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Introduction: Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe haemophilia A with inhibitors. Since the risk of inhibitor development is greater among Black and Hispanic persons, it has been hypothesized that race and ethnicity may influence ITI success. Limited studies have evaluated this hypothesis., Aim: To examine the success of ITI according to race and ethnicity., Methods: Participants who entered the Community Counts (CC) Registry between 2013 and 2017, were aged ≥3 years at study entry, and received ITI were included (n = 559). The proportion of participants with successful ITI was examined with adjusted prevalence ratios (aPRs) and corresponding 95% confidence intervals (95% CIs)., Results: Among 559 participants, 56.9%, 19.1%, 18.1% and 4.3% were Non-Hispanic (NH) White, NH Black, Hispanic and Asian, respectively, and 1.7% were coded as other or missing. Approximately 80% of Hispanic, NH Black and NH White participants had good/very good prognosis, defined as having a pre-ITI peak inhibitor of < 200 Bethesda Units per millilitre. Nearly 60% of participants (59.7%) achieved successful ITI, 20.7% and 19.5% experienced partially successful or failed ITI, respectively. Successful ITI was non-significantly lower in NH Black (54.2%; aPR = 0.95, 95% CI 0.62-1.44) and Hispanic (55.4%; aPR = 0.89, 95% CI 0.71-1.13) relative to NH White participants (62.6%)., Conclusion: In this study, 60% of participants in the CC Registry had successful ITI, consistent with previous studies. The proportion with successful ITI was generally comparable across racial and ethnic groups with similar prognosis. These findings do not support the hypothesis that ITI response varies according to race or ethnicity., (© 2024 John Wiley & Sons Ltd.)

Introduction: The development of inhibitors against factor FIX (FIX) is the most serious complication of FIX replacement therapy in haemophilia B (HB) patients. Currently, only few cohorts of HB inhibitor patients have been reported worldwide., Aim: This Chinese nationwide study of HB inhibitor patients explored their risk factors for FIX inhibitor development and experience on their management., Methods: We retrospectively analysed patient characteristics, F9 genotypes, treatment strategies and outcomes of HB inhibitor patients registered to the Chinese National Registry and Patient Organization Registry., Results: Forty-four unique HB inhibitor patients were identified in 4485 unique HB patients registered by year 2021 to the two Registries. Inhibitor diagnosis were usually delayed and the low prevalence (.98%) may suggest some inhibitor patients were not identified. Their median age at inhibitor diagnosis was 7.5 (IQR, 3.0-14.8) years. Most patients (95.5%) had high-titre inhibitors. Allergic/Anaphylactic reactions occurred in 59.1% patients. Large deletions and nonsense mutations were the most common F9 mutation types in our FIX inhibitor patients. Patients with large F9 gene deletions were more likely to develop inhibitors (p = .0002), while those with missense mutations had a low risk (p < .0001). Thirteen (29.5%) patients received immune tolerance induction (ITI) therapy using low-dose prothrombin complex concentrate regimens. Twelve completed ITI with three (25.0%) achieving success. Nephrotic syndrome developed in two (16.7%) patients during ITI., Conclusion: This study reports the largest Chinese cohort of HB inhibitor patients. Large deletions were most significantly associated with inhibitor development. Low-dose ITI might be feasible for FIX inhibitor eradication., (© 2022 John Wiley & Sons Ltd.)

