Immune Tolerance Induction Treatment Research Articles

AKATSUKI 48-Week Interim Analysis: Emicizumab and Immune Tolerance Induction in People with Hemophilia A and Factor VIII Inhibitors

Background: Immune tolerance induction (ITI) therapy, for the eradication of factor (F)VIII inhibitors, is indicated for people with hemophilia A (PwHA) with FVIII inhibitors. There are limited data regarding the safety of emicizumab treatment in combination with ITI, particularly regarding thrombotic events (TEs). This study, conducted in Japan, aims to evaluate the safety profile of emicizumab during and immediately after ITI. Methods: AKATSUKI is a Phase IV, open-label, non-randomized, interventional, multicenter study; the methods have been previously published (Matsushita et al. BMJ Open 2022). PwHA with FVIII inhibitors received an approved dose of emicizumab and ITI therapy. Any standard half-life (SHL) FVIII concentrate could be used for ITI, with a dosing regimen of 50IU/kg, three times a week; when using an extended half-life (EHL) FVIII concentrate, 50IU/kg twice a week was permitted. Those who achieved ITI partial success received prophylaxis with emicizumab and a FVIII concentrate starting from the date of their next study visit following investigator confirmation of partial success. Any FVIII concentrate could be used for post-ITI maintenance therapy, given as 50IU/kg once a week for the first 24 weeks followed by 50IU/kg once every 2 weeks for the next 24 weeks, followed by discontinuation of the FVIII concentrate at the investigator's discretion. The primary endpoint was evaluation of adverse events (AEs), with a key focus on TEs, and abnormal laboratory values over time during and immediately after ITI. The main secondary endpoints included number of treated bleeds and the proportion of participants meeting ITI success criteria. Partial success was achieved on the same date that the participant's blood sample showed normal FVIII recovery in addition to the participant receiving a negative FVIII inhibitor titer. Normalized FVIII recovery was defined as a FVIII recovery rate of ≥66% of the predicted value on two consecutive occasions ≥2 weeks apart, and a negative FVIII inhibitor titer was defined as achieving FVIII inhibitor levels of <0.6 BU/mL on two consecutive occasions ≥2 weeks apart. Results: Twelve participants, all of whom were male (median [range] age 2.5 [1-54] years) were included in this interim analysis (evaluation period, median [range]: 437.5 days [224-749]. Data cut-off date: December 22, 2022). Prior to the study, participants had received emicizumab (n=11), ITI (n=9), or both (n=7), and the median (range) duration of ITI in combination with emicizumab was 203.0 (7-1,002) days. Three participants used a SHL FVIII product for their ITI treatment regimen, and nine participants used an EHL FVIII product. Additional baseline characteristics are presented in Table 1. Overall, 30 AEs occurred, none of which were considered emicizumab- or FVIII concentrate-related. Two participants each experienced one serious AE: one case of pneumonia, initially caused by transmission of a viral infection, and one wound hemorrhage, which was recorded as accidental; both recovered. No participants experienced a TE. Three participants reported a total of 10 treated bleeds, all of which were categorized as traumatic and were treated with recombinant activated FVII. At data cut-off, one participant had achieved partial ITI success, having reached a negative inhibitor titer at Week 5 and normalized FVIII recovery by Week 17. This participant was then treated with emicizumab and FVIII concentrate (50IU/kg once a week). No bleeds or AEs were reported for this participant during the observational period. The changes in FVIII inhibitor titer across the study for all participants are presented in Figure 1. Conclusions: At this 48-week interim analysis, no new safety concerns or TEs were reported in PwHA receiving emicizumab and ITI. This study continues to evaluate the safety of emicizumab in conjunction with, and following, ITI therapy in PwHA with FVIII inhibitors.

Characteristics Associated with the Success of Immune Tolerance Induction Among People with Severe Hemophilia a in the United States

Introduction: Immune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe hemophilia A with inhibitors (PwSHAi). An earlier study reported lower receipt of ITI treatment in non-Hispanic (NH) Black and Hispanic compared to NH White PwSHAi (Kempton CL, 2022). Since risk of inhibitor development is greater among Black and Hispanic persons with hemophilia, it has been hypothesized that race and ethnicity may impact the success of ITI. Limited studies have evaluated this hypothesis. This study examined the success of ITI by race and ethnicity among PwSHAi in the Community Counts (CC) Registry between 2013-2017 in the United States (US). Methods: This cross-sectional study used data from the CC Registry, which is a collaboration of the American Thrombosis & Hemostasis Network (ATHN), Centers for Disease Control and Prevention (CDC), and the Hemophilia Center Network (HTCN) using ATHN Study Manager. The CC Registry collects data from people who received care from >135 US hemophilia treatment centers (HTCs). PwSHAi who entered the CC Registry between 2013-2017 and received ITI were selected (n=679); those who were <3 years old at Registry enrollment (n=41) and had history of an inhibitor for <3 years (n=79) were excluded, resulting in 559 people were available for the analyses. Data from 2013-2017 were chosen to represent the pre-emicizumab era where ITI was the standard of care without debate. The 3-year age and inhibitor history cut-point was chosen to ensure ample time for PwSHAi to receive and respond to ITI. The primary outcome was ITI response defined as 1) successful (PwSHAi receiving FVIII replacement therapy at standard doses); 2) partially successful (receiving FVIII replacement therapy at increased dosing); and 3) failed (receiving bypassing agents). Primary independent variables included race/ethnicity, likelihood of ITI success defined with pre-ITI peak inhibitor values alone, grouped as very good [<25 Bethesda Units (BU)], good (25-199 BU), poor (200-999 BU), and very poor (≥1000 BU) prognosis, based on the Future of Immunotolerance Treatment (FIT) group's recent management algorithm (Carcao, 2019). Unadjusted (PR) and adjusted prevalence ratios (aPR) and corresponding 95% confidence intervals (CI) were computed with logistic models with predicted marginals. Results: Among 559 PwSHAi included, 318 (56.9%) were NH White, 107 (19.1%) were NH Black, 101 (18.1%) were Hispanic, 24 (4.3%) were Asian, and 9 (1.7%) were coded as other or missing (Table 1). The median age at Registry enrollment and inhibitor detection was 16 years and 2 years, respectively. Approximately 64% of NH Black, Hispanic, and NH White PwSHAi had either good or very good prognosis, though less than half (41.7%) of Asian PwSHAi had very good or good prognosis. While 59.7% of PwSHAi achieved successful ITI, 20.7% and 19.5% only achieved partially successful or experienced failed ITI, respectively (Table 1). Success of ITI linearly increased according to prognostic group where 21.7%, 36.3%, 55.6% and 69.6% of those with very poor, poor, good, and very good prognosis achieved successful ITI, respectively (χ 2 p-value<.001, Cochran-Armitage Trend p-value<.001). The proportion with successful ITI was non-significantly lower in NH Black (54.2%; PR=0.87,95%CI 0.71,1.05), Hispanic (55.4%; PR=0.89,95%CI 0.73,1.08), and Asian (58.3%; PR=0.93, 95%CI 0.66,1.32) PwSHAi relative to NH White (62.6%) PwSHAi in both crude and adjusted analyses (Table 2). In analyses restricted to those PwSHAi with very good or good prognosis, successful ITI prevalence was nearly identical in NH Black (63.8%) and NH White (64.9%). ITI success was similar across age at inhibitor detection, registry enrollment, health insurance and HTC size (Table 2). Conclusion: Using US CC Registry data, approximately 60% of PwSHAi treated with ITI had a successful response, a proportion similar to previous studies. The proportion of PwSHAi who had successful ITI linearly improved with predicted prognosis, defined by the peak inhibitor titer alone. In our study, prognosis category was generally similar in Hispanic, NH White, and NH Black PwSHAi and the proportion with successful ITI did not vary significantly according to race/ethnicity. These findings do not support the hypothesis that ITI response varies according to race/ethnicity, and it suggests that the benefits of ITI are similar across race and ethnicity.

