Can B‐domain deletion alter the immunogenicity of recombinant factor VIII? A meta‐analysis of prospective clinical studies

• Published in: Journal of thrombosis and haemostasis 2011-11, Vol.9 (11), p.2180-2192
• Main Authors: ALEDORT, L. M., NAVICKIS, R. J., WILKES, M. M.
• Format: Article
• Language: English
• Subjects: Antibodies - analysis; blood coagulation factor inhibitors; Clinical Trials as Topic - statistics & numerical data; Data Collection; factor VIII; Factor VIII - genetics; Factor VIII - immunology; Factor VIII - therapeutic use; hemophilia; hemophilia A; Hemophilia A - drug therapy; Hemophilia A - immunology; Humans; Immunogenetic Phenomena; immunogenicity; incidence; previously treated patients; Recombinant Proteins; Sequence Deletion; thromboembolism
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2011.04472.x

See also Iorio A, Marcucci M, Makris M. Concentrate‐related inhibitor risk: is a difference always real? This issue, pp 2176–9. Summary.  Background: As a result of the infrequency of inhibitors in previously treated patients (PTPs) with hemophilia A and the small size of available clinical studies, the immunogenicity of factor (F)VIII products has been difficult to assess. Objectives: A meta‐analysis of prospective clinical studies was conducted to test the hypothesis that de novo inhibitor incidence differs between PTPs receiving full‐length recombinant FVIII (FL‐rFVIII) and B‐domain deleted recombinant FVIII (BDD‐rFVIII). Methods: Prospective studies with data on inhibitors in PTPs receiving FL‐rFVIII or BDD‐rFVIII were sought using systematic methods including bibliographic database searches. Data were secured from published study reports and inquiries to investigators. Between‐group differences in inhibitor incidence rates were evaluated using mixed effects Cox regression. Results: Twenty‐nine studies with 3012 total PTPs were included. Patients were at risk of de novo inhibitor development for a median of 79 exposure days. A total of 35 de novo inhibitors were observed. The cumulative hazard for all de novo inhibitors was 1.25% with a 95% confidence interval (CI) of 0.63–1.88%. The corresponding rate for high‐titer de novo inhibitors [> 5 Bethesda units (BU)] was 0.29% (CI, 0.01–0.57%). Exposure to BDD‐rFVIII was associated with an increased risk of all de novo inhibitors (hazard ratio, 7.26; CI, 2.12–24.9; P = 0.0016) and of high‐titer de novo inhibitors (hazard ratio, 10.8; CI, 2.17–53.7; P = 0.0037), compared with FL‐rFVIII. Conclusions: This meta‐analysis of prospective clinical studies suggests that recombinant FVIII products may differ in immunogenicity.