Introduction: The development of inhibitors with factor VIII (FVIII) replacement therapy is one of the most common and challenging complications of haemophilia A (HA) treatment, jeopardising treatment efficacy and predisposing patients to high risks of morbidity and mortality. The management of patients with inhibitors is particularly challenging in countries where resources are limited., Aim: To provide a comprehensive summary of the management of HA with inhibitors while focusing on differences in practice between Western and non-Western countries and how resource scarcity can impact HA management, leading to suboptimal outcomes in patients with inhibitors., Methods: Summary of key evidence and regional expert opinion., Results: We address, particularly, the diagnosis of and testing for inhibitors, as well as the epidemiology of inhibitors, including incidence, prevalence and disease burden. Secondly, we provide an overview of the current treatment landscape in HA with inhibitors regarding the eradication of inhibitors with immune tolerance induction and the treatment and prevention of bleeding with bypassing agents, non-factor replacement agents and other experimental therapies. This is complemented with insights from the authors around the applicability of, and challenges associated with, such therapies in their settings of practice., Conclusions: We conclude by proposing some key steps towards bridging the gaps in the management of HA with inhibitors in resource-limited countries, including: (1) the collection of quality data that can inform healthcare reforms and policies; (2) improving disease knowledge among healthcare practitioners and patients with the aim of standardising disease management across centres and (3) working towards promoting equal access to HA care and therapies for everyone., (© 2022 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications., Aim: To characterize clinical features and outcome of ITI on HBI., Methods: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low-dose ITI (25-50 FIX IU/kg/three-times-weekly to every-other-day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens., Results: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7-512) BU, and 15 (93.8%) had high-titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen-1), four achieved tolerization in 1.4-43.3 months. Two subsequently relapsed but re-tolerized after a second course of IS Regimen-1. During ITI, the median treated bleed was .39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen-2) using multiple-IS-drugs, and two had rapid tolerization (.8 and 1.8 months)., Conclusions: Inhibitor eradication could be achieved by low-dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen-2 is more effective with less complications., (© 2022 John Wiley & Sons Ltd.)

Introduction: The development of inhibitory antibodies is a severe complication of clotting factor replacement therapy in patients with severe haemophilia A (HA). Current World Federation of Hemophilia (WFH) guidelines for haemophilia care indicate that eradication of inhibitors is best achieved through immune tolerance induction (ITI) therapy., Aim: The European Collaborative Haemophilia Network conducted a survey to determine whether ITI is still used in the routine management of patients with HA, and whether the availability of emicizumab prophylaxis has influenced treatment decisions., Methods: The survey was conducted in late 2020/early 2021 in 18 centres representing 17 countries in the Europe/Middle East region treating a total of 4955 patients, and included sections specific to patient and centre demographics, treatment protocols (both ITI and prophylactic), inhibitor development and initiation of ITI, treatment success, and the incidence of adverse events., Results: While our results indicate that ITI can still be considered a mainstay of treatment for patients with HA with inhibitors, less than daily dosing of ITI in combination with emicizumab prophylaxis is becoming commonplace across the spectrum of disease severity, with initiation being guided by bleeding patterns. The most frequently cited reasons for not initiating emicizumab prophylaxis were availability or reimbursement issues., Conclusion: ITI remains a mainstay for haemophilia treatment of patients with HA with inhibitors, but emicizumab has become a preferred first-line approach to protect against bleeds and represents an alternative to burdensome ITI in certain patient groups., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: In good risk patients (historic inhibitor peak < 200BU), the International Immune Tolerance Study demonstrated equal efficacy to induce tolerance between high (200iu/kg/day) and low dose (50iu/kg ×3 times/week) immune tolerance induction (ITI) regimens. However, the trial stopped early on account of the excessive bleed rate in the low dose ITI arm., Methods: United Kingdom Haemophilia Centre Doctors' Organization (UKHCDO) Paediatric and Inhibitor working parties considered available ITI data alongside the bi-phenotypic antibody emicizumab (Hemlibra®) efficacy and safety data to develop a consensus guideline for the future UK ITI guideline., Results: This revision of UKHCDO ITI guidance incorporates the recommendation to use emicizumab as a prophylaxis haemostatic agent to reduce bleeding rates and to facilitate low dose and reduced frequency of FVIII CFC for ITI in the majority of children., Conclusion: This consensus protocol will facilitate future evaluation of ITI outcomes in the evolving landscape of haemophilia therapeutics and ITI strategies., (© 2021 John Wiley & Sons Ltd.)

