title: Immune tolerance induction with a high purity von Willebrand factor/VIII complex concentrate in haemophilia A patients with inhibitors at high risk of a poor response.
abstract: Immune tolerance induction (ITI) is effective in approximately 70% of haemophilia patients with inhibitors. Poor prognostic factors are age >6 years, ITI started >1 year from inhibitor development, inhibitor peaks >200 BU, inhibitor titre >10 BU when ITI is started and previously failed ITI. The objective of this study was to identify the effectiveness in ITI of a high purity von Willebrand factor/factor VIII (VWF/FVIII) complex concentrate in inhibitor patients at high risk of failure. Patients with severe or moderate haemophilia A and high responding inhibitors who had at least one poor prognostic factor for ITI failure were prospectively followed-up. Success was defined by undetectable inhibitor, recovery and half life >66% of expected values. ITI dose regimens were chosen by each haemophilia centre. Seventeen haemophiliacs (16 severe, one moderate), aged 4-54 years (median 23) were followed-up for 6-71 months. Poor prognostic factors were delayed-onset ITI (n = 16), age >6 years (n = 16), previously failed ITI (n = 4), inhibitor peak >200 BU (n = 2) and inhibitor >10 BU when ITI was started (n = 4). Complete success was obtained in nine patients (53%) after 4-30 months of treatment (median 24), including two of four patients who had previously failed ITI. Seven patients achieved a partial success, with sustained low inhibitor titres (median 1.5 BU, range 1.1-2.8) but abnormal recovery and/or half-life, while the remaining patient withdrew ITI after 12 months when the inhibitor titer was still 70 BU. These findings suggest that high purity VWF/FVIII complex concentrates are effective in ITI, even in patients at high risk of failure.
authors.affiliation: A. Bianchi Bonomi Haemophilia and Thrombosis Centre, Department of Medicine and Medical Specialties, University of Milan and IRCCS Maggiore Hospital, Milan, Italy. alessandro.gringeri@unimi.it
authors.forename: A
authors.initials: A
authors.lastname: Gringeri
authors.forename: R
authors.initials: R
authors.lastname: Musso
authors.forename: M G
authors.initials: MG
authors.lastname: Mazzucconi
authors.forename: G
authors.initials: G
authors.lastname: Piseddu
authors.forename: M
authors.initials: M
authors.lastname: Schiavoni
authors.forename: P
authors.initials: P
authors.lastname: Pignoloni
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
mesh_terms: D000293:Adolescent; D000328:Adult; D019774:Blood Coagulation Factor Inhibitors / Q000097:blood; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006467:Hemophilia A / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007165:Immunosuppression Therapy / Q000379:methods; D008875:Middle Aged; D018570:Risk Assessment; D014841:von Willebrand Factor / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D014841:von Willebrand Factor