Start Of Immune Tolerance Induction Research Articles

Native American Ancestry Is Associated with Successful Immune Tolerance Induction in Admixed Brazilians with Hemophilia a

Immune tolerance induction (ITI) is the treatment of choice for eradicating neutralizing antibodies (inhibitors) against factor VIII (FVIII) in patients with hemophilia A (PwHA). Previous studies have investigated the association of ethnicity with inhibitor development with conflicting results. However, to our concern, studies targeting the role of ethnicity on ITI outcomes are still missing. Since unfavorable ITI response occurs in 30%-40% of these patients, establishing predictors of ITI response is needed. To evaluate genetic determinants of ITI outcome beyond FVIII genotype, we investigated the association of genomic ancestry and ITI response by analyzing the exomes of PwHA from the Brazilian Immune Tolerance Study (Camelo et al. 2021). PwHA were enrolled in 15 hemophilia treatment centers from all Brazilian regions. We collected clinical data and blood samples for DNA extraction. ITI was carried out using a single protocol, regardless of selection based on “good” or “bad” risk of ITI outcome. Inclusion criteria comprised patients with severe and moderately-severe (FVIII<2%) HA with high-responding inhibitors who completed a first course of ITI. Since the characteristics of PwHA who responded with partial and complete success yielded similar results, these groups were analyzed together. Exomes were obtained with high quality using the xGen Exome Research Panel v2 (Illumina). Quality control filters evaluated average coverage and deep coverage, phred score, genomic position, sex, heterozygosity, and duplicated SNPs. In a multiple regression analysis, we used geographic location, inhibitor levels, presence or absence of null mutations (i.e., frameshift, deletions, nonsense, and inversions; Oldenburg et al., 2002), and kinship coefficients as explanatory variables. Inhibitor levels were evaluated as historical inhibitor peak, titer immediately before the start of ITI, and inhibitor peak during ITI. We included 150 PwHA, of whom 136 (91%) had severe (FVIII<1%) HA, median age 0.9 years [IQR, 0.5,1.4] at diagnosis of HA. A total of 44 (29%) PwHA had ITI failure, 60 (40%) had partial success, and 46 (31%) had complete ITI success. Functional annotation showed that most SNPs were intronic (48%) and exonic (29%). We identified 808,706 variants, of which 90,075 were not reported in the dbSNP. Average ancestries of European, African, and Native American were 79.4% [IQR:75.4,83.4], 17.3% [IQR:17.0,17.6), and 3.3% [IQR:2.6,4.0], respectively (Table 1). There was an association between a higher Native American ancestry in patients with successful ITI (2% [IQR:1.95,2.05] ancestry mean) when compared with patients who failed ITI (1% [IQR:0.97,1.03] ancestry mean). A 1% increase in the Native American ancestry proportion was associated with a rise of ~10% in the probability of successful ITI ( odds ratio [OR], 10.43 [95% CI,7.45,13.41], p = 0.040 (Table 2). Neither European nor African ancestry was associated with ITI outcome. In conclusion, Native American ancestry was associated with successful ITI. To our concern, this is the first study to evaluate genomic ancestry as a predictor of ITI response and the first to enroll an admixed population of HA. Identifying ancestry as a predictor of ITI outcome may elicit different therapeutic approaches for inhibitor eradication. However, our findings may not apply to other populations due to a particular characteristic of admixture of the Brazilian population. REFERENCES Camelo, R.M. et al. (2021) ‘Predictors of the outcome of immune tolerance induction in patients with haemophilia A and inhibitors: The Brazilian Immune Tolerance (BRAZIT) study protocol’, PLOS ONE, 16(8). doi:10.1371/journal.pone.0256265. Oldenburg, J., El-Maarri, O. and Schwaab, R. (2002) ‘Inhibitor development in correlation to factor VIII genotypes’, Haemophilia, 8(s2), pp. 23-29. doi:10.1046/j.1351-8216.2001.00134.x.

