Determinants of Immune Tolerance Induction Outcomes in 237 Persons With Severe Hemophilia A

Immune tolerance induction (ITI) to eradicate an immune response against factor VIII (FVIII) has been used in hemophilia A (HA) with various success rates, costs, and treatment burden. The present study aimed to identify markers predictive of ITI success. Data were accrued from 237 patients with severe HA (FVIII level < 1%), history of persistent FVIII inhibitors ≥ 1 BU/mL and having performed ITI. Constitutional and clinical variables associated with ITI outcome were evaluated and multivariable logistic regression models developed. The F8 variant, age at inhibitor detection, and historical peak inhibitor titer were associated with ITI outcome. HLA DRB1*1501 and DQB1*0602 were linked to each other, but not associated with ITI outcome. In a multivariable-adjusted model, large gene deletions, peak titer ≥ 25 BU/mL, and higher age at inhibitor detection were associated with a significantly lower ITI success rate. The discriminatory power of a predictive model was 0.87 (95% confidence interval [CI], 0.85-0.93) with the historical peak titer and 0.69 (95% CI, 0.64-0.80) without. We conclude that the peak inhibitor titer is a key determinant for ITI outcome and additional constitutional markers need to be defined for useful prediction in the clinical setting.