Factor VIII products and inhibitor development in previously treated patients with severe or moderately severe hemophilia A: a systematic review

Unlabelled Box Essentials • Data on product‐related immunogenicity in previously treated haemophilia A patients is scarce. • A systematic review and meta‐analysis of all currently available evidence was conducted. • The overall incidence rate was 2.06 per 1000 person‐years (95% confidence interval: 1.06‐4.01). • Some recombinant factor VIII products were associated with increased immunogenicity. Summary: Background Patients with severe hemophilia A who have been treated extensively with factor VIII products have a low but potentially serious risk of inhibitor development. It is unknown why these patients develop inhibitors, and data on product‐related immunogenicity are scarce. Aims To summarize the currently available evidence on the relationship between inhibitor development and recombinant FVIII product type in previously treated patients (PTPs) with severe hemophilia A. Methods Longitudinal studies were included that reported on de novo inhibitor formation in patients with baseline FVIII activity levels of < 0.02 IU mL−1 who had been treated with FVIII for at least 50 days. Pooled incidence rates of inhibitor development according to product types were calculated with a random intercept Poisson regression model. Results Forty‐one independent cohorts were included; 39 patients developed de novo inhibitors during 19 157 person‐years of observation. The overall incidence rate was 2.06 per 1000 person‐years, with a 95% confidence interval (CI) of 1.06–4.01. According to product type, the pooled incidence rates were 0.99 (95% CI 0.37–2.70) per 1000 person‐years for patients treated with Advate, 5.86 (95% CI 0.25–134.92) per 1000 person‐years for those treated with Kogenate/Helixate, 1.35 (95% CI 0.66–2.77) per 1000 person‐years for those treated with Kogenate FS/Helixate NexGen, 12.05 (95% CI 1.53–94.78) per 1000 person‐years for those treated with Refacto, and 4.64 (95% CI 0.82–26.43) per 1000 person‐years for those treated with Refacto AF. Conclusion These results suggest that some products may be associated with increased immunogenicity. However, the low incidence of inhibitors in PTPs and the differences in study design may cause significant variation in estimates of risk.