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
(2025) In Journal of Thrombosis and Haemostasis 23(10). p.3134-3147- Abstract
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... (More)
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.
(Less)
- author
- Carcao, Manuel ; Königs, Christoph ; Andersson, Nadine G. LU ; de Kovel, Marloes ; de Boer-Verdonk, Elsbeth ; Motwani, Jayashree ; Blatny, Jan ; Olivieri, Martin ; van den Berg, Marijke and Fischer, Kathelijn
- organization
- publishing date
- 2025-10
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- alloantibodies against FVIII, hemophilia A, immune tolerance induction, inhibitor, tolerance
- in
- Journal of Thrombosis and Haemostasis
- volume
- 23
- issue
- 10
- pages
- 14 pages
- publisher
- Elsevier
- external identifiers
-
- pmid:40706963
- scopus:105013147076
- ISSN
- 1538-7933
- DOI
- 10.1016/j.jtha.2025.07.010
- language
- English
- LU publication?
- yes
- id
- 90adfbe7-fcaa-4efd-89ba-e76fd29edbf7
- date added to LUP
- 2026-01-08 11:02:02
- date last changed
- 2026-01-08 11:02:48
@article{90adfbe7-fcaa-4efd-89ba-e76fd29edbf7,
abstract = {{<p>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.</p>}},
author = {{Carcao, Manuel and Königs, Christoph and Andersson, Nadine G. and de Kovel, Marloes and de Boer-Verdonk, Elsbeth and Motwani, Jayashree and Blatny, Jan and Olivieri, Martin and van den Berg, Marijke and Fischer, Kathelijn}},
issn = {{1538-7933}},
keywords = {{alloantibodies against FVIII; hemophilia A; immune tolerance induction; inhibitor; tolerance}},
language = {{eng}},
number = {{10}},
pages = {{3134--3147}},
publisher = {{Elsevier}},
series = {{Journal of Thrombosis and Haemostasis}},
title = {{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}},
url = {{http://dx.doi.org/10.1016/j.jtha.2025.07.010}},
doi = {{10.1016/j.jtha.2025.07.010}},
volume = {{23}},
year = {{2025}},
}