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Key Clinical Message: Recommendations advise factor IX desensitization before immune tolerance induction in severe hemophilia B, supported by immunosuppression. A child with inhibitor and anaphylaxis to factor IX showed successful immunosuppression‐free immune tolerance induction using very low and slowly increasing doses of a factor IX extended‐half‐life product. Immune tolerance to factor IX based on this protocol merits further study. [ABSTRACT FROM AUTHOR]

Introduction: Surgeries are implicated in the development of anti-factor VIII (FVIII) neutralizing antibodies (inhibitors) in hemophilia A individuals with immune tolerance induction (ITI) treatment being the recommended therapy to eradicate these inhibitors. We evaluated the association of surgical procedures performed during ITI and treatment outcome. Methods: Patients were treated according to the Brazilian ITI Protocol with outcomes being defined as successful (i.e., recovered responsiveness to exogenous FVIII) and failed (i.e., unresponsiveness to exogenous FVIII thus requiring bypassing agents for bleeding control). Surgical procedures during induction therapy were managed following international recommendations. Results: Treatment success rate was 68.7 % in 163 patients; 33 (20.2 %) were submitted to 43 (96 %) minor and two major surgeries. Personal, hemophilia, inhibitor, and treatment characteristics were similar between patients submitted to surgical procedures or not while on ITI; the success rates were 72.7 % and 67.7 % (p-value = 0.577), respectively. Conclusion: No association was found between having a minor surgical procedure and ITI treatment outcome.

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. [ABSTRACT FROM AUTHOR]

• Immunogenicity is a recurring concern across all therapies for Hemophilia A. It impacts the safety and efficacy of new and old recombinant Factor VIII products, the long-acting FVIII versions, as well as other clinical options such as bypassing agents and gene-based therapies. • The risk of anti-drug antibody development for any given Hemophilia A patient remains under investigation but a multitude of factors, related to the patient's genetic mutations, health status, and treatment or product history, have been recognized. • Gene replacement and gene editing therapies for Hemophilia A represent new treatment options for generating long-term production of factor VIII in patients, but pre-existing and de novo immunity against the vector capsids and transgene products pose significant impediments in their development. The introduction and development of biologics such as therapeutic proteins, gene-, and cell-based therapy have revolutionized the scope of treatment for many diseases. However, a significant portion of the patients develop unwanted immune reactions against these novel biological modalities, referred to as immunogenicity, and no longer benefit from the treatments. In the current review, using Hemophilia A (HA) therapy as an example, we will discuss the immunogenicity issue of multiple biological modalities. Currently, the number of therapeutic modalities that are approved or recently explored to treat HA, a hereditary bleeding disorder, is increasing rapidly. These include, but are not limited to, recombinant factor VIII proteins, PEGylated FVIII, FVIII Fc fusion protein, bispecific monoclonal antibodies, gene replacement therapy, gene editing therapy, and cell-based therapy. They offer the patients a broader range of more advanced and effective treatment options, yet immunogenicity remains the most critical complication in the management of this disorder. Recent advances in strategies to manage and mitigate immunogenicity will also be reviewed. [ABSTRACT FROM AUTHOR]

