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

Authors:  Carcao, M; Königs, C; Andersson, NG; Kovel, M de; Boer-Verdonk, E de; Motwani, J; Blatny, J; Olivieri, M; van den Berg, M; Fischer, K

Affiliations: Division of Haematology/Oncology, Department of Paediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada. Goethe University, Department of Pediatrics and Adolescent Medicine, Clinical and Molecular Haemostasis, Frankfurt, Germany. Center for Thrombosis and Hemostasis, Department of Pediatrics, Skåne University Hospital, Malmö, and Department of Clinical Sciences and Pediatrics, Lund University, Lund, Sweden. PedNet Haemophilia Research Foundation, Baarn, The NetherlandsDepartment of Haematology, Birmingham Children’s Hospital, Birmingham, UK. Department of Paediatric Haematology and Biochemistry, Children’s University Hospital, Brno, Czech Republic (Supported by Ministry of Health, Czech Republic – conceptual development of research organization (FNBr, 65269705)). Pediatric Thrombosis and Hemostasis Unit, Pediatric Hemophilia Center, Dr. von Hauner Children’s Hospital, LMU Munich, Munich, Germany.

Publication: Journal of thrombosis and haemostasis; 2025

ABSTRACT: 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.