4  Prophylaxis

Authors
Affiliations

Eva Funding

Hemophilia Centre Copenhagen, Department of Hematology, Rigshospitalet, Copenhagen, Denmark

Nadine Gretenkort Andersson

Department for Paediatric Haematology and Oncology, Children’s Hospital, Skåne University Hospital, Malmö, Sweden

Marianne Hoffmann

Haemophilia Centre Copenhagen, Department of pediatrics, Rigshospitalet, Copenhagen, Denmark

Heidi Knudsen

Centre for Rare Disorders, Oslo University Hospital, Oslo, Norway

Minna Koskenvuo

Division of Hematology-Oncology and Stem Cell Transplantation, New Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

Anna-Elina Lehtinen

Department of Hematology and Comprehensive Cancer Center, Unit of Coagulation Disorders, Helsinki University Hospital, Helsinki, Finland

Susanne Ranta

Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Sweden and Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden

1 Introduction

1.1 Prophylaxis

  • The goal of prophylactic treatment in hemophilia is to prevent bleedings, primarily joint bleeds, with subsequent development of arthropathy. Importantly, prophylactic treatment will also offer protection from other serious bleeds such as intracranial bleeds, muscle bleeds and intra-abdominal bleeds.

  • Cohort studies, especially from Sweden and the Netherlands, clearly show the long-term benefit of prophylaxis [1,2]. In comparison with on demand treatment, the outcome of the Swedish prophylactic strategy was superior but at a much higher cost [2]. A Swedish health technology assessment [3] concluded that concentrate treatment is efficacious, and prophylaxis is superior to on demand treatment in terms of number of bleeds.

1.2 Primary prophylaxis

  • Primary prophylaxis aims to start prior to initiation of joint disease. Even a small number of joint bleeds can result in irreversible damage and damage may progress despite prophylactic therapy [4]. The randomized clinical trial by Manco-Johnson et al. showed a much better outcome on prophylaxis after only 5 years follow up. The number of joint bleeds before starting prophylaxis has a stronger association with outcome than the age at which prophylaxis starts [5].

  • The aim of early prophylactic treatment is to enable the child to live a life as normal as possible without hemorrhages and overprotection.

1.3 RECOMMENDATION

  • Primary prophylaxis is recommended in severe hemophilia from around the age of one before joint bleeds occur.

1.4 RECOMMENDATION

  • Patients with moderate hemophilia with a factor level of 1-2 IU/dL should be offered primary prophylaxis.

1.5 RECOMMENDATION

  • Prophylaxis should continue during adulthood and in elderly patients.

2 Choice of prophylactic treatment

2.1 Plasma-derived or recombinant factor products

  • Recombinant rather than plasma derived FVIII/IX products should be used when available due to the possibility of the transmission of infectious agents. The first randomized study comparing recombinant and plasma derived FVIII products showed higher rate of inhibitors using recombinant FVIII concentrate [6]; however, Pharmacovigilance Risk Assessment Committee of the European Medicines Agency judges that the evidence is not sufficient to show difference between the different classes of FVIII concentrates. As the question is currently unsolved, it is suggested that the choice of factor concentrate and inhibitor risk is discussed with high-risk families, i.e., those with history of inhibitors in the family.

2.2 Extended half-life factor products

  • Recombinant factor concentrates modified to extend the half-life (EHL) are marketed in the Nordic countries, with varying availability and pricing. EHL products can be considered as an alternative to standard factor products also for initiating prophylaxis in PUPs.

  • For FVIII, modifications of the manufacturing process using single chain FVIII, using a human cell line instead of a hamster cell line, or optimizing post-translational glycosylation and sulfation, has resulted in half-life’s of on average 14.2 to 14.4 hours. Pegylation, or fusion of recombinant FVIII to the human IgG1 Fc-domain, prolongs the average half-life to 18.4 to 19 hours. In clinical trials [7], this has in selected cases allowed for prolonging the interval between infusions up to 3 to 7 days. However, reducing injection frequency means fewer peak concentrations, a challenge for physically very active patients. Infants and young children have short half-life’s even with EHL FVIII products, not allowing for injection every third day.

  • The PUPs A-LONG study demonstrated that the inhibitor development, including high-titre inhibitors, were consistent with or lower than rates reported for standard FVIII products [8].

  • Extension of FIX half-life with pegylation or fusion with the human IgG1 Fc-domain or albumin has resulted half-lives of 85 to 105 hours, with dosing every 7-14 days in clinical trials [7]. EHL FIX have a clear advantage compared to standard FIX products, and EHL FIX will allow for once weekly dosing in most patients. EHL FIX products has been reported to be effective and well tolerated, with an adverse event profile as expected in PUPs with HB [9].

