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November 16th, 2004 WFH Joint Symposium Review – Natural Proteins in the Treatment of Blood Disorders: Return to Reason
Professor Gringeri reviewed the main points of the clinical and biochemical background on the subject of concentrates in inhibitor development before presenting data from Italy and other European countries. The presence of VWF has been suggested by Amano et al to participate in the immunogenicity of FVIII concentrates since 1995. In 1996, Berntorp reported the different plasma activity after infusions of FVIII-VWF concentrate or monoclonally purified concentrate in a haemophilic patient with inhibitors. The different product reactivity could be confirmed in vitro. In the same year, Suzuki et al suggested that the C2 specificity of VWF could play a role in lowering the inhibitor reactivity of FVIII concentrates containing VWF. In 2000, the group of Sukhu showed a different inhibitor reactivity against monoclonally purified FVIII and pdFVIII-VWF concentrates in 8 patients with acquired haemophilia A. Kallas et al and Gensana et al suggested in 2001 an association between the inhibitor specificity for the FVIII light chain and the protective effect of VWF in FVIII concentrates. The systematic review of Wight and Paisley, University of Sheffield, UK, in 2003 evaluated the influence of different types of FVIII products in inhibitor development and brought together some key findings: The cumulative risk of inhibitor development in PUPs when treated with different pd concentrates was in the range of 20-33 %; however, when treated with a single pd concentrate, this risk was 0 % to slightly more than 12 %; when treated with a recombinant concentrate, the cumulative risk was in the range of 36 % to greater than 38 %. Professor Gringeri then compared almost 16 years of clinical experience in Italy with the product Emoclot (Kedrion), an ion exchange purified, solvent-detergent, virus-inactivated FVIII concentrate, without human albumin in the final formulation and without removal of VWF. In a retrospective study in 47 haemophilia centres, a total of 97 patients (70 [72 %] severe and 27 [28%] moderate) haemophilia patients were surveyed who had been treated with the concentrate in the period 1987 to 2003. These were either PUPs or minimally treated patients (MTPs) who had been exposed for no more than 5 days to other concentrates. The number of PUPs was 30 (31 %) and the number of MTPs 67 (69 %). The median age of the patients was 21.1 (6.0 – 64.0) years. The median number of exposure days was 64.5 (21 – 438).
The results of inhibitor development in this cohort of haemophilia A patients are shown. There were 7 inhibitors, all in the group of severe patients. Of these, 5 were low responders (< 5 BU) and 2 were high responders (> 5 BU). Of the low responders, 2 cleared inhibitors spontaneously. One high responder underwent ITI with complete resolution.
Taking the data from 8 European countries together (table), despite the fact that the study populations are heterogeneous and different inhibitor testing methods were used, a body of evidence now exists for the low immunogenicity of VWF-containing FVIII products. These show an overall figure for inhibitor development of 33/302 or 10.9 %. |
