review
The current status of prophylactic replacement therapy in children and adults with haemophilia Rolf Ljung1,2 and Nadine Gretenkort Andersson2 1
Department of Clinical Sciences Lund-Paediatrics, Lund University, Lund, and 2Department of Paediatrics and Malm€o Centre for Thrombosis and Haemostasis, Sk ane University Hospital, Malm€o, Sweden
Summary Initiating prophylactic treatment at an early age is considered to be the optimal form of therapy for a child with haemophilia A or B. The pioneering long term experiences of prophylactic treatment from Sweden and The Netherlands demonstrated the benefit of prophylaxis in retrospective and observational studies. Decades later, these benefits were confirmed in a randomized controlled study in USA. We review the current status of prophylactic replacement therapy of haemophilia in children, adolescents, adults and the elderly. Prophylaxis should begin at an early age and there are arguments for continuing it into adulthood. The dose of prophylaxis is dependent on the goal of treatment, economic resources and venous access and should be tailored individually. Starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on-demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer-acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels. Keywords: haemophilia A, haemophilia B, factor VIII, factor IX, prophylaxis. Haemophilia A and B are hereditary, X-chromosomal recessive disorders caused by deficiency or absence of coagulation factors VIII (FVIII) or IX (FIX) in the blood and, depending on the concentration of FVIII or FIX coagulant activity, the disorders may be classified as severe (5% to >40%). In patients with the more severe forms of the disease, i.e. FVIII or IX concentrations in plasma 1 iu/dl and at the same time reduced bleeding episodes compared with conventional FIX prophylaxis (Powell et al, 2015). ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 777–786
Review
Prophylactic treatment in different periods of life Childhood It has been suggested in several studies that in haemophilia A patients, starting the first 20 exposures as prophylactic treatment, instead of on-demand due to a bleed, decreases the frequency of inhibitors (Morado et al, 2005; Santagostino et al, 2005; Gouw et al, 2007; Kurnik et al, 2014). In the Italian case–control study (n = 25 cases/32 controls) reported by Santagostino et al (2005), the OR was 03 [95% confidence interval (CI) 01–09] for development of an inhibitor if treatment was started as prophylaxis. Similar results were obtained by Gouw et al (2007) in the CANAL (Concerted Action on Neutralizing Antibodies in severe haemophilia A) study, which was a retrospective observational study (n = 366), where the risk rate was 05 (95% CI 02–09) for inhibitor in the prophylactic group. The RODIN [Research Of Determinants of INhibitor Development among previously untreated patients (PUPs) with haemophilia] study (Gouw et al, 2013a), which is a prospective observational study (n = 574), did not show any difference in the rate of inhibitors during the first 20 exposure days between prophylaxis and on-demand treatment. However, after the first 20 exposure days, prophylaxis was associated with a hazard ratio of 068 (95% CI 047–099), i.e. a protective effect and the inhibitors that developed were mainly low titre. The interpretation of these results is that some patients with high-risk mutations will develop inhibitors whatever treatment they receive during the first 20 exposure days. However, in the non-high risk patients it seems that it may be possible to modify the risk of inhibitors by the way they are treated, i.e. prophylactic or on-demand. Another aspect to discuss when beginning treatment of haemophilia A, is the avoidance of ‘immunological danger signals’ such as inflammation/infection/vaccination, vigorous treatment with high doses on consecutive days or surgical procedures. Two German centres reported an unexpectedly low frequency of inhibitors after starting prophylaxis at a young age before the onset of bleeds and avoiding ‘immunological danger signals’ (Auerswald et al, 2012). However, these results were not reproduced in the Early Prophylaxis Immunologic Challenge study that was designed to address this hypothesis, the prospective study being interrupted when frequency of inhibitors was above 30% (https://clinicaltrials.gov/ct2/show/study/NCT01376700, Gomez et al, 2014). However, data from the RODIN study as well as a study from the UK show that peak treatment moments, usually defined as treatment with high doses (30–50 units/ kg) during 3–5–10 consecutive days during the first 20 exposure days increases the risk of inhibitor by a factor of 2–3 (Maclean et al, 2011; Gouw et al, 2013a). It should be borne in mind, however, that the discussion of mode of treatment and risk of inhibitors has been limited to ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 777–786
