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Keywords:

  • haemophilia A;
  • Factor VIII inhibitors;
  • immune tolerance induction;
  • factor VIII bypassing activity

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

Summary.  Anamestic inhibitors represent the major complication of haemophilia therapy now that clotting factor concentrates are virtually free of pathogen-transmission risk. Conventional clotting factor replacement is usually insufficient to prevent or treat bleeding in a haemophilia patient with a high responding inhibitor so that alternative treatment with bypassing agents is required. Despite their relative efficacy, their use does not achieve the same invariable haemostasis that patients without inhibitors do following treatment with factor concentrate replacement. This has led to the attempt to eradicate such inhibitors with immune tolerance induction. Success is not invariable, however, and many patients with long-term persistent high-titre inhibitors continue to experience great morbidity. Recently, this has given rise on a limited basis to attempts to use bypassing agents in prophylaxis regimens in an effort to alleviate this extreme morbidity. Each of these strategies is discussed in the context of their relative benefits and risks.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

The development of inhibitory antibodies continues to jeopardize the effectiveness of haemophilia treatment. In the case of low-responding inhibitors, the neutralizing effect can be overcome with saturating levels of the deficient factor. However, high responding inhibitors present special therapeutic challenges: factor VIII (FVIII) is rarely effective so that bypassing agents such as factor eight inhibitor bypassing activity (FEIBA) or recombinant factor VIIa (rFVIIa) are typically required to treat acute bleeding. Despite these options, efficacy usually does not approach FVIII in the non-inhibitor setting. Hence, an attempt to eradicate the inhibitor through immune tolerance induction (ITI) is often warranted despite the hurdles that typically accompany this strategy. For severe situations (either when ITI has failed or is not feasible, for example), prevention of bleeding (secondary prophylaxis) with bypassing agents may be warranted. Each of these therapeutic options will be considered in this discussion.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

Bypassing therapies for patients with inhibitors

Factor eight inhibitor bypassing activity (FEIBA) is an activated prothrombin complex concentrate (APCC) consisting of the vitamin K-dependent proteins: FII, FVII, FIX and FX in the native as well as in the activated forms together with some minor anticoagulant activity [1]. The pharmacodynamic half-life of FEIBA is 4–7 h as measured by thrombin generation assay [2]. The main contributors to the haemostatic activity are the complex formation of activated FX (FXa) and FII generating thrombin in the prothrombinase complex [1]. FVIIa in FEIBA enhances the haemostatic effect, but otherwise plays no major role in the mechanism of action.

Recombinant factor VIIa enhances thrombin formation on the platelet surface by activating FX to FXa [3]. Importantly, high concentrations of rFVIIa have the ability to activate FX independent of tissue factor (TF). However, the presence of this cofactor will substantially improve the haemostatic potential. The half-life of rFVIIa is shorter than for APCC, i.e. between 2 and 3 h in adults and 1.5 h in children [4].

Haemostatic effect of bypassing agents

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

A number of studies have evaluated the effect of FEIBA and rFVIIa, but to date, only two head-to-head studies have been conducted. In the FENOC study, the haemostatic effect of each drug was evaluated in a cross-over equivalence study design in 48 subjects with two consecutive joint bleeds [5,6]. The efficacy of each drug at the primary end-point of 6 h was measured by a dichotomous outcome (effective/not effective). The results showed a rating of 80.1% effective for FEIBA and 78.1% for rFVIIa, close to the predetermined criteria for declaring equivalence. Self-reported pain scores on a visual analogue scale (VAS) were shown to be statistically equivalent between the two drugs. One of the main findings of the study, however, was that despite the high efficacy of both drugs, substantial within-individual discordance with respect to ratings between the products was observed. At the 2-h time point, 43.8% of the subjects rated one product effective and the other product not effective in their haemostatic effect. There was no significant preference for either drug. At the primary endpoint at 6 h, the corresponding figure was 31.9.

The study by Young and co-workers consisted of three arms evaluating the effect at 9 h of three doses of 90 μg kg−1 rFVIIa administered every 3 h, one dose of 270 μg kg−1 rFVIIa and one dose FEIBA 75 IU kg−1 in 21 of 42 randomized patients [7]. No significant differences in the treatment response were observed among the three arms using a global assessment score (54.5%, 37.5% and 27.3%, respectively), but a higher percentage of subjects required additional haemostatics after the dose of FEIBA (36.4%) compared with the higher dose of rFVIIa (8.3%). No significant findings were reported for the group receiving repeated 90 μg doses of rFVIIa.