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. To explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. 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. 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. 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. • The interval-time is the time from inhibitor detection to starting ITI. • Interval-time for predicting low-dose ITI outcomes remained unclear, for high-risk-inhibitors patients. • Interval-time had a strong predictive value for outcomes in our low-dose ITI strategy. • Interval-time cut-off values were 22.3 for success and 9.4 months for early-success. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Immune tolerance induction (ITI) is the gold standard approach for eradicating inhibitors and increasing patient tolerance to factor VIII. The success rate of ITI may vary depending on patient variables and factors relating to the pattern of treatment for the induction of immune tolerance. Children with recently diagnosed inhibitors are the best candidates for ITI, and those with favourable expected results should be offered ITI as soon as inhibitors are identified. Recombinant factor VIII Fc fusion protein has proved a therapeutic advantage in patients with high factor VIII inhibitor titers AIMS AND OBJECTIVES: To evaluate the clinical characteristics and outcomes of ten hemophilic pediatric patients who underwent ITI therapies to eliminate FVIII inhibitors at Tawam Hospital, UAE MATERIALS AND METHODS: The data of ten hemophilia A children aged 2–7 years with high inhibitor titers who underwent ITI therapy at Tawam Hospital, UAE, were retrospectively collected for this case series. A comparison of bleeds before and after the ITI therapy was also made. Patients with either failed or partially successful primary ITI therapy underwent rescue ITI therapy. Data analysis was performed using SPSS version 26. RESULTS: Full success was achieved in 60% (6/10) of the patients, 10% (1/10) achieved partial success, whereas 30% (3/10) failed the primary ITI therapy. The rescue ITI therapy was successful in 50% (2/4) of the patients and the remaining 50% (2/4) achieved partial success [Table 2]. The rescue ITI was successful in 66% (2/3) of those patients who received Elocta and partially successful in 33% (1/3) CONCLUSION: ITI therapy is the gold standard for the eradication of antibodies against FVIII. The patients with good expected outcomes should be offered ITI as soon as the inhibitors are confirmed. The use of extended half life rFVIIIFc demonstrated therapeutic benefit, particularly in challenging ITI patients with high inhibitor titers [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Inhibitor (neutralizing antibodies) development remains the most significant complication in patients with severe congenital hemophilia A receiving exogenous factor VIII (FVIII). Although our understanding of the pathophysiology of inhibitor development has advanced, the knowledge gained has not yet translated into a robust decline in incidence, with the overall risk remaining at ∼30%. Immune Tolerance Induction (ITI) is the only current method to successfully eradicate an inhibitor and achieve long-term tolerance. Although current practice utilizes a wide variety of ITI regimens, identification of an optimal regimen has not emerged. Over the last decade, the number of replacement products available in hemophilia has greatly expanded. The cumulative evidence with each product for use in ITI is often lacking. Most recently emicizumab, a humanized monoclonal bi-specific antibody that substitutes for the scaffolding effect of FVIIIa was approved; this agent prevents bleeding in both inhibitor and non-inhibitor patients. The use of emicizumab will bring about a new era in care that will require clinicians to challenge current practice paradigms including use and administration of ITI. This review will summarize the main clinical ITI data and practices for patients with severe congenital hemophilia A with inhibitors (CHAwI) over the last four decades and will highlight current studies in the field, with attention to open questions. [ABSTRACT FROM AUTHOR]

The development of inhibitors against factor VIII (FVIII) concentrates represents a significant treatment complication for hemophilia. Immune tolerance induction (ITI) therapy eradicates inhibitors in 60–80% of patients, resulting in a normal FVIII response. This article, based on presentations at the 6th International Coagulation Meeting, held in Barcelona, Spain, in September 2017, provides an overview of management approaches for patients with inhibitors and briefly tabulates four cases of ITI therapy (first-line or rescue ITI therapy in pediatric and adult patients) with successful outcomes. Switching FVIII product from recombinant FVIII to plasma-derived FVIII/VWF concentrate may be helpful in eradicating inhibitors. The rate of decline of inhibitor titer in the initial stages of ITI therapy is a good indicator of the success or failure of therapy, although prognostic biomarkers are needed. The development of the bispecific monoclonal antibody emicizumab, which was recently shown to reduce bleeding in inhibitor patients, offers a potential alternative therapeutic option. However, the benefits of inhibitor eradication, including a wider choice of cheaper therapeutic products for preventing and treating bleeds, suggest that at least one attempt of ITI therapy should be offered to patients who develop inhibitors. [ABSTRACT FROM AUTHOR]

Summary: Development of inhibitors to coagulation factor VIII or IX is still the most challenging complication in haemophilia care. ‘Bypassing agents’ may be used to treat a bleed but the eradication of the inhibitor by immune tolerance induction (ITI) is the main objective in the treatment of a patient with haemophilia who has developed neutralizing antibodies. Several options exist for ITI and the patient may be at ‘good’ or ‘bad risk’ for successful outcome with different regimens. This paper offers a review of current regimens to be considered in the treatment of a bleed in a patient with an inhibitor but the main focus is the aspects of different choices in the management of the child or the adult with severe or mild forms of haemophilia A or B, who has developed an inhibitor. There are also some final outlooks on new and emerging treatment possibilities. [ABSTRACT FROM AUTHOR]