haemophilia A and cannot be extrapolated to patients with haemophilia B. Venous access may be a problem, particularly in the youngest children. The first choice should be a peripheral vein and in most cases this will be successful. However, venous access can be very difficult or even impossible and it may be necessary to consider a central venous line. Several reports have described various adverse effects associated with the use of central venous catheters in patients with haemophilia, and infections were the most frequent complication (Ljung, 2007). The decision to use a central venous catheter is a compromise between the medical goal, the bleeding tendency, the social situation of the patient and familiarity with the devices at the particular haemophilia centre. Teenagers and young adults. Problems with adherence to a prophylactic regimen and denial often occur in the teenage period (Fischer et al, 2001) and can be challenging to deal with. The average age at which patients start to take primary responsibility of haemophilia is 141 years (Lindvall et al, 2006). From several studies we know that peers are important and a multidisciplinary approach together with parents, nurses and physicians may be the best way forward. Many teenagers with severe and moderate haemophilia have already learned to practise self-infusion as children and will thus be more independent during their teenage years. The intensity of physical activity is often a matter of discussion. A recent study showed that children and adolescents with moderate and severe haemophilia undergoing vigorous physical activity (e.g. wrestling) only showed a transient and small increased risk of bleeds (Broderick et al, 2012a). Electronic devices can be of supportive help and mobile technology can help to give information about haemophilia and networks, it can help to remind patients to take their treatment, get data for stock control and payer purposes, give instant guidance or treatment advice and enable a fast communication between healthcare professionals and the patient (Khair, 2014). For example, short message texting can help to facilitate prompt information about bleeding episodes (Broderick et al, 2012b). Adults. While prophylaxis in children has become the standard treatment in developed countries, the continuation of prophylaxis in adulthood is still under debate, even though there is evidence that it is beneficial in adults too. The recently published SPINART (Trial to Evaluate the Effect of Secondary Prophylaxis With rFVIII Therapy in Severe Hemophilia A Adult and/or Adolescent Subjects Compared to That of Episodic Treatment) study (Manco-Johnson et al, 2013a) is the first, prospective, controlled, randomized, parallel group design study comparing routine prophylaxis with ondemand treatment in adults with severe haemophila A. Eighty-four patients, mean age, 306 years, were enrolled and randomized to prophylaxis 25 units/kg per three times a week (n = 42) or on-demand treatment (n = 42). The 781
Review median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on-demand treatment (total: 0 vs. 545; total per year: 0 vs. 279; both P < 00001), demonstrating the benefits of secondary prophylaxis in an adult population. Lifelong prophylaxis in severe haemophilia almost eliminates joint bleeds even later in life as a Swedish retrospective study showed: only 36% of all patients experienced a joint bleed in a 3-year period and more than a half of those had only one or two bleeds in this period (Khawaji et al, 2012). In comparison, patients treated on-demand are likely to have 30–35 joint bleeds per year (Aledort et al, 1994). Quality of life measurements show significant improvement of ‘bodily pain’ and ‘physical component summary’ when patients are on prophylaxis compared to those given on-demand treatment (Valentino et al, 2012). Many adults discontinue their prophylaxis at some point, often for the first time in their early 20s. Because of early prophylaxis as a child, many of these patients have experienced very few joint bleeds at this time, a median of three in one study (van Dijk et al, 2005). In a 18-month, observational, case–controlled, multicentre study (TEEN/TWEN study) which evaluated long-term prophylaxis and the consequences of switching from prophylaxis to on-demand treatment in late teens and young adults with severe haemophilia A, the number of bleeding events increased and health-related quality of life worsened in late teens and young adults with severe haemophilia A who switched to on-demand treatment (MancoJohnson et al, 2013b). The switch to on-demand treatment can be successful, but those who discontinue