Introduction: Inhibitors develop less frequently in haemophilia B (HB) than haemophilia A (HA). However, when present, the success of tolerization by immune tolerance induction (ITI) therapy is lower and the risk of complications higher., Aim: To evaluate the use and outcome of ITI in patients with HB and inhibitors., Methods: Subjects include singletons or siblings with a current/history of inhibitors enrolled in B-Natural-an observational study designed to increase understanding of clinical management of patients with HB. Patients were followed for 6 months and information on demographics, medical and social history, and treatment were recorded., Results: Twenty-nine patients with severe HB and inhibitors were enrolled in 24 centres. Twenty-two underwent one or more courses of ITI with or without immune suppression. Eight patients (36.4%) were successfully tolerized after the first course of ITI. One of these successes (12.5%) experienced allergic manifestations, whereas the corresponding number for the 10 treatment failures was five (50%). One of seven (14.2%) patients with large deletions and three of eight (37.5%) with nonsense mutations were tolerized at the first attempt, and all patients experiencing nephrosis either failed or were on-going. At study end, 11 (50%) were considered successfully tolerized after one or more ITI courses, three were unsuccessful, and eight were still undergoing treatment., Conclusion: Our data underscore the possibilities and difficulties of achieving tolerization in patients with HB with inhibitors. The type of mutation and complications appear to correlate with ITI outcome, but more accurate definitions of successful ITI are warranted., (© 2021 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Standard treatment of haemophilia A is based on replacing the missing coagulation factor VIII (FVIII) to treat and prevent bleeding episodes. The most challenging complication of FVIII therapy is the development of neutralizing antibodies (inhibitors) that can render treatment ineffective. Eradication of the inhibitor through immune tolerance induction (ITI) remains the most effective strategy for managing these patients. Bypassing agents can be used to help restore haemostasis in inhibitor patients. Several novel agents have recently been developed, such as the FVIII mimetic agent emicizumab, which has been effective in reducing the annualized bleeding rate in haemophilia A patients with inhibitors. When coadministered with repetitive high doses of activated prothrombin complex concentrate (ie >100 U/kg/d for ≥24 hours), emicizumab was associated with thrombotic microangiopathy and thrombosis events. As a consequence the United Kingdom Haemophilia Centres Doctors' Organisation (UKHCDO) issued the first guidance on the treatment of bleeding episodes in patients receiving emicizumab. To build on and extend this work, a panel of German haemophilia specialists met to discuss the UK guidance, review current evidence and provide additional guidance for German healthcare professionals on how to optimize the management of patients with haemophilia A receiving emicizumab. Recommendations are provided on the use of bypassing and other agents to manage breakthrough bleeding, ITI in the emicizumab era, haemostatic support during surgery and issues relating to laboratory monitoring., (© 2020 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Emicizumab is a bispecific antibody that recognizes FIX(a)/FX, and mimics FVIIIa cofactor activity. Due to its unique characteristics including longer half-life and subcutaneous injectability, treatment for haemophilia A dramatically improved regardless of the presence of FVIII inhibitor. Protection from pathological change in joints, avoidance of inhibitor development and intra-cranial haemorrhage could be expected by introduction of emicizumab in early childhood. Applications in mild/moderate patients should be also considered. Clinical assessment tool should be standardized; however, since there are limitations to conventional ABR-based assessment. Laboratory monitoring is another practical issue due to the mode of action of emicizumab. Chromogenic assays and global assays could be utilized. The other emicizumab-related practical issue is immune tolerance induction for the inhibitor patients, since ITI remains the only effective means to inhibitor eradication. With the recently introduced Atlanta protocol, emicizumab prophylaxis is given in combination with 50-100 IU/kg FVIII three times a week. A single manuscript has been published, and multiple clinical trials are open to address the efficacy of this strategy. Whether the Atlanta protocol will be fully embraced is yet to be seen, but there is widespread consensus about attempts to tolerize every haemophilia A patient with an inhibitor., (© 2020 John Wiley & Sons Ltd.)

Background: The appearance of inhibitors is the most serious complication in haemophilia A (HA) patients. The primary objective is their eradication. Up to date, immune tolerance induction (ITI) was the only therapeutic option to achieve this., Aim: To assess the efficacy of moroctocog-alpha as an ITI regimen in a population of HA patients with high-titre inhibitors., Methods: The REF.IT Registry is a retrospective-prospective study that collected data on all patients with HA and high-titre inhibitors treated with moroctocog-alpha as an ITI regimen at twelve Italian Haemophilia Centres., Results: We enrolled 27 patients, 85.2% were children. All patients were high responders, 88.9% had severe HA. We found 69.3% of them had one or more risk factors for poor ITI prognosis, 14.8% were ITI rescue. Overall 59.3% achieved a complete/partial success (complete in 51.9%). ITI failed in 11 patients, 63.6% of them with poor-prognosis risk factors. Inhibitors appeared after a mean of 27 exposure days. Mean historical peak was 78.8 BU/mL. The primary ITIs started on average 20.2 months after the diagnosis. A partial or complete success after a mean of 15 months of treatment was achieved in 56.6% of the children while the same result was obtained by 75.0% adults after 22 months from ITI onset. Patients who were treated with high-dose moroctocog-alpha (200 UI/kg/day) were 63.0%., Conclusion: Our Registry showed that the use of moroctocog-alpha in the setting of ITI was effective and safe also in a population of patients with high-titre inhibitors, presenting one or more risk factors for poor ITI prognosis., (© 2019 John Wiley & Sons Ltd.)