Large Deletion in the Factor VIII Gene Is a Predictor of Immune Tolerance Induction Failure in People with Severe and Moderately-Severe Hemophilia a and High-Responding Inhibitors

Introduction Immune tolerance induction (ITI) is a therapeutic approach to eradicate inhibitors against factor VIII (FVIII) in people with inherited hemophilia A (PwHA). The success of ITI is highly variable, ranging from 60% to 80% across studies. Beyond inhibitor titers, other predictors of ITI outcome are unknown. Deleterious variants in FVIII gene ( F8) are well established risk factors for alloantibodies development in PwHA, although few studies have investigated the role of F8 variants on ITI outcome.Therefore we aimed to comprehensively analyze the association of F8 pathogenic variants on ITI outcome in severe PwHA with high-responding inhibitors. Methods We included severe (FVIII < 1 international units [IU]/dL) and moderately-severe (FVIII 1-2 IU/dL) unrelated PwHA and high-responding inhibitors who completed ITI from a large, admixed population of two well-characterized cohorts - the HEMFIL and the Brazilian Immune Tolerance (BrazIT) studies. We collected socio-demographic, clinical and laboratory data. ITI outcomes were defined according to previous definitions as failure, partial and total successes. Inversions of intron 1 and 22 (Inv22) were detected by polymerase chain reaction (PCR), and high-throughput sequencing approaches were used to unveil the additional F8 variants. The association between F8 pathogenic variants and ITI outcome was adjusted for inhibitor levels. To investigate whether F8 variants associated with inhibitor development were also related to ITI outcome, variants were categorized as “high-risk”, “intermediate-risk”, and “low-risk” categories. These categories for inhibitor development were then compared with the outcomes of ITI (total and partial successes and failure) using data from this study. Results We included158 PwHA, median age 6.6 years at ITI start, 90.5% were severe (Table 1). Inv22 was the most prevalent variant (55.1%) (Table 1). In comparison with Inv22-1, the risk of ITI failure was about 9 times higher (adjusted odds ratio [adjOR] 9.29; 95% confidence interval [95% CI] 1.95-53.70) among carriers of large deletions (Table 2). Conversely, Inv22-2 was associated with favorable ITI outcome in a univariate analysis (OR 0.15; 0.01-0.84), and after adjustment (adjOR 0.32; 95% CI 0.02-1.96) (Table 2). F8 deleterious variants sorted as high-risk and intermediate-risk according to a previously published classification on inhibitor development were associated with failure and successful outcomes, respectively. Conclusion Our study showed that F8 large deletions are independent predictors of ITI failure, and Inv22-2 is likely to be a predictor of successful ITI. We found a correspondence between variants classified as high-risk and intermediate-risk to inhibitor development with ITI failure and success, respectively. We suggest that F8 genotyping should be considered before indication of ITI, as ITI outcome can vary according to individual variant burden.

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.

Protocol and Primary Analysis of Lome: A Randomized Trial of Low- Versus Intermediate-Dose Immune Tolerance Induction with Recombinant Factor VIII (Omfiloctocog alfa, SCT800) in China