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 (< 50 IU/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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 US 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Immune tolerance induction ( ITI) can eliminate factor VIII ( FVIII) inhibitory antibodies that appear during FVIII replacement therapy. If first-line ITI fails, switching to a different FVIII concentrate, especially one containing von Willebrand factor ( VWF), has been advocated. The objective of the study was to assess the efficacy and safety of Haemate® P, a plasma-derived FVIII concentrate containing high levels of VWF, as ITI in severe haemophilia A patients who had failed at least one prior ITI attempt with a different FVIII concentrate. In this multicentre, observational study, Haemate® P was administered at a starting dose of 83-308 IU kg−1 day−1 (1500-6000 IU day−1). Efficacy was assessed by standard criteria (e.g. Bethesda titre, FVIII recovery and half-life), and bleeding characteristics. Nine patients from six haemophilia centres were treated with Haemate® P after failing one ( n = 2), two ( n = 5) or three ( n = 2) prior ITI courses. The median time from inhibitor detection to Haemate® P treatment was 5.4 years. The median Haemate® P dose was 134 IU kg−1, and the median treatment duration 32 months. During median of 47 months of follow-up, complete response, partial response and treatment failure were observed in one, three and five patients respectively. Five patients experienced seven adverse events (AEs), including two serious AEs (sepsis). Haemate® P was discontinued due to an AE in one patient with a partial response. Haemate® P salvage ITI resulted in complete or partial tolerization in four of nine patients (44%) who had failed previous ITI attempts using different FVIII concentrates. [ABSTRACT FROM AUTHOR]

Approximately 20-30% of patients with severe haemophilia A develop alloantibodies ('inhibitors') to infused FVIII rendering use of such replacement therapy ineffective. Once an inhibitor emerges, immune tolerance induction ( ITI) is the standard treatment. ITI involves giving regular doses of FVIII concentrate to eradicate the inhibitor and achieve immunogenic acceptance of administered FVIII. In the early 2000s, a retrospective analysis of inhibitor patients treated at a single centre in Germany indicated that success rates were higher when patients were treated with von Willebrand factor ( VWF)-containing plasma-derived FVIII (pd FVIII/ VWF) concentrate compared with recombinant or non- VWF-containing pd FVIII products. Importantly, pd FVIII/ VWF as rescue therapy was able to convert 8 of 10 patients who had failed primary ITI with recombinant or non- VWF-containing pd FVIII product. A subsequent study from Italy in patients with poor prognostic factors for ITI success also reported good success rates with pd FVIII/ VWF as rescue therapy (53% success; 41% partial success). The Grifols-Immune Tolerance Induction (G- ITI) Study represents the largest group of haemophilia A inhibitor patients treated with a single pd FVIII/ VWF concentrate (Alphanate®/Fanhdi®) to be reported to date. Data have been collected for 95 patients who underwent primary or rescue ITI at 46 centres in Europe and the US. Currently, published data are available for 33 patients in the US cohort (11 centres), and data from the European cohort are being analysed. Both groups contained patients with poor prognostic factors and most patients received a high-dose regimen (≥100 IU pd FVIII/ VWF kg−1 daily). As expected, the success rate was better for primary vs. rescue ITI and for patients with good vs. poor prognostic factors. However, more than half the patients in the US cohort receiving rescue ITI achieved success (33% complete success; 20% partial success). These results should encourage clinicians to consider the use of pd FVIII/ VWF concentrates for rescue ITI. Published outcomes data from the total global G- ITI cohort (95 patients) are awaited with anticipation. [ABSTRACT FROM AUTHOR]

