Predictors of immune tolerance induction success in 231 children with severe hemophilia A with high-titer inhibitors – lessons learned from the PedNet prospective cohort study

Abstract

Background: Previously untreated patients with severe hemophilia A exposed to factor (F)VIII are at risk of developing high-titer inhibitors. Traditionally, such children were tried on immune tolerance induction (ITI). With availability of nonfactor therapies, recommendations regarding whether to continue trying ITI and how are lacking. Objectives: To provide data to address these questions, we reviewed the experience of ITI in Pediatric Network (PedNet) centers. Methods: The outcomes of 231 previously untreated patients with severe hemophilia A and high-titer inhibitors to FVIII, who were followed over a 20-year period and underwent ≥1 course of ITI, were reviewed. Results: The success of the first course of ITI was predicted by pre-ITI peak inhibitor titers (PITs), a family history of inhibitors, high-risk F8 gene variants, and the start of ITI within 10 months of inhibitor diagnosis. Pre-ITI PITs were a strong predictor of eventual ITI success with 1 or more ITI courses: 76.4% of those with pre-ITI PITs of 5 to 39 Bethesda Units (BUs) achieved tolerance (median, 0.72 years) vs 70.9% of those with pre-ITI PITs of 40 to 200 BU (median, 2.1 years) vs 42.1% of those with pre-ITI PITs of >200 BU (median, 5.1 years). A PIT of >200 BU during the first course of ITI was a strong predictor of ultimately failing ITI. The ITI regimen, whether administered daily or nondaily at a high or low dose, was not a predictor of ITI success with the first course of ITI. Conclusion: These predictors of success may be used to decide whether and how to initiate ITI when nonreplacement prophylaxis is available.