Genetic risk stratification to reduce inhibitor development in the early treatment of hemophilia A: a SIPPET analysis

Abstract

A recent randomized trial, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET), showed a higher risk of inhibitor development with recombinant factor VIII (rFVIII) than plasma-derived concentrates (pdFVIII). We investigated whether risk stratification by F8mutation identifies patients who do not suffer this deleterious effect of rFVIII. Among235 randomized patients with severe hemophilia A previously untreated with FVIII concentrate, 197 with null mutations were classified as high risk and 38 with non-null mutations were classified as low risk. With pdFVIII, no inhibitors occurred in those with low genetic risk, whereas high-risk patients had a cumulative incidence of 31%. The risk among low-and high-risk patients did not differ much when they were treated with rFVIII (43% and 47%, respectively). This implies that patients with low genetic risk suffer disproportionate harm when treated with rFVIII (risk increment 43%), as also shownby the number needed to harm with rFVIII, whichwas 6.3 for genetically high-risk patients and only 2.3 for low-risk patients. Risk stratification by F8mutation does not identify patients who can be safely treated with rFVIII, as relates to immunogenicity.