STUDY: Factor VIII Products and Inhibitor Development in Severe Hemophilia A

Samantha C. Gouw, M.D., Ph.D., Johanna G. van der Bom, M.D., Ph.D., Rolf Ljung, M.D., Ph.D., Carmen Escuriola, M.D., Ana R. Cid, M.D., Ségolène Claeyssens-Donadel, M.D., Christel van Geet, M.D., Ph.D., Gili Kenet, M.D., Anne Mäkipernaa, M.D., Ph.D., Angelo Claudio Molinari, M.D., Wolfgang Muntean, M.D., Rainer Kobelt, M.D., George Rivard, M.D., Elena Santagostino, M.D., Ph.D., Angela Thomas, M.D., Ph.D., and H. Marijke van den Berg, M.D., Ph.D. for the PedNet and RODIN Study Group

N Engl J Med 2013; 368:231-239 January 17, 2013 DOI: 10.1056/NEJMoa1208024

Background

For previously untreated children with severe hemophilia A, it is unclear whether the type of factor VIII product administered and switching among products are associated with the development of clinically relevant inhibitory antibodies (inhibitor development).

Methods

We evaluated 574 consecutive patients with severe hemophilia A (factor VIII activity, <0.01 IU per milliliter) who were born between 2000 and 2010 and collected data on all clotting-factor administration for up to 75 exposure days. The primary outcome was inhibitor development, which was defined as at least two positive inhibitor tests with decreased in vivo recovery of factor VIII levels.

Results

Inhibitory antibodies developed in 177 of the 574 children (cumulative incidence, 32.4%); 116 patients had a high-titer inhibitory antibody, defined as a peak titer of at least 5 Bethesda units per milliliter (cumulative incidence, 22.4%). Plasma-derived products conferred a risk of inhibitor development that was similar to the risk with recombinant products (adjusted hazard ratio as compared with recombinant products, 0.96; 95% confidence interval [CI], 0.62 to 1.49). As compared with third-generation full-length recombinant products (derived from the full-length complementary DNA sequence of human factor VIII), second-generation full-length products were associated with an increased risk of inhibitor development (adjusted hazard ratio, 1.60; 95% CI, 1.08 to 2.37). The content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development.

Conclusions

Recombinant and plasma-derived factor VIII products conferred similar risks of inhibitor development, and the content of von Willebrand factor in the products and switching among products were not associated with the risk of inhibitor development. Second-generation full-length recombinant products were associated with an increased risk, as compared with third-generation products. (Funded by Bayer Healthcare and Baxter BioScience.)

Supported by unrestricted research grants from Bayer Healthcare and Baxter BioScience.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

We thank the study coordinator, Ella Smink; Emma Smid and Mojtaba Hashemi for their support in data cleaning; Yves Guillaume, Kate Khair, Karin Lindvall, Monique Spoor, and Bep Verkerk for their assistance in the study; and J. Michael Soucie (Division of Blood Disorders, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention) for repeating the analyses.

Source Information

The authors’ affiliations are listed in the Appendix.

Address reprint requests to Dr. van den Berg at the University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Rm. No. Stratenum 5.125, P.O. Box 85500, 3508 GA Utrecht, the Netherlands, or at h.m.vandeberg@umcutrecht.nl.

Investigators in the European Pediatric Network for Hemophilia Management (PedNet) and the Research of Determinants of Inhibitor Development (RODIN) study group are listed in the Supplementary Appendix, available at NEJM.org.

Appendix

The authors’ affiliations are as follows: the Department of Pediatrics, Wilhelmina Children’s Hospital (S.C.G.), and the Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht (S.C.G., H.M.B.), Utrecht, and the Department of Clinical Epidemiology, Leiden University Medical Center, and the Center for Clinical Transfusion Research, Sanquin Foundation, Leiden (J.G.B.) — all in the Netherlands; Lund University, Department of Pediatrics and Malmö Center for Thrombosis and Hemostasis, Skånes Universitetssjukhus, Malmö, Sweden (R.L.); Department of Pediatrics, J.W. Goethe University Hospital, Frankfurt, Germany (C.E.); Unidad de Hemostasia y Trombosis, Hospital Universitario y Politécnico La Fe, Valencia, Spain (A.R.C.); Centre Regional d’Hemophilie, Centre Hospitalier Universitaire, Toulouse, France (S.C.-D.); the Department of Pediatrics, University Hospitals Leuven, and the Department of Cardiovascular Sciences, KU Leuven — both in Leuven, Belgium (C.G.); National Hemophilia Center, Ministry of Health, Sheba Medical Center, Tel Hashomer, Israel (G.K.); Hospital for Children and Adolescents, University of Helsinki, Helsinki (A.M.); Dipartimento di Ematologia ed Oncologia, Unità Trombosi ed Emostasi, Ospedale Pediatrico Giannina Gaslini, Genoa (A.C.M.), and Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan (E.S.) — both in Italy; Universitätsklinik für Kinder- und Jugendheilkunde, Graz, Austria (W.M.); Hämophiliezentrum, Wabern and Children’s Hospital of the University of Bern, Bern, Switzerland (R.K.); Division of Hematology/Oncology, Hôpital St. Justine, Montreal (G.R.); and Royal Hospital for Sick Children, Edinburgh (A.T.).

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