prophylaxis successfully are those with a milder bleeding pattern (Fischer et al, 2001). The adult often has a more scheduled, sedentary lifestyle with planned physical activities and a job that makes it possible to follow a tailored individual prophylaxis programme. Opinions vary as to whether adults should continue on prophylaxis, which can be illustrated by a survey of the treatment regimens at 21 European centres treating 5000 patients (Richards et al, 2007). The ageing patient. Today, life expectancy for people with severe and moderate haemophilia has increased dramatically and reaches 75 years for men with mild or moderate haemophilia and 63 years for those with severe haemophilia and without HIV in a study in the UK (Darby et al, 2007). However, the clinical experience of patients with haemophilia over 65 years of age is limited. The main issues in the elderly patient with haemophilia are – as for the general population – ischaemic heart disease, atrial fibrillation, cancer, neurological diseases and musculoskeletal diseases. The general consensus is that the ageing patient with haemophilia should be a candidate for secondary prophylaxis treatment, so that they are able receive similar treatment as the general population for various disorders (Coppola et al, 2013). However, more research is needed for evidence-based recommendations on prophylaxis in elderly patients. 782
Choice of FVIII/IX product Plasma-derived (pd) products were the first products to be commercially available and are derived from large pools of human plasma. The main discussion to date has been their safety regarding the transmission of pathogens. With the use of several methods of viral inactivation and elimination, pathogen transmission with hepatitis B and C and HIV has not been reported since 1986 and has dramatically improved safety, especially in the prevention of transmission of known lipid-enveloped blood-borne viruses (Key & Negrier, 2007). No transmission of any pathogen has been reported so far with recombinant clotting factor concentrates (Di Minno et al, 2013). Theoretically, cell culture media or growth factors could contain pathogens, but today the latest generations of FVIII/IX concentrates do not contain animal or human components. However, the first generation rFVIII contained bovine or human serum albumin, the second generation had non-protein stabilizers but still used trace amounts of animal/human derived material, while the third generation rFVIII and rFIX totally lack bovine and/or human protein. rFVIII may be ‘full-length’ or ‘B-domain deleted’ produced in baby hamster kidney or Chinese hamster ovary cells. A rFVIII produced in a human cell line is currently undergoing phase III study (Valentino et al, 2014). The immunogenicity of pd factor concentrates compared to recombinant (r) products, but also differences between recombinant products, has been, and is still, discussed, but mainly in patients with haemophilia A. One view is that pdFVIII, which contains substantial amounts of von Willebrand factor could be less immunogenic (Mannucci, 2010). Contradictory results have been found in several recent studies and reviews (Gouw et al, 2007; Iorio et al, 2010). The RODIN study, which observed 574 PUPs with severe haemophilia A, found a similar risk for inhibitor development in patients treated with rFVIII and pdFVIII (Gouw et al, 2013b) as did the CANAL study (Gouw et al, 2007). Furthermore, no difference has been observed in inhibitor development when switching between different products in previously treated patients (Vermylen, 1998). Studies are still on-going, such as the Survey of Inhibitors in Plasma-Product Exposed Toddlers study (Mannucci et al, 2007), which compares pd with recombinant products. Three recent studies have suggested a higher frequency of inhibitors in previously untreated patients with severe haemophilia A when using specific second- generation products (Gouw et al, 2013b; Calvez et al, 2014; Collins et al, 2014). These findings still need to be confirmed convincingly and explained biologically. Novel longer-acting products are now being introduced or are in the pipeline from several manufacturers (Oldenburg & Albert, 2014). The half-life is only moderately prolonged in rFVIII (15-fold) but significantly prolonged in rFIX (fourto fivefold). It will be a challenge for the clinicians and the haemophilia centres to deal with an extended variety of ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 777–786
Review break-through bleeds, subclinical micro-bleeds and allowance of sport activities (Fig 1). On the other hand, depending on costs, it opens a scenario that persons with haemophilia with today’s frequency of injections can reach a trough level of mild haemophilia, which would be a paradigm shift.
