More than a decade of international experience with a pdFVIII/VWF concentrate in immune tolerance

Approximately 20-30% of patients with severe haemophilia A develop alloantibodies ('inhibitors') to infused FVIII rendering use of such replacement therapy ineffective. Once an inhibitor emerges, immune tolerance induction (ITI) is the standard treatment. ITI involves giving regular doses of FVIII concentrate to eradicate the inhibitor and achieve immunogenic acceptance of administered FVIII. In the early 2000s, a retrospective analysis of inhibitor patients treated at a single centre in Germany indicated that success rates were higher when patients were treated with von Willebrand factor (VWF)-containing plasma-derived FVIII (pdFVIII/VWF) concentrate compared with recombinant or non-VWF-containing pdFVIII products. Importantly, pdFVIII/VWF as rescue therapy was able to convert 8 of 10 patients who had failed primary ITI with recombinant or non-VWF-containing pdFVIII product. A subsequent study from Italy in patients with poor prognostic factors for ITI success also reported good success rates with pdFVIII/VWF as rescue therapy (53% success; 41% partial success). The Grifols-Immune Tolerance Induction (G-ITI) Study represents the largest group of haemophilia A inhibitor patients treated with a single pdFVIII/VWF concentrate (Alphanate(®)/Fanhdi(®)) to be reported to date. Data have been collected for 95 patients who underwent primary or rescue ITI at 46 centres in Europe and the US. Currently, published data are available for 33 patients in the US cohort (11 centres), and data from the European cohort are being analysed. Both groups contained patients with poor prognostic factors and most patients received a high-dose regimen (≥ 100 IU pdFVIII/VWF kg(-1) daily). As expected, the success rate was better for primary vs. rescue ITI and for patients with good vs. poor prognostic factors. However, more than half the patients in the US cohort receiving rescue ITI achieved success (33% complete success; 20% partial success). These results should encourage clinicians to consider the use of pdFVIII/VWF concentrates for rescue ITI. Published outcomes data from the total global G-ITI cohort (95 patients) are awaited with anticipation.