This issue was addressed specifically within the framework of the Italian ITI Registry (the PROgnostic Factors in Immune Tolerance [PROFIT] study). The Italian ITI registry was established in 2005 by the Italian Association of Haemophilia Centres to monitor clinical practice in Italy and investigate predictors

of ITI outcome. In an era of randomized trials including the ITI setting, the new ITI Registry was planned for several reasons. Over the past two decades, Italian haemophilia centres have gained a wealth of experience with use of ITI but, for the most part, the data have not been collected systematically. Despite the introduction of randomized clinical trials in haemophilia, many patients who are candidates for ITI do not fulfil specific inclusion criteria for randomized clinical trials or refuse randomized treatment choices; data from these patients

IWR-1 are therefore omitted from such trials. Moreover, modern registries can provide useful information with regard to the definition of ITI success or failure in clinical practice as well as address new issues such as the role for genetic or immunological factors in ITI outcome. In this respect, the Ibrutinib PROFIT Registry consists of a retrospective analysis of ITI courses completed between 1996 and 2005 and a prospective study of ITI courses ongoing or started after approval of the Italian ITI registry (2005–2010). Coordinated in Naples and Milan, 25 Italian haemophilia centres from across the country participated in the study. A central genetics

laboratory in Foggia, Italy, assessed F8 gene mutations in individual patients. For study purposes, ITI outcomes were reviewed centrally and defined according to currently 上海皓元医药股份有限公司 accepted criteria [9, 12]. Specifically, success was defined as an inhibitor titre <0.5 BU mL−1, recovery ≥66% and half-life ≥6 h. Partial success was defined as an inhibitor titre <5 BU mL−1 and/or recovery <66% and/or half-life <6 h (a clinical response to FVIII). Failure was defined as an inhibitor decline <20% of peak titre on ITI (for any 6-month period after the first 3 months), with no success or partial success within 33 months. The first report from the Registry was published in 2009 [12], and an update of data analysis was more recently presented at the World Federation of Haemophilia Congress in 2012 [13]. Of 133 ITI courses in total, 23 were excluded from analysis for the following reasons: 12 courses were administered after previous ITI failure; four patients had low-responding inhibitors and two patients had mild/moderate haemophilia; ITI was ongoing in five patients. Therefore, this analysis focused on 110 patients with severe haemophilia and high-responding inhibitors who underwent a first ITI course, irrespective of regimen or type of FVIII concentrates used, according to the choice of the reporting physician. The demographic and clinical characteristics of patients at baseline and at the start of ITI therapy are summarized in Table 2.