Conclusions
Fig 1. An illustration of the differences in peak and trough levels as well as area under the curve between a conventional and a long-acting factor IX (FIX) product. What is the impact on the number of breakthrough bleeds and allowance for sport activities?
products with different pharmacokinetics and need of modified FVIII assays. One principle for prolonging half-life is to fuse FVIII/IX with the Fc of immunoglobulin G or albumin. BiogenIdec is using Fc, resulting in a rFIX-Fc and a B-domain deleted rFVIII-Fc, while CSL-Behring is using albumin as the fusion protein, rIX–FP. The other principle for prolonging action is pegylation, which reduces the interaction with clearance receptors, resulting in prolongation of elimination by the kidneys and liver. To date, there are three pegylated FVIII in clinical phase III studies, all showing a prolonged FVIII half-time of approximately 15-fold, similar to the fusion proteins (Mei et al, 2010; Turecek et al, 2012; Coyle et al, 2014). The new prolonged FIX products have been more successful, with a four- to fivefold increase in half-time (Powell et al, 2013); for example, the pegylated FIX product by Novo Nordisk showed a fivefold prolongation in clinical studies (Negrier et al, 2011). Products with a prolonged half-life will be helpful for patients with difficult venous access and will most certainly boost compliance. However, experience gained from the shorter-acting products may not be transferable without some considerations. Depending on the dose and frequency of injections, most patients will probably spend a longer time under a certain area under the curve concentration and have fewer peak concentrations, which we need to establish the consequences for in terms of the risk of
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Initiating prophylactic treatment at an early age, primary prophylaxis, is considered to be the optimal form of therapy for a child with haemophilia. The aim of secondary prophylaxis is to avoid progression of joint disease, although it has been shown that secondary prophylaxis is also beneficial in patients who have already developed joint disease and there are arguments for continuing it into adulthood. In the ageing patient with haemophilia, and often with co-morbidities, the general consensus is that secondary prophylaxis should be given, although more research in this patient population is needed. There is no evidence for treating children with haemophilia A any differently to those with haemophilia B. The dose of prophylaxis is dependent on the aim of treatment, the bleeding phenotype, daily activity, economic resources and venous access and should be tailored individually. PK is helpful in this respect. Application of PK monitoring will be even more important with the new long-acting concentrates now being introduced. Several studies have suggested that starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on-demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer-acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels. While potentially improving life for the patient with haemophilia, the challenge for clinicians and haemophilia centres will be how to deal with these new products with their different PK and possible need of modified FVIII assays.
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Oldenburg, J. & Albert, T. (2014) Novel products for haemostasis – current status. Haemophilia, 20, 23–28. Oldenburg, J., Zimmermann, R., Katsarou, O., Theodossiades, G., Zanon, E., Niemann, B., Kellermann, E. & Lundin, B.; Cross-sectional MRI study investigators. (2014) Controlled, cross-sectional MRI evaluation of joint status in severe haemophilia A patients treated with prophylaxis vs. on demand. Haemophilia, doi:10.1111/ hae.12539 [Epub ahead of print]. Pettersson, H., Ahlberg, A. & Nilsson, I.M. (1980) A radiologic classification of hemophilic arthropathy. Clinical Orthopaedics and Related Research, 149, 153–159. Powell, J.S., Pasi, K.J., Ragni, M.V., Ozelo, M.C., Valentino, L.A., Mahlangu, J.N., Josephson, N.C., Perry, D., Manco-Johnson, M.J., Apte, S., Baker, R.I., Chan, G.C., Novitzky, N., Wong, R.S., Krassova, S., Allen, G., Jiang, H., Innes, A., Li, S., Cristiano, L.M., Goyal, J., Sommer, J.M., Dumont, J.A., Nugent, K., Vigliani, G., Brennan, A., Luk, A. & Pierce, G.F.; B-LONG Investigators. (2013) Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B. New England Journal of Medicine, 369, 2313–2323. Powell, J., Shapiro, A., Ragni, M., Negrier, C., Windyga, J., Ozelo, M., Pasi, J., Baker, R., Potts, J., Li, S., Mei, B., Pierce, G.F. & Robinson, B. (2015) Switching to recombinant factor IX Fc fusion protein prophylaxis results in fewer infusions, decreased factor IX consumption and lower bleeding rates. British Journal of Haematology, 