Immune tolerance induction ( ITI) is recognized as the first choice treatment in haemophilic patients with inhibitors, with the aim of restoring safe and effective standard factor VIII replacement and, particularly, prophylaxis in children. For the latter, literature data and clinical practice support the optimal cost utility ratio of ITI. Indeed, the high success rate, the low incidence of inhibitor recurrence after successful ITI and the possibility of preventing joint deterioration, enable one to predict a considerable long-term reduction of costs in the majority of treated patients. Therefore, in spite of high costs and open issues about optimal regimens, ITI is actually attempted in virtually all children with inhibitors. Few patients with long-standing inhibitors presently undergo ITI, particularly in the case of severe bleeding tendency. In this setting, uncertainties concerning management are amplified by the paucity of literature data and psychological reluctance by both patients and treaters due to the perceived poor prognosis and the demanding treatment (also in terms of costs). However, clinical data suggest that the role of age at ITI start and of time interval from inhibitor diagnosis, as predictors of ITI outcome, should be considered in a larger framework of proposed and more established prognostic factors. Moreover, optimising ITI management, particularly with respect to inhibitor titre at ITI start and avoidance of adverse events or interruption of treatment, may also contribute to improve outcomes. Although the economic constraints of the present era significantly affect resources for such a high-cost treatment, the individual cost-utility ratio (bleeding tendency and risk of fatal bleeding, arthropathy and need for orthopaedic surgery, comorbidities, quality of life) should be assessed carefully to determine whether ITI is a suitable option and thus not preclude adults from the opportunity of inhibitor eradication. [ABSTRACT FROM AUTHOR]

Among the proposed predictors for immune tolerance induction ( ITI) outcome, the therapeutic regimen - specifically the dose and frequency of administered factor VIII (FVIII) as well as FVIII product type - is intensely debated. Are there any advantages for low-dose regimens (50 IU FVIII kg−1 three times a week) over high-dose regimens (200 IU FVIII kg day−1) or vice versa? Are von Willebrand factor ( VWF)-containing plasma-derived concentrates superior to recombinant FVIII concentrates for tolerance induction? A review of the available literature indicates that patients with good prognostic factors can achieve success with either low-dose or high-dose ITI regimens. Retrospective data suggest that patient characteristics such as maximum historical inhibitor titres and pre- ITI inhibitor titres are better predictors of treatment success than dose. Results of the prospective International ITI Study have recently become available. In inhibitor patients with good prognosis, success rates were similar between low-dose (50 IU FVIII kg−1 three times a week) and high-dose (200 IU FVIII kg−1 daily) regimens. However, patients receiving low-dose ITI took longer to achieve various ITI milestones and had a significantly higher bleed rate per month compared with the high-dose group (0.62 vs. 0.28; P = 0.00024), findings with important clinical implications. Inhibitor patients with poor prognostic features should be treated with a high-dose protocol. This conclusion is supported by a meta-analysis of the International Immune Tolerance Registry and North American Immune Tolerance Registry and by data from Germany showing good success rates with the high-dose, high-frequency Bonn protocol in poor prognosis patients. Type of concentrate also appears to have an influence on ITI success rates in this patient subgroup, with evidence suggesting an advantage for VWF-containing plasma-derived FVIII concentrates over recombinant or VWF-free concentrates. The ongoing prospective studies REScue Immunotolerance STudy and Observational Immune Tolerance Induction are evaluating ITI outcome with respect to product type and are expected to answer this important clinical question as well as provide greater insight into patient- and therapy-related variables in inhibitor patients with poor prognostic features. [ABSTRACT FROM AUTHOR]