In other studies, in which only one of the drugs has been evaluated, efficacy in the acute setting varies between 50% and 100% depending on the time between the onset of the bleed and start of treatment, the dose, the dose interval, the number of doses given, the time of evaluation as well as the location of the bleed [8–21]. Altogether, the data clearly demonstrate the potency of the drugs to promote haemostasis, but also that neither of them is the ultimate option for inducing an optimal haemostatic effect in all patients and for all type of bleeds. Hence, monotherapy will fail in a fraction of patients and bleeds, and this will further contribute to the harm that a bleed might cause, both in the short and long term. Unfortunately, there is currently no reliable method to predict the outcome of treatment in vitro, and therefore, recent data comparing the effect of each drug in siblings might add valuable information for the clinical management of patients [22]. In the study by Klintman and co-workers, there was a significantly lower variation in the thrombin formed within families compared with that between unrelated individuals (< 0.001 for both drugs, respectively).

Reasons for a differential response

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

A differential effect of the bypassing activity based on the impact on clot stability and the amount of thrombin and FXa formed has been suggested [23]. A rapidly propagated and sustained thrombin formation is pivotal for preventing a premature breakdown of fibrin by fibrinolytic activation, thrombin-activated FXIIIa-mediated crosslinking of fibrin monomers and α2-antiplasmin as well as TAFI activation. In addition, thrombin might counteract the binding of PAI-1 to FXa, thereby facilitating the tPA-induced fibrinolysis.

The amount of thrombin formed is dependent on the surface at which the coagulation cascade will act, and in this context, the platelets will constitute an important role [3,24]. In addition, platelets supply factors that further promote haemostasis. Hence, the number of platelets as well as platelet characteristics including platelet-binding proteins will potentially have a major impact on the procoagulant activity of both drugs.

Tissue factor is a member of the cytokine receptor superfamily and exerts in the complex with factor VII/VIIa both procoagulant and signalling activities [25]. As the TF expression is tissue-dependent and probably also to some extent varies between individuals, this is another factor that might be relevant for the differential haemostatic effect of the two agents in some subjects and the reason why the location of the bleed might be important [26].

A modulation of the bleeding tendency in patients with haemophilia by factors in the anticoagulant and fibrinolytic systems has been suggested and this might also apply to the differential response [27]. Fifteen of 35 patients with severe haemophilia but a mild bleeding phenotype had abnormal thrombophilia markers compared with five of 37 patients with a severe phenotype (< 0.05). Given that several different mechanisms are involved, the significance of these findings remains unclear. In none of the cases, with the exception of TAFI, were the mean levels different between the two groups.

Allen and colleagues have shown that the FX and prothrombin concentration will influence thrombin generation in a cell-based model of haemophilia treated with rFVIIa [28]. At all concentrations of rFVIIa, increased prothrombin concentrations led to higher peak and rate of thrombin generation. This suggests that the level of prothrombotic factors besides FVIII and FIX will be able to modulate the effects of the bypassing products and also implies a benefit of the combined use of the two drugs.

Finally, cross-reacting antibodies towards rFVIIa have been described in both patients with haemophilia A and B and inhibitors [29]. In strict biological terms, this is not unexpected in patients with haemophilia B, as FIX is structurally similar to the other vitamin K-dependent factors. In the case of haemophilia A, however, it is harder to explain, although antibodies to FVIII have also been described in healthy subjects [30].

The future of bypassing therapy

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

Emerging data suggest that sequential and even the combined use of the two drugs with lower doses can be successful in cases of bleeds that are resistant to monotherapy [31,32]. Based on the different mechanisms of action, this is indeed an attractive approach. To help the physician in the management of resistant bleeds, an algorithm was recently published [33]. However, the thrombotic risk must be considered and more studies performed before sequential and combined use can be generally accepted as a therapeutic option in daily practice. This is also true for the new improved bypassing agents currently under exploration and trying to make their way to the market.

Immune tolerance induction

Immune tolerance induction is the only strategy proven to eradicate persistent inhibitors in severe haemophilia A patients [34]. Thirty-year ITI experience has shown high success rates (60–80%) with heterogeneous dose regimens [35] and has helped to define the patients’ prognostic profile. In the last years, international efforts have been focused on two large-scale randomized trials [36,37] aimed at providing solid evidences to support the choice of ITI regimens in different patient settings.

