Ablation of hemophillic FVIII inhibitors with FVIII priming, cyclophosphamide immune suppression, and rapid tapering of FVIII immune tolerance

The efficacy and toxicity of factor VIII (FVIII) priming, cyclophosphamide immune suppression, and rapid tapering of concurrent FVIII immune tolerance for subjects with hemophilic inhibitors were evaluated. Four subjects with hemophilic inhibitors were studied. Before treatment, inhibitors were present for a median of 8 months (mean 13 +/- 14.0 months). The median FVIII inhibitor titer was 16 BU/mL (mean 27.2 +/- 29.2 BU/mL). Following FVIII priming (80.0 +/- 70.2 U/kg), subjects received cyclophosphamide 1,418 +/- 636 mg/M-2 i.v. q3 weeks for 4.4 +/- 1.7 courses. Subjects concurrently received a low (6 U/kg/day), moderate (30 U/kg/ day), or high (100 U/kg/day) dose of FVIII followed by a rapid taper as the inhibitor titer decreased or resolved. During treatment, the inhibitor titer initially increased but then rapidly declined. Inhibitors resolved in 3.9 +/- 2.9 months. One inhibitor recurred at 2.8 years, but it was successfully re-treated. Effectiveness did not depend on the FVIII dose. Toxicity was minimal. Cyclophosphamide (1,400 mg/M-2)administered after a priming dose of FVIII (80 U/kg) i.v. q3 weeks for 2-6 cycles with a rapid taper of concurrently administered daily FVIII as the inhibitor titer falls is an effective approach to hemophilic inhibitor ablation. (C) 2004 Wiley-Liss, Inc.