. von Willebrand factor (VWF) has the capacity to form a complex with factor VIII (FVIII) which may modulate the immunogenicity of FVIII. It has been proposed that a significant fraction of recombinant FVIII (rFVIII) is unable to bind VWF. In an experimental model studied at the McMaster University in Canada, this VWF-unbound rFVIII fraction showed no coagulant function. Sulphation of FVIII tyrosine (Tyr) 1680 has been reported as essential for the interaction with VWF. In a study performed at the Grifols and CNS-CSIC in Spain, Tyr1680 sulphation was observed to be incomplete in rFVIII and complete in plasma-derived FVIII (pdFVIII). This could explain the incapability of some rFVIII molecules to bind VWF. Experience with immune tolerance induction (ITI) at the Bonn Haemophilia Centre indicates that only eradication of FVIII inhibitors allows safe haemostasis control and the option of prophylactic treatment. Various clinical trials were planned to evaluate the clinical role VWF-containing FVIII concentrates (FVIII/VWF). RES.I.ST (an acronym for REScue Immunotolerance STudy) is an international, prospective study aimed at assessing whether FVIII/VWF can induce ITI in high-risk haemophilia patients (RES.I.ST naïve) and whether patients who previously failed ITI with FVIII alone can be rescued with FVIII/VWF (RES.I.ST experienced). Enrolment started in November 2009. In the FAIReSt.Will (Fanhdi and Alphanate Italian Retrospective Study in Willebrand disease) study, 120 von Willebrand disease (VWD) patients treated with Fanhdi® or Alphanate® were retrospectively analysed. Efficacy was excellent and no side effects were reported. The ongoing PRO.Will study is a prospective, multicenter trial aimed at assessing the efficacy, safety and pharmacoeconomics of secondary long-term prophylaxis in patients with severe inherited VWD. [ABSTRACT FROM AUTHOR]

For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zürich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda units (BU) and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For patients with hemophilia B, there may be a benefit of genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (≥5 BU) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens, there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications. [ABSTRACT FROM AUTHOR]

Immune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors in severe haemophilia A patients. Thirty years experience has shown high success rates (60–80%) with heterogeneous dose regimens and has led to the identification of clinical features that define the patients’ prognostic profile. Children with recently diagnosed inhibitors are the best candidates for ITI and adequate management may further contribute to improve the short- and long-term ITI outcome. In these patients inhibitor eradication represents a cost-effective option because it enables the restoration of FVIII prophylaxis and consequently prevents arthropathy development. Adults with long-standing inhibitors often show bad predictors of ITI outcome, however, ITI may be considered as a suitable and cost-effective approach in cases with frequent bleeds that are not satisfactorily controlled by by-passing treatment and/or when orthopaedic surgery is needed. Optimal ITI regimens should be established in these different settings and randomized trials are addressing these issues. This article reviews the available literature evidence and clinical implications with current recommendations on ITI management, and highlights the issues still unsolved. [ABSTRACT FROM AUTHOR]

Different regimens are used to achieve immune tolerance in patients with severe haemophilia A and inhibitory allo-antibodies against factor VIII (FVIII). In this study, results of 26 years of low dose immune tolerance induction are evaluated. We evaluated 21 patients, who were treated with regular infusions of low dose FVIII (25–50 IU kg−1 every other day or three times a week) to obtain immune tolerance. Several risk factors for success rate and time to success were analysed. In 18 of 21 patients (86%) immune tolerance induction (ITI) was successful. The median of the maximum inhibitor titre before start of ITI was 4.5 BU mL−1. Success rate was associated with both a pre-ITI titre and a maximum titre during ITI below 40 BU mL−1 ( P = 0.003). The time to success was significantly shorter if the maximum inhibitor level during ITI was below 40 BU mL−1 ( P = 0.040). In low titre inhibitors (<5 BU mL−1) this effect was even stronger ( P = 0.033). Low dose immune tolerance induction therapy was successful in severe haemophilia A patients with a pre-ITI titre below 40 BU mL−1. The time to success is predicted by a maximum ITI titre below 40 BU mL−1, and is even shorter in low titre inhibitors (<5 BU mL−1). We suggest that all patients with severe haemophilia A and a pre-ITI inhibitor titre below 5 BU mL−1, should be treated with low dose immune tolerance induction therapy. Patients with a maximum titre below 40 BU mL−1 may also strongly benefit from the beneficial effects of low dose immune tolerance induction therapy. [ABSTRACT FROM AUTHOR]

