Immune Tolerance Induction in Severe Hemophilia a Patients Using Wilate®, a Von Willebrand Factor/Factor VIII Concentrate

Abstract Introduction: To prevent and treat bleeding episodes, hemophilia A patients undergo factor VIII (FVIII) replacement therapy with either recombinant FVIII (r-FVIII) or plasma-derived FVIII (pd-FVIII). Approximately 32% of patients develop neutralizing antibodies to the FVIII protein rendering FVIII therapy ineffective (Gouw et al. N Engl J Med. 2013; 368:231-239). Development of these neutralizing antibodies, or ‘inhibitors’ is the most serious and challenging complication in the treatment of hemophilia A patients and represents the highest economic burden for a chronic disease (Gringeri et al. Blood 2003; 102:2358-2363). The standard approach for eradicating inhibitors is to tolerize the patient to FVIII through prolonged, daily exposure to high-dose FVIII – a process termed immune tolerance induction (ITI). Although costly, ITI can successfully eliminate inhibitors in a large proportion of low-risk patients, however there are several risk factors that reduce the likelihood of ITI success. For high-risk patients, the choice of drug product (r-FVIII versus pd-FVIII) may be particularly important. Several small studies have demonstrated the superiority of pd-FVIII for ITI, as these products contain the FVIII stabilizing protein, von Willebrand Factor (VWF) (Gringeri et al., Haemophilia 2007; 13:373-379). Wilate® (Octapharma) is a high-purity pd-FVIII complex that contains the two proteins (VWF and FVIII) in a 1:1 ratio. In this retrospective study, we present the patient history and outcome for four severe hemophilia A patients that have undergone ITI with Wilate®. Patients and Methods. All patients presented with severe FVIII deficiency (<1%). Only 1/4 patients had undergone and failed a previous ITI attempt using a rFVIII product. The Wilate ITI dosing regimen ranged from 90 U/Kg to 100 U/Kg daily. Three of the four patients presented with high-risk factors for poor ITI outcome: 1 patient had 1, 1 patient had 3 and 1 patient had 5 poor prognostic factors. The definition of ITI success and failure were consistent with the definitions described in the consensus recommendations of the 2006 International ITI workshop (DiMichele et al. Haemophilia 2007;13 Suppl. 1: 1-22). Complete success (CS) was defined as having an undetectable inhibitor titer, FVIII recovery ≥66% and half-life ≥6 hours; partial success (PS) was defined as having a clinical response allowing for commencement of FVIII therapy associated with an inhibitor titer of <5 BU/mL (and with FVIII recovery <66% and/or half-life <6 hours). Results. ITI with Wilate was found to be well tolerated, with no reported drug-related adverse events. Although 75% of the patients presented with high-risk factors for poor ITI outcome, Wilate ITI reduced inhibitor levels below 5 BU/mL for 3 out of 4 patients. The clinical outcome of Wilate ITI correlated with the presence and number of high-risk factors. Patient 1 did not respond to Wilate, and was considered a failure. This patient had 3 high risk factors for poor ITI outcome including FVIII gene mutation type, peak historical titer >50, and inhibitor titer at ITI onset > 10 BU/mL. Of the three patients that responded to Wilate ITI, patient 4 experienced a CS to Wilate ITI in 4 months. For the remaining 2 patients, Wilate ITI is currently ongoing. Despite the presence of high risk factors, these two patients have thus far achieved a PS with inhibitor levels stable for several months at or below 1 BU/mL. One of these patients (patient 2) presented with 5 high-risk factors, including having failed a previous ITI attempt. The frequency of bleeding episodes were significantly reduced upon commencement of Wilate ITI, allowing for the eventual cessation of FEIBA prophylaxis. Conclusion. Despite the presence of high-risk factors, 3 out of 4 patients (75%) experienced a clinical response to Wilate ITI. The patients experienced improved quality of life. Wilate ITI resulted in a significant reduction in bleed episodes in a high-risk patient. The type of FVIII product to use during ITI has been debated, however, some have observed a higher success rate when plasma-derived FVIII products containing VWF are used. From our experience, we conclude that Wilate for ITI in patients with inhibitors is effective and produces high rates of ITI success in high-risk patients. Disclosures Wu: Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxter: Honoraria; Pfizer: Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees. Woo:Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Crilly:Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Baxter: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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