Low-dose Immune Tolerance Induction Research Articles

Low-dose immune tolerance induction for severe hemophilia A inhibitor patients: Immunosuppressants are generally not necessary for inhibitor-titer below 200 BU/mL.

It remained unclear that the efficacy comparison between low-dose immune tolerance induction (LD-ITI) incorporating immunosuppressants (IS) when severe hemophilia A (SHA) patients had inhibitor-titer ≥200 Bethesda Units (BU)/mL (LD-ITI-IS200 regimen) and LD-ITI combining with IS when SHA patients had inhibitor-titer ≥40 BU/mL (LD-ITI-IS40 regimen). To compare the efficacy of the LD-ITI-IS200 regimen with that of the LD-ITI-IS40 regimen for SHA patients with high-titer inhibitors. A prospective cohort study on patients receiving LD-ITI-IS200 compared to those receiving LD-ITI-IS40 from January 2021 to December 2023. Both received LD-ITI [FVIII 50 IU/kg every other day]. IS (rituximab + prednisone) was added when peak inhibitor tier ≥200 BU/mL in the LD-ITI-IS200 regimen and ≥40 BU/mL in the LD-ITI-IS40 regimen. Success is defined as a negative inhibitor plus FVIII recovery ≥66% of the expected. We enrolled 30 patients on LD-ITI-IS200 and 64 patients on LD-ITI-IS40, with similar baseline clinical characteristics. A lower IS-use rate was discovered in the LD-ITI-IS200 regimen compared to the LD-ITI-IS40 regimen (30.0% vs. 62.5%). The two regimens (LD-ITI-IS200 vs. LD-ITI-IS40) had similar success rate (70.0% vs. 79.7%), median time to success (9.4 vs. 10.6 months), and annualized bleeding rate during ITI (3.7 vs. 2.8). The cost to success was lower for LD-ITI-IS200 than for LD-ITI-IS40 (2107 vs. 3256 US Dollar/kg). Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS200 regimen) and 28 IS-using (on LD-ITI-IS40 regimen) had similar success rates (70.0% vs. 78.6%) and time to success (9.0 vs. 8.8 months). In LD-ITI, IS are not necessary for inhibitor titer <200 BU/mL.

Chinese Severe Hemophilia a Children with High-Titer Inhibitors Obtain More Benefit from Intermediate-Dose Immune Tolerance Induction: The Interim Result of Lome Part a

