However, various risk factors are http://www.selleckchem.com/products/PLX-4032.html associated with a poor outcome of primary ITT, and abandoning ITT and starting prophylaxis or on-demand therapy with bypassing agents (e.g. recombinant factor VIIa, activated prothrombin complex concentrate) leads to worse outcomes in terms of bleeding prevention [25]. Lifelong use of bypassing agents also poses a huge financial burden to healthcare

payors [26]. A delay in inhibitor identification, particularly in geographic regions with limited availability of inhibitor monitoring, is associated with a poor response to ITT. The same is true if the delay between inhibitor diagnosis and the time of starting ITT is >6 months, if ITT is interrupted, or if patients have inhibitor

titres >10 BU before starting ITT or historical peak inhibitor titres >200 BU [27]. In addition, patients of African or Afro-Caribbean descent have an increased incidence of inhibitors and are less likely to be tolerized with ITT [28]. Globally, marked variability exists in clinical ‘thresholds’ for a switch from primary to secondary (‘rescue’) ITT. At our institution, for instance, the threshold for switching is relatively high: that is, after a peak anamnestic response, a rising or unchanged inhibitor titre at three consecutive mTOR inhibitor measurements ≥1 month apart, and in the absence of any intercurrent illness, leads to a change of ITT. Definitions of primary ITT failure, and thresholds for switching to another strategy, vary markedly at other institutions and in clinical trials, thus making it particularly difficult to interpret success rates for secondary ITT. Nonetheless, historical data and retrospective results from small case series at single centres on ITT are available for pdFVIII (i.e. from before the commercial introduction of rFVIII). Generally, success rates for pdFVIII are as good as, or sometimes

better than, those for induction therapy with rFVIII, but the caveats of historical comparison and caution when interpreting selleck compound data from small, retrospective assessments must be carefully considered. Although the ongoing REScue Immunotolerance STudy (RES.I.ST) is expected to clarify the efficacy of pdFVIII as a secondary ITT [29], there are currently no data available confirming that children who fail ITT with high-dose rFVIII will experience a strong secondary benefit from plasma-derived products. Nevertheless, the UKITIP (United Kingdom Immune Tolerance Induction in Paediatrics) study attempted to address this issue, albeit on a small scale. This study was a retrospective review of case records for all children aged <16 years in the UK who received ITT with high-dose, high-purity pdVWF/FVIII (Fanhdi®; Instituto Grifols, S.A., Barcelona, Spain) between 2003 and 2010. The trial involved a total of 6 centres and 11 patients, all of whom had previously received rFVIII for ≥1 year, and in many cases, for up to 3–4 years.