English Español

Immune Tolerance Induction (ITI)

For inhibitor patients the replacement therapy with clotting factor concentrates is ineffective unless inhibitors are eliminated. Presence of inhibitors not only has major adverse implications for quality of life, but also impacts dramatically on the cost of care in haemophilia by increasing overall treatment costs of 3 to 5 fold 1-2. Therefore Immune Tolerance Induction (ITI) has become the strategy of choice for these patients. ITI, involving repeated and persistent treatment with FVIII replacement, is the only proven strategy for FVIII inhibitor eradication as has been firstly demonstrated by Brackman & Gormsen in 1977 3-4.

During these investigations high dose FVIII treatment according to the "Bonn Protocol" has been proven efficacious in more than 80 % of the patients.

Success rates of ITI treatment may vary depending on the patient variables (age, inflammation, maximum inhibitor titre and underlying genetic defect). Another factor is the therapeutic approach (inhibitor titre at start of ITI, ITI regimen, interval between detection of inhibitor and start of ITI, interruption of ITI, concomitant use of bypassing agents, vaccination and surgery) as well as the chosen product, in particular the purity and content of von Willebrand factor (VWF). Several in-vitro studies testing inhibitor plasma samples against FVIII concentrates with high VWF content have shown lower FVIII inhibitor titres compared to products with low VWF content 5-6. Moreover, clinical experience in Germany showed that before and early 1990s ITI was successful in 87% (Bonn/Bremen) and 91% (Frankfurt) of patients when Bonn protocol and VWF-containing FVIII concentrates were used. Since 1993 success rates dropped to 54% and 29% when high-purity concentrates, recombinant or monoclonally purified, lacking VWF were primarily used. Resumed use of VWF-containing FVIII concentrates enabled tolerisation rates to return to 82% and 80% 7-8. Further studies are needed to better understand how to best achieve tolerance for inhibitors and in particular the effect of different FVIII concentrates on ITI success rate.

The present observation study will for the first time allow a systematic prospective and retrospective data documentation and analysis on the ITI success rate by using individualized concentrate selection. In addition, the investigators can also further correlate the success rate of therapy with the outcome of several satellite studies, which will enlighten the mechanism and risk factors of immune tolerance formation.

1 Leissinger CA. Prevention of bleeds in Haemophilia patients with inhibitors: emerging data and clinical direction. Am J Hematol 2004; 77: 187-93
2 Dimichele D et al. Inhibitors in haemophilia: clinical aspects. Haemophilia 2004; 10 (Suppl 4): 140-145
3 Brackmann H et al. Immune tolerance for the treatment of FVIII inhibitors - Twenty years "Bonn protocol". Vox Sang 1996; 70 (Suppl. 1):30-35
4 Hay CR et al. The diagnosis and management of factor VIII and IX inhibitors: A guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 2006; 133(6): 591-605.
5 Berntorp E et al. Variation in factor VIII inhibitor reactivity with different commercial factor VIII preparations. Haemophilia 1996; 2:95-96
6 Tagariello G et al. In vitro reactivity of factor VIII inhibitors with von Willebrand factor in different commercial factor VIII concentrates. Am J Hematol 2007; 82:460-462
7 Auerswald G et al. The role of plasma-derived factor VIII/von Willebrand factor concentrates in the treatment of haemophilia A patients. Haematologica 2003; 88:EREP05
8 Kreuz W et al. Immune tolerance induction (ITI) in haemophilia A - patients with inhibitors- the choice of concentrate affecting success. Haematologica 2001; 86 (Suppl 4):16-22

International open-label, uncontrolled, non-interventional, multi-centre observational program conducted by the HZRM, Frankfurt-Mörfelden, Germany