A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency

Abstract Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A. Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours. Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life. Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. Disclosures Belletrutti: Baxter Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring Canada: Honoraria.

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