The ObsITI research program, an international, open-label, uncontrolled, non-interventional, multicentre, observational study, is designed to evaluate and document data on the success rate of ITI in haemophilia A patients with newly developed/already existing FVIII inhibitors, or patients who have failed earlier ITI [35]. The ObsITI study is assessing the possible influence of a large range of secondary parameters, including the dynamics of lymphocytes and other immunological parameters, on the duration and

success rate of ITI. Success criteria in the ObsITI study are stringent, including an inhibitor titre <0.6 BU, FVIII in vivo recovery ≥80% and a FVIII half-life ≥7 h. ObsITI has currently enrolled 256 patients with inhibitors and poor prognosis for ITI success. As of February Luminespib manufacturer Venetoclax in vivo 2013, 59/81 (72.8%) patients were completely tolerized with pdFVIII/VWF and the failure rate was 12% (10/81 patients), with treatment ongoing in 136 patients [36]. Interim data from ObsITI, evaluating outcomes with use of a specific pdFVIII/VWF concentrate (Octanate®; Octapharma AG, Lachen, Switzerland), indicated an overall success rate >70%, with a mean time of 4 months until inhibitor titre <0.6 BU and a mean time of 10 months until normalized FVIII half-life [36]. Emerging knowledge that pdFVIII/VWF concentrates may

have a particular role in candidate patients with poor prognosis for success also suggests a role in patients with mild/moderate haemophilia with inhibitors. This latter group of patients check details develop inhibitors that do not always exhibit the same behaviours as those seen in patients with acquired haemophilia; some have second-order kinetics and some have bleeding manifestations more closely resembling those in patients with severe haemophilia (e.g. subcutaneous bleeds). Moreover, these patients often have a poor response to traditional ITI (25% success rate in poor-risk patients due to excessive bleeding [37]) and an improved response with immunosuppression [38]. Some of the proposed advantages

of VWF-containing FVIII products include a VWF-induced reduction in FVIII immunogenicity. Inhibitors recognize epitopes in the A2, A3 and C2 domains; as VWF binds to A3 and C2 domains, it has a role in patients with C2 domain inhibitors [28, 39, 40]. VWF may protect against inhibitor activation [41] and impurities in pdFVIII/VWF concentrates may influence the immune response [42]. In summary, favourable clinical results for use of pdFVIII/VWF in ITI based on success rates and time to tolerization continue to be reported. In particular, pdFVIII/VWF has a role in patients who require rescue ITI, and those with a poor prognosis for success. In the meantime, data from prospective, randomized, controlled clinical studies such as RES.I.ST are eagerly awaited. C. M. KESSLER E-mail: kesslerc@georgetown.