Predictors of ITI success in 231 children with Severe hemophilia A with high titer inhibitors - lessons learned from the PedNet prospective cohort study.

Background: Previously untreated patients (PUPS) with severe hemophilia A exposed to FVIII are at risk of developing high titer inhibitors (HTI). Traditionally such children were tried on immune tolerance induction (ITI). With availability of non-factor 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 PedNet centers.

Patients/methods: Outcomes of 231 PUPS with severe hemophilia A and HTIs to FVIII followed over a 20-year period who underwent ≥1 course of ITI were reviewed.

Results: Success with the 1^st course of ITI was predicted by pre-ITI peak inhibitor titers (pre-ITI PITs), family history of inhibitors, high risk F8 gene variants, and start of ITI within 10 months of inhibitor diagnosis. Pre-ITI PITs were a strong predictor of eventual ITI success with one or more ITI courses: 76.4% of those with pre-ITI PITs of 5-39 BU achieved tolerance (median 0.72y) vs 70.9% of those with pre-ITI PITs of 40-200 BU (median 2.1y) vs 42.1% of those with pre-ITI PITs of >200 BU (median 5.1y). A PIT of >200 BU during 1^st course of ITI was a strong predictor of ultimately failing ITI. ITI regimen, and whether daily or non-daily, high or low dose was not a predictor of ITI success with the 1^st course of ITI.

Conclusion: These predictors of success may be used in deciding whether and how to initiate ITI when non-replacement prophylaxis is available.