VWF/FVIII concentrates in high-risk immunotolerance : the resist studies

Background: Inhibitor eradication with immune tolerance induction (ITI) is the best long-term therapeutic strategy in Haemophilia A (HA) patients with inhibitors. Several parameters are known to be related to the ITI success. One that has more recently been proposed is the type of FVIII concentrate. Recent clinical findings indicate that plasma-derived FVIII products containing von Willebrand factor (VWF/FVIII) could have an impact on ITI success rate, even in poor prognosis patients. Study design: Two key prospective clinical studies have been designed to confirm the previous results supporting the use of VWF/FVIII in ITI: RESIST experienced (RESISTexp) and RESIST naïve (RESIST-naïve). RESIST: Exp is a prospective, nonrandomized study designed to assess rescue treatment with VWF/FVIII at high dosage (200 IU/kg daily) in patients who failed a previous ITI attempt with any dose of a VWF-free FVIII concentrate (plasma-derived or recombinant). RESISTnaïve is a prospective, controlled, randomized, open-label study comparing two types of FVIII concentrates (VWF-free FVIII and VWF/FVIII) in their ability to induce tolerance in high responding HA patients, with no previous ITI attempt and with poor prognosis for success. Both types of concentrates will be administered at high dosage (200 IU/kg daily). Enrolment criteria are: severe haemophilia A (FVIII < 1%), any age, high responding inhibitors (peak inhibitor levels > 5 BU), any inhibitor level at study enrolment, and at least one of the following risk factors for ITI failure: (a) peak inhibitor titer > 200 BU, (b) titer at ITI start > 10 BU, (c) age > 7 years, (d) time between inhibitor occurrence and ITI > 2 years. Patient undergoing concomitant immunosuppressive treatment are not eligible for either study. Primary end point is success in achieving ITI defined as: complete or partial. Secondary endpoints are: ITI maintenance, time to success, safety/compliance to treatment and cost of care. Conclusions: The results of RESIST studies will be crucial in understanding the role of VWF/FVIII in ITI outcome and will contribute to providing effective treatment for the devastating complication of FVIII antibody development in HA patients