2.3 Non-factor replacement therapy

  • Emicizumab is the first non-factor product for hemophilia A to reach the market, approved for prophylaxis in all age groups, in patients with moderate or severe hemophilia A with or without inhibitors.

  • Emicizumab is monoclonal antibody binding FIX and FX and thereby playing the role of FVIII in the coagulation cascade. It is administered subcutaneously once weekly to every second or fourth week. Steady state is reached after the first month with loading dose.

  • Emicizumab cannot stand alone as monotherapy, as patients eventually will need supplemental on demand treatment with FVIII in case of trauma or surgery.

  • The effect of emicizumab is not readily measured with standard coagulation assays. Emicizumab concentration can be indirectly measured with a modified FVIII OSA or Chromogenic assay with human reagents. ROTEM/TEG are used to some extent in all Nordic centers.

  • Emicizumab prophylaxis may be associated with adverse events such as thrombosis, thrombotic microangiopathy, anti-drug antibody development, breakthrough bleeds and loss of efficacy [10,11].

  • It is an unsolved question how to maintain FVIII tolerance during emicizumab treatment in patients who have been successfully tolerized to FVIII, and how to avoid de novo inhibitor development. The Nordic centers do not routinely continue regular FVIII exposure after switch to emicizumab in non-inhibitor patients.

  • Emicizumab is reimbursed in all Nordic countries in hemophilia A with inhibitors. In Sweden and Finland emicizumab is reimbursed in all patients with severe hemophilia A. In Denmark, reimbursement in non-inhibitor patients is restricted to patients where factor replacement is not possible, e.g., venous access does not allow for sufficient prophylaxis with factor replacement to avoid breakthrough bleeds. Emicizumab is not reimbursed in non-inhibitor patients in Norway.

2.4 RECOMMENDATION

  • Recombinant rather than plasma derived products should be preferred when available. In families with high risk of inhibitors, the choice should be discussed (see chapter Inhibitors).

2.5 RECOMMENDATION

  • EHL is recommended for prophylaxis in PUP’s.

2.6 RECOMMENDATION

  • FVIII EHL is recommended to improve troughs. In less active patients, FVIII EHL can be considered to reduce frequency of injections.

2.7 RECOMMENDATION

  • FIX EHL is recommended for most patients with hemophilia B, especially when there are break through bleeds on prophylaxis with standard FIX, or adherence issues.

2.8 RECOMMENDATION

  • Emicizumab is recommended for prophylaxis in patients with hemophilia A and inhibitors (see chapter Inhibitors).

2.9 RECOMMENDATION

  • When reimbursed, it is recommended to discuss the choice of emicizumab prophylaxis in non-inhibitor patients.

2.10 RECOMMENDATION

  • Adjusting intervals to use whole vials of emicizumab is recommended when possible.

3 Initiating prophylaxis with factor products

  • A large multicenter study comparing three different prophylaxis regimens, i.e. 1) full early prophylaxis, 2) early initiation with increasing frequency as soon as possible (asap) and 3) starting and increasing frequency according to bleeding phenotype, showed that the full early prophylaxis was most effective in prevention of joint bleeds before the age of four years (32% full vs. 27% asap and 8% phenotype), though at the cost of using most CVADs (88% full vs. 34% asap and 22% phenotype) [5]. Full-scale prophylaxis also offers almost complete protection against intracranial hemorrhage (ICH) [12].

  • An early therapeutic approach is initiated by giving a dose of FVIII around 25 IU/kg once or twice a week, or FIX around 50 IU/kg once a week via a peripheral vein, with the aim of increasing the frequency of administration as soon as possible. It is common to apply anesthetic cream to the skin of the child to minimize pain.

  • The aim is full scale prophylaxis. For hemophilia A, that corresponds to a dose of 20-40 IU/kg standard FVIII every second day, or at least three times weekly, or 20-50 IU/kg EHL FVIII two or three times weekly. For hemophilia B the dose is 30-40 IU/kg standard FIX every third day, or twice weekly, or 30-50 IU/kg EHL FIX once weekly.

3.1 CVAD

  • Achieving venous access via a peripheral vein will be successful in most cases. However, with difficulties with venous access it may be necessary to consider a central venous access device (CVAD) – usually a subcutaneous fully implanted central venous catheter (port). In fact, current practice differs and in Finland and Denmark where most PUP’s used to get ports.

  • A port ensures reliable venous access, enables early home treatment carried out by parents and helps to prevent major bleeds especially when distance to the hemophilia center is long. The decision to use a central venous port is often a compromise between the medical goal, the bleeding tendency and familiarity with the devices at the hemophilia centre.

