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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.)

Background: The predictors of immune tolerance induction (ITI) outcomes in hemophilia A (HA) patients with the same F8 genetic background have not yet been evaluated, although the F8 genotype is strongly associated with ITI response. This study aims to explore the predictors of ITI outcomes in the same F8 genetic background by focusing on intron 22 inversion (Inv22) patients with high-responding inhibitors., Methods: HA children with Inv22 and high-responding inhibitors who received low-dose ITI therapy over 24 months were included in this study. ITI outcomes were centrally assessed at the 24th month of treatment. The predictive ability of clinical variables to identify ITI success was determined using the receiver operating characteristic (ROC) curve, and the predictor of ITI outcomes was analyzed on the multivariable Cox model., Results: Among the 32 patients investigated, 23 (71.9 %) achieved success. In univariate analysis, interval time from inhibitor diagnosis to ITI start (interval-time) was significantly associated with ITI success (P = 0.001); however, inhibitor titers showed no significance (P > 0.05). The interval-time demonstrated a good predictive value for ITI success with the area under the ROC curve of 0.855 (P = 0.002), and the cutoff value was 25.8 months (sensitivity, 87.0 %; specificity, 88.9 %). In the multivariable Cox model which considered success rate and time to success, interval-time was the only independent predictor (<25.8 months vs. ≥25.8 months, P = 0.002)., Conclusions: The interval-time was first identified as a unique predictor of ITI outcomes in HA patients with high-responding inhibitors under the same F8 genetic background (Inv22). An interval-time of <25.8 months was associated with increased ITI success and reduced time to success., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Shorter interval-time from inhibitor detection to starting immune tolerance induction (ITI) might predict better ITI outcomes for severe Hemophilia A (SHA) patients with high-risk-inhibitors. However, the prediction-impact of interval-time for these patients on low-dose ITI strategy remained unclear., Objectives: To explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors., Methods: This was a single-center, retrospective study on SHA children with high-risk-inhibitors (each with immediate pre-ITI inhibitor titer>10 Bethesda Units/mL) undergoing low-dose ITI strategy for ≥24 months. ITI outcomes and their predictive factors were evaluated at the 24th month treatment for each patient. The predictive ability of interval-time on ITI success was determined using receiver operating characteristic (ROC) curve., Results: Among 47 patients investigated, 34 (72.3 %) achieved success. Independent predictor for ITI-outcome on multivariate analysis included the interval-time (p = 0.007) and peak inhibitor-titer (p = 0.011). Shorter interval-time predicted ITI success [cut-off value = 22.3 months, area under ROC-curve (AUC) = 0.701] and early-ITI success within 12 month (cut-off value = 9.4 months AUC = 0.704). Linear regression analysis suggested each month interval-time delay delayed success by 0.1552 month. Unlike the interval-time, peak inhibitor-titer had no success-predictive value in high-peak inhibitor-titer patients on ITI with immunosuppressants., Conclusions: Interval-time represented a strong predictive value for outcomes in our low-dose ITI strategy for SHA patients with high-risk-inhibitors. Shorter interval-time was associated with higher success rate and earlier success achievement. The respective interval-time cut-off values were 22.3 months for ITI success and 9.4 months for early-success., Competing Interests: Declaration of competing interest The authors stated that they had no conflicts of interest or bias., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: The development of inhibitory antibodies (inhibitors) in persons with hemophilia B (PwHB) causes significant morbidity. Data on the impact of the F9 variant and immune tolerance induction (ITI) outcome are limited. The aim of this study was to investigate the presence of neutralizing and non-neutralizing antibodies (NNA) in severe hemophilia B (HB) and to evaluate ITI outcome and complications in relation to the pathogenic F9 variant., Materials and Methods: Persons with severe HB in the Nordic countries were enrolled and information on F9 variants, inhibitors, ITI and complications were collected. Analyses of anti-FIX antibodies with a fluorescence-immunoassay (xFLI) and an ELISA method were conducted., Results: Seventy-nine PwHB were enrolled. Null variants were seen in 33 (42 %) PwHB and 12 (15 %) had a current or former inhibitor. Eleven (92 %) of the inhibitor patients had experienced allergic manifestations and three (25 %) nephrotic syndrome. Of 10 PwHB with at least one ITI attempt, eight (80 %) were considered tolerant at enrolment. Immunosuppression was included in seven of eight successful or partially successful attempts. Five PwHB had at least one ITI failure before a successful or partially successful ITI. No NNA could be identified., Conclusion: A high proportion of severe F9 gene defects among persons with severe HB in the Nordic countries may explain the observed relatively high prevalence of inhibitors. ITI success was independent of the F9 variant and attained despite allergic manifestations and previous ITI failures. Inclusion of immunosuppression tentatively enhances the chances of ITI success. No NNA were observed., (Copyright © 2022. Published by Elsevier Ltd.)

