Inhibitor development and clinical characteristics in children with severe hemophilia A in the ATHN 8 US Cohort Study Open Access

1. Data from the ATHN 8 US cohort study demonstrate that inhibitor development remains a significant clotting factor concentrate complication.

2. Inhibitor surveillance is critical to identify clinically significant inhibitors in young children with severe hemophilia A.

Clotting factor concentrate (CFC), used to treat and prevent bleeding in hemophilia, is rendered ineffective if clotting factor neutralizing antibodies (inhibitors) develop. Inhibitors occur most often in children, early in treatment. ATHN 8: US Cohort Study of Previously Untreated Patients (PUPs) with Congenital Hemophilia, conducted in children born in 2010-2020 with severe or moderate hemophilia, was designed to determine the percentage of participants who developed a confirmed, clinically significant inhibitor within the first 50 CFC exposure days (ED). Cox Proportional Hazards models were used to evaluate risk factors for inhibitor development in PUPs with severe hemophilia A (HA). One hundred seventy-one males with severe HA enrolled. Thirty-nine (22.8%) developed an inhibitor; 30 (17.5%) developed a high-titer inhibitor and 9 (5.3%) developed a low-titer inhibitor; 82.1% within 20 ED. Product exposure at <1 month (Hazard ratio = 2.57, 95%CI 1.22-5.44), large structural changes (Hazard ratio = 16.59, 95%CI 1.94-142.20), and nonsense variants (Hazard ratio =12.53, 95%CI = 1.41-111.49) were associated with inhibitor development. Overall, inhibitor development remains a significant CFC complication especially in the first 10 to 20 ED. Further study should evaluate the impact of new treatments on inhibitor rates and age at inhibitor development and identify strategies to reduce inhibitor development.