Background: Although the cohort and registry data support low-dose (LD; 50 IU/kg once every other day) and intermediate-dose (MD; 100 IU/kg daily) immune tolerance induction (ITI) are almost equally effective in inducing tolerance in people with severe hemophilia A, with inhibitors (PwHI)1-3, there has been no prospective randomized trials, especially in China. Here, we present the protocol and results of the primary analysis in LOME (ChiCTR2200056603). Methods LOME is a multicenter, prospective, randomized comparison of LD and MD ITI, in severe hemophilia A (HA) patients (FVIII level < 1%) with peak historical inhibitor ≥ 5 and < 200 Bethesda Unite (BU/ml). In the first year of recruitment (Part A), patients with age ≤ 8 years at time of randomized will be included. In the second year of recruitment (Part B), patients with age ≤ 12 years at time of randomized will be included. Patients have received ITI therapy before randomization will be excluded. Subjects were randomized 1:1 to LD or MD ITI with the first domestic recombinant factor VIII (rFVIII) (Omfiloctocog alfa, SCT800) approved in China. Factor III (FVIII) inhibitor screening, ITI monitoring and dose tapering will be based on the consensus from United Kingdom Hemophilia Center Doctors' Organization (UKHCDO)4. If (a) there is an upward trend in titer over 3-6 months period; or (b) fall in chromogenic Bethesda titer of less than 20% in 6 months period after initial peak inhibitor titer; or (c) titer ≥ 200BU/ml during ITI therapy; or (d) spontaneous bleeding > 1 monthly over 3-6 months period, modify the regimen as below: In the LD arm, increase to 100IU/kg daily;In the MD arm, rituximab 375 mg/m2 weekly × 4 weeks (maximum 600 mg) and prednisone 2 mg/kg daily × 1 month (maximum 60 mg, tapering over 3 months) would be added. Once the patient had achieved Success, taper dose as below: In the LD arm, the FVIII dose would be reduced slowly to 25IU/kg three times a week for continuing prophylaxis;In the MD arm, the FVIII dose would be reduced slowly to LD ITI, then same as LD arm. The primary endpoints are ITI outcomes (Success: negative inhibitor titer and FVIII recovery ≥ 66% of expected) and the time taken to ITI Success, in PwHI with LD ITI compared to those with MD ITI. Key secondary endpoints include annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) for any bleeds and treated bleeds; joint and bone health assessed by Hemophilia Joint Health Score 2.0 (HJHS 2.0) and ultrasound; quality of life measured by the Canadian Hemophilia Outcomes-Kids Life Assessment Tool 2.0 (CHO-KLAT 2.0) and numbers of days out of school; average consumption cost (per kg body weight) was calculated based on the intermediate number of treatment doses consumed to achieve Success. This included the cost of rFVIII and rituximab for ITI, prothrombin complex concentrate (PCC) or recombinant activated factor VII (rFVIIa) for treatment of breakthrough bleed, and intravenous immunoglobulin (IVIG) for infection prevention in patients receiving immunosuppressants. Safety was also a secondary endpoint. Results: Ten subjects were randomized into the study with median follow-up time of 1.64 [range (minimum, maximum), 0.23, 3.91] months in LD arm, and 2.66 (0.26,3.91) months in MD arm. Baseline includes age at time of randomized, age of inhibitor detection, exposure days before inhibitor detection, initial inhibitor titer, inhibitor titer at start of ITI and so on, between two arms are summarized in Table 1. Twenty percent (1/5) in MD arm achieved Success after 7 weeks of treatment and still maintained until the latest follow-up. No one achieved Success in LD arm. The bleeds between the treatment arms are summarized in Table 2. Nearly 2-fold difference in mean ABR and AJBR for treated bleeds, between treatment arms, and 3- to 4-fold in ABR and AJBR for any bleeds. Conclusions: It is planned to enroll 40 patients in Part A and 60 patients in Part B, who will be followed for up to 2 years. The study is ongoing and, currently, 10/40 (25%, in Part A) PwHI from 4 HTCs have been included. LOME study is the first, multicenter, prospective, randomized trial of LD vs MD ITI with domestic rFVIII (Omfiloctocog alfa, SCT800) in Chinese PwHI. This study is likely to contribute with the choice of optimal ITI regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Time between inhibitor detection and start of immune tolerance induction: Association with outcome in the BrazIT study

BackgroundImmune tolerance induction (ITI) is the treatment of choice for eradication of anti‐factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high‐responding inhibitor (PwHA‐HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI (∆tinhi‐ITI) is debatable. ObjectiveThe aim of this study was to evaluate this association among a large cohort of severe PwHA‐HRi. MethodsSevere (factor VIII activity level <1%) PwHA‐HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA‐HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). ResultsMedian ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6–8.1) and 6.9 years [IQR, 2.6–20.1), respectively. PwHA‐HRi were stratified according to ∆tinhi‐ITI quartiles: first (0.0–0.6 year), second (>0.6–1.7 year), third (>1.7–9.2 years), and fourth quartile (>9.2–24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. ConclusionIn conclusion, delayed ITI start is not associated with failure of ITI in PwHA‐HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.

Low‐dose immune tolerance induction in children with severe hemophilia A with high‐titer inhibitors: Type of factor 8 mutation and outcomes

BackgroundNo studies evaluated the role of F8 mutations in outcomes for low‐dose immune tolerance induction (ITI) in people with severe hemophilia A (SHA) with high‐titer inhibitors. ObjectivesTo explore the association between F8 mutation types and low‐dose ITI outcomes in children with SHA with high‐titer inhibitors. MethodsChildren SHA with high‐titer inhibitors who received low‐dose ITI therapy at least for 1 year were included instudy. Based on the risk of inhibitor development, F8 mutations were classified into a high‐risk group and a non–high‐risk group. Rapid tolerance and the final ITI outcomes were assessed at the 12th and 24th month of treatment, respectively, and the predictor of outcomes was analyzed. ResultsOf 104 children included, 101 had F8 mutations identified. The children with non–high‐risk mutations presented a higher rate of rapid tolerance than those with high‐risk mutations (61.0% vs. 29.2%; p = 0.006). Among 72 children beyond 24 months of ITI, 55 children (76.4%) achieved success, 3 (4.2%) achieved partial success, and 14 (19.4%) failed. The children in the non–high‐risk group showed a higher success rate (86.8% vs. 43.8%; p = 0.001) and a shorter time to success (mean time, 9.3 months vs. 13.2 months; p = 0.04) compared to those in the high‐risk group. In multivariable logistic regression, F8 mutations were an independent predictor of ITI success (non–high‐risk group vs. high‐risk group, adjusted odds ratio [OR], 20.3; 95% confidence interval [CI], 3.5–117.8), as was the interval from inhibitor diagnosis to ITI start (adjusted OR, 0.95; 95% CI, 0.90–0.99). They remained the significant predictors when success time was taken into account in a Cox model. ConclusionsTypes of F8 mutation were a key predictor of outcomes for low‐dose ITI in children with SHA with high‐titer inhibitors. It can help to stratify the prognosis and guide clinical decisions.