Background We previously showed that low-dose immune tolerance induction (LD-ITI) strategy [incorporating immunosuppressants (IS) partially] for severe hemophilia A (SHA) patients with high-titer inhibitors (HTI) had relatively equivalent success rate with lower cost compared to those on high-dose ITI from international (I)-ITI randomized clinical trial (RCT). However, it is lack of RCT to compare the efficacy, safety, and cost of LD-ITI strategy to higher-dose ITI [intermediate-dose (MD)-ITI] strategy in China. Currently, the domestic recombinant FVIII (rFVIII) sponsored by the SinoCelltech Ltd., provides an opportunity to conduct the LOME study: a multicenter controlled randomized clinical trial of LOw- versus InterMEdiate-dose immune tolerance induction with recombinant factor VIII in China, to answer this question. Objectives Conduct the RCT to compare the efficacy, safety and cost of LD- to MD-ITI strategy using rFVIII (Omfiloctocog alfa, SCT800) for SHA children with HTI in China. Methods A perspective, multicenter RCT, enrolled SHA children ≤8year-old at enrollment, with peak historical inhibitor-titer 5 - 200 Bethesda Unit (BU)/mL, 1:1 randomized in LD- (Omfiloctocog alfa, rFVIII 50 IU/kg once-every-day) or MD- (Omfiloctocog alfa, rFVIII 100IU/kg/day) ITI group. IS was added (the initial regimen) in patients who met the criteria as follows: (i) the inhibitor titer during ITI increased to ≥200 BU/mL; (ii) the peak titer did not appear within 3 months after ITI-start; (iii) inadequate reduction (&amp;lt;20%) in titer over 6 months. Success: negative inhibitor titer twice consecutively at least 4 weeks apart and FVIII recovery ≥66% of expected within 24 months of treatment. Partial success: negative inhibitor titer twice consecutively at least 4 weeks apart, but with persistently abnormal FVIII recovery. Average consumption cost (per kg body weight) was calculated based on the median number of treatment doses consumed to achieve success. This included the cost of rFVIII and rituximab for ITI, PCC and rFVIIa for treatment of breakthrough bleeding, and IVIG for infection prevention in IS patients. The rituximab and IVIG were calculated based on the actual IS-using rate in 2 groups. Additionally, PCC and rFVIIa were calculated based on the actual using-rate in all breakthrough bleedings. Trial registration number: ChiCTR2200056603. This was the interim analysis. The first participant was enrolled on March 2022. Results Total 31 patients (16 in MD-, 15 in LD-ITI group) from 3 hemophilia centers with median followed-up 9 months since ITI-start (Table 1). A total 26 (83.9%) patients underwent peripherally inserted central catheter (PICC) (14 in MD-, 12 in LD-ITI group). A total 10 (32.3%, 2 in MD-, and 8 in LD-ITI group) patients received IS at median 2.9 months since ITI-start. Among them, 6 patients added IS because of inhibitor titer ≥200BU/mL during ITI, and the rest for delayed-occurred peak-titer or unsatisfactory decrease of titer. The MD- and LD-ITI group achieved similar success rate (75% vs. 40%). None success patients relapsed over a median follow-up period of 5.1 months since achieving success. The Kaplan-Meier curves demonstrated that patients in MD-ITI group had significantly shorter time to success (median, 2.9 months vs. 9.0 months), and partial success (2.4 months vs. 5.7 months). (Figure 1A and Figure 1B) Patients in MD-ITI group had lower mean bleeding rate (bleedings/month) (0.38 vs. 1.40) and joint bleeding rate (0.11 vs. 0.83) before achieving partial success, compared with those in LD-ITI group (Figure 1C and Figure 1D). But during the phase from achieving partial success to achieving success, the 2 groups had similar bleeding rate (0.09 vs. 0.11) and joint bleeding rate (0.07 vs. 0.16). A total 6 (23.1%) patients occurred PICC-related complications (5 in MD-, 1 in LD-ITI group) with mean follow-up period of 270 days. All complications including infection (1 person-time), thrombosis (1 person-time), rashes (3 person-time), accidental detachment (3 person-time). Similar per kg treatment cost from ITI-start to ITI success was found in 2 groups (US$ 2905.18 vs. US$ 2838.23). Conclusions Similar success rate was found in LD-ITI (rFVIII) strategy and MD-ITI (rFVIII) strategy for SHA children with HTI. On the premise of similar cost, shorter time to success, less bleedings were observed in MD-ITI strategy. PICC implantation is a safe option to conduct ITI.

Low-Dose Immune Tolerance Induction Therapy for Severe Hemophilia a Inhibitor Patients: Immunosuppressants Improve Outcomes but Are Generally Not Necessary for Inhibitor-Titer below 200 BU/Ml