Predictors of ITI success

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

Predictors of ITI success were identified on the basis of the results from large retrospective ITI registries, i.e. the International Immune Tolerance Registry (IITR [38]), the North American Immune Tolerance Registry (NAITR [39]) and the German Immune Tolerance Registry (GITR [40]).

Low inhibitor titre before ITI start (<10 BU mL−1) and lack of intense anamnestic response (historical inhibitor peak titre <200 BU mL−1) were the most consistent predictors of ITI success. In the meta-analysis of data from the IITR and the NAITR [41]), low pre-ITI inhibitor titre (<10 BU mL−1) was also associated with a more rapid tolerization. Inhibitor peak titre during ITI resulted in a significant predictor of outcome according to the NAITR [39] and the PROFIT study [42]. Patients older than 20 years or with long-standing inhibitors (>5 years from diagnosis) showed poorer success rates in the IITR [38]; however, these findings were not confirmed in other Registries. Finally, the PROFIT study highlighted that severe FVIII gene defects were associated with a poorer likelihood of ITI success in comparison with less severe mutations [42], although this observation still needs to be confirmed in other series.

ITI dose regimens

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

Controversial data were provided by the registries with respect to the influence of FVIII dose on ITI outcome. A direct relationship between the dose and the ITI success was found in the IITR [38]; this finding was not confirmed in the NAITR, in which, however, the time to success was shorter when higher doses were administered [39].

Overall, these evidences provided the rationale for the International ITI (I-ITI) study aimed at evaluating the success rate and time to success in 150 patients with good prognostic profile randomized to receive FVIII doses of either 50 IU kg−1 three times weekly or 200 IU kg−1 daily. This study was prematurely terminated when 116 subjects had been randomized because a significantly greater number of bleeds (joint and non-joint sites) was observed in the low-dose arm during ITI and post-ITI prophylaxis, but particularly when inhibitors were still detectable [43]. ITI success rates were not different in the two treatment arms. However, ITI success was achieved more slowly in patients receiving the low-dose regimen [43].

These preliminary results raise concerns on the use of low-dose, non-daily ITI regimens in children with good prognostic profiles. Scarce data are available on the bleeding frequency of inhibitor patients before and during ITI. However, bypassing agent prophylaxis has been used in cases with severe bleeding or at risk of joint morbidity [44–46]. At this stage, further clinical studies and cost-effectiveness analysis are still warranted to identify safe and affordable ITI regimens in different patient settings.

Type of FVIII product and ITI outcome

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

Some results from retrospective series suggested a decline of ITI success rate after the introduction of monoclonal and recombinant FVIII (rFVIII) concentrates [47,48]. The influence of several confounding factors could not be ruled out in these uncontrolled series. However, the presence of von Willebrand factor (VWF) in pdFVIII has been proposed to contribute to ITI success. In addition, satisfactory success rates were reported in patients with poor prognostic factors receiving ITI with VWF-containing concentrates [49,50,51]. By contrast, the meta-analysis of data from the IITR and NAITR [41] as well as the PROFIT Registry [42] did not show any association between the type of FVIII product and ITI outcome. Predicated on these conflicting results, a randomized trial (the Rescue Immune Tolerance study, RESIST [37]) comparing high-dose (200 IU kg−1 day−1) ITI with either rFVIII or VWF/FVIII products is underway in patients with poor risk factors for successful ITI.

Current ITI practice and future perspectives

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References

Inhibitor eradication represents a cost-effective option in children with recently diagnosed inhibitors because, when successful, it enables FVIII prophylaxis for preventing or limiting arthropathy development [1,52]. To justify ITI strategies in adults, careful cost-utility considerations are required. However, ITI may represent a suitable approach in patients with frequent bleeding, which is not satisfactorily controlled by bypassing treatment and/or when orthopaedic surgery is urgently needed.

Data from small series have suggested that the addition of rituximab may increase the chance of ITI success in patients who have failed conventional ITI regimens [53,54]. However, the lack of data on long-term efficacy and safety of this approach raises concerns, particularly with respect to its use in paediatric patients [52].

Immune tolerance induction still needs to be improved because treatment interruptions, often caused by patients’ lack of adherence or venous access-related complications, are associated with failures and prolonged time to success [40]. Recent results from the I-ITI study showed that catheter-related infections occurred frequently during ITI, although the impact of infections on ITI outcome was not confirmed [43].

Increasing knowledge of genetic and immunological aspects of immune response to FVIII has already allowed the development of new approaches for achieving tolerization [55] and, although are many challenges to overcome in translating these insights to the clinic, strategies based on immune modulation appear to be an attainable perspective.

