Alloantibodies against factor VIII (FVIII; inhibitors) are the main complication of hemophilia A. Immune tolerance induction (ITI) eradicates inhibitors in about 70% of people with hemophilia A. Few studies have evaluated the role of FVIII gene (F8) variants on ITI outcome.

We evaluated the role of F8 pathogenic variants on ITI outcome in people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction. F8 sequencing was carried out for all people.

We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6-years at ITI start. Intron 22 inversion was the most prevalent variant (53.6%), followed by nonsense (16.1%), small insertion/deletion (11.3%), and large deletion (10.7%). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (Odds Ratio [OR = 15.50]; 95% Confidence Interval [95% CI 4.59‒71.30]) and 4.25 times higher (95% CI 1.53‒12.3) among carriers of F8 large deletions and small insertions and deletions, respectively.

F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study showing F8 large deletions and frameshift variants as determinants of ITI failure.