Low‐dose immune tolerance induction in children with severe hemophilia A with high‐titer inhibitors: Type of factor 8 mutation and outcomes

BACKGROUND: No studies evaluated the role of F8 mutations in outcomes for low‐dose immune tolerance induction (ITI) in people with severe hemophilia A (SHA) with high‐titer inhibitors. OBJECTIVES: To explore the association between F8 mutation types and low‐dose ITI outcomes in children with SHA with high‐titer inhibitors. METHODS: Children SHA with high‐titer inhibitors who received low‐dose ITI therapy at least for 1 year were included in this study. Based on the risk of inhibitor development, F8 mutations were classified into a high‐risk group and a non–high‐risk group. Rapid tolerance and the final ITI outcomes were assessed at the 12th and 24th month of treatment, respectively, and the predictor of outcomes was analyzed. RESULTS: Of 104 children included, 101 had F8 mutations identified. The children with non–high‐risk mutations presented a higher rate of rapid tolerance than those with high‐risk mutations (61.0% vs. 29.2%; p = 0.006). Among 72 children beyond 24 months of ITI, 55 children (76.4%) achieved success, 3 (4.2%) achieved partial success, and 14 (19.4%) failed. The children in the non–high‐risk group showed a higher success rate (86.8% vs. 43.8%; p = 0.001) and a shorter time to success (mean time, 9.3 months vs. 13.2 months; p = 0.04) compared to those in the high‐risk group. In multivariable logistic regression, F8 mutations were an independent predictor of ITI success (non–high‐risk group vs. high‐risk group, adjusted odds ratio [OR], 20.3; 95% confidence interval [CI], 3.5–117.8), as was the interval from inhibitor diagnosis to ITI start (adjusted OR, 0.95; 95% CI, 0.90–0.99). They remained the significant predictors when success time was taken into account in a Cox model. CONCLUSIONS: Types of F8 mutation were a key predictor of outcomes for low‐dose ITI in children with SHA with high‐titer inhibitors. It can help to stratify the prognosis and guide clinical decisions.