New early prophylaxis regimen that avoids immunological danger signals can reduce FVIII inhibitor development

Abstract

The most problematic complication of haemophilia A treatment is the development of inhibitors to FVIII. The highest risk of developing inhibitors is during the first 20 exposure days (EDs). If the patient can be brought through this high risk period without inhibitor development, the subsequent risk is low. Therefore, as a pilot project, we developed a prophylaxis regimen for the first 20-50 EDs specifically designed to induce tolerance to the administered FVIII and to minimize inhibitor development by avoiding immunological danger signals. Twenty-six consecutive previously untreated patients (PUPs) with severe haemophilia A were treated with the new prophylaxis regimen and the incidence of inhibitor development in this group was compared with that in a historical control group of 30 consecutive PUPs treated with a standard joint protection prophylaxis regimen (40-50 IU kg(-1), three times a week). There were no significant differences between the study and control groups in patient-related inhibitor risk factors such as ethnicity (all Caucasian), severity of haemophilia (all <1% FVIII), severity of FVIII gene mutation (P < 0.0006) nor in some treatment-related factors such as product type, age at first exposure, vaccination regimen or the need for surgery. 14 of 30 subjects given standard prophylaxis but only one of the 26 subjects given the new regimen developed an inhibitor (P = 0.0003, odds ratio 0.048, 95% CI: 0.001-0.372). Our results indicate that minimizing danger signals during the first 20 EDs with FVIII may reduce the risk of inhibitor formation. These results should be confirmed in a larger prospective clinical study.