168, 113–123. Ramgren, O. (1962) Haemophilia in Sweden. III. Symptomatology, with special reference to differences between haemophilia A and B. Acta Medica Scandinavica, 171, 237–242. Richards, M., Altisent, C., Batorova, A., Chambost, H., Dolan, G., de Moerloose, P., Fraga, M., Hermans, C., Karafoulidou, A., Klamroth, R., Lassila, R. & Rothschild, C. (2007) Should prophylaxis be used in adolescent and adult patients with severe haemophilia? An European survey of practice and outcome data. Haemophilia, 13, 473–479. Richards, M., Williams, M., Chalmers, E., Liesner, R., Collins, P., Vidler, V. & Hanley, J.; Paediatric Working Party of the United Kingdom Haemophilia Doctors’ Organisation. (2010) A United Kingdom Haemophilia Centre Doctors’ Organization guideline approved by the British Committee for Standards in Haematology: guideline on the use of prophylactic factor VIII concentrate in children and adults with severe haemophilia A. British Journal of Haematology, 149, 498–507. Santagostino, E., Mancuso, M.E., Rocino, A., Mancuso, G., Mazzucconi, M.G., Tagliaferri, A., Messina, M. & Mannucci, P.M. (2005) Environmental risk factors for inhibitor development in children with haemophilia A: a case–control study. British Journal of Haematology, 130, 422– 427.
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The current status of prophylactic replacement therapy in children and adults with haemophilia Rolf Ljung1,2 and Nadine Gretenkort Andersson2 1
Department of Clinical Sciences Lund-Paediatrics, Lund University, Lund, and 2Department of Paediatrics and Malm€o Centre for Thrombosis and Haemostasis, Sk ane University Hospital, Malm€o, Sweden
Summary Initiating prophylactic treatment at an early age is considered to be the optimal form of therapy for a child with haemophilia A or B. The pioneering long term experiences of prophylactic treatment from Sweden and The Netherlands demonstrated the benefit of prophylaxis in retrospective and observational studies. Decades later, these benefits were confirmed in a randomized controlled study in USA. We review the current status of prophylactic replacement therapy of haemophilia in children, adolescents, adults and the elderly. Prophylaxis should begin at an early age and there are arguments for continuing it into adulthood. The dose of prophylaxis is dependent on the goal of treatment, economic resources and venous access and should be tailored individually. Starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on-demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer-acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels. Keywords: haemophilia A, haemophilia B, factor VIII, factor IX, prophylaxis. Haemophilia A and B are hereditary, X-chromosomal recessive disorders caused by deficiency or absence of coagulation factors VIII (FVIII) or IX (FIX) in the blood and, depending on the concentration of FVIII or FIX coagulant activity, the disorders may be classified as severe (5% to >40%). In patients with the more severe forms of the disease, i.e. FVIII or IX concentrations in plasma 1 iu/dl and at the same time reduced bleeding episodes compared with conventional FIX prophylaxis (Powell et al, 2015). ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 777–786
Review
Prophylactic treatment in different periods of life Childhood It has been suggested in several studies that in haemophilia A patients, starting the first 20 exposures as prophylactic treatment, instead of on-demand due to a bleed, decreases the frequency of inhibitors (Morado et al, 2005; Santagostino et al, 2005; Gouw et al, 2007; Kurnik et al, 2014). In the Italian case–control study (n = 25 cases/32 controls) reported by Santagostino et al (2005), the OR was 03 [95% confidence interval (CI) 01–09] for development of an inhibitor if treatment was started as prophylaxis. Similar results were obtained by Gouw et al (2007) in the CANAL (Concerted Action on Neutralizing Antibodies in severe haemophilia A) study, which was a retrospective observational study (n = 366), where the risk rate was 05 (95% CI 02–09) for inhibitor in the prophylactic group. The RODIN [Research Of Determinants of INhibitor Development among previously untreated patients (PUPs) with haemophilia] study (Gouw et al, 2013a), which is a prospective observational study (n = 574), did not show any difference in the rate of inhibitors during the first 20 exposure days between prophylaxis and on-demand treatment. However, after the first 20 exposure days, prophylaxis was associated with a hazard ratio of 068 (95% CI 047–099), i.e. a protective effect and the inhibitors that developed were mainly low titre. The interpretation of these results is that some patients with high-risk mutations will develop inhibitors whatever treatment they receive during the first 