Background We previously showed that low-dose immune tolerance induction (ITI) incorporating immunosuppressants (IS) for severe hemophilia A patients with inhibitor titer ≥40 Bethesda Units (BU)/mL (LD-ITI-IS 40 regimen) had relatively high success rate with lower cost compared to those on high-dose ITI. Recent evidence suggested that patients with inhibitor titer &amp;lt;200 BU/mL do not need high-dose ITI raising the question that IS may also not be necessary. Objectives To compare the efficacy of LD-ITI incorporating IS only for inhibitor titer ≥200 BU/mL (LD-ITI-IS 200 regimen) with that of LD-ITI-IS 40 regimen. Methods A prospective, single-arm, single-center cohort study on patients receiving LD-ITI-IS 200 beginning 2021, compared to those receiving LD-ITI-IS 40 before 2021. The inclusion criteria were: (i) patients with an established diagnosis of SHA [FVIII clotting activity (FVIII: C) &amp;lt;1% before inhibitor development]; (ii) patients ≤14 years age at the ITI-start; (iii) patients with high-titer inhibitors (≥5BU/mL). All study patients received a LD-ITI with pd-FVIII/VWF (at 50 FVIII IU/kg) every-other-day. IS (rituximab + prednisone) were added for peak inhibitor-tier ≥40 BU/mL in LD-ITI-IS 40 regimen and ≥200 BU/mL in LD-ITI-IS 200 regimen. IS used for each regimen included rituximab 375 mg/m 2/week (maximum 600 mg) for 4 weeks, together with prednisone 2 mg/kg/day (maximum 60 mg) for one month, then tapered over 3 months. For patients receiving rituximab, intravenous immunoglobulin (200 mg/kg/month for 6 months) was administered for infection prophylaxis. Success is defined as negative inhibitor plus FVIII recovery ≥66% of the expected. Partial success is defined as achieving inhibitor elimination but with persistently abnormal FVIII recovery. Results We enrolled 30 patients on LD-ITI-IS 200 and 64 patients on LD-ITI-IS 40, with similar baseline clinical characteristics (Table 1). Given that IS was initiated at a higher peak inhibitor-titer in the LD-ITI-IS 200 regimen, IS in the LD-ITI-IS 200 group was introduced at a significantly lower rate than that in the LD-ITI-IS 40 regimen group (30% vs. 62.5%, p = 0.003). The 2 regimens (LD-ITI-IS 200 vs.LD-ITI-IS 40) had similar success rate (66.7% vs. 79.7%), median time to success (7.4 vs. 10.6 months) (Figure 1), and ABR during ITI (3.7 vs. 2.8). The per kg treatment cost from ITI-start to ITI success in the LD-ITI-IS 200 (US$2167) was significantly lower than that in the LD-ITI-IS 40 (US$3349). Among patients taking IS in the two regimens rituximab infusion-related side effects were similar, being 22.2% (2/9) for the LD-ITI-IS 200 patients and 22.5% (9/40) for the LD-ITI-IS 40 patients. All these side effects could be resolved and subsequently prevented by antihistamine drugs. No severe adverse events occurred. Among patients with peak inhibitor-titer 40-199 BU/mL, 10 non-IS-using (on LD-ITI-IS 200 regimen) and 28 IS-using (on LD-ITI-IS 40 regimen) had similar success rate (60% vs. 78.6%) and time to success (9.0 vs. 8.8 months). The per kg treatment cost from ITI-start to ITI partial success in the LD-ITI-IS 200 (US$891) was significantly lower than that in the LD-ITI-IS 40 (US$2819). Between the two protocols, there were 12 patients with peak inhibitor-titer ≥200BU/mL (all using IS, 7 in LD-ITI-IS 200, 5 in LD-ITI-IS 40). Among them, 8 patients (66.7%, 4 on each regimen) achieved success over a median 10.1 months, and none relapsed at median 13.5 months follow-up since achieving success. Between the 2 protocols, there were 44 patients (13 in LD-ITI-IS 200, 31 in LD-ITI-IS 40) with peak inhibitor-titer 5-39 BU/mL. Their overall success rate was 79.5%. Nine of the 44 patients (2 in LD-ITI-IS 200, 7 in the LD-ITI-IS 40) received IS because they failed to have adequate inhibitor titer decline in the first 3 months of ITI. All 9 achieved success at median 11.3 months from ITI-start with no relapsed after a median 22.6 months follow-up since success. Conclusions We have optimized the use of IS in our low-dose ITI protocol for SHA patients with high-titer inhibitors. We showed that more restrictive use of IS only for patients with peak inhibitor-titer ≥200 BU (instead of at a lower titer of ≥40 BU) maintained the same efficacy while decreasing the cost. Decreasing use of IS would decrease its potential side effects including infection risks.

PB0658 Low-Dose Immune Tolerance Induction in Patients with Hemophilia A and Inhibitor Receiving Emicizumab Prophylaxis: Preliminary Results of the Brazilian Experience

PB0658 Low-Dose Immune Tolerance Induction in Patients with Hemophilia A and Inhibitor Receiving Emicizumab Prophylaxis: Preliminary Results of the Brazilian Experience

Early immune tolerance induction is a unique predictor of favorable outcomes in hemophilia A children with intron 22 inversion and high-responding inhibitors