Introduction: As a result of the new treatment paradigm that the haemophilia community will face with the availability of novel (non-factor) therapies, an updated consensus on ITI recommendations and inhibitor management strategies is needed., Aim: The Future of Immunotolerance Treatment (FIT) group was established to contemplate, determine and recommend the best management options for patients with haemophilia A and inhibitors., Discussion and Conclusions: Despite the considerable success of emicizumab in the management of inhibitor patients, the FIT group still sees the importance of eradicating inhibitors. However, the availability of emicizumab and other non-factor therapies in the future might impact greatly on how ITI is undertaken. Theoretically, concomitant use of emicizumab and FVIII might allow emicizumab to effectively prevent bleeding with lower dose ITI regimens. This might allow for the greater adoption of low-dose/low-frequency FVIII ITI regimens, which may result in a reduced need for central venous access devices while still maintaining a reasonable likelihood of ITI success. The FIT group proposes a new management algorithm for current ITI (without emicizumab) and a hypothetical new approach with the availability of emicizumab. As there are no published data regarding the concomitant use of emicizumab and FVIII for ITI, the FIT Expert group encourages the undertaking of properly conducted prospective studies to explore these approaches further., (© 2019 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: Immune tolerance induction (ITI) was the primary therapeutic approach to eradicate inhibitors in haemophilia patients. Several large ITI registries had been reported, but successful predictors of ITI outcome are still debated. No reports are available on large ITI studies in non-caucasian countries., Aim: We designed a retrospective cohort study of ITI in Japanese haemophilia patients with inhibitor., Methods: Retrospective data were collected from 155 haemophilia (H)A (140 severe-type) and 7 HB (7 severe-type) patients treated at 45 institutions. ITI outcome was centrally reviewed. We defined "success" as undetectable inhibitor after 2 consecutive measurements., Results: The ITI success rate was 71.2% for HA and 83.3% for HB. Cumulated success rates for HA achieving 50% and 75% were 0.7 and 2 years after treatment, respectively. Significant successful predictors in HA were low-responding inhibitors compared to high-responding inhibitors, shorter time to the start of ITI, and lower historical and treatment peak titres of inhibitor. Dose regimen (high dose; ≥90 IU/kg every day, low dose; ≤75 IU/kg, 3 d/wk) and the type of therapeutic product did not affect outcomes. The success rate of salvage ITI using von Willebrand factor-containing factor VIII was 50% (n = 6/12), and patient age at the start of salvage ITI was a significant predictor. The inhibitor recurred in 6 HA cases (3.9%)., Conclusion: The results provided potentially important information for improving future success rates for ITI in inhibitor patients., (© 2018 John Wiley & Sons Ltd.)

The development of high-titre inhibitory antibodies (inhibitors) against factor VIII (FVIII) remains a challenge in the management of patients with haemophilia A (HA). Patients with high-titre inhibitors are more likely to experience uncontrolled bleeding, physical disability from chronic arthropathy and premature death compared with those without this complication. Immune tolerance induction (ITI), utilizing repeated infusions of FVIII, is an effective therapeutic approach to eliminating inhibitory antibodies. This strategy can eradicate FVIII inhibitors, so that FVIII-specific tolerance is induced. However, patients undergoing ITI are still vulnerable to the development of serious and/or repeated bleeding events. The efficacy of bypassing agents in preventing bleeding episodes has been widely proven in patients with HA and inhibitors to FVIII. Evidence suggests that reducing bleeding during ITI can also shorten the time to tolerance. There are concerns with the use of bypassing agents, including the cost of treatment, short half-life, management of non-responders and the risk of thrombosis. Despite these concerns, and the still limited evidence from prospective studies and consensus reports, the use of prophylaxis with bypassing agents during ITI has been gaining support. This review presents a rationale and current data supporting the use of prophylactic bypassing agents as effective and safe therapies to reduce the incidence of joint bleeding due to inhibitors and improve quality of life in patients with HA undergoing ITI., (© 2018 John Wiley & Sons Ltd.)

