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Multicenter Study
. 2025 Oct;23(10):3134-3147.
doi: 10.1016/j.jtha.2025.07.010. Epub 2025 Jul 22.

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

Manuel Carcao  1 , Christoph Königs  2 , Nadine G Andersson  3 , Marloes de Kovel  4 , Elsbeth de Boer-Verdonk  4 , Jayashree Motwani  5 , Jan Blatny  6 , Martin Olivieri  7 , Marijke van den Berg  4 , Kathelijn Fischer  8
Affiliations
Multicenter Study

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

Manuel Carcao et al. J Thromb Haemost. 2025 Oct.

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 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.

Keywords: alloantibodies against FVIII; hemophilia A; immune tolerance induction; inhibitor; tolerance.

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Conflict of interest statement

Declaration of competing interests M.C. reports receiving research support from Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda and honoraria for speaking/participating in advisory boards from Bayer, LFB, Novo Nordisk, Pfizer, Roche, Sanofi, and Takeda. C.K. reports receiving fees for clinical trials and research from Bayer, Biotest, CSL Behring, Intersero, Novo Nordisk, Pfizer, Roche/Chugai, Takeda, Sobi/Sanofi, EU H2020 ITN, State of Hesse, and FUSE e.V., and speaker’s fees/advisory board fees from Bayer, CSL Behring, Florio, MSD, Novo Nordisk, Roche/Chugai, Sobi/Sanofi, and Takeda. N.G.A. has served as a speaker for lectures, educational courses, and/or on advisory boards for CSL Behring, Octapharma, and Sobi/Sanofi, and has received grants/research support to the institution from Novo Nordisk and Sanofi. M.d.K. has nothing to declare. E.d.B.-V. has nothing to declare. J.M. has received educational grants, speaker fees, or honoraria from Bayer, CSL Behring, Roche, and Sobi. J.B. has received consultation and/or speaker’s fees from CSL Behring, Novo Nordisk, Pfizer, Roche, Sobi, and Takeda. M.O. has received grants/research support from Bayer, Takeda, CSL Behring, Pfizer, and Sobi, and consultancy and speaker fees from Bayer, BioMarin, Biotest, Novo Nordisk, Takeda, CSL Behring, Pfizer, Roche, Sobi, and Stago. M.v.d.B. has nothing to declare. K.F. has acted as a consultant and participated in expert groups for Bayer, Biogen, CSL Behring, Novo Nordisk, and Sobi, has received research grants from Bayer, Novo Nordisk, and Pfizer, has given invited educational lectures for Bayer, Novo Nordisk, Pfizer, and Takeda, and has received travel support from Sobi and Bayer.

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