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.

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.