Introduction: Inhibitor development in people with haemophilia is a serious complication that may require intensive and costly interventions. The goal of inhibitor management should be permanent inhibitor eradication through immune tolerance induction (ITI), but well-designed studies are lacking and the management of patients is therefore defined by the experience and views of the clinician., Objectives: To explore the current clinical practice and outcome of ITI therapy in Europe and how this may have changed over the last decade, as well as to provide consensus recommendations to guide clinicians in their clinical practice., Methods: A survey was conducted among 16 European haemophilia comprehensive care centres to evaluate current ITI treatment regimens and success rates in severe and mild/moderate haemophilia A and haemophilia B. In addition, an updated literature review was performed as guidance for providing recommendations., Results: We demonstrated successful inhibitor treatment in 86% of severe haemophilia A patients with low responding (LR) and 59% of patients with high responding (HR) inhibitors. Some new trends in the management of patients with inhibitors were identified, including a tendency to use low-dose regimens (<50IU/kg/d) in both children and adults with HR inhibitors possibly based on similar success rates demonstrated in the I-ITI study compared to a high-dose protocol. Data on ITI therapy in mild and moderate haemophilia as well as haemophilia B were limited., Conclusions: The outcome of ITI therapy seems to be stable over time, and treatment regimens remain heterogeneous. The use of low dose regimens however is considered more frequently., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Nijmegen-Bethesda assay is the gold standard to assess inhibitory antibodies against factor (F) VIII. This method has some limitations, including high coefficient of variation and possible interference of residual endogenous or exogenous factor VIII. Heat-treatment of samples at 56 °C for 30 min could be a strategy to improve the sensitivity of this test. The aim of this study was to compare inhibitor quantification in hemophilia patients with and without inhibitor performed in previously heated and non-heated samples. A total of 109 analyses from 46 patients with severe hemophilia A were performed. Patients were divided into three groups: 20 patients with no history of inhibitor, recently and not recently exposed to FVIII (group I), 21 patients with history of inhibitor not exposed to FVIII (group II), and 5 patients (68 samples) undergoing an immune tolerance induction (ITI) protocol (group III). For patients with no history of inhibitor, heat-treatment did not modify the results (p=0.24). However, differences in inhibitor levels between heated and non-heated samples were observed in patients with history of inhibitor (group II, p<0.05) and in patients in ITI (group III, p<0.001). In 11 samples, inhibitor quantification shifted from negative to positive. Additionally, a longitudinal evaluation of each ITI patient showed similar trend line for the results of heated and non-heated samples. In this study, we demonstrated that heating samples increase sensitivity of Nijmegen-Bethesda assay, with no shift from negative to positive results in patients with no history of inhibitor. Furthermore, this procedure has an important role to patients undergoing an ITI protocol., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Introduction: It has been postulated that factor VIII (FVIII) products containing von Willebrand factor (VWF) may improve immune tolerance induction (ITI) success rate in patients with haemophilia A and poor prognostic factors., Materials and Methods: We conducted a retrospective cohort analysis of a FVIII/VWF concentrate (BIOSTATE) for ITI in paediatric patients with severe haemophilia A (SHA) and inhibitors, from January 2003 to December 2011 at 3 paediatric-only Haemophilia Treatment Centres in Australia. Response to ITI was assessed at or before 33 months and at completion of ITI. Fifteen male patients with SHA were included in the analysis., Results: BIOSTATE was used for primary ITI in 8 patients (2 years, range 1.1-11.5 years) and for salvage ITI in 7 patients (9.9 years, range 1.1-15.4). At the end of the observation period there were 11 patients who achieved a complete response with BIOSTATE after a median duration of 21 months (range 5-85 months); a partial response was achieved in 2 patients in whom ITI is ongoing. Therefore, the overall response rate was 86.6%. Two patients were deemed treatment failures: one due to non-compliance after 18 months of ITI and another in whom a partial response had not been achieved after 22 months of ITI., Conclusion: BIOSTATE was well-tolerated and effective when used for primary or salvage ITI in this cohort of paediatric patients with SHA and a high-level inhibitor., (Copyright © 2014. Published by Elsevier Ltd.)