A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A
Flora Peyvandi, Pier M Mannucci, Isabella Garagiola, Amal El-Beshlawy, Mohsen Elalfy, Vijay Ramanan, Peyman Eshghi, Suresh Hanagavadi, Ramabadran Varadarajan, Mehran Karimi, Mamta V Manglani, Cecil Ross, Guy Young, Tulika Seth, Shashikant Apte, Dinesh M Nayak, Elena Santagostino, Maria Elisa Mancuso, Adriana C Sandoval Gonzalez, Johnny N Mahlangu, Santiago Bonanad Boix, Monica Cerqueira, Nadia P Ewing, Christoph Male, Tarek Owaidah, Veronica Soto Arellano, Nathan L Kobrinsky, Suvankar Majumdar, Rosario Perez Garrido, Anupam Sachdeva, Mindy Simpson, Mathew Thomas, Ezio Zanon, Bulent Antmen, Kaan Kavakli, Marilyn J Manco-Johnson, Monica Martinez, Esperanza Marzouka, Maria G Mazzucconi, Daniela Neme, Angeles Palomo Bravo, Rogelio Paredes Aguilera, Alessandra Prezotti, Klaus Schmitt, Brian M Wicklund, Bulent Zulfikar, Frits R Rosendaal, Flora Peyvandi, Pier M Mannucci, Isabella Garagiola, Amal El-Beshlawy, Mohsen Elalfy, Vijay Ramanan, Peyman Eshghi, Suresh Hanagavadi, Ramabadran Varadarajan, Mehran Karimi, Mamta V Manglani, Cecil Ross, Guy Young, Tulika Seth, Shashikant Apte, Dinesh M Nayak, Elena Santagostino, Maria Elisa Mancuso, Adriana C Sandoval Gonzalez, Johnny N Mahlangu, Santiago Bonanad Boix, Monica Cerqueira, Nadia P Ewing, Christoph Male, Tarek Owaidah, Veronica Soto Arellano, Nathan L Kobrinsky, Suvankar Majumdar, Rosario Perez Garrido, Anupam Sachdeva, Mindy Simpson, Mathew Thomas, Ezio Zanon, Bulent Antmen, Kaan Kavakli, Marilyn J Manco-Johnson, Monica Martinez, Esperanza Marzouka, Maria G Mazzucconi, Daniela Neme, Angeles Palomo Bravo, Rogelio Paredes Aguilera, Alessandra Prezotti, Klaus Schmitt, Brian M Wicklund, Bulent Zulfikar, Frits R Rosendaal
Abstract
Background: The development of neutralizing anti-factor VIII alloantibodies (inhibitors) in patients with severe hemophilia A may depend on the concentrate used for replacement therapy.
Methods: We conducted a randomized trial to assess the incidence of factor VIII inhibitors among patients treated with plasma-derived factor VIII containing von Willebrand factor or recombinant factor VIII. Patients who met the eligibility criteria (male sex, age <6 years, severe hemophilia A, and no previous treatment with any factor VIII concentrate or only minimal treatment with blood components) were included from 42 sites.
Results: Of 303 patients screened, 264 underwent randomization and 251 were analyzed. Inhibitors developed in 76 patients, 50 of whom had high-titer inhibitors (≥5 Bethesda units). Inhibitors developed in 29 of the 125 patients treated with plasma-derived factor VIII (20 patients had high-titer inhibitors) and in 47 of the 126 patients treated with recombinant factor VIII (30 patients had high-titer inhibitors). The cumulative incidence of all inhibitors was 26.8% (95% confidence interval [CI], 18.4 to 35.2) with plasma-derived factor VIII and 44.5% (95% CI, 34.7 to 54.3) with recombinant factor VIII; the cumulative incidence of high-titer inhibitors was 18.6% (95% CI, 11.2 to 26.0) and 28.4% (95% CI, 19.6 to 37.2), respectively. In Cox regression models for the primary end point of all inhibitors, recombinant factor VIII was associated with an 87% higher incidence than plasma-derived factor VIII (hazard ratio, 1.87; 95% CI, 1.17 to 2.96). This association did not change in multivariable analysis. For high-titer inhibitors, the hazard ratio was 1.69 (95% CI, 0.96 to 2.98). When the analysis was restricted to recombinant factor VIII products other than second-generation full-length recombinant factor VIII, effect estimates remained similar for all inhibitors (hazard ratio, 1.98; 95% CI, 0.99 to 3.97) and high-titer inhibitors (hazard ratio, 2.59; 95% CI, 1.11 to 6.00).
Conclusions: Patients treated with plasma-derived factor VIII containing von Willebrand factor had a lower incidence of inhibitors than those treated with recombinant factor VIII. (Funded by the Angelo Bianchi Bonomi Foundation and others; ClinicalTrials.gov number, NCT01064284; EudraCT number, 2009-011186-88.).
Source: PubMed