40% mild disease.3 Phenotypically, patients with severe disease experience spontaneous bleeds into joints and muscles, with significant morbidity and possible mortality. Patients with moderate disease tend to have fewer spontaneous bleeds but still have excessive bleeding with minor trauma, and patients with mild disease generally don’t experience spontaneous bleeds but do experience excessive bleeding from major trauma.3
Historically, treatment of hemophilia has centered around replacing the missing factor with intravenous clotting factor concentrates. The 1970s and 1980s saw the dawn of human plasma-derived factor concentrates, and so too came the emergence of blood-borne viral infections.2,4 The 1990s brought the advent of the recombinant factor concentrates, which abrogated the risk of viral transmission.4 Regardless of source, factor concentrates are administered either routinely to prevent spontaneous bleeds (‘prophylaxis’), or on-demand in response to an active bleed (‘episodic’).
For severe disease, prophylaxis has been the mainstay of treatment.6 Inhibitor development, which refers to the emergence of neutralizing antibodies against exogenous factor, is one of the most significant complications of clotting factor concentrates. Inhibitors to FVIII or FIX represent a dangerous and costly development that gravely complicates hemophilia management.7
Management of the Pediatric Patient
In its most recent 2020 guideline update, the World Federation of Hemophilia (WFH) maintains the importance of early initiation of prophylaxis for children with severe hemophilia A or B.6 Ideally, prophylaxis is initiated before the child’s 3rd birthday and prior to the development of any joint disease; early initiation of factor prophylaxis confers better long-term joint outcomes and significantly reduces the risk for intracranial hemorrhage.6,8-10 Choice of prophylaxis regimen should be tailored to the child’s and family’s needs and can be broken in two broad categories: factor and non-factor.
Factor Prophylaxis (Children without Inhibitors)
Factor prophylaxis has been the mainstay of therapy for decades, with well-known limitations. FVIII and FIX concentrates require intravenous access and frequent administration (typically 3-4 times per week for standard half-life FVIII concentrates and 2-3 times per week for standard half-life FIX concentrates), often with caregivers as the ones establishing intravenous access in their children.6 Such regimens can be unwieldy in a young child, and oftentimes central venous access devices (CVADs) are implanted to aid factor administration in the home. CVADs can be a nidus for infection and/or thromboses and are only meant to be used for the shortest period possible.
Prophylactic factor regimens can and should be personalized to the child when able. Hematology/oncology pharmacists can assist with performing pharmacokinetic studies of the child’s factor, either manually and/or ideally with the assistance of a Bayesian modeling program, such as WAPPS-Hemo.11-13
The emergence of extended half-life (EHL) factor products has been an exciting development in recent years, particularly for children with hemophilia B.14 The half-life of a clotting factor can be prolonged by either conjugating the factor with polyethylene glycol (PEG) or fusing the factor to either albumin or the Fc component of IgG1. The degree to which the half-life is extended differs between the factors: for currently licensed EHL FIX products, the half-life is extended ~4-5x from that of a standard half-life FIX; for currently licensed EHL FVIII products, the half-life is only extended ~1.5-fold.14 For children with hemophilia B, this translates to the attractive possibility of once-weekly FIX prophylaxis.15 For children with hemophilia A, despite the only modest half-life extension, this has the potential to translate to one less factor infusion per week— which can be meaningful for the child and caregiver alike.16
Non-Factor Prophylaxis (Children with Hemophilia A with or without Inhibitors)
In 2017, emicizumab-kxwh ushered in a new era in hemophilia management, becoming the first non-factor prophylactic therapy approved by the United States Food and Drug Administration (FDA).17 Emicizumab is a bispecific monoclonal antibody that mimics FVIII function but shares no homology to the native protein, making it a viable therapeutic in the presence of inhibitors.17 Its initial approval was in hemophilia A with inhibitors, followed shortly thereafter by its approval in hemophilia A without inhibitors. The pivotal HAVEN trial series generated efficacy and safety data to support its licensing in children and adults alike, with or without inhibitors, and at an array of dosing regimens.18-21
Since the original HAVEN 2 publication in children with inhibitors, a growing number of publications have described the successful use of emicizumab in pediatric patients ranging from infancy to adolescence.19, 22-26 Unlike intravenous factor concentrates, emicizumab is administered subcutaneously. The subcutaneous route of administration is especially attractive in very young children for whom a CVAD would have otherwise been needed and makes prophylaxis reasonably attainable in this vulnerable population.24
Emicizumab dosing is weight-based, and after a standard 4-week loading period, maintenance doses can be administered every 1, 2, or 4 weeks at a dose of 1.5 mg/kg, 3 mg/kg, or 6 mg/kg, respectively.27 As the child grows, clinicians will need to continually adjust doses to fit the child; a variety of vial sizes exist to achieve a target dose. It is important to note that unlike factor VIII concentrates, with which caregivers are generally advised to use a whole vial, partial vials of unused emicizumab should be discarded.
