The implication from these observations was that rFVIII is less useful as an ITI option in patients with a number of poor prognostic factors. Numerous uncontrolled studies followed these initial German observations but, unfortunately, no clear pattern emerged of ITI outcome in relation to product purity and the situation became complex. It is interesting to note that the I-ITI study which evaluated patients with good prognostic factors [11], showed no difference in time to tolerization between patients receiving pdFVIII/VWF

(n = 13) or rFVIII (n = 102) although this is merely an observation as the study was insufficiently powered to detect such a difference. Poor prognostic factors for ITI include age >6 years, initiation of ITI >1 year from inhibitor selleck chemicals development, inhibitor peaks >200 BU, inhibitor titre >10 BU at the start of therapy, and previously failed ITI [24]. ITI success rates reported with pdFVIII/VWF in patients with predominantly poor prognostic factors range from approximately 60–100% [24-32] (Fig. 2). A retrospective analysis of six haemophilia centres in France, conducted by Orsini et al. [30], evaluated eight eligible

patients who had received a highly purified FVIII/VWF ATM/ATR inhibitor product (Factane®; LFB, Les Ulis, France), of whom seven achieved complete success and one partial success. The median duration of ITI was 8 (range 4.7–23) months. Following on from this small French analysis, Gringeri et al. prospectively evaluated high purity pdFVIII/VWF (Fanhdi®, Grifols, Barcelona, Spain) in poor prognosis patients (including four patients on rescue ITI); 9/17 (53%) patients achieved complete success, including two of four patients who had previously failed ITI, and 7/17 (41%) patients had partial success [24]. Published data from the US cohort Niclosamide of the Grifols-ITI (G-ITI) study also showed that, in 33 poor prognosis paediatric patients receiving pdFVIII/VWF (Alphanate®, Grifols, Barcelona, Spain), the

overall success rate was 75% in primary ITI (complete success: 37.5%; partial success: 37.5%), and 52% in rescue ITI (complete success: 32%; partial success: 20%) [25]. Furthermore, a UK case study of five boys, aged 8–16 years, with severe haemophilia A and resistant inhibitors (duration of inhibitors: 3–13 years) who were treated with pdFVIII/VWF (Fanhdi®) according to the Bonn protocol with concurrent immunosuppression, reported markedly reduced inhibitor titres [33]. To evaluate the impact of pdFVIII/VWF concentrates compared with rFVIII products as ITI in patients with poor prognostic factors, it is essential to conduct prospective randomized, controlled studies. The Rescue Immune Tolerance Study (RES.I.ST study) is currently evaluating ITI in two arms: RES.I.ST naïve patients (ITI-naïve, high responders, poor prognostic factors, randomized to pdFVIII/VWF or rFVIII); and RES.I.