20 exposure days. However, in the non-high risk patients it seems that it may be possible to modify the risk of inhibitors by the way they are treated, i.e. prophylactic or on-demand. Another aspect to discuss when beginning treatment of haemophilia A, is the avoidance of ‘immunological danger signals’ such as inflammation/infection/vaccination, vigorous treatment with high doses on consecutive days or surgical procedures. Two German centres reported an unexpectedly low frequency of inhibitors after starting prophylaxis at a young age before the onset of bleeds and avoiding ‘immunological danger signals’ (Auerswald et al, 2012). However, these results were not reproduced in the Early Prophylaxis Immunologic Challenge study that was designed to address this hypothesis, the prospective study being interrupted when frequency of inhibitors was above 30% (https://clinicaltrials.gov/ct2/show/study/NCT01376700, Gomez et al, 2014). However, data from the RODIN study as well as a study from the UK show that peak treatment moments, usually defined as treatment with high doses (30–50 units/ kg) during 3–5–10 consecutive days during the first 20 exposure days increases the risk of inhibitor by a factor of 2–3 (Maclean et al, 2011; Gouw et al, 2013a). It should be borne in mind, however, that the discussion of mode of treatment and risk of inhibitors has been limited to ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 777–786
haemophilia A and cannot be extrapolated to patients with haemophilia B. Venous access may be a problem, particularly in the youngest children. The first choice should be a peripheral vein and in most cases this will be successful. However, venous access can be very difficult or even impossible and it may be necessary to consider a central venous line. Several reports have described various adverse effects associated with the use of central venous catheters in patients with haemophilia, and infections were the most frequent complication (Ljung, 2007). The decision to use a central venous catheter is a compromise between the medical goal, the bleeding tendency, the social situation of the patient and familiarity with the devices at the particular haemophilia centre. Teenagers and young adults. Problems with adherence to a prophylactic regimen and denial often occur in the teenage period (Fischer et al, 2001) and can be challenging to deal with. The average age at which patients start to take primary responsibility of haemophilia is 141 years (Lindvall et al, 2006). From several studies we know that peers are important and a multidisciplinary approach together with parents, nurses and physicians may be the best way forward. Many teenagers with severe and moderate haemophilia have already learned to practise self-infusion as children and will thus be more independent during their teenage years. The intensity of physical activity is often a matter of discussion. A recent study showed that children and adolescents with moderate and severe haemophilia undergoing vigorous physical activity (e.g. wrestling) only showed a transient and small increased risk of bleeds (Broderick et al, 2012a). Electronic devices can be of supportive help and mobile technology can help to give information about haemophilia and networks, it can help to remind patients to take their treatment, get data for stock control and payer purposes, give instant guidance or treatment advice and enable a fast communication between healthcare professionals and the patient (Khair, 2014). For example, short message texting can help to facilitate prompt information about bleeding episodes (Broderick et al, 2012b). Adults. While prophylaxis in children has become the standard treatment in developed countries, the continuation of prophylaxis in adulthood is still under debate, even though there is evidence that it is beneficial in adults too. The recently published SPINART (Trial to Evaluate the Effect of Secondary Prophylaxis With rFVIII Therapy in Severe Hemophilia A Adult and/or Adolescent Subjects Compared to That of Episodic Treatment) study (Manco-Johnson et al, 2013a) is the first, prospective, controlled, randomized, parallel group design study comparing routine prophylaxis with ondemand treatment in adults with severe haemophila A. Eighty-four patients, mean age, 306 years, were enrolled and randomized to prophylaxis 25 units/kg per three times a week (n = 42) or on-demand treatment (n = 42). The 781