The next decade promises to build upon the era that emicizumab has brought forth, as several novel therapeutics are currently undergoing late stage development. Concizumab is a monoclonal antibody directed against tissue factor pathway inhibitor (TFPI).28 TFPI inhibition yields increased thrombin generation, and as part of the extrinsic pathway of the coagulation cascade, is a viable therapeutic target for both hemophilia A and B.29 Concizumab is administered as a daily subcutaneous injection and has achieved FDA Breakthrough Therapy designation for hemophilia B with inhibitors.28
An alternate approach to increase thrombin generation is to decrease antithrombin expression. Fitusiran is a small interfering RNA that targets antithrombin mRNA in hepatocytes.30 Like concizumab, fitusiran demonstrates activity in both hemophilia A and B and is administered subcutaneously. The ATLAS-PEDS trial (NCT03974113) is actively recruiting boys 1-12 years of age with hemophilia A or B to receive fitusiran prophylaxis.
Gene therapy is perhaps the most highly anticipated development in hemophilia, with several candidate products having completed enrollment in their respective phase 3 trials.31-33 Hemophilia gene therapy involves the administration of a modified transgene (either F8 or F9, often paired with a liver-specific promoter) enveloped in a viral vector.34 Most candidate products to date rely on an adeno-associated virus (AAV) vector platform. This is advantageous as it circumvents the insertional mutagenesis possible with lentiviral vectors, but is potentially problematic in children as their episomal nature may predispose to diluting out as the child (and his liver) grows over time.31 Children have been excluded from hemophilia gene therapy trials to date.
In summary, with novel therapeutics and gene therapies on the horizon, coupled with the present-day reality of EHL factors and emicizumab, babies born with hemophilia today do not have to accept the fate of generations before them. As the paradigm continues to shift and novel therapies continue to emerge, hematology/oncology pharmacists must stay abreast of current literature to provide attentive and compassionate care to these patients.
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- Mancuso ME, Mahlangu JN, Pipe SW. The changing treatment landscape in haemophilia: from standard half-life clotting factor concentrates to gene editing. Lancet 2021; 397(10274):630-640.
- Srivastava A, Brewer AK, Mauser-Bunschoten EP et al. Guidelines for the management of hemophilia. Haemophilia 2013; 19(1):e1-47.
- Mannucci PM, Tuddenham EG. The hemophilias—from royal genes to gene therapy. N Eng J Med 2001; 344(23):1773-9.
- Iorio A, Stonebraker JS, Chambost H et al. Establishing the prevalence and prevalence at birth of hemophilia in males: a meta-analytic approach using national registries. Ann Intern Med 2019; 171(8):540-546.
- Srivastava A, Santagostino E, Dougall A et al. WFH guidelines for the management of hemophilia, 3rd edition. Haemophilia 2020; 26 Suppl 6:1- 158.
- Ljung R, Auerswald G, Benson G et al. Inhibitors in haemophilia A and B: management of bleeds, inhibitor eradication and strategies for difficult-to-treat patients. Eur J Haematol 2019; 102(2):111-122.
