Immune tolerance in hemophilia with factor VIII inhibitors: predictors of success.

BACKGROUND AND OBJECTIVES: Long term administration of high doses of factor VIII (FVIII) was shown to eliminate alloantibodies to FVIII (FVIII inhibitors). This procedure is widely referred to as immune tolerance (IT). DESIGN AND METHODS: In 1989 an international registry of IT protocols was created which recruited 314 patients with severe hemophilia A (HA) and an inhibitor who were given IT treatment. RESULTS: Fifty hemophilia care centers worldwide contributed data to the registry; 94.8% of the patients were high responders. The median inhibitor titer prior to IT (pre-titer) was 7 BU (range 0-720). The FVIII doses ranged from <50 International Units (I.U.)/kg/b.w./day to >200. At the end of IT, 140 patients had undetectable inhibitor titers, including 128 who also had normal FVIII kinetics. The remaining 174 patients included 66 with treatment failure, 23 who achieved partial responses, 48 patients in whom treatment was ongoing and 37 with data inadequate to evaluate outcome. Using logistic regression, the best predictive model for success included maximum inhibitor titer, pre-titer, dose and age at treatment. FVIII dose and pre-titer were also associated with treatment duration, as was the time between inhibitor detection and treatment. The risk of relapse was approximately 15% after 15 years of follow-up. INTERPRETATION AND CONCLUSIONS: This study underscores the importance of starting IT as early as possible, at the lowest inhibitor titer and with high FVIII doses in order to maximize the chance of treatment success and minimize treatment costs.