Race, ethnicity, and immune tolerance induction in hemophilia A in the United States

BackgroundIn racially diverse communities, treatment of chronic diseases can vary across racial and ethnic groups. ObjectivesTo examine healthcare disparities in hemophilia care in the United States by evaluating receipt of immune tolerance induction (ITI) among different racial and ethnic groups. MethodsIn this cross-sectional study, people with severe hemophilia A with an inhibitor who entered the Center for Disease Control and Prevention Community Counts registry between 2013 and 2017, were aged ≥5 years at study entry, and had a history of an inhibitor (n = 614) were included. The proportion of participants receiving ITI was examined according to race and ethnicity in bivariable analysis and multivariable analysis adjusting for demographic and clinical covariates. Unadjusted and adjusted prevalence ratios and corresponding 95% CIs were computed. ResultsAmong 614 participants included in the study, 56.4% were non-Hispanic (NH) White, 19.7% were NH Black, 18.4% were Hispanic, and 4.9% were Asian. ITI was received by 85.2% of participants. On bivariable analysis, ITI treatment did not vary by race or ethnicity. On multivariable analysis, NH Black and Hispanic participants were significantly less likely to receive ITI compared to NH White participants (adjusted prevalence ratio, 0.91 [95% CI, 0.84-0.99] and 0.84 [95% CI, 0.75-0.93], respectively). ConclusionAlthough the role of ITI may evolve with growing use of emicizumab and the introduction of new hemophilia treatment products, understanding characteristics that influence care, particularly race and ethnicity, where physician bias and patient mistrust can occur, will remain relevant and applicable to other complex therapies, including gene therapy.

Application of peripherally inserted central catheter in immune tolerance induction treatment of children with hemophilia A and accompanying inhibitors in China

ABSTRACTObjective:To explore the feasibility, safety and cost effectiveness of the use of peripherally inserted central catheter (PICC) in children with hemophilia A and inhibitors who underwent ITI treatment.Method:This retrospective cohort study evaluated the effect of PICC placement and ITI on bleeding rates, costs, and parents’ satisfaction before and within 6 months after PICC placement in children with hemophilia A and inhibitors.Results:A total of 20 children with hemophilia A and high-titer inhibitors were included, with a success rate for PICC placement of 100%, at a cost of ¥6730.50. Parents’ satisfaction with PICC was 100%, and the total length of catheter indwelling was 6055 days. In terms of curative effect, the success rate of ITI treatment was 75%, and the annualized bleeding rate was decreased from 10.90 ± 12.16 times before placement to 2.10 ± 3.32 times (p < 0.05). The transportation expense for children and their parents to the clinic decreased from ¥20,920 ± 32,274.57 before catheter placement to ¥2915 ± 2195.99 (p < 0.05). Time of children missed school and their parents missed work decreased from 10.85 ± 22.36 days to 1.90 ± 3.58 (p < 0.05) days and 40.33 ± 46.11 days to 3.83 ± 7.11 days (p < 0.05), respectively.Conclusion:The use of PICC for ITI treatment in children with hemophilia A and accompanying inhibitors in developing countries (e.g. China) can ensure the effect of ITI, reducing expense and improving the quality of life without obvious side effects.

Assessing the value of bypassing agent therapy used prophylactic versus on-demand, during immune tolerance induction for treatment of inhibitors: a retrospective chart review

BackgroundHaemophilia A is a bleeding disorder caused by deficiency of coagulation factor VIII (FVIII) which leads to severe and repeated bleedings. There is a need to understand the optimal treatment pathway for FVIII inhibitors with the use of immune tolerance induction (ITI) and the role of haemostatic ‘bypassing’ agents (BPA) on-demand (OD) or prophylactically (Px). The aim of this study was to gain a better understanding of the real-world use of BPA therapy administered prophylactically or on-demand concomitant with ITI, for the treatment of an inhibitor to FVIII replacement therapy in patients with severe haemophilia A.MethodsRetrospective observational data were used to capture disease management information for patients who were aged 16 or under and had received ITI and BPA treatment for their most recent inhibitor from Jan-2015 to Jan-2019, for 47 patients in the UK and Germany. Descriptive comparisons of the clinical effectiveness and resource utilisation of Px and OD BPA therapy during ITI were conducted.ResultsDuring ITI and BPA treatment, for an inhibitor, bleeding events averaged 1.5 and 1.2 for Px and OD treatment respectively. Compared to only BPA therapy we see 3.4 and 1.4 bleeding events for Px and OD respectively during an inhibitor.ConclusionBaseline disease characteristics differed between BPA therapy cohorts and this resulted in higher clinical effectiveness of ITI treatment alongside BPA Px than BPA OD during an inhibitor.