Review median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on-demand treatment (total: 0 vs. 545; total per year: 0 vs. 279; both P < 00001), demonstrating the benefits of secondary prophylaxis in an adult population. Lifelong prophylaxis in severe haemophilia almost eliminates joint bleeds even later in life as a Swedish retrospective study showed: only 36% of all patients experienced a joint bleed in a 3-year period and more than a half of those had only one or two bleeds in this period (Khawaji et al, 2012). In comparison, patients treated on-demand are likely to have 30–35 joint bleeds per year (Aledort et al, 1994). Quality of life measurements show significant improvement of ‘bodily pain’ and ‘physical component summary’ when patients are on prophylaxis compared to those given on-demand treatment (Valentino et al, 2012). Many adults discontinue their prophylaxis at some point, often for the first time in their early 20s. Because of early prophylaxis as a child, many of these patients have experienced very few joint bleeds at this time, a median of three in one study (van Dijk et al, 2005). In a 18-month, observational, case–controlled, multicentre study (TEEN/TWEN study) which evaluated long-term prophylaxis and the consequences of switching from prophylaxis to on-demand treatment in late teens and young adults with severe haemophilia A, the number of bleeding events increased and health-related quality of life worsened in late teens and young adults with severe haemophilia A who switched to on-demand treatment (MancoJohnson et al, 2013b). The switch to on-demand treatment can be successful, but those who discontinue prophylaxis successfully are those with a milder bleeding pattern (Fischer et al, 2001). The adult often has a more scheduled, sedentary lifestyle with planned physical activities and a job that makes it possible to follow a tailored individual prophylaxis programme. Opinions vary as to whether adults should continue on prophylaxis, which can be illustrated by a survey of the treatment regimens at 21 European centres treating 5000 patients (Richards et al, 2007). The ageing patient. Today, life expectancy for people with severe and moderate haemophilia has increased dramatically and reaches 75 years for men with mild or moderate haemophilia and 63 years for those with severe haemophilia and without HIV in a study in the UK (Darby et al, 2007). However, the clinical experience of patients with haemophilia over 65 years of age is limited. The main issues in the elderly patient with haemophilia are – as for the general population – ischaemic heart disease, atrial fibrillation, cancer, neurological diseases and musculoskeletal diseases. The general consensus is that the ageing patient with haemophilia should be a candidate for secondary prophylaxis treatment, so that they are able receive similar treatment as the general population for various disorders (Coppola et al, 2013). However, more research is needed for evidence-based recommendations on prophylaxis in elderly patients. 782
Choice of FVIII/IX product Plasma-derived (pd) products were the first products to be commercially available and are derived from large pools of human plasma. The main discussion to date has been their safety regarding the transmission of pathogens. With the use of several methods of viral inactivation and elimination, pathogen transmission with hepatitis B and C and HIV has not been reported since 1986 and has dramatically improved safety, especially in the prevention of transmission of known lipid-enveloped blood-borne viruses (Key & Negrier, 2007). No transmission of any pathogen has been reported so far with recombinant clotting factor concentrates (Di Minno et al, 2013). Theoretically, cell culture media or growth factors could contain pathogens, but today the latest generations of FVIII/IX concentrates do not contain animal or human components. However, the first generation rFVIII contained bovine or human serum albumin, the second generation had non-protein stabilizers but still used trace amounts of animal/human derived material, while the third generation rFVIII and rFIX totally lack bovine and/or human protein. rFVIII may be ‘full-length’ or ‘B-domain deleted’ produced in baby hamster kidney or Chinese hamster ovary cells. A rFVIII produced in a human cell line is currently undergoing phase III study (Valentino et al, 2014). The immunogenicity of pd factor concentrates compared to recombinant (r) products, but also differences between recombinant products, has been, and is still, discussed, but mainly in patients with haemophilia A. One view is that pdFVIII, which contains substantial amounts of von Willebrand factor could be less immunogenic (Mannucci, 2010). Contradictory results have been found in several recent studies and reviews (Gouw et al, 2007; Iorio et al, 2010). The RODIN study, which observed 574 PUPs with severe haemophilia A, found a similar risk for inhibitor development in patients treated with rFVIII and pdFVIII (Gouw et al, 2013b) as did the CANAL study (Gouw et al, 2007). Furthermore, no difference has been observed in inhibitor development when switching between different