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Introduction: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome., Material and Methods: We included 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, followed by F8 sequencing., 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 to show F8 large deletions and small insertions/deletions as predictors of ITI failure., Competing Interests: Declaration of competing interest RMC received speaker fees from Bayer, NovoNordisk, Hoffman-La Roche, and Takeda, consultancy fees from Hoffman-La Roche and Takeda, and sponsorship to attend scientific event grants from Bayer, NovoNordisk, Hoffman-La Roche, and Takeda. AGO received speaker fees and scientific event grants from NovoNordisk and Takeda. MRFR received speaker fees from NovoNordisk, scientific event grants from Hoffman-La Roche, Takeda and NovoNordisk, and consultancy fees from the Brazilian Ministry of Health. FMRAC received sponsorship to attend scientific event grants from Hoffman-La Roche and NovoNordisk. LYE received scientific event grants from Hoffman-La Roche. MAFC received sponsorship to attend scientific event grants from Hoffman-La Roche and NovoNordisk. ISSP received speaker fees from Hoffman-La Roche, NovoNordisk and Takeda, sponsorship to attend scientific event grants from Hoffman-La Roche, Takeda and NovoNordisk, consultancy fees from the Hoffman-La Roche, NovoNordisk, Bayer and Biomarin, and grants for scientific publication from Takeda. AAG received speaker fees from Takeda and NovoNordisk, sponsorship to attend scientific event grants from Takeda and NovoNordisk, and consultancy fees from NovoNordisk. THA received sponsorship to attend scientific event grants from Hoffman-La Roche and Takeda. DCFN received sponsorship to attend scientific event grants from Takeda. LWZ, RPS, MMD, MAPS, LLJ, RAR, MHC, CSL, DMT, VKBF, RPT, DGC, JVDB and SMR declare they have no competing interests which might be perceived as posing as a conflict., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

VONCENTO (CSL Behring Gmbh, Marburg, Germany) is a plasma-derived, high concentration, lower volume [relative to HAEMATE P (CSL Behring)], high-purity von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a VWF/FVIII ratio similar to HAEMATE P. This open-label, multicentre study investigated the pharmacokinetic, haemostatic efficacy, and safety profiles of VONCENTO in study participants at least 12 years of age with von Willebrand disease (VWD) who required treatment of nonsurgical bleeding (NSB) events or underwent surgery or prophylaxis. The first 12-month on-demand treatment period comprised a pharmacokinetic investigation and an efficacy analysis. After 12 months, qualifying study participants were switched to prophylactic therapy and included in a further 12-month efficacy analysis. In total, 21 study participants (including three adolescents, and 13 study participants with VWD type 3) received VONCENTO as on-demand treatment for 12 months. 'Excellent'/'good' haemostatic efficacy was achieved in 98.3% of the 407 NSB events assessed by investigators. Following the switch to prophylactic treatment, the total number of NSBs in eight patients markedly decreased from 304 to 10 (with haemostatic efficacy judged to be 'excellent' for all). The annualised bleeding rate also significantly decreased from a median of 26.5 events to one event. Safety assessments showed no inhibitory antibodies to either FVIII or VWF, no transmission of infectious agents, no thromboembolic events and no treatment-related serious adverse events. VONCENTO was shown to be well tolerated and provided excellent haemostatic efficacy in the treatment of bleeds or during prophylaxis in study participants with VWD, including also those with type 3, the severest form of VWD.