Induction of immune tolerance with recombinant factor VIII in haemophilia A patients with inhibitors

Abstract

We report on 11 patients (nine unrelated and a brother pair) with severe haemophilia A and factor VIII (FVIII) inhibitor, in whom immune tolerance (IIT) was induced with recombinant FVIII (r-FVIII). Their age ranged from 11 months to 47 years. The number of exposure days (ED) at inhibitor detection varied from 11 to 130. Nine of the 11 patients were high responders ¿>10 Bethesda units (BU) with peak inhibitor levels ranging from 10 to 566 BU. The other two were low responders with peak levels between 0.7 and 2 BU. Before inhibitor detection, the patients had been receiving products of various purities. The IIT regimens were very heterogeneous, and the treatment schedule varied from a short period with 50 IU kg-1 every 2 days, followed by 100 IU kg-1 every 2 days and then 220 IU kg-1 daily. The outcome was considered successful when the inhibitor level fell to 0.6 BU or lower after IIT treatment. The outcome overall was successful in nine out of 11 patients (81.8%), with the nine successful cases comprising seven of the nine high responders (77.8%) and the two low responders. Definite failure of IIT was observed in one high responder after two different IIT regimens. A second high responder is still on IIT treatment. All patients in whom IIT was successful are currently receiving r-FVIII on demand or prophylactically at various dosages. Despite the variability of the patient characteristics and the IIT schedules, this study demonstrates that r-FVIII represents an effective alternative for the eradication of inhibitors through IIT.

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

“…Relapse rates ranging from 3AE8% to 12AE5% have been reported in the small retrospective series (Mauser-Bunschoten et al, 1995;Batlle et al, 1999;Unuvar et al, 2000;Rocino et al, 2006) over variable follow-up periods (5-8AE5 years). In the IITR, six of 128 patients (4AE7%) who achieved the normalization of FVIII pharmacokinetics, relapsed 1-15 years after ITI success (Mariani & Kroner, 2001).…”

“…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). Nevertheless, some reports highlighted satisfactorily high success rates in patients with poor prognostic factors receiving ITI treatment with VWF-containing concentrates Grenninger et al, 2008;Kurth et al, 2008).…”

“…In addition, a number of other low or intermediate FVIII dose regimens (£100 iu/kg/d) have been used (Ewing et al, 1988;Kucharski et al, 1996;Unuvar et al, 2000;Rocino et al, 2001) in the attempt to improve the costeffectiveness of ITI treatment (Table I). In some cases, the association of immune modulating agents was still proposed (Gruppo et al, 1992;Batlle et al, 1999).…”

“…Assessment of ITI success was not based on pharmacokinetic criteria in variable proportions of treated patients in some studies (Gruppo et al, 1992;Batlle et al, 1999;Mariani & Kroner, 2001;Barnes et al, 2006). The definition of success was established at each participating centre in the NAITR.…”

Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A

“…3,4 Patients with such antibodies require additional therapies to eliminate the undesired anti-fVIII immune response. The current strategy to induce immune tolerance is frequent infusions of high doses of fVIII, 5,6 and this is usually successful but very expensive. 7 In this study, we have used fVIII knockout mice generated by targeted disruption of exon 16 of the fVIII gene.…”