products in previously treated patients (Vermylen, 1998). Studies are still on-going, such as the Survey of Inhibitors in Plasma-Product Exposed Toddlers study (Mannucci et al, 2007), which compares pd with recombinant products. Three recent studies have suggested a higher frequency of inhibitors in previously untreated patients with severe haemophilia A when using specific second- generation products (Gouw et al, 2013b; Calvez et al, 2014; Collins et al, 2014). These findings still need to be confirmed convincingly and explained biologically. Novel longer-acting products are now being introduced or are in the pipeline from several manufacturers (Oldenburg & Albert, 2014). The half-life is only moderately prolonged in rFVIII (15-fold) but significantly prolonged in rFIX (fourto fivefold). It will be a challenge for the clinicians and the haemophilia centres to deal with an extended variety of ª 2015 John Wiley & Sons Ltd British Journal of Haematology, 2015, 169, 777–786
Review break-through bleeds, subclinical micro-bleeds and allowance of sport activities (Fig 1). On the other hand, depending on costs, it opens a scenario that persons with haemophilia with today’s frequency of injections can reach a trough level of mild haemophilia, which would be a paradigm shift.
Conclusions
Fig 1. An illustration of the differences in peak and trough levels as well as area under the curve between a conventional and a long-acting factor IX (FIX) product. What is the impact on the number of breakthrough bleeds and allowance for sport activities?
products with different pharmacokinetics and need of modified FVIII assays. One principle for prolonging half-life is to fuse FVIII/IX with the Fc of immunoglobulin G or albumin. BiogenIdec is using Fc, resulting in a rFIX-Fc and a B-domain deleted rFVIII-Fc, while CSL-Behring is using albumin as the fusion protein, rIX–FP. The other principle for prolonging action is pegylation, which reduces the interaction with clearance receptors, resulting in prolongation of elimination by the kidneys and liver. To date, there are three pegylated FVIII in clinical phase III studies, all showing a prolonged FVIII half-time of approximately 15-fold, similar to the fusion proteins (Mei et al, 2010; Turecek et al, 2012; Coyle et al, 2014). The new prolonged FIX products have been more successful, with a four- to fivefold increase in half-time (Powell et al, 2013); for example, the pegylated FIX product by Novo Nordisk showed a fivefold prolongation in clinical studies (Negrier et al, 2011). Products with a prolonged half-life will be helpful for patients with difficult venous access and will most certainly boost compliance. However, experience gained from the shorter-acting products may not be transferable without some considerations. Depending on the dose and frequency of injections, most patients will probably spend a longer time under a certain area under the curve concentration and have fewer peak concentrations, which we need to establish the consequences for in terms of the risk of
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Initiating prophylactic treatment at an early age, primary prophylaxis, is considered to be the optimal form of therapy for a child with haemophilia. The aim of secondary prophylaxis is to avoid progression of joint disease, although it has been shown that secondary prophylaxis is also beneficial in patients who have already developed joint disease and there are arguments for continuing it into adulthood. In the ageing patient with haemophilia, and often with co-morbidities, the general consensus is that secondary prophylaxis should be given, although more research in this patient population is needed. There is no evidence for treating children with haemophilia A any differently to those with haemophilia B. The dose of prophylaxis is dependent on the aim of treatment, the bleeding phenotype, daily activity, economic resources and venous access and should be tailored individually. PK is helpful in this respect. Application of PK monitoring will be even more important with the new long-acting concentrates now being introduced. Several studies have suggested that starting the first exposures to clotting factor concentrates as prophylactic treatment, instead of on-demand in response to a bleed, may decrease the frequency of inhibitors in patients with haemophilia A. Novel longer-acting products are being introduced that could be helpful for patients with difficult venous access and enable higher trough levels. While potentially improving life for the patient with haemophilia, the challenge for clinicians and haemophilia centres will be how to deal with these new products with their different PK and possible need of modified FVIII assays.
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