Introduction: Immune tolerance induction (ITI) is the gold standard for eradication of factor VIII inhibitors in severe haemophilia A; however, it usually requires treatment for extended periods with associated high burden on patients and healthcare resources., Aim: Review outcomes of ITI with recombinant factor VIII Fc fusion protein (rFVIIIFc) in patients with severe haemophilia A and high-titre inhibitors., Methods: Multicentre retrospective chart review of severe haemophilia A patients treated with rFVIIIFc for ITI., Results: Of 19 patients, 7 were first-time ITI and 12 were rescue ITI. Of 7 first-time patients, 6 had at least 1 high-risk feature for ITI failure. Four of 7 first-time patients were tolerized in a median of 7.8 months. The remaining 3 patients continue on rFVIIIFc ITI. Of 12 rescue patients, 7 initially achieved a negative Bethesda titre (≤0.6) in a median of 3.3 months, 1 had a decrease in Bethesda titre and continues on rFVIIIFc ITI and 4 have not demonstrated a decrease in Bethesda titre. Of these 4, 3 continue on rFVIIIFc ITI and 1 switched to bypass therapy alone. Two initially responsive patients transitioned to other factors due to recurrence. Overall, 16 of 19 patients remain on rFVIIIFc (prophylaxis or ITI). For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events reported., Conclusions: Recombinant factor VIII Fc fusion protein demonstrated rapid time to tolerization in high-risk first-time ITI patients. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI with other products. These findings highlight the need to further evaluate the use of rFVIIIFc for ITI., (© 2018 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction/background: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment., Aim: The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors., Patients/methods: Forty-eight prospective patients in this interim analysis received a single plasma-derived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg(-1) daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg(-1) every 12 h., Results: Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success., Conclusion: Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success., (© 2015 The Authors. Haemophilia Published by John Wiley & Sons Ltd.)

Introduction: The development of anti-factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment-related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs., Aim: Formulate evidence-based guidelines for optimizing immune tolerance induction (ITI) in patients with hemophilia A and inhibitors., Methods: Results from the International ITI study and other available evidence were used to develop guidelines for ITI., Results: Predictors of ITI success were identified and recommendations made for ITI with regard to candidates, timing, product, regimen, monitoring, defining success, concurrent immunomodulation, duration of treatment, and bleed management before and during ITI., Conclusion: Evidence-based recommendations to guide treatment decisions may increase the likelihood of successful inhibitor eradication and the induction of FVIII tolerance in patients with hemophilia A who develop inhibitory antibodies., (© 2015 John Wiley & Sons Ltd.)

Current guidelines recommend delaying the start of immune tolerance induction (ITI) until the inhibitor titre is <10 Bethesda units (BU) to improve success. This study was conducted to evaluate ITI outcome relative to time to start ITI from inhibitor detection irrespective of inhibitor titre. Data were retrospectively collected from two U.S. haemophilia treatment centres (HTCs) on subjects with severe/moderate factor VIII (FVIII) deficiency with inhibitors who underwent ITI. Outcomes were defined pragmatically: success--negative inhibitor titre and ability to use FVIII concentrate for treatment/bleed prevention; partial success--inhibitor titre 1 to <5 BU with ability to use FVIII concentrate for treatment of bleeding; failure--ITI ongoing >3 years without achieving success/partial success, or ITI discontinuation. Fifty-eight subjects were included; 32 of 39 (82%) with high-responding inhibitor (HRI) achieved success, 7 failed. HRI subjects were subdivided based on ITI start time: 23/39 subjects started within 1 month of detection and 22/23 (96%) achieved success. Of these 23, 13 started ITI with an inhibitor titre ≥10 BU; all were successes. Eleven of 39 HRI subjects had an interval >6 months until ITI start; 7 (64%) achieved success. Time from inhibitor detection to ITI start may play a critical role in outcome. A titre ≥10 BU at ITI start did not influence outcome in subjects when ITI was initiated within 1 month of detection. Prompt ITI should be considered a viable therapeutic option in newly identified patients with inhibitors regardless of current inhibitor titre., (© 2014 John Wiley & Sons Ltd.)