Haemophilia therapy is aimed at treating and preventing bleeding episodes and related complications and clinical studies have shown that regular prophylaxis, started at an early age, is able to reduce physical impairment from haemophilic arthropathy. Today, the development of anti-Factor VIII (FVIII) inhibitors is the most serious treatment-related complication of haemophilia therapy and a number of genetic and environmental risk factors have been identified in the past years. Clinical data show that early start of prophylaxis and the avoidance of intensive treatment periods may protect patients from inhibitor development. The mechanisms are not completely understood; yet, recent experimental data suggest that pro-inflammatory or ‘danger signals’ may be involved in inducing tolerance vs. an effector immune response. So, exposure to a factor concentrate by itself may not be enough to trigger an immune response, while an intensive exposure to FVIII in the presence of such ‘danger signals’ can activate antigen-presenting cells, up-regulating co-stimulatory signals for T lymphocytes and ultimately enhancing antibody production. The ‘optimal’ regimen for primary prophylaxis is still not identified and barriers to prophylaxis implementation remain relevant. Key issues include the optimal age at prophylaxis onset, the optimal dosage/schedule, the proper clinical and laboratory monitoring and patients’ compliance. Practical approaches to early prophylaxis as implemented in the haemophilia centres in Milan and Bremen are discussed in this respect. [ABSTRACT FROM AUTHOR]

Immune tolerance induction (ITI), through the regular infusion of coagulation factor concentrates over a time period ranging from 1 to more than 24 months, is successful in about 75% of high responders. Among the issues of ITI treatment that are still open, the choice of the product to use is one of the most difficult. In fact, common practice is to start with the same product that induced the inhibitory response, but recent findings indicated that plasma-derived products containing large amounts of von Willebrand factor (VWF) can play a positive role. Two retrospective cohorts in Germany and in France and one prospective cohort have shown a high rate of success when VWF/factor VIII (FVIII) products are used to induce ITI. For these reasons, two prospective studies have been planned to complement the international ITI study already started: an observational study in patients who had already experienced a failure with a VWF-free FVIII concentrate, called RESISTexp (experienced); a randomized, controlled study in patients who have never tried an ITI treatment before and at high risk to fail, called RESISTnaïve (naïve). [ABSTRACT FROM AUTHOR]

The incidence of inhibitors in haemophilia A is 21–33%. The development of inhibitors to factor VIII (FVIII) is one of the most serious complications in haemophilia therapy and is an important challenge in haemophilia care. The main short-term objective of the treatment of haemophilic patients with inhibitors is to control bleeding episodes, and the long-term one is to eradicate the inhibitor by means of immune tolerance induction (ITI).The choice of treatment for bleeding in inhibitor patients is dictated by the current inhibitor titre, the severity of the bleed and the previous anamnesic response to FVIII. In low responder inhibitor patients the best treatment is large doses of concentrates of FVIII to attain haemostatic levels of the factor infused. The same approach can also be considered in high responders who have a temporarily low inhibitor level and major haemorrhage. High responders patients with high inhibitors titre or with minor haemorrhage must be treated with bypassing agents, such as FEIBA (factor VIII inhibitor bypassing activity) or recombinant activated FVII (rVIIa); there is no agreement which of both agents should be chosen in the different clinical situations. Only in patients waiting to start ITI treatment the rFVIIa use is clearly recommended, in order to avoide an anamnesic responce. In case of failure with this agents, extracorporeal immunoadsortion may be considered. All haemophiliac children who develop an inhibitor should be considered for ITI. The start of ITI should be deferred until the inhibitor has declined below 10 Bethesda units/mL (BU ml−1) where possible. Starting the treatment when inhibitor titre is below 10 BU ml−1 is the strongest predictor of success. However, there are many other points to clarify: recommended FVIII doses in the ITI; if the results can be affected by concomitant infections during ITI; if there are any differences using plasma derived or recombinant concentrates, even more if the plasma-derived concentrate contains large amounts von willebrand factor or not; age of starting the ITI and the delay in beginning it; if using immunosupresors can help in the treatment of patients with a bad prognosis; and when the treatment must be left in patients without a clear failure. [ABSTRACT FROM AUTHOR]

Although immune tolerance induction (ITI) has been used for 30 years to eliminate inhibitors and restore normal factor pharmacokinetics in patients with hemophilia, there is a paucity of scientific evidence to guide therapeutic decision-making. In an effort to provide direction for physicians and hemophilia treatment center staff members, an international panel of hemophilia opinion leaders met to develop consensus recommendations for ITI in patients with severe and mild hemophilia A and hemophilia B. These recommendations draw on the available published literature and the collective clinical experience of the group and are rated based on the level of supporting evidence . [ABSTRACT FROM AUTHOR]

