Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance induction of hemophilia A patients with high‐responding inhibitors

Abstract

, OR 11.8, 95% CI 3.5-40.2, P < 0.001), and peak titer during ITI (< 100 BU mL )1 , OR 11.4, 95% CI 3.2-40.8, P < 0.001). Conclusions: ITI success is influenced by F8 genotype. This knowledge should contribute to the stratification of prognosis, and to the clinical choices made for ITI in patients with highresponding inhibitors.

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence‐based approaches

“…The large majority of patients recruited in the ITI registries were treated with pdFVIII, with the exception of the NAITR where no difference in success rates (Table IV) was found in patients receiving intermediate/high-purity pdFVIII or monoclonal/rFVIII (DiMichele, 2009). Recently, the type of FVIII concentrate was not reported as a predictor of ITI success in the multivariate analysis of the Italian PROFIT Registry (Coppola et al, 2009). Moreover, case series in the literature (Table IV) reported similar success rates in patients achieving tolerance with pdFVIII (Mauser-Bunschoten et al, 1995;Brackmann et al, 1996;Orsini et al, 2005) or with monoclonal or rFVIII products (Rothschild et al, 1998;Batlle et al, 1999;Smith et al, 1999;Rocino et al, 2001Rocino et al, , 2006Barnes et al, 2006;Valentino et al, 2009).…”

“…In this compilation of 278 cases, low pre-ITI inhibitor titre (<10 BU/ml) was also associated with a shorter mean time to successful ITI (85% success, 11 months vs. 33%, 15 months in patients with pre-ITI titre >10 BU/ml). Inhibitor peak titre during ITI resulted a significant predictor of outcome according to the NAITR (DiMichele, 2009) and the PROFIT study (Coppola et al, 2009), whereas this variable was not evaluated in the IITR and the GITR.…”

“…The PROFIT study was the first ITI Registry to specifically address the relationship between F8 genotype and ITI outcome (Coppola et al, 2009). The results of this Registry indicated that the relationship that exists between F8 mutations and inhibitor risk is also likely to exist between F8 genotype and ITI outcome.…”

“…To gain knowledge of the optimal ITI regimen, national and international ITI registries were established in the late 1980s and in the 1990s (Table II): the International Immune Tolerance Registry (IITR, Mariani & Kroner, 2001), the North American Immune Tolerance Registry (NAITR, DiMichele, 2009), and the German Immune Tolerance Registry (GITR, Lenk, 2000). A smaller registry from Spain has also been published (Haya et al, 2001) and, more recently, a retrospective-prospective registry is still ongoing in Italy (the PROFIT study, Coppola et al, 2009). With the exception of the latter registry, the large majority of data were retrospectively collected using different forms or questionnaires, which hampered direct comparisons of data.…”

“…Thus, the higher number of bleeds observed in the low-dose arm of the I-ITI study could have contributed to the prolonged time to success. In this light, peaks and fluctuations in inhibitor titres during ITI may reflect the immunological stimulation occurring in individual patients during treatment, and thus may represent a better predictor of ITI outcome than the historical peak titres (Coppola et al, 2009;DiMichele, 2009). Indeed, higher peak titres were recently reported in patients who experienced adverse events on ITI than in patients with uneventful treatment (Coppola et al, 2009).…”