Achievements, challenges and unmet needs for haemophilia patients with inhibitors: Report from a symposium in Paris, France on 20 November 2014

Abstract

Over the past 20 years, there have been many advances in haemophilia treatment that have allowed patients to take greater control of their disease. However, the development of factor VIII (FVIII) inhibitors is the greatest complication of the disease and a challenge in the treatment of haemophilia making management of bleeding episodes difficult and surgical procedures very challenging. A meeting to discuss the unmet needs of haemophilia patients with inhibitors was held in Paris on 20 November 2014. Topics discussed were genetic and non-genetic risk factors for the development of inhibitors, immunological aspects of inhibitor development, FVIII products and inhibitor development, generation and functional properties of engineered antigen-specific T regulatory cells, suppression of immune responses to FVIII, prophylaxis in haemophilia patients with inhibitors, epitope mapping of FVIII inhibitors, current controversies in immune tolerance induction therapy, surgery in haemophilia patients with inhibitors and future perspectives for the treatment of haemophilia patients with inhibitors. A summary of the key points discussed is presented in this paper.

Keywords: FVIII products; genetics; haemophilia; inhibitors; prophylaxis; surgery.

Fig. 1

Cumulative incidence of inhibitor development: all inhibitors, and high- and low-titre inhibitors [11].

Fig. 2

Levels of anti-FVIII IgG in un-injured mice and those treated 1 or 14 days after injury. From Peyron et al. Haemophilia 2015 [29].

Fig. 3

Clinical application of engineered Treg therapy.

Fig. 4

New target joints and associated bleeding episodes [58].

Fig. 5

Predictive performance of the best markers. (a–e) The plasma levels, expressed as relative antigenic reactivity (RAR), of IgGs against the (a) heavy chain (HC) (b) A1 domain, (c) A2 domain, (d) light chain (LC) and (e) C2 domain of FVIII, measured before immune tolerance induction (ITI) initiation in 15 children with haemophilia A who had successful ITI (n = 7) (white boxplot) in whom ITI failed (n = 8) (grey boxplot), were compared by use of the Wilcoxon test. Similar analyses were carried out for currently used indicators. (f) An example of the highest inhibitor peak recorded before ITI (PEAK BEF–ITI), expressed in Bethesda Units (BU) per mL. The Tukey boxplots show the median value as a dash within the box, and outside dots mark the outliers. The significance level was set at 5% [76].

Fig. 6

Influence of pre-ITI titre on treatment success [87,88].

Fig. 7

Regular prophylaxis and the cumulative incidence of inhibitor development. The RR for regular prophylaxis was 1.0 in the period from 1 to 10 exposure days, 0.95 from 11 to 20 exposure days, 0.22 from 21 to 30 exposure days, 0.27 from 31 to 40 exposure days and 0.32 from 41 to 75 exposure days [135].