Haemophilia A (HA) patients with high responding inhibitors require therapies with bypassing agents to control bleedings or Immune Tolerance Induction (ITI) to attempt inhibitor eradication and restore FVIII therapy. The aim of this study was to assess the therapeutic management and product consumption of HA inhibitor patients and the relative costs in Italy. A retrospective survey was performed utilizing data from the National Registry of Congenital Coagulopathies and from a specific questionnaire on product consumption of HA inhibitor patients over the year 2011. Among HA patients, 10% had currently detectable inhibitors; 24% of patients were undergoing ITI (mostly children) and 76% utilized bypassing agents. Patients on ITI consumed 45,000,000 IU of FVIII (median consumption/patient of 1,200,000 IU year(-1)). Patients receiving bypassing agents utilized 21,000,000 IU of aPCC (median consumption/patient of 360,000 IU year(-1)), and 38,000 mg of rFVIIa (median consumption/patient of 440 mg year(-1)). The annual cost/patient on ITI and on bypassing agents therapy was analysed. Recombinant products represented the product of choice for children therapies in >90% of the cases. FVIII prophylaxis of severe HA patients without inhibitor costs about half than therapy with bypassing agents and is three times less expensive than prophylaxis with such agents. Therefore, the possibility to restore FVIII prophylaxis, having eradicated the inhibitor through ITI, can justify the high costs of ITI treatment needed in the short term. Consistent with this notion, over the last years a 50% increase in the number of patients undergoing ITI in Italy was registered., (© 2014 John Wiley & Sons Ltd.)

Immune tolerance induction (ITI) is the preferred management of haemophilia A patients who develop high titre inhibitors against factor VIII. However, the optimal ITI regimen, predictors of ITI outcome and definitions of successful and unsuccessful ITI remain unclear. The aim of this project was to develop a consensus on the definition of ITI treatment failure for Australian clinical practice using a modified Delphi approach. Three consecutive surveys were distributed to the directors of 17 haemophilia treatment centres in Australia. Participants were asked to rate their agreement with definitions of ITI treatment failure generated from a literature review. Thirty-five statements regarding ITI achieved consensus (majority agree or strongly agree) during the three survey rounds. After round 3, four statements achieved majority disagreement, and for two statements no consensus was reached. Our study demonstrates that clinicians in Australia necessitate an arbitrary time to assess ITI failure, but that clinical outcomes of ITI are important in assessing response. Assessment over any 3- to 6-month period without a 20% reduction in inhibitor titre is suggestive of failure, but a reduction in bleeding phenotype alone may be sufficient to continue ITI. Overall, a period of 3 or 5 years of ITI may be required to determine response to ITI. Documentation of improvement in clinical measures, supported by the laboratory features of factor VIII inhibitor levels and pharmacokinetics, is essential in assessing the success of failure of ITI in these patients., (© 2014 John Wiley & Sons Ltd.)

Immune tolerance induction (ITI) has been shown to successfully eliminate factor VIII (FVIII) inhibitors in haemophilia patients with inhibitors. We performed a literature search to identify reports from January 1980 to October 2012 on the use of the plasma-derived, von Willebrand factor (VWF)-containing FVIII concentrate Haemate P/Humate-P in the setting of ITI. Six reports were identified that specifically evaluated the use of Haemate P/Humate-P including 32 children and 9 adults. Dosing regimens ranged from 20 IU kg(-1) every 2-3 days in patients with low-responding (LR; n = 5) inhibitors to 300 IU kg(-1) day(-1) in patients with high-responding (HR; n = 36) inhibitors. Complete success was achieved in all five LR patients, in all three HR patients with good prognostic factors (age ≤7 years, pre-ITI inhibitor titre <10 BU, historical inhibitor titre <200 BU, time between inhibitor detection and ITI start <2 years), and in 24 of 33 (73%) HR patients with poor prognostic factors. The time to complete success was 0.5-4 months in good-prognosis patients and 0.5-42 months in poor-prognosis patients. Few adverse events were observed during ITI, and no cases of inhibitor relapse were reported with follow-up periods of up to 12 years. On the basis of this retrospective review of a diverse range of studies and case reports, we conclude that Haemate P/Humate-P for ITI in patients with inhibitors is effective and produces high rates of ITI success., (© 2013 John Wiley & Sons Ltd.)