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).

Immune Tolerance Induction with Simoctocog Alfa (Nuwiq®) in Six Patients with Severe Haemophilia a and FVIII Inhibitors

Introduction and Objective: Inhibitors to coagulation factor VIII (FVIII) are the most serious complication of haemophilia A treatment. Previously untreated patients (PUPs) are at the greatest risk of inhibitors, which generally occur within the first 20 exposure days (ED) to FVIII. Immune tolerance induction (ITI) is the only clinically proven strategy for eradication of inhibitors. We present a case series of six PUPs with severe haemophilia A and inhibitors who underwent ITI with simoctocog alfa (Nuwiq®), a 4th generation human cell-line-derived recombinant FVIII approved for treatment of haemophilia A.Materials and Methods: Six male PUPs with severe haemophilia A who developed FVIII inhibitors after treatment with simoctocog alfa were started on ITI with simoctocog alfa. Primarily, we assessed the success of simoctocog alfa in patients with inhibitors. Success of ITI was determined based on undetectable inhibitor titre (< 0.6 BU/ml), FVIII recovery ≥ 66% and half-life ≥ 6 hours. Secondary objectives were to assess bleeding rate, tolerability and safety in patients with inhibitors treated with simoctocog alfa ITI.Results: The age of the patients at the start of ITI ranged from 8 to 186 months. Four of the patients were Caucasian, and two were African. All patients had a F8 mutation associated with high risk of ITI failure and two patients had an additional risk factor for ITI failure. The number of EDs prior to inhibitor development ranged from 9 to 33, and the peak inhibitor titre ranged from 0.9 to 114 BU. For ITI, five patients were treated with 100 IU/kg simoctocog alfa daily, and one with 90 IU/kg every other day. One patient achieved complete tolerisation and is now on prophylaxis at normal doses, having achieved an undetectable inhibitor titre after 9 months. This was despite an inhibitor titre ≥ 10 BU/mL at ITI start, which is considered a poor prognosis factor for ITI success. Three other patients achieved an undetectable inhibitor titre after 1, 6 and 18 months of ITI, and FVIII recovery has normalised but half-life remains short and they are on weaning doses as the half-life extends. One patient discontinued ITI with simoctocog alfa after 15 months due to an increasing inhibitor level. This patient was 15 years old at ITI start, and older age is associated with poor ITI outcome. Additionally, his haemophilia A was untreated for 15 years, during which time he developed severe arthropathy. One patient, who started ITI 3 months ago, has an ongoing inhibitor titre and continues on ITI with simoctocog alfa.Conclusions: In a case series of six patients treated with simoctocog alfa for ITI, who all had poor prognosis factors for ITI success, four patients (67%) to date have achieved an undetectable inhibitor titre. These data suggest that ITI with simoctocog alfa may be an effective treatment approach in haemophilia A patients with inhibitors. DisclosuresKhair:Shire, SOBI, Pfizer, Roche, Novo Nordisk, Octapharma: Speakers Bureau; shire, SOBI, Pfizer, Roche: Research Funding. Liesner:Roche: Research Funding; Novo Nordisk: Research Funding, Speakers Bureau; Baxalta: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Octapharma: Consultancy, Other: Clinical study investigator for NuProtect Study (Octapharma sponsored), Research Funding, Speakers Bureau; Sobi: Speakers Bureau. Belyanskaya:Octapharma AG: Employment.

The Atlanta Protocol: Immune Tolerance Induction in Pediatric Patients with Hemophilia a and Inhibitors on Emicizumab