Inhibitors are an uncommon complication of mild haemophilia A but represent a severe disease, typically with high titre inhibitors and an associated high rate of bleeding. We present data from three patients with MHAI who were successfully treated with Rituximab alone and unequivocally prove that such inhibitors respond to this agent. A treatment protocol is suggested. [ABSTRACT FROM AUTHOR]

The Italian Association of Haemophilia Centres reviewed and finally approved in November 2004 the new Italian Guidelines for the diagnosis and treatment of patients with clotting factor inhibitors. The recommendations have been based on the identification of levels of clinical evidence derived from the systematic review carried out in 2003 by the School of Health and Related Research, the University of Sheffield, UK, and further integrated by clinical studies published from 2003 to 2004. The Italian guidelines consist of six major domains concerning inhibitor definition, epidemiology, risk factors, diagnosis, inhibitor eradication, management of bleeding episodes, in patients with congenital and acquired coagulation disorders, with 121 statements, 59 synthesis and 54 recommendations. We report here recommendations and open issues concerning the diagnosis and monitoring of inhibitors, inhibitor eradication and the management of bleeding in patients with haemophilia A and B. [ABSTRACT FROM AUTHOR]

Summary. In some patients with haemophilia A, therapeutically administered factor VIII (FVIII) comes to stimulate the production of antibodies (inhibitors) which react with FVIII to render it ineffective. As a result, FVIII cannot be used prophylactically and patients become liable to recurrent bleeds. There are two elements to the management of patients with inhibitors: the treatment of bleeding episodes, and attempts to abolish inhibitor production through the induction of immune tolerance. This paper reports a systematic review of the best available evidence of clinical effectiveness in relation to immune tolerance induction (ITI) in patients with haemophilia A with inhibitors. Owing to the lack of randomized controlled trials on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. As a result of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. The International Registry provides the most reliable estimate of the proportion of successful cases of ITI [48.7%, 95% confidence interval (CI) 42.6–52.7%]. The duration of effect is unclear, but relapses appear to be infrequent. The International Registry shows a rate of relapse of 15% at 15 years. The comparative effectiveness of different protocols is uncertain, as no trials have been undertaken which compare them directly. However, the evidence suggests that the Bonn protocol may be more effective than the Malmö or low-dose protocols. There is no good evidence that immunosuppressive drug regimens are effective. [ABSTRACT FROM AUTHOR]

Summary. This paper reports a systematic review of the cost-effectiveness of treatment options in patients with haemophilia A with inhibitors. As very little relevant published evidence was identified, an economic modelling exercise was undertaken to calculate the cost-effectiveness of different strategies in the treatment of high-responding haemophilia A patients with inhibitors. A decision analysis approach was used to model the expected lifetime clinical outcomes and costs of the more common regimens currently used in UK in treating severe haemophiliacs with inhibitors. The model attempts to reflect the outcomes of clinical events, costs and life expectancy for each different treatment regimen for haemophilic boys with inhibitors who are high responders (defined as inhibitor level ≥10 BU) throughout their life. The basic model structure is centred on a Markov decision process, which was used to simulate, at quarter-yearly intervals, the movement through discrete health states and their complications. The model allows a comparison of cost-effectiveness between three immune tolerance induction (ITI) regimens (Bonn, Mälmo and Low-Dose protocols) and against a relevant ‘on-demand’ (OD) regimen. It also shows the cost-effectiveness of different OD regimens using different bypassing agents. The results of the economic modelling indicate that treating haemophilia A patients who have high-responding inhibitors OD with recombinant activated factor VII is cost-effective compared to treatment with activated prothrombin complex concentrates. However, when OD treatment regimens are compared with the three ITI protocols, the Malmö ITI protocol is the preferred treatment strategy, generating more quality adjusted life-years (QALYs) and less cost than either an OD regimen or the Bonn or Low-Dose ITI protocols. [ABSTRACT FROM AUTHOR]