Timing and severity of inhibitor development in recombinant versus plasma‐derived factor VIII concentrates: a SIPPET analysis

Unlabelled Box Essentials • Recombinant factor VIII (rFVIII) was contrasted with plasma‐derived FVIII (pdFVIII). • In previously untreated patients with hemophilia A, rFVIII led to more inhibitors than pdFVIII. • Inhibitors with rFVIII developed earlier, and the peak rate was higher than with pdFVIII. • Inhibitors with rFVIII were more severe (higher titre) than with pdFVIII. Summary: Background The development of neutralizing antibodies (inhibitors) against factor VIII (FVIII) is the most severe complication in the early phases of treatment of severe hemophilia A. Recently, a randomized trial, the Survey of Inhibitors in Plasma‐Product Exposed Toddlers (SIPPET) demonstrated a 2‐fold higher risk of inhibitor development in children treated with recombinant FVIII (rFVIII) products than with plasma‐derived FVIII (pdFVIII) during the first 50 exposure days (EDs). Objective/Methods In this post‐hoc SIPPET analysis we evaluated the rate of inhibitor incidence over time by every 5 EDs (from 0 to 50 EDs) in patients treated with different classes of FVIII product, made possible by a frequent testing regime. Results The highest rate of inhibitor development occurred in the first 10 EDs, with a large contrast between rFVIII and pdFVIII during the first 5 EDs: hazard ratio 3.14 (95% confidence interval [CI], 1.01–9.74) for all inhibitors and 4.19 (95% CI, 1.18–14.8) for high‐titer inhibitors. For patients treated with pdFVIII, the peak of inhibitor development occurred later (6–10 EDs) and lasted for a shorter time. Conclusion These results emphasize the high immunologic vulnerability of patients during the earliest exposure to FVIII concentrates, with the strongest response to recombinant FVIII products.