  • The most frequent complications with CVADs are infections, mechanical problems and catheter related thromboses (usually clinically silent). Most ports can be used for several years without complications [13,14].

  • To avoid inhibitor development especially in hemophilia A, intensive treatment should be avoided until after the first 20 FVIII exposure days, as intensive treatment longer than 5 days raises the risk of inhibitors [15–17]. However, there is no strong support for the role of port implantation as a risk factor for inhibitor development [15,17,18]. According the RODIN study [17], a surgery for central venous access during the first 75 EDs did not enhance ID risk.

  • Most children can be treated at home by their parents, and from the age of 10-12, the child can usually start self-injections.

3.2 RECOMMENDATION

  • Prophylaxis is initiated with a dose of FVIII around 25 IU/kg once or twice a week or FIX around 50 IU/kg once a week.

3.3 RECOMMENDATION

  • The frequency is increased as soon as venous access allows.

3.4 RECOMMENDATION

  • CVAD is recommended when necessary to initiate prophylaxis.

3.5 RECOMMENDATION

  • When reimbursed, prophylaxis with emicizumab is recommended over CVAD for prophylaxis.

4 Initiating prophylaxis with non-factor products

4.1 The risk of intracranial hemorrhage

  • The aim of prophylactic treatment is to avoid not only arthropathy but also other serious bleedings such as intracranial hemorrhage (ICH). Prophylaxis offers good protection against ICH [12].

  • However, since prophylaxis is commenced at one year of age and full-scale prophylaxis often takes several months to establish, ICH remains a threat. Infants have a high risk for head traumas and ICH may occur even without trauma in severe hemophilia, sometimes with life-threatening consequences.

4.2 RECOMMENDATION

  • When reimbursed, it is recommended to discuss initiation of ICH prophylaxis with emicizumab in infants at 6 months of age.

5 Assement

5.1 Pharmakokinetics of factor treatment

  • Both the dose and the dose interval must be individually tailored owing to bleeding phenotype, the patient’s physical activity and pharmacokinetic differences between patients. PK analysis using the Bayesian method should be used to describe and optimize treatment. The Canadian WAPPS HEMO website offer PK calculations without cost.

5.2 Bleeding frequency

  • The patients should be instructed to document bleedings and home treatment in a prospective diary, either on paper or electronically. To motivate patients, the reports should be actively used during consultations with the haemophilia center and taken into consideration when planning dosing schedules.

5.3 Quality of life

  • To evaluate quality life standardized quality of life formulas can be used where the simplest is EQ-5D but also SF-36 is used in many centres. The EQ-ED assess pain and mobility. Hemo-QoL is a validated, disease specific QoL instrument useful in children which exist in different versions depending on the need. As generic instruments, SF-36 may be used.

5.4 Physical score

  • Physical score is performed mainly by physiotherapist (see chapter Physiotherapy) and the recommended score is HJHS (hemophilia joint health score) which takes into consideration function, pain and signs of arthropathy.

  • HJHS was developed to study early joint disease in hemophilia and has been validated in children up to the age of 18 years [19]. The HJHS asseses structural changes. HJHS has been widely implemented as an assessment tool in clinical studies, also in adults.

  • Other scores such as the Gilbert score are not sensitive enough in patient with no or just minimal joint damage but are still used in some clinical trials.

5.5 Imaging technique scores

  • Different imaging techniques exist, and MRI is the most sensitive method to detect early signs of joint damage. MRI is also used in clinical studies.

  • Due to the high cost MRI cannot be recommended for routine assessment of joint damage.

  • The method of choice when physical signs of joint damage occur is X-ray of the joint, and in selected cases subsequently MRI.

  • Validated scoring systems exist for plain X-ray (Pettersson score), MRI (IPSG score and several others) and are being developed for US [20–22].

5.6 Ultra-sound

  • Evaluation with a ultrasound-based scoring system, Hemophilia Early Arthropathy Detection with UltraSound (HEAD-US) performed by non-imaging specialists, such as physiotherapist, hemophilia nurse or doctor, has recently emerged as a complement to the clinical score and seems to correlate well with HJHS.

  • HEAD-US may be more sensitive in detecting early signs of hemophilia arthropathy than HJHS but longer follow-up studies are required to show the relevance of findings by HEAD-US and the need for intervention.

5.7 RECOMMENDATION

  • Bleeding rate and joint score should be assessed.

5.8 RECOMMENDATION

  • Ultrasound is recommended as a supplement in joint assessment.

5.9 RECOMMENDATION

  • QOL should be assessed.