Genetic Determinants of the Outcome of Immune Tolerance Induction therapy in patients with severe haemophilia A and inhibitors

What is known: The bleeding tendency in patients with haemophilia A can be
effectively corrected by intravenous administration of the deficient FVIII.
Regular prophylactic infusions of FVIII enable people with haemophilia to have
a normal life. However, treatment with FVIII may be complicated by the
formation of inhibiting antibodies, directed towards FVIII in 25-35% of the
patients. These inhibitors preclude treatment with FVIII products by
neutralizing FVIII activity. Even though alternative hemostatic treatments that
bypass FVIII are available, it is generally more challenging to treat bleeding
and prevent arthropathy in individuals with inhibitors. This results in a
greater rate of bleeding complications, disability and costs. Antibody
eradication is the ultimate goal of inhibitor management. The only clinically
proven strategy is immune tolerance induction (ITI) therapy, which consists of
frequent administration of high doses of FVIII. Successful ITI eradicates the
inhibitor and restores the efficacy of FVIII replacement therapy with
consequent improvement in the patient*s quality of life. However, 10 to 40% of
patients who undergo immune tolerance induction do not achieve immune tolerance.
What is not yet known: It is currently unknown whether genetic factors are
associated with the chance of successful immune tolerance induction therapy in
patients with severe haemophilia A and inhibitor development.
What this study may add: Knowledge on genetic determinants for inhibitor
eradication after immune tolerance induction therapy in haemophilia A will
enable the identification of patients who are at an increased risk of failing
immune tolerance induction therapy. In these individuals, a tailored, more
intensive immune tolerance induction regimen including immune suppressive
medication may be needed. Patients with a good prognosis may benefit from
avoiding a demanding and costly immune tolerance treatment course and be
treated with a less intensive regimen that may nevertheless be effective.
Our hypothesis is that genetic factors are associated with the outcome of
immune tolerance induction in patients with haemophilia A and inhibitors.

The aim of this study is to identify genetic determinants that are associated
with successful immune tolerance induction in patients with haemophilia A and
inhibitors.

This study is an observational multicenter cohort study among patients with
severe haemophilia A who underwent immune tolerance induction therapy.

The participants* burden is a single blood draw for DNA collection during a
routine venipuncture at a outpatient clinic visit. The risk associated with
drawing extra blood is minimal. No direct benefit is expected from
participation in this study. Participation in this study may have benefits for
future patients with haemophilia with inhibitors. Because inhibitor development
occurs during childhood, it is important that children participate in this
study.