- Manco-Johnson MJ, Abshire TC, Shapiro AD et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Eng J Med 2007; 357(6):535-44.
- Andersson 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(2):298-307.
- Fischer K, Collins PW, Ozelo MC et al. 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(5):1105-9.
- Shapiro AD, Korth-Bradley J, Poon MC. Use of pharmacokinetics in the coagulation factor treatment of patients with haemophilia. Haemophilia 2005; 11:571-582.
- Dargaud Y, Delavenne X, Hart DP et al. Individualized PK-based prophylaxis in severe haemophilia. Haemophilia 2018; 24 Suppl 2:3-17.
- Hajducek D, Chelle P, Hermans C et al. Development and evaluation of the population pharmacokinetic models for FVIII and FIX concentrates of the WAPPS-Hemo project. Haemophilia 2020; 26(3):384-400.
- Mannucci P. Hemophilia therapy: the future has begun. Haematologica 2020; 105(3):545-553.
- Kenet G, Chambost H, Male C et al. Long-acting recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in children. Thromb Haemost 2016; 116:659-668.
- Mullins ES, Stasyshyn O, Alvarez-Roman MT et al. Extended half-life pegylated, full-length recombinant factor VIII for prophylaxis in children with severe haemophilia A. Haemophilia 2017; 23:238-246.
- Scott LJ, Kim ES. Emicizumab-kxwh: first global approval. Drugs 2018; 78(2):269-274.
- Oldenburg J, Mahlangu JN, Kim B et al. Emicizumab prophylaxis in hemophilia A with inhibitors. N Engl J Med 2017; 377:809-818.
- Young 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(24):2127-2138.
- Mahlangu J, Oldenburg J, Paz-Priel I et al. Emicizumab prophylaxis in patients who have hemophilia A without inhibitors. N Engl J Med 2018; 379:811-822.
- Pipe SW, 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-e305.
- Shima 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(6):979-987.
- Cohen CT, Diaz R. Emicizumab in pediatric hemophilia: bleeding and surgical outcomes from a single-center retrospective study. Pediatr Blood Cancer 2021; 68(11)e29325.
- Mason JA, Young G. Emicizumab prophylaxis in infants with severe haemophilia A without inhibitors: illustrative real-world cases to support shared decision-making. Haemophilia 2021; 27(5):724-29.
- Garcia J, Zia A. 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.
- Batsuli G, Greene A, Meeks SL et al. Emicizumab in tolerized patients with hemophilia A with inhibitors: a single-institution pediatric cohort assessing inhibitor status. Res Pract Thromb Haemost 2021; 5(2):342-348.
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- Shapiro AD. Concizumab: a novel anti-TFPI therapeutic for hemophilia. Blood Adv 2021; 5(1):279.
- Shapiro AD, Angchaisuksiri P, Astermark J et al. Long-term efficacy and safety of subcutaneous concizumab prophylaxis in hemophilia A and hemophilia A/B with inhibitors. Blood Adv 2022; bloodadvances.2021006403. [online ahead of print]
- Manchin N, Ragni MV. An investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia A and B. J Blood Med 2018; 9:135-140.
- Batty P, Lillicrap D. Hemophilia gene therapy: approaching the first licensed product. HemaSphere 2021; 5(3):e540.\
- Pipe SW, Leebeek FW, Recht M et al. 52 week efficacy and safety of etranacogene dezaparvovec in adults with severe or moderate-severe hemophilia B: data from the phase 3 HOPE-B gene therapy trial [abstract]. Res Pract Thromb Haemost 2021; 5(Suppl 2).
- Ozelo MC, Mahlangu J, Pasi KJ et al. Valoctocogene roxaparvovec gene therapy for hemophilia A. N Eng J Med 2022; 386:1013-1025.
- Pierce GF. Gene therapy for hemophilia: anticipating the unexpected. Blood Adv 2020; 4(15):3788.