Introduction: The formation of neutralizing anti-factor VIII (fVIII) antibodies, called inhibitors, is a challenging complication in hemophilia A care. While novel non-factor therapies significantly reduce bleeding symptoms in patients with hemophilia A and inhibitors, the absence of fVIII tolerance remains unchanged. Additionally, there are concerns regarding the hemostatic efficacy and safety of bypassing agents necessary for the management of breakthrough bleeds in patients with inhibitors on these novel therapies. Immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII. Here we report on the response to ITI in pediatric patients following initiation of the bispecific humanized monoclonal antibody Emicizumab.Methods: Patients between the ages of 1 - 11 years old with hemophilia A and an active inhibitor (≥0.6 Bethesda Units (BU)/mL) treated at the Emory Pediatric Hemophilia Treatment Center were included in this analysis. In general, ITI was initiated after four weekly loading doses of Emicizumab with standard or extended half-life recombinant (rfVIII) or plasma-derived (pdfVIII) fVIII at 100 units/kg three times per week. Factor choice was determined by the fVIII product used for the ITI attempt prior to initiation of Emicizumab or a standard half-life third generation rfVIII product if no prior ITI attempts. FVIII pharmacokinetics during ITI including the estimated fVIII half-life, fVIII incremental recovery of expected, and inhibitor titers were measured with chromogenic-based assays using bovine reagents. Bleeding symptoms and treatment regimens for bleeds/procedures were also monitored.Results: Eight patients are currently receiving ITI according to this Atlanta Protocol. Details regarding this cohort are outlined in Table 1. Three of the 8 patients required central venous access for ITI fVIII infusions. These eight patients have historical peak inhibitor titers, defined as the highest inhibitor titer prior to this ITI regimen, ranging from 2.0 - 198 BU/mL. Four patients have just recently started ITI. The other 4 patients (patients 1, 2, 4, and 5) have been treated with Emicizumab and ITI for a median duration of 15 weeks (range 13-18 weeks). Two of the 4 patients are on ITI with a standard half-life third generation rfVIII product, 1 is on a standard half-life third generation B domain deleted (BDD) rfVIII product, and 1 is on an extended half-life (EHL) rfVIII-Fc fusion product. Their last measured inhibitor titers after initiation of ITI range from 0.3 - 3.7 chromogenic BU (CBU). All inhibitor titers declined with the start of ITI, and none of the 4 patients experienced an amnestic response (Figure 1). The fVIII incremental recovery improved in 3 of the 4 patients from a median of 30% of expected (range 17-69%) prior to Emicizumab with ITI to 85% of expected (range 67-85%) at the last clinical evaluation. The 1 patient remaining has an fVIII incremental recovery <10% of expected at the last clinical evaluation. Only one patient has required treatment with a single dose of recombinant activated factor VII (rfVIIa) for a right knee hemarthrosis during ITI without complication. There were 3 additional mild bleeding symptoms in 2 patients that did not require intervention including 1 trauma-induced forehead hematoma that self-resolved and 2 episodes self-resolving epistaxis lasting <5 minutes. Two of the 4 patients reported no bleeding symptoms. There were no episodes of thrombosis or thrombotic microangiopathy.Conclusions: This is the first report detailing the Atlanta Protocol for ITI in hemophilia A patients with inhibitors receiving Emicizumab prophylaxis. Although early, these results suggest that ITI can be safely administered in these patients and is able to achieve continued improvement in clinical indicators of tolerance. DisclosuresBatsuli:Bayer: Other: Advisory Board; Genentech: Other: Advisory Board; Octapharma: Other: Advisory Board. Zimowski:National Hemophilia Association/Shire: Other: Funding for clinical fellowship in Hemostasis/Thrombosis. Meeks:Bioverativ: Other: Advisory Board; Bayer: Other: Advisory Board; CSL Behring: Other: Advisory Board; Catalyst Biosciences: Other: Advisory Board; Genentech: Other: Advisory Board; HEMA Biologics: Other: Advisory Board; Shire: Other: Advisory Board; Pfizer: Research Funding. Sidonio:Genentech: Other: Advisory Board, Research Funding; Bioverativ: Other: Advisory Board, Research Funding; Biomarin: Other: Advisory Board; Novo Nordisk: Other: Advisory Board; Octapharma: Other: Advisory Board; Grifols: Other: Advisory Board, Research Funding; Uniqure: Other: Advisory Board; CSL Behring: Other: Advisory Board; Shire: Other: Advisory Board, Research Funding; Kedrion: Research Funding.

Treatment of Haemophilia a (HA) Patients with Inhibitors: Immune Tolerance Induction with a Single Factor VIII/Von Willebrand Factor Concentrate in an Observational Immune Tolerance Induction Study (ObsITI)

Introduction and objectives:Development of neutralising inhibitors against factor VIII (FVIII) is one of the most serious and costly complications in the treatment of HA. An ongoing international, open-label, uncontrolled, multicentre observational study, ObsITI (ClinicalTrials.gov. NCT 02207894) started in 2005 to assess immune tolerance induction (ITI), the standard of care in patients with inhibitors. The study evaluates patient- and therapy-related variables on ITI course, outcome and morbidity in HA patients