Secondary prophylaxis in patients with inhibitors

Primary prophylaxis has been demonstrated to prevent haemarthroses in young patients with severe haemophilia without inhibitors [56]. Whether an alternative treatment strategy (such as the use of a bypassing agent) could prove effective in preventing joint disease in a child with a new-onset high-titre inhibitor with pristine joints that develops while he is receiving primary prophylaxis has yet to be demonstrated. To date, all efforts to prevent bleeding have entailed a secondary prophylaxis strategy.

The use of bypassing agents for secondary prophylaxis has been described in the literature primarily through case reports for several decades, most notably during the first generation of the Bonn protocol for ITI [57,58]. Among infants, use of regular dosing of either FEIBA or rFVIIa following intracranial or intracerebral haemorrhage in neonates with inhibitors in an effort to forestall further central nervous system (CNS) bleeding following successful therapy of the primary event has become commonplace among haemophilia treaters in the developed world. Prophylaxis has also been utilized in other instances of intractable bleeding among haemophilia patients, particularly children [59].

Despite such use, controlled studies to determine efficacy have been few. Notably, Hilgartner, et al. undertook a prospective non-randomized study to determine whether prophylaxis with FEIBA could forestall joint disease progression in a small cohort of inhibitors with pre-existing joint disease. The authors concluded that while bleeding was attenuated, it was of sufficient clinical impact to prevent deterioration in joint function [60]. Leissinger et al. [61] in a retrospective study showed that FEIBA was effective in reducing the frequency of bleeding in paediatric patients. This generated a prospective study to determine comparative efficacy of prophylaxis vs. on-demand therapy with FEIBA (Pro-FEIBA) to assess whether there is sufficient amelioration of haemarthroses incidence to justify the cost and effort of prophylaxis. Results are pending.

The only published study of a randomized, controlled trial of a bypassing agent to ameliorate bleeding patterns among patients with historically high bleeding frequency was by Konkle, et al. [62]. In this study, 22 adult patients with severe haemarthropathy and documented high prevalence of haemarthroses subjects were randomized to receive one of two doses of rFVIIa (90 μg kg−1 dose−1 vs. 270 μg kg−1 dose−1) daily for three consecutive months. This followed a 3-month period of intensely monitored therapy during which time these individuals received their usual on-demand therapy. After completing the 3 months of secondary prophylaxis with rFVIIa, the study subjects also were followed during the final 3 months of on-demand therapy to ascertain whether any carry-over effects would attain from the prophylaxis. The primary prospective endpoint was number of haemarthroses for each 3-month period with each subject serving as his own control. Results showed a highly statistically significant reduction (P < 0.0001) for the cohort in haemarthrosis frequency during the period of secondary prophylaxis with rFVIIa, regardless of the dose to which they were randomized. Although there was a trend for the higher dose to produce greater reduction in haemarthrosis frequency compared with the 90 μg kg−1 daily dose (59% vs. 45% reduction), these differences were not statistically significant. The authors concluded that the results provide evidence that secondary prophylaxis with rFVIIa is feasible and perhaps, clinically justified.

In a companion paper, Hoots et al. [63] showed that in this rFVIIa study (Konkle et al. [62]), individuals exhibited a statistically significant improved attendance at work or school, improved health-related quality of life (HRQoL) as measured by the standardized EQ-5D, VAS and a time trade-off scale during the period they were receiving secondary prophylaxis. Furthermore, some of the improvements persisted during the third 3-month period of observation despite their being treated with on-demand therapy. For each variable examined, improvements paralleled those seen in joint bleeding frequency. The authors suggest that secondary prophylaxis may offer an avenue to sustained improvement in quality of life in patients with inhibitors. This is of particular importance as HRQoL has been demonstrated to be inferior in patients with inhibitors compared with those without inhibitors [64]. Financial costs of secondary prophylaxis for inhibitor patients can be very high [65]. This issue may limit the availability of secondary prophylaxis for many patients. It also provides an exigency for confirming the efficacy of each of the bypassing agents in controlled trials to justify the application of such substantial resources.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Discussion
  5. Haemostatic effect of bypassing agents
  6. Reasons for a differential response
  7. The future of bypassing therapy
  8. Predictors of ITI success
  9. ITI dose regimens
  10. Type of FVIII product and ITI outcome
  11. Current ITI practice and future perspectives
  12. Disclosures
  13. References