Characteristics Associated with Receipt of Immune Tolerance Induction Among Patients with Severe Hemophilia a in the United States in the Pre-Emicizumab Era

Introduction: Immune tolerance induction (ITI) has long been the standard of care for treatment of patients with hemophilia A complicated by an inhibitor. Although the approval of emicizumab to treat hemophilia has led to new debate as to the role of ITI, many continue to advocate for its use to restore the effectiveness of factor VIII for treatment of bleeding events and major surgery. Unfortunately, ITI is cumbersome to undertake, and providers may perceive that some families are unable to complete the complex treatment. This opens the door for bias and health inequities. To better understand potential health inequities in hemophilia care, we sought to explore the association of race and ethnicity, as well as patient and facility characteristics, on the receipt of ITI among patients with hemophilia A in the United States (US). Methods: This cross-sectional study used data from the Community Counts (CC) Registry, which is a collaboration of the American Thrombosis & Hemostasis Network (ATHN), Centers for Disease Control and Prevention (CDC), and the Hemophilia Center Network (HTCN) using the ATHN study manager. The Registry collects data from patients that received care from more than 135 hemophilia treatment centers (HTC) across the US. Included in this analysis were patients with severe hemophilia A who entered the CC Registry between 2013-2017, were ≥5 years of age at the study entry, and had a history of an inhibitor (n=614). Data from 2013-2017 were selected to represent the pre-emicizumab era. The primary outcome was ever receiving ITI treatment, which was ascertained in the initial CC Registry visit form. The proportion receiving ITI was examined according to race/ethnicity, the age and year that an inhibitor was detected, age at study entry, current health insurance, pre-ITI peak inhibitor titer, and HTC size, dichotomized into having <40 or ≥40 patients with severe hemophilia A in the CC registry. Unadjusted prevalence ratios (PR) and corresponding 95% exact confidence intervals (CI) were computed with contingency tables. Results: Among 614 patients included in the study, slightly over half (56.4%) were White, 19.7% were Black, 18.4% were Hispanic, and 4.9% were Asian (Table 1). The average age at the study entry was 22.2 [standard deviation (SD =14.3)] years and the average age at inhibitor detection was 5.6 (SD=9.9) years. Most patients had a high titer inhibitor (≥5 BU/mL). Approximately 85.2% of patients in the study received ITI; results were not statistically different by race-ethnicity. However, in an analysis restricted to patients whose inhibitors were detected ≤5 years of age, Black (PR=0.94, 95%CI 0.86, 1.02) and Hispanic (PR=0.91, 95%CI 0.83, 1.00) patients were non-significantly less likely to receive ITI compared to White patients (Table 2). Receipt of ITI was also significantly lower among people currently receiving care from HTCs with <40 vs ≥40 patients (PR=0.92, 95%CI 0.86,0.99). Patients who were older when their inhibitor was detected (ages 5-19 years and ≥20 years vs. ≤5 years), were older during the study (ages ≥40 years vs. 5-19 years), had their inhibitor detected in 1995 or earlier vs 2006 or later, or had Medicare insurance vs commercial insurance were less likely to receive ITI. Additionally, those who had an inhibitor titer ≥5 BU/ml vs < 5 BU/ml were less likely to be treated with ITI (Table 2). Conclusion: Most patients with severe hemophilia A with history of an inhibitor were treated with ITI. However, larger HTCs were more likely to implement ITI and those receiving Medicare were less likely to receive ITI. Additionally, among patients whose inhibitors were detected at ≤5 years of age, Black and Hispanic patients with severe hemophilia A had non-significantly lower rates of ITI for the treatment of inhibitors compared to White patients. Although the role of ITI may evolve with growing use of emicizumab and the introduction of new products, understanding characteristics that influence care will be relevant going forward and potentially applicable to other complex therapies such as gene therapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Low-dose immune tolerance induction therapy in children of Arab descent with severe haemophilia A, high inhibitor titres and poor prognostic factors for immune tolerance induction treatment success.

IntroductionImmune Tolerance Induction (ITI) is the first‐choice therapy to eradicate Factor VIII (FVIII) neutralizing antibodies in patients with haemophilia A (HA). There is limited published data on ITI from East Mediterranean countries.AimTo assess the effectiveness of a low‐dose ITI regimen to eradicate FVIII neutralizing antibodies in children with severe HA and high‐titre inhibitors.MethodsA prospective, single‐arm study was conducted in children with HA (FVIII < 1 IU/dl), high‐titre inhibitors and poor prognostic factors for successful ITI. Patients were treated with ∼50 IU/kg plasma‐derived FVIII containing von Willebrand factor (pdFVIII/VWF) concentrate (Koate‐DVI, Grifols) three times a week. Time to achieve tolerance, total and partial success were analysed after ITI. Annual bleeding rate (ABR), number of target joints, FVIII recovery and school absence were compared before and after ITI.ResultsTwenty patients with median (range) age of 6.2 (3–12) years and pre‐ITI inhibitor titre of 36.5 (12–169) BU were enrolled. ITI lasted ≤12 months (early tolerization) in 45% of patients. Median follow‐up was 12 months (3–22) and total response rate was 80% (60% total success; 20% partial success). Patients with two and three poor prognosis factors achieved overall success rate of 60% and 50%, respectively. ABR, target joints and school absence were reduced after ITI by 60%, 50% and 44.1%, respectively. In successful ITI tolerized patients, FVIII recovery was 90 (60–100)%.ConclusionA low‐dose ITI therapy using a pdFVIII/VWF concentrate achieved at least partial tolerance in 80% of patients, and reduced annual bleeds in children with high inhibitor titres and at least one poor prognosis factor for ITI treatment success.

Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BrazIT) Study protocol.

