Low-dose immune tolerance induction in hemophilia A patients with inhibitors

Abstract

In patients with hemophilia A and inhibitory alloantibodies against factor VIII, various dosage schedules are used to obtain immune tolerance. In this study, we have evaluated the results of 13 years of low-dose immune tolerance induction and factors that are predictive of a positive result. The effect of immune tolerance induction in relation to age at inhibitor development, number of exposure days, age at start of therapy, maximum inhibitor titer, factor VIII products involved, and virologic status were determined. We evaluated 24 patients with severe hemophilia A and inhibitors who were treated with regular infusions with low-dose (25 U/kg every other day) factor VIII to obtain immune tolerance. In 21 of 24 patients (87%), immune tolerance induction was successful. The response time was determined by two factors: the highest inhibitor level and the age at inhibitor development. In patients with maximum inhibitor levels of less than 40 Bethesda units (BU)/mL, immune tolerance was obtained sooner than in patients with inhibitor levels exceeding 40 BU/mL (P = .005). Patients in whom an inhibitor developed before the age of 2.5 years also tended to have a quick immune response (P = .014). Immune tolerance with low-dose factor VIII is often successful in hemophilia A patients with inhibitors. Young children and patients with maximum inhibitors of less than 40 BU/mL show a relatively rapid response.

IgG subclasses of anti‐FVIII antibodies during immune tolerance induction in patients with hemophilia A

“…Plasma samples were analysed using the Nijmegen modification of the Bethesda method (Verbruggen et al, 1995). Samples measured before 1996 were analysed using the standard Bethesda assay (Kasper et al, 1975;Mauser-Bunschoten et al, 1995).…”

Mechanisms of action of immune tolerance induction against factor VIII in patients with congenital haemophilia A and factor VIII inhibitors

“…Therefore, it is difficult to compare results obtained in clinical studies using different protocols. The most commonly used protocols, summarised in Table I, are known as the Bonn (Brackmann et al, 1996), the Van Creveld (Mauser-Bunschoten et al, 1995) and the Malmö (Nilsson et al, 1988;Berntorp et al, 2000) protocols. Despite their considerable differences, the success rates of all three protocols seem to be comparable.…”

“…The Van Creveld protocol uses a low-dose protocol (Mauser-Bunschoten et al, 1995). Initially, patients receive a 'neutralising dose' of 25-50 U/kg FVIII twice a day for 1-2 weeks.…”

Diagnosis and treatment of factor VIII and IX inhibitors in congenital haemophilia: (4th edition)

“…Poor risk patients 100-200 iu/kg/d probably more effective Good risk patients No difference between 200 iu/kg/d and 50 iu/kg 3 times a week but tolerance achieved more rapidly with higher dose regimens and with less intercurrent bleeds Mariani et al (1994) Kroner (1999), Mauser-Bunschoten et al (1995), Brackmann et al (1996), DiMichele and Kroner (2002) DiMichele ( • All patients who require replacement therapy with concentrate, including previously untreated patients, should be treated with recombinant FVIII/IX (Grade 1C).…”

“…The I-ITI and NAITI suggest that poor-risk patients (peak titre >200 BU/ml, starting titre >10 BU/ml) are best tolerized using a high-dose regimen (100-200 iu/kg/d FVIII) (Mariani et al, 1994;DiMichele & Kroner, 2002). These registries and the I-ITI study suggest that high dose and lowdose (50 iu/kg three times weekly) regimens are equally effective in inducing tolerance in good risk patients (Mariani et al, 1994;Mauser-Bunschoten et al, 1995;DiMichele & Kroner, 2002;Hay & DiMichele, 2012). By implication, therefore, 200 and 100 iu/kg/d can be assumed to be equally efficacious for inducing tolerance in good risk patients (Hay & DiMichele, 2012) but the relative effect of these high dose regimens on bleeding is unknown.…”