LARGE DELETIONS AND SMALL INSERTIONS AND DELETIONS IN THE FACTOR VIII GENE PREDICT FAILURE TO IMMUNE TOLERANCE INDUCTION IN PEOPLE WITH SEVERE HEMOPHILIA A AND HIGH-RESPONDING INHIBITORS

Abstract

Introduction: 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. Material and methods: 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. Results: 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. Conclusion: 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.