The development of inhibitors is the main complication of haemophilia A (HA) treatment. Immune tolerance induction (ITI) is the treatment of choice for inhibitor eradication. We describe the methodology of the Brazilian Immune Tolerance Induction (BrazIT) Study, aimed to identify clinical, genetic, and immune biomarkers associated with response to ITI and inhibitor recurrence. This cohort study includes people with HA (PwHA) and inhibitors (a) who require bypassing agents to treat and/or prevent bleeding, and (b) who are at any stage of ITI treatment. Patients are included in each haemophilia treatment centre (HTC). Factor VIII (FVIII) and inhibitor assessments are performed at local laboratories of each HTC. The ITI regimen followed the national protocol of the Brazilian Ministry of Health. All PwHA starts with low-dose ITI (50 IU/kg three times weekly); high-dose regimen (100 IU/kg daily) is used if there is lack of response to the low-dose ITI. Outcomes are classified as total or partial success, and failure. Standardized case report forms with clinical, laboratory, and treatment data are collected from medical files and interviews. Blood samples are collected for genetic and immune biomarkers at the time of inclusion in the study and at the end of ITI. The study is ongoing and, currently, 202/250 (80.8%) PwHA from 15 HTCs have been included. BrazIT Study is the largest cohort of PwHA and inhibitor under treatment with the same ITI regimen reported to date. This study is likely to contribute with novel predictors of ITI response.

Current status of haemophilia inhibitor management in mainland China: a haemophilia treatment centres survey on treatment preferences and real-world clinical practices.

To investigate the current experience and expertise for haemophilia inhibitor patient management in haemophilia treatment centres (HTCs) in mainland China. Questionnaires were distributed to 'tertiary tier A' hospital HTCs across China to collect information on treatment preferences for bleeding control, prophylaxis and inhibitor eradication, as well as their regimens in real-world clinical practice. Of 40 questionnaires distributed, 39 were returned. In all, 38 were analysable for treatment preferences and 34 for actual clinical practice. For haemostatic treatment, 76·3% (29/38) HTCs preferred activated recombinant human Factor VII (rFVIIa). In clinical practice, the most widely used by-pass agent was prothrombin complex concentrate (26 HTCs). Although 65·8% (25/38) of HTCs believed prophylaxis treatment was necessary, it was prescribed in only 12. Similarly, 65·8% (25/38) of HTCs believed immune tolerance induction (ITI) therapy was necessary but only 14·8% (92/622) of patients in 19 HTCs received low-dose ITI treatment. HTCs in relatively economically developed cities (with higher-than-average per-capita gross domestic product) had better access to haemostatic treatment, coagulation testing and were more likely to provide prophylaxis and ITI in practice. The present survey showed there were gaps in haemophilia inhibitor care between the HTC physicians' preferences and their actual clinical practice. More specific care guidelines, education and clinical decision support tools are needed to guide clinical practice.

Evaluation of Predictors of Outcome in Immune Tolerance Induction Treatment of Hemophilia Α Patients with High-Responding Inhibitors

Introduction: Inhibitor development remains a major complication for patients with hemophilia A. Inhibitors are alloantibodies that neutralize factor (F) VIII activity, which impairs the hemostatic effect of infused FVIII concentrate. Immune tolerance induction (ITI) consists of regular FVIII administration in an attempt to eliminate the presence of inhibitors. There are several ITI protocols with similar success rates around 70%. Still, the ideal ITI regimen and the factors that can influence its success are not well defined.Objective: This study aimed to evaluate the predictors factors for ITI response among Brazilian hemophilia A patients with high-responding inhibitors who have undergone ITI protocol for the first time.Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer >5 Bethesda Unit (BU) and anamnestic response to FVIII) from eight Brazilian Hemophilia Treatment Centers, who underwent ITI treatment for the first time. ITI outcome was defined as: (i) complete success, negative inhibitor (<0.6 BU) on at least two consecutive measurements, FVIII recovery >66%, and half-life >7 h, with absence of anamnestic response to FVIII; (ii) partial success, negative inhibitor titer and absence of one or two of the PK parameters of ITI success (FVIII recovery > 66% or half-life ≥7 h); (iii) clinical response, inhibitor titer <5 BU and/or FVIII recovery <66% and/or FVIII half-life <7 h, with clinical response to FVIII infusions and no increase of inhibitor titer >5 BU; and (iv) failure, lack of criteria for complete or partial success or clinical response within 33 months of treatment. Statistical analysis were carried out using the Kruskal-Wallis H test.Results: In this study, we accessed data from 88 patients, from which 61 were analyzed for ITI outcome, having achieved ITI complete success or reached 33 months under ITI protocol. Low-dose ITI protocol was initially used for all patients and started with FVIII concentrate 25-50 IU/kg 3x/week, with dose increment to up to 100 IU/kg daily when a minimum of 20% decrease in the inhibitor titer was not achieved in 6 months. 41/61 (67.2%) achieved complete ITI success criteria, in a median period of 17 months (interquartile range (IQR) 10.3-22.6) after starting ITI. 4 (6.5%) remained as partial ITI success over 33 months of treatment. Among the remaining 16 patients, 3 (5%) had clinical response to FVIII concentrate, without requirement of bypassing agents to achieve hemostatic response, and 13 (21.3%) failed ITI treatment. When comparing groups with different outcomes, statistical analysis revealed that the historical peak titer (p= 0.002), inhibitor titer at the moment of ITI protocol started (p= 0.013) and the peak titer during ITI protocol (p< 0.0001) were important predictors factors of ITI success (table 1). Other clinical factors that possibly interfered with ITI outcome were bleeding rates during ITI treatment, both annualized bleeding rate (ABR) (p=0.047) and annualized joint bleeding rate (AJBR) (p=0.014). Although there was no difference in age at ITI onset, a statistically significance was also observed in the difference of central venous catheter use between complete success and failure groups (5% vs 38.5%; p= 0.023). A possible explanation could be the need for a more intense treatment in the failure group, with a higher demand for venous access. However, the higher risk of infection and thrombosis in this group can also result in lower ITI success. In the group with no ITI outcome analyzed (27/88), 10 (11.4%) discontinued ITI treatment for several reasons and at least 4 of them are no longer using bypassing agents. 16 are still under ITI treatment, from which 7 (43.8%) already achieved clinical response to FVIII concentrate.Conclusion: In this study, we observed a complete ITI success rate of 67.2% among hemophilia A patients with inhibitor submitted to ITI treatment for the first time. In this cohort, inhibitor titer influenced ITI success throughout different treatment phases, such as historical peak, titer before ITI onset and peak during ITI. The frequency of bleeding episodes during ITI and the use of central venous access were also important predictors of ITI success. This knowledge should contribute to the stratification of prognosis and contribute to decision making in clinical care of patients with high-responding inhibitors under ITI treatment. [Display omitted] DisclosuresOzelo:Pfizer: Consultancy, Research Funding, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Biogen: Consultancy, Research Funding, Speakers Bureau; CSL Behing: Consultancy; Shire: Consultancy, Research Funding, Speakers Bureau; Grifols: Speakers Bureau; Novo Nordisk: Consultancy, Research Funding, Speakers Bureau.

Immune Tolerance Induction in Hemophilia A Patients Using Wilate® —a Canadian 10 Year Study (PREVAIL)

Introduction:Hemophilia A patients with inhibitors experience a higher morbidity, a worse orthopedic condition and a decreased quality of life. In children with severe hemophilia A, attempting to eliminate inhibitors with immune tolerance induction (ITI) is standard of care; however, in adults with longstanding inhibitors ITI has been less extensively studied. Although practical guidelines in adults are scarce there has been an increase in case reports highlighting the success of ITI in patients with long-standing inhibitors.The possibility that the type of factor VIII (FVIII) product used for ITI could influence the likelihood of successful tolerization is the subject of intense debate. It has been postulated that FVIII products containing von Willebrand factor (VWF) may improve the ITI success rate in some patients with inhibitors, especially those with poor prognostic characteristics, i.e., a historical peak inhibitor level >200 BU/mL, an inhibitor level >10 BU/mL at the start of ITI, age >5 years, or >24 months between inhibitor detection and start of ITI.Study RationaleWilate® is the most extensively used plasma-derived FVIII/VWF concentrate for hemophilia A in Canada. Wilate® has been successful in eliminating inhibitors and reducing bleeding in Canadian children and adults who had developed inhibitors during treatment with other FVIII concentrates, including poor-prognosis patients. Wilate® was well tolerated at the high doses required for ITI. Furthermore, anecdotal clinical experience with Wilate® ITI therapy suggest that patients may have less bleeding, which may limit the need for bypassing agents.This research study was designed to evaluate the efficacy of Wilate® in achieving complete or partial ITI success in severe and moderate hemophilia A patients with inhibitors. Secondary objectives are to determine: the time to achieve immune tolerance; bleeding frequency while on Wilate® ITI treatment; quality of life while on Wilate® ITI treatment; joint health while on Wilate® ITI treatment; relapse rate; and time to relapse following successful ITI using Wilate® .Additional optional sub-studies have been incorporated into this study to gain insight into the biology of ITI, including biomarkers that might predict ITI success or failure: genotyping, anti-FVIII antibody characterization including epitope mapping, and thrombin generation.Study ProceduresThis 10-year Canadian study is an open-label, uncontrolled, multi-centre observational trial with both prospective and retrospective cohorts. A total of at least 80 hemophilia A patients with inhibitors will be enrolled into this study.The dose and frequency of ITI treatment will be at the discretion of the treating physician. However, use of risk-determined treatment protocols is recommended. Patients with high-titre inhibitors (defined as one with historical peak titre ≥5 BU/m) who have inhibitor titre ≤10 BU/mL at the start of ITI are “good-risk” for ITI success, and those who have inhibitor titre >10 BU/mL at the start of ITI are “poor-risk”. Patients with high-titre inhibitors who are good-risk should receive 50 IU FVIII/kg BW every other day or 3 times per week; daily treatment may also be considered. Patients with high-titre inhibitors who are poor-risk should receive 100-200 IU FVIII/kg BW daily. Patients with low-titre inhibitors (defined as one with historical peak titre < 5 BU/mL) should receive 50 IU FVIII/kg BW every other day to 3 times per week.For complete success, an individual must achieve the following three criteria: inhibitor titre <0.6 BU (at least 2 separate blood samplings; incremental recovery of FVIII in the normal range (≥66% of normal); FVIII half-life ≥6 hours. For partial success an individual must meet two of the three criteria. In a partial response, one of the three criteria above is met. In a partial failure : none of the three criteria are met, but inhibitor titre has decreased to <5 BU. In a complete failure none of the three criteria are met, and inhibitor titre is still ≥5 BU.ConclusionThis research study aims to evaluate and document data on the success of Wilate ® ITI in hemophilia patients with FVIII-inhibitors. It is the first 10-year study of its kind in a Canadian setting. The results of this study will provide further insights into addressing one of the most serious complications of hemophilia A treatment. DisclosuresMoorehead:Bioverativ: Honoraria; Pfizer: Speakers Bureau; Octapharma: Honoraria; Bayer: Honoraria; Baxalta: Honoraria, Speakers Bureau. Klaassen:Baxalta: Honoraria; Agios Pharmaceuticals: Consultancy; Hoffman-La Roche LTD: Consultancy; Biogen Canada LTD: Consultancy; Amgen: Consultancy; Octapharma: Honoraria. Carcao:Octapharma: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Biogen: Honoraria, Research Funding; Baxter: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Biotest: Honoraria.

ITI Treatment is not First-Choice Treatment in Children with Hemophilia A and Low-Responding Inhibitors: Evidence from a PedNet Study.

Limited data exist on the clinical impact of low-responding inhibitors and the requirement for immune tolerance induction (ITI) treatment to establish tolerance, reduce bleeding, and improve outcome. The aim of this article is to describe the therapeutic management of children with severe hemophilia A and low-responding inhibitors and its effect on bleeding phenotype. The REMAIN (Real-life Management of Inhibitors) study is a satellite study of the PedNet registry. It included unselected children with severe hemophilia A (factor VIII [FVIII] < 0.01 IU/mL) born between January 1, 1990 and December 31, 2009 who developed clinically relevant inhibitors and were followed-up for at least 3 years after the first positive inhibitor test. A total of 260 patients with inhibitors were identified and 68 of them (26%) had low-responding inhibitors (peak < 5 BU/mL). Five patients were lost to follow-up and 63 were included in this study. The median follow-up was 3.7 years (interquartile range: 3.0-7.5). ITI was started in 51/63 (81%) patients. The median time from ITI start to first negative inhibitor titer was similar with low-dose and high-dose ITI regimens (2.5 and 3.1 months, respectively). Ten of the 12 patients who did not receive ITI were treated with regular prophylaxis and reached a negative titer after a median of 6.5 months. Bleeding rate was low in all patients with no difference between treatment regimens. In children with low-responding inhibitors negative titers were reached with regular FVIII treatment irrespective of the regimen (i.e., prophylaxis or ITI).

Real-World Data of Immune Tolerance Induction Using rFVIIIFc in Subjects With Severe Hemophilia A With Inhibitors at High Risk for ITI Failure

Real-World Data of Immune Tolerance Induction Using rFVIIIFc in Subjects With Severe Hemophilia A With Inhibitors at High Risk for ITI Failure

Prospective Study of the Immunological Mechanisms of Immune Tolerance Induction in Severe Haemophilia a Patients with Inhibitors: Preliminary Analysis of a Multi-Center Longitudinal Study

BackgroundThe development of an immunogenic response to FVIII and the appearance of neutralizing antibodies - “inhibitors” - against FVIII is the most important adverse event in hemophilia treatment. Immune Tolerance Induction (ITI) via the long-term, intravenous administrations of high-dose FVIII is the only proven strategy to eradicate inhibitors. The success rate is about 60-70% and no formal demonstration of its mechanism of action has been provided yet. Indeed, the mechanisms underlying successful ITI have been unclear, and not much is known about the major factors determinant of success vs. failure.Our aim is to understand the process of activation and immune regulation in response to FVIII in patients undergoing ITI, and comparing the immunological events in patients who successfully eradicate anti-FVIII antibody to those in patients failing to achieve FVIII tolerance.MethodsThis is a multicenter, observational, prospective cohort study enrolling severe HA patients who developed high-titer inhibitors, candidate to ITI. A blood sample has been collected before starting and during the course of ITI, until ITI ends (5 blood samples during the first year, 3 during the second year if ITI treatment is not already ended, plus a final sample 30 days after ITI conclusion). Total PBMCs have been used to establish cell cultures where cells are re-stimulated with the same FVIII used during the ITI or medium alone.To identify candidate genes, key proteins and cell subsets associated to differential outcomes to ITI, immune cells are used for gene expression profiling (Human Inflammation & Immunity Transcriptome Targeted RNA Panel, Qiagen) together with extensive phenotypic characterization of immune cells via the CyTOF (Cytometry by Time Of Flight mass spectrometry) technology. To identify potential biomarkers predictors of ITI outcomes metabolomics analysis and multiplex cytokine arrays are performed in plasma collected at each time point during ITI and in supernatants from cells cultures. Plasma samples, are collected at each time point and stored at -80°C for cytokine determination and metabolomic analysis. Total anti-FVIII antibody (and their isotypes) and inhibitor titer are also determined in plasma samples by Nijmegen methodology in the central laboratory as described previously (1).ResultsCurrently, 18 subjects have been enrolled among 8 Hemophilia Centers. Among these 5 subjects, two patients reached the study endpoint of ITI success by study criteria (negative inhibitor titer, a normal FVIII recovery, a normal FVIII half-life and the absence of anamnesis upon further FVIII exposure) while three were assessed as ITI failure. The analysis of anti-FVIII antibody isotypes revealed the presence of IgG4 as the most relevant component of the total anti-FVIII antibodies. The inhibitor clearance was also accompanied by the disappearance of IgG4 anti-FVIII antibodies in both tolerized patients, while those who failed to eradicate the inhibitor showed a sustained IgG4 anti-FVIII response (Fig. 1). The evaluation of the cytokines in the supernatants from in vitro cultured cells showed a consistent increase in production of pro-inflammatory cytokines in response to FVIII (IL-1β, IL-6, IL-12, IL-17A, IL-15) at all time points only in patients who continued to produce high-titer inhibitors.ConclusionsHere we report an interim analysis of a prospective study of the immunological mechanisms of immune tolerance induction. The preliminary results obtained so far suggest that anti-FVIII IgG4 are a major component of the total anti-FVIII antibodies and their persistence is associated with unfavourable ITI outcome. We expect that the ongoing immune gene expression profiling, immune-phenotypic characterization and determination of soluble marker of activation/regulation of the immune system in supernatants and plasma in this cohort of patients will provide substantial knowledge to increase our current understanding of the complex immunological pathways involved in the development of tolerance to FVIII. Ultimately, this could lead to the discovery of biomarkers of ITI success/failure and to the generation of focused and strategic intervention to modulate the immune system during this treatment.

Economic Impact of Immune Tolerance Induction (ITI) with Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) Compared to Conventional Recombinant Factor VIII (rFVIII)

Introduction:Hemophilia A results from a clotting protein factor VIII (FVIII) deficiency, which leads to the need for the use of exogenous FVIII. Such therapy is effective unless alloantibodies (inhibitors) develop and render FVIII replacement ineffective. Patients with high-titer inhibitors may try to eradicate the presence of these inhibitors by undergoing ITI, an often costly process that requires the prolonged use of frequent doses of FVIII to induce FVIII antigen-specific tolerance. There is no consensus on the best approach to achieve tolerance and no product has been approved by any regulatory agency for ITI treatment in hemophilia A patients with inhibitors. The Fc portion of rFVIIIFc has shown immunomodulatory properties in mice, and chart reviews and case reports suggest that tolerization with rFVIIIFc in first-attempt ITI patients can potentially be achieved rapidly (i.e., ≤18 months) and therefore may possibly offer cost savings compared to conventional rFVIII. This analysis assessed the economic consequences and budget impact of using rFVIIIFc vs. conventional rFVIII for first-attempt immune tolerance induction (ITI) in hemophilia A patients with inhibitors.Methods:A literature-based model was developed to estimate the effect of rFVIIIFc vs conventional rFVIII on drug cost of first-attempt ITI, based on modelled ITI duration and outcome (rates and time to ITI success or failure) for US patients with varying clinical profiles (e.g., historical peak titer, FVIII dose) over a 3-year period. In the model, at any given time after ITI initiation (on either rFVIIIFc or rFVIII), a patient was categorized as ongoing ITI, post-ITI as success, or post-ITI as failure. The duration and outcomes for patients treated with rFVIIIFc ITI were based on observed data for first-attempt ITI patients with varied clinical profiles and ITI regimens from in chart reviews and case reports (n = 9). In the absence of direct head-to-head observations, the duration and outcome of ITI for the exact same patients in a scenario in which they received rFVIII (instead of rFVIIIFc) at the same doses were estimated indirectly using a previously published regression model (Bojke et al. 2009, Value in Health, 12(7), A378-A379) based on data for 113 patients from international and national registries that adjusts for historical and pre-ITI titer levels, time from inhibitor diagnosis to ITI start, and ITI factor dose. To place the cost comparison results in the perspective of a third-party US payer, a budget impact analysis was undertaken on a population of typical hemophilia A patients (after adjusting for patient characteristics) who are embarking on first-attempt ITI in a plan of 10 million insured members. In this analysis, the number of patients starting ITI each year was assumed constant, and patients who successfully eradicated inhibitors with ITI would transition back to FVIII prophylaxis.Results:The model predicted that, compared to rFVIII, rFVIIIFc would result in a reduction in estimated time to ITI success (rFVIIIFc: 9.43 months, rFVIII: 16.80 months), increased success probability at 20 months (rFVIIIFc: 67%, rFVIII: 25%), and lower 3-year per-patient costs (rFVIIIFc: $1,709,000, rFVIII: $3,630,000), respectively. In the budget impact analysis for a US health plan of 10 million insured members, 11.2 patients were expected to be newly diagnosed hemophilia A patients, among whom 1.17 patients were expected to develop inhibitors to FVIII and initiate ITI each year. By year 3, the predicted number of successful ITI patients increased by 23% and the budget savings for the plan were $103,738 per patient per year (for the ~1 patient who started ITI each year) after the inclusion of rFVIIIFc for ITI and subsequent prophylaxis when patients successfully eradicated inhibitors.Conclusions:Based on this mathematical economic model of first-attempt ITI patients, the modeled faster time to tolerization with rFVIIIFc vs. rFVIII, resulted in estimated per-patient and overall budget savings in ITI from a US payer perspective. Current prospective studies (e.g. verITI-8) will provide additional evidence on the efficacy of rFVIIIFc for ITI in Hemophilia A patients with inhibitors. DisclosuresLi:Bioverativ: Employment. Wilson:SOBI: Employment. Botteman:Daiichi Sankyo Incorporated: Research Funding; BMS: Research Funding; Pharmerit International: Employment, Equity Ownership, Research Funding; Celgene: Research Funding; Bioverativ: Consultancy, Other: Provided consulting to Bioverativ, Research Funding. Nicoloso:Bioverativ: Other: an employee of Pharmerit, which provided consulting to Bioverativ. Krishnan:Bioverativ: Employment. Su:Bioverativ: Employment.

Innowacyjna metoda prowadzenia ITI za pomocą preparatu czynnika VIII z frakcją Fc u pacjentów z hemofilią A z obecnością inhibitora czynnika VIII – przegląd literaturowy

Eradication of factor VIII inhibitors using Immune tolerance induction (ITI) treatment is the standard of care for severe haemophilia A patients presenting with factor VIII inhibitors, but is not always effective. A description of the potential immunological tolerance effect of the IgG Fc domain of recombinant factor VIII Fc fusion protein (rFVIIIFc), as well as published experience with rFVIIIFc for ITI in patients with severe haemophilia A and high-titre inhibitors. Review of published literature describing cases of ITI with rFVIIIFc in patients with severe haemophilia A and high-titre inhibitors between November 2015 and June 2018. Four publications has been found. Of 56 patients with haemophilia A who presented with FVIII inhibitors, 28 achieved a negative Bethesda titre (&lt; 0.6) after ITI treatment using rFVIIIFc. Additional patients continued on rFVIIIFc ITI at the time of publication, while a few were reported to have switched to bypass therapy alone or other factors . For those still undergoing ITI, longer follow-up is needed to determine final outcomes. No adverse events were reported. Based on literature review, preliminary evidence of FVIIIFc use in high risk, first-time ITI suggests rapid time to tolerization. For rescue ITI, rFVIIIFc showed therapeutic benefit in some patients who previously failed ITI. These findings give hope but highlight the need for further evaluation in ongoing clinical trials.

The Immune Tolerance Induction Factor Utilizations and Costs for the Management of Male Hemophilia-a Patients Who Developed Inhibitors

Background: Hemophilia-A is a chronic inherited bleeding disorder that results from deficiencies in factor VIII. Prophylactic replacement of coagulation factor VIII (FVIII) is the standard of care. However, about 20-30% of patients with severe hemophilia A may develop neutralizing antibodies (inhibitors) against the coagulation factor VIII. The Immune Tolerance Induction (ITI) method, consist in the regular infusion of variable FVIII doses to induce FVIII antigen-specific tolerance. It has proven the most effective inhibitor eradication treatment in patients with high-titer inhibitors. Current published studies reported wide range of findings on the factor usage and cost of treatment. The objective of this study is to describe the consumption, duration, and cost of ITI treatment in US healthcare settings.Methods: This retrospective analysis used MarketScan, an US health insurance claim database from January 2010 to September 2015. Eligible patients were: male hemophilia-A inhibitor patients who received ITI treatment. ITI treatment was identified as patients who tested Bethesda/Nijmegen assays between 30 days prior to an ITI index date and the end of study period; and used high dose of factor therapy (>3 times of the median IU factors dispensed for patients in the same age group for more than 5 consecutive months, allowing one month gap). Conclusion of ITI treatment was defined as when the amount of IU dispensed has fallen under 1.5 times of the median amount dispensed, or remaining in ITI treatment at the end of study period. Patients, who used by-pass agents to treat bleeding without undergoing ITI, were excluded. The total cost of ITI treatment was focused only on the cost of factor therapy. The treatment duration, cost, and IU consumption were further stratified by age groups and specific factor therapies.Results: Of the 2,302 hemophilia-A patients, 231 inhibitor patients were identified. A total of 72 patients used high dose short-acting factors for ITI treatment. No patient receiving long-acting factor was captured in the inhibitor population. Table 1 lists the patient counts, duration and cost of ITI treatment by age groups. Higher percentages of younger patient groups developed inhibitor compared with older age groups. About 14% of hemophilia-A patients aged 7 and under had ITI treatment. The older groups (aged 16 and older) had higher total costs as they required higher IU of factor therapy. The average duration of ITI treatment was 18.7 months, and the average total cost was $1,463,668 per patient regardless of the type of short acting factor therapy used.Conclusions: This US health insurance claim database study reflects that the current utilization of short acting factor for ITI treatment is associated with high cost burden. Products that decrease or eliminate inhibitor formation should be developed. [Display omitted] DisclosuresSu:Novartis Pharmaceuticals Corporation: Employment; Biogen: Employment, Equity Ownership. Zhou:Biogen: Employment, Equity Ownership. Buckley:Biogen: Employment, Equity Ownership. Rising:Biogen: Employment, Equity Ownership. Hou:Biogen: Employment, Equity Ownership. Jain:Biogen: Employment, Equity Ownership.

Current view and outcome of ITI therapy - A change over time?

IntroductionInhibitor 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. ObjectivesTo 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. MethodsA 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. ResultsWe 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. ConclusionsThe 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.

Early eradication of factor VIII inhibitor in patients with congenital hemophilia A by immune tolerance induction with a high dose of immunoglobulin.

The production of factor VIII (FVIII) inhibitory antibodies is a serious problem in patients with hemophilia A. Immune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors and has been shown to be successful in 70 % of patients with hemophilia A. However, a minority of hemophilia patients present life-long inhibitors. To eliminate such inhibitors, we designed an intravenous immunoglobulin (IVIG) strategy in combination with high dose recombinant FVIII for ITI in hemophilia A children with inhibitors. Four previously untreated patients produced inhibitors within 16 exposures to FVIII. The peak inhibitor titers in these patients ranged from 3 to 14 BU/mL. The patients received ITI combined with IVIG within 1.5 months after the inhibitors were detected. All patients showed a negative titer for inhibitors by 28 days, with no anamnestic responses. The recovery of FVIII in the plasma concentration was normalized within three months after initiation of ITI. An additional course of IVIG administration led to induction of complete tolerance by 20 months after initiation of ITI therapy in all patients. ITI treatment with high-dose FVIII combined with IVIG may be effective for the early elimination of inhibitors.

Immune Tolerance Induction Treatment Is Cost-Effective in Adult Patients with Long-Standing High-Responding Inhibitors

Introduction: Despite treatment of hemophilia having achieved considerable improvement over the last decades, inhibitor development remains a major complication for these patients. Inhibitors are alloantibodies that neutralize factor (F) VIII coagulation activity, and occur in approximately 25% of hemophilia A patients. Immune tolerance induction (ITI) is the choice therapy to eradicate these antibodies. There are several ITI protocols with similar success rates, approximately 70%. The presence of long-standing inhibitors in the adult population has usually been associated with poor ITI outcome. In Brazil, as in other countries with constrained resources, limited access to factor concentrates prevented the use of ITI. Thus, almost all patients with inhibitors remained a long time with this complication. Only after 2013 with increased availability of factor concentrates in the country, has assured long-term prophylaxis and ITI treatment been possible.Objective: This study aimed to describe the Brazilian experience in managing ITI in adult patients from seven Hemophilia Treatment Centers with long-standing inhibitor using bypassing agents to control bleeding episodes, considering bleeding frequency, treatment barriers and economic impact of therapy.Patients and Methods: We retrospectively analyzed clinical and laboratory data of hemophilia A patients with high-responding inhibitors (peak titer > 5 Bethesda Unit (BU), anamnestic response to FVIII) over 18 yo who underwent ITI treatment and were using bypass agents before ITI. The initial ITI protocol used was low-dose FVIII concentrate (25-50 IU/kg 3x/week)Results: In Brazil, since the availability of ITI, 39 adult hemophilia A patients with inhibitors, have been submitted to ITI for the first time. In this study, we accessed data from 26 patients, of these 13 (50%) already achieved complete ITI success criteria (inhibitor titer < 0.6 BU; FVIII recovery ≥ 66%, and half-live ≥ 6 h). Another 4 patients with ongoing ITI achieved inhibitor titer < 5 BU and are no longer using bypassing agents. Thus, 17/26 (65%) patients discontinued the bypassing agents in a median period of 2 mo (range 0 to 18 mo) after starting ITI. After 24 months of irregular treatment 2 patients abandoned ITI protocol. Analyses of the 13 patients with complete success revealed mean age at first reported inhibitor of 16.21y (SD ± 11.6; median 21y, range 0.7 to 37y), and mean age at ITI onset of 31.2y (SD ± 10.6; median 27y, range 19 to 47y). The mean period from the first inhibitor detected until starting ITI was 15y (SD ± 5.1), with a 16y median (range 7 to 22y). The historical peak inhibitor mean was 53.1 BU (SD ± 49.5; median 39.4 BU, range 5.5 to 163 BU). The mean pre ITI inhibitor titer was 6.6 BU (SD ± 5.5; median 5.5 BU, range 0.6 to 20.8 BU). Low-dose ITI protocol was initially used for all patients, however 3 patients had the dose increased during treatment (100 IU/kg from 3 to 7 x/week). During ITI, 10/13 patients received prophylaxis with bypassing agents, and 9 began prophylaxis before ITI started. The mean time to achieve inhibitor titer < 0.6 BU was 11.6 mo (SD ± 12.5; median 7 mo, range 0.5 to 44 mo). All 13 patients achieved other ITI success criteria. However, a delay was observed in the majority of patients in FVIII recovery and half-life. Regarding clinical outcome, we observed a significant reduction in both, annualized bleeding rate (ABR), and annualized joint bleeding rate (AJBR), comparing 12 months before ITI, during ITI, and after achieving complete success (figure 1). Regarding economic evaluation, we observed a significant reduction in the median cost of clotting factor consumption, comparing 12 months before starting ITI, and the following years after achieving ITI success. No significant difference was observed between the median cost of 12 months before, and ITI period (figure 2).Conclusion: This study indicated that this treatment is worthwhile even for inhibitor patients with poor prognostic factors for ITI considering both effectiveness to control and prevent bleeding episodes, and economic impact. In this group, 65% of adult hemophilia A high-responding inhibitors patients stopped using bypassing agents after a median period of 2 months after starting ITI. Despite being a high cost treatment, ITI can be cost-effective, especially for patients using bypassing agents. These results reinforce the positive impact of the ITI even in long time inhibitor adult patients. [Display omitted] [Display omitted] DisclosuresOzelo:Baxter: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Biogen: Research Funding.