Novel therapies for immune tolerance in haemophilia A

Standard treatment for an inhibitory antibody to factor VIII (FVIII) in a patient with severe congenital haemophilia A is to attempt to induce immune tolerance with high-dose FVIII, either alone or in combination with immunosuppression. Patients in whom the inhibitor is not eradicated or who have prognostic features suggestive of a poor response may be suitable for experimental approaches to immune tolerance induction. The two options that are currently under investigation in clinical practice are anti-CD20 antibody therapy using rituximab and the use of von Willebrand factor (VWF)-containing FVIII concentrate in immune tolerance regimens. Immunomodulation with rituximab has been reported to eradicate inhibitors in some patients with severe haemophilia A who have previously failed standard immune tolerance. Similarly, some patients who have failed to be tolerized with high-purity FVIII have been successfully treated with VWF-containing concentrates. Neither of these treatment modalities is supported by controlled clinical trial data, and reported observational data require confirmation. Immunomodulation via interference with B-cell/T-cell interactions by blocking CD40/CD40 ligand or a gene therapy approach using FVIII peptides in IgG heavy chain transfected into B-cell blasts has been reported to suppress inhibitors in animal models and may lead to clinically useful therapies. Further understanding of the aetiology of inhibitor formation and how FVIII leads to tolerance in some patients with an inhibitor may suggest further approaches in the future.