BackgroundThe predictors of immune tolerance induction (ITI) outcomes in hemophilia A (HA) patients with the same F8 genetic background have not yet been evaluated, although the F8 genotype is strongly associated with ITI response. This study aims to explore the predictors of ITI outcomes in the same F8 genetic background by focusing on intron 22 inversion (Inv22) patients with high-responding inhibitors. MethodsHA children with Inv22 and high-responding inhibitors who received low-dose ITI therapy over 24 months were included in this study. ITI outcomes were centrally assessed at the 24th month of treatment. The predictive ability of clinical variables to identify ITI success was determined using the receiver operating characteristic (ROC) curve, and the predictor of ITI outcomes was analyzed on the multivariable Cox model. ResultsAmong the 32 patients investigated, 23 (71.9 %) achieved success. In univariate analysis, interval time from inhibitor diagnosis to ITI start (interval-time) was significantly associated with ITI success (P = 0.001); however, inhibitor titers showed no significance (P > 0.05). The interval-time demonstrated a good predictive value for ITI success with the area under the ROC curve of 0.855 (P = 0.002), and the cutoff value was 25.8 months (sensitivity, 87.0 %; specificity, 88.9 %). In the multivariable Cox model which considered success rate and time to success, interval-time was the only independent predictor (<25.8 months vs. ≥25.8 months, P = 0.002). ConclusionsThe interval-time was first identified as a unique predictor of ITI outcomes in HA patients with high-responding inhibitors under the same F8 genetic background (Inv22). An interval-time of <25.8 months was associated with increased ITI success and reduced time to success.

Low-dose immune tolerance induction therapy in severe hemophilia a children in China: Starting earlier resulted in better inhibitor eradication outcomes

BackgroundShorter 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. ObjectivesTo explore the relationship between interval-time and low-dose ITI outcomes in Chinese SHA children with high-risk-inhibitors. MethodsThis 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. ResultsAmong 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. ConclusionsInterval-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.

Shorter Time Interval from Inhibitor Detection to Starting Low-Dose Immune Tolerance Induction Therapy Is Associated with Better Inhibitor Eradication Outcomes in Severe Hemophilia a Children with High-Titer Inhibitors in China

Background Shorter time from inhibitor detection to immune tolerance induction (ITI) start (interval-time) might play a critical role in ITI outcomes for severe Hemophilia A (SHA) children with high-titer inhibitors. However, the acceptable interval-time hasn't well been confirmed yet, especially for treatment-delay patients undergoing low-dose ITI therapy in China. Aim To explore the interval-time in Chinese SHA children with high-titer inhibitors, undergoing low-dose ITI strategy with outcomes. Methods A retrospective study in single center, 47 Chinese SHA children with high-titer inhibitors [> 10 Bethesda Unite (BU)/ml] undergoing low-dose ITI strategy with more than 24 months follow-up period. ITI outcomes were evaluated at the 24th month of treatment. The association between interval-time and outcomes was analyzed. Success was defined as negative inhibitor titer and FVIII recovery ≥ 66% of expected. The predictive ability of interval-time to identify ITI success was determined using receiver operating characteristic (ROC) curve. Results Forty-seven cases enrolled in this study, the median age of inhibitor detection was 2.4 (range, 0.6, 10.4) years and the interval-time was 5.8 (0, 61.1) months with the peak inhibitor titer of 55.8 (10.1, 512.0) BU/ml, 42.6% (20/47) using ITI-alone and 57.4% using ITI combined with Rituximab based immunosuppression (IS). Over a follow-up time of 31.3 (24.0, 69.5) months, 34 patients (72.3%) achieved success with the time to success of 11.0 (3.1, 23.0) months. (Table 1) The interval-time in ITI success group was shorter than in non-success group significantly [2.8 (0. 59.1) vs 28.1 (0, 61.1) months, p = 0.04]. Multivariate logistic regression model demonstrated the peak inhibitor titer and the interval-time were two independent predictors of ITI success (P < 0.05). The area under ROC curve (AUC) was 0.701 (95%CI: 0.507 - 0.896, p = 0.034) and reliable cut-off value of 22.3 months could be calculated in the prediction of ITI outcomes with the sensitivity of 0.853 and the specificity of 0.615. (Figure 1) Univariable linear regression demonstrated the relationship between the time to success and the interval-time, the equation y=0.1552*x+9.285 (R2 = 0.2252, p = 0.005). ROC curve describing the accuracy of the predictor of early-success (ITI time < 12 months); the AUC was 0.704 (95%CI: 0.521 - 0.887, p = 0.049); the cut-off value was 9.4 months with the sensitivity of 0.824 and the specificity of 0.533. (Figure 1) Conclusions Our study shows that shorter interval-time was associated with better inhibitor eradication outcomes in terms of ITI success rate and time to success in our SHA children with high-titer inhibitors (> 10BU/ml) undergoing low-dose ITI strategy. We showed that an interval-time of ≤ 22.3 months was associated with higher ITI success rate. And an interval-time of ≤ 9.4 months was related to shorter time to success. Our study on low-dose ITI in a developing country setting support the findings using higher dose ITI in developed countries setting that ITI should be started as soon as possible after inhibitor development. However, stronger evidence is needed from further clinical studies with better study design. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Factor IX inhibitors in haemophilia B: A report of National Haemophilia Registry in China.

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

Eradication of FIX inhibitor in haemophilia B children using low‐dose immune tolerance induction with rituximab‐based immunosuppressive agent(s) in China

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

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.

Immune tolerance induction in severe haemophilia A: A UKHCDO inhibitor and paediatric working party consensus update.

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

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.

Estimating the Cost Savings and Cost Effectiveness of Low Dose Immune Tolerance Induction (ITI) Therapy with Bypassing Agent Prophylaxis Compared to High Dose ITI and Low Dose ITI

Introduction: The International Immune Tolerance Study (I-ITI) demonstrated comparable success rates between low (FVIII 50 IU/kg/TIW) and high dose (FVIII 200 IU/kg/day) ITI regimens for hemophilia A patients with high-titer inhibitors. While costlier, the high dose ITI regimen was associated with shorter time-to-treatment success and with fewer bleeding episodes compared to the low dose ITI regimen. Kenet (2017) estimated that adding aPCC prophylaxis to a low dose ITI regimen may be cost saving to achieve negative titer compared to high dose ITI, while achieving comparable bleeding outcomes. Low dose ITI is certainly the least costly treatment option; however, due to increased bleeds in this arm, many treaters are now using low dose ITI with bypassing-agent prophylaxis (BAP). The choice of which ITI regimen to use is enhanced by a cost effectiveness analysis (CEA) comparing the cost and clinical outcomes of low dose ITI with and without BAP.Methods: An economic model was developed to compare all three regimens: high dose ITI, low dose ITI and low dose ITI with BAP. All model inputs were derived from clinical trials. In the I-ITI study, patients on the high and low dose regimens were treated for a median of 4.6/6.9/10.6 versus 9.2/13.6/15.5 months, respectively, until achieving negative inhibitor titer/first normal recovery/tolerance, and experienced an average of 0.28/0.09/0.03 versus 0.62/0.13/0.15 bleeds/month, respectively, in each phase. Based on the BAP trials, the addition of aPCC (85 U/kg/TIW) and rFVIIa (90 μg/kg/day) achieved a 62% and 45% reduction in bleeding frequency, respectively. The CEA is based on a Markov model structure and simulates costs and outcomes for each treatment regimen over three years to allow for the average patient to complete ITI and achieve tolerance on either regimen. The analysis uses US third party payer perspective, applies a 3% discount rate, and regimen costs are limited to drug costs. One-way and probabilistic sensitivity analyses were performed.Results: The estimated treatment costs over three years were $216,024, $57,366, and $30,506 per kilogram body weight for high dose ITI, low dose ITI with aPCC prophylaxis, and low dose ITI alone, respectively. The estimated number of bleeds that occur with each regimen over three years were 3.9, 6.1, and 10.9, respectively.Adding aPCC prophylaxis to a low dose ITI regimen was estimated to prevent 4.8 bleeds and cost $5,642 per kg per bleed avoided relative to low dose ITI alone in the base case. The addition of rFVIIa prophylaxis to low dose ITI also improved bleeding with a higher cost; however, compared to aPCC prophylaxis, low dose ITI with rFVIIa prophylaxis was associated with higher cost, and less improvement in outcomes. Model results were robust in the majority of sensitivity analyses performed. Given the addition of aPCC prophylaxis is expected to reduce the risk of bleeding during ITI, this may improve the time to negative titer, and thus further lower the cost per bleed, i.e. a 50% reduction in time to negative titer results in a 52.8% reduction in cost per bleed avoided due to aPCC prophylaxis.Conclusion: A low dose ITI regimen with aPCC prophylaxis may be cost saving compared to a high dose ITI regimen, with a comparable risk for breakthrough bleeds. While more costly than low dose ITI alone, adding aPCC prophylaxis to a low dose ITI regimen may be a cost-effective option to control bleeding during ITI, especially if the addition of aPCC prophylaxis leads to a subsequent reduction in the length of time until a negative titer is achieved. DisclosuresKenet:Alnylam: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Opko biologics: Consultancy, Research Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Membership on an entity's Board of Directors or advisory committees. Oladapo:Shire: Employment. Epstein:Shire: Consultancy. Christin:Shire: Consultancy. Novack:Shire: Employment, Equity Ownership. Nugent:Genentech: Consultancy; Novo Nordisk: Consultancy; Shire: Consultancy; Bayer: Consultancy.

Immun Tolerance Induction in Hemophilia with Inhibitors: Istanbul Experience

Introduction: The development of inhibitors against factor VIII or IX is the most serious complication in hemophilia, occurring in approximately 30% and 5% of severe hemophilia A and B patients, respectively. Management of hemophilia with inhibitors presents certain challenges. The best treatment strategy for inhibitor eradication is immune tolerance induction (ITI). The aim of this study was to evaluate patients who were treated by ITI at our center.Material-Method: A retrospective data collection and analysis of patients were obtained. Data from all subjects with Hemophilia A with inhibitors undergoing ITI between 1999 and 2017 were collected from Istanbul University Hemophilia Centre.Results: Fifteen patients with severe Hemophilia A were enrolled in the study of whom 13 were eligible for analysis. After the exclusion of ineffective ITI treatments, median age of the beginning ITI was 10 years old (range:1,25-52), median maximum inhibitor titer before ITI was 30 BU (range:4.48-135) and during ITI was 3,4 BU (range:0-158.7). Median inhibitor titre was 1.25 BU (range:0-5.6) at the beginning of ITI. Median time interval between inhibitor development and starting of ITI was 5 years (range:0.58-22). In totally, 4 of the 12 patients (33.3%) had complete response, 2 of 12 (16.6%) had partial response and 2 of 12 (16.6%) had decreasing of inhibitor titer and ITI is going on. Four of the 12 patients (33.3%) had failure of ITI.Conclusion: Management of hemophilia with inhibitors presents certain challenges. Immun tolerance induction is the best treatment model. But high-dose daily regimen ITI could not be given in Turkey due to high cost of treatment. Our results showed that low dose ITI could be a choice for patients with inhibitors. DisclosuresNo relevant conflicts of interest to declare.

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.

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).

Low-Dose Immune Tolerance Induction for Hemophilia a Children with Poor-Risk High-Titer Inhibitors

Background: Low-dose immune tolerance induction (ITI) +/- immunosuppression as a practical ITI strategy in China showed a relatively satisfactory success rate and economic advantages in pilot study. However, the outcome still needs to be verified by larger cohort. Aim: To report the efficacy of this low-dose ITI +/- immunosuppression strategy in hemophilia A children ≥ 10 BU. Methods: This was a single center, prospective study in 53 hemophilia A subjects from Sep 2016 to Apr 2019. All subjects having ≥ 10 BU receiving ~50IU/kg FVIII every other day using domestic intermediate purity pdFVIII/VWF products, either alone or in combination with rituximab and prednisone judging by inhibitors and ITI response. Results: Finally, 46 subjects received this strategy at a median of 3.2 (IQR, 2.3-6.5) years old, their pre-ITI inhibitor titer was median 30.0 (range, 10.1-416) BU. Analysis at median 15.1 (range 3.0-34.4) months follow-up, success (inhibitor &lt;0.6BU) was achieved in 32 (69.6%) subjects, partial success (inhibitor &lt;5BU but &gt;0.6BU) in 11 (23.9%) subjects, and failure in 5 (10.9%) subjects. Between subjects administered ITI-alone and ITI- immunosuppression, no significant difference was observed in time to success (median 8.5; IQR 6.7-11.7 vs 10.2; IQR 5.1-25.1, P=0.164). The mean monthly bleeding rate on ITI was 0.49 which declined 59.3% compared with pre-ITI period. Subjects administered ITI-immunosuppression (0.54 ± 0.46) was higher than ITI-alone (0.42 ± 0.69) although with no significantly difference (P=0.089). Seven (21.9%) subjects experienced inhibitor recurrence, 4 subjects treated with ITI-alone, 3 with ITI-immunosuppression. Recurrence occurred at a median of 4.8 (range, 2.8-10.8) months after successful ITI with inhibitor titer transiently rising to median 0.7 (range, 0.7-1.5) BU. Conclusion: This low-dose ITI +/- immunosuppression therapy in subjects with pre-ITI inhibitor ≥ 10 BU showed a success rate similar to other high/intermediate-dose regimen for the whole inhibitor patients. The subjects treated with ITI-immunosuppression did not showed higher recurrence at present, while a longer time follow-up is still needed. Disclosures Poon: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bioverativ/Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; World Federation of Hemophilia: Other: Not-for-profit organization affiliation: volunteer ; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participation in sponsored research; CSL-Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Grant Funding; Takeda/Shire: Consultancy, Membership on an entity's Board of Directors or advisory committees; Octapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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.

Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B.

The occurrence of factor inhibitory antibodies, or inhibitors, is a significant complication in the care of individuals with congenital haemophilia A or B. Currently, immune tolerance induction is the only known intervention to successfully eradicate inhibitors. However, ideal dosing regimens, and the comparative safety and efficacy of different immune tolerance induction regimens have not yet been established. The objective of this review was to assess the effects of immune tolerance induction (different protocols of this therapy versus each other, or versus only bypassing agents) for treating inhibitors in people with congenital haemophilia A or B. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched: MEDLINE (from 1946 to 15 July 2013); Embase (from 1980 to 15 July 2013) via the OVID platform; CINAHL (from conception to 15 July 2013); and ClinicalTrials.gov (most recent search: 15 July 2013). We also searched the reference lists of relevant articles and reviews. Randomised controlled trials comparing either different immune tolerance induction regimens or immune tolerance induction versus only bypassing therapy for the eradication of factor inhibitory antibodies in patients with congenital haemophilia A or B. Two review authors independently completed data collection, extraction and assessment of the risk of bias of trials. One methodologically sound randomised controlled trial met the inclusion criteria and was included in the review. One further randomised controlled trial has been recently stopped, but it has not yet been reported.The included multinational trial randomised 115 paediatric participants with severe haemophilia A and high-responding inhibitors, for whom this was the first attempt at immune tolerance induction, to receive either a low dose (50 IU/kg of factor VIII concentrate three times per week) or a high dose (200 IU/kg of factor VIII daily). Although, there was no statistically significant difference in the success of immune tolerance induction between treatment arms, the confidence intervals were too wide to infer no effect: 24 out of 58 participants (46.6%) in the low-dose group and 22 out of 57 (38.6%) in the high-dose group experiencing full tolerance, risk ratio 1.07 (95% CI 0.68 to 1.68) (moderate quality evidence). The rate of infection was not statistically different between groups, but again confidence intervals were too wide. Of those patients who had a central venous catheter device, 19 out of 47 participants (40.4%) in the low-dose arm had 69 infections, and 22 out of 52 participants (42.3%) in the high-dose arm had 55 infections, risk ratio 0.96 (95% CI 0.60 to 1.53) (moderate quality evidence). However, participants in the low-dose immune tolerance induction group experienced significantly more bleeding episodes (50 out of 58 participants (86.2%) experienced one or more bleeding events) than those in the high-dose group (36 out of 57 participants (63.1%) experienced one or more bleeding events), risk ratio 1.36 (95% CI 1.09 to 1.71) (low quality evidence). One factor VIII reaction, one incidence of trauma and 13 incidences of needing to insert or remove the catheter were reported as trial-related serious adverse events; however, the treatment group where these events occurred was not specified. No incidence of nephrotic syndrome was reported. We did not find any randomised controlled trial-based comparison of immune tolerance induction with alternate treatment schemes (i.e. bypassing agents for bleeding only). In a single randomised trial, there were no significant differences in the immune tolerance induction success rate between different dosing regimens, which may have been due to imprecision of the estimate. There is low-quality evidence to suggest that high-dose immune tolerance induction may induce tolerance more quickly which is associated with fewer bleeding complications. The choice of immune tolerance induction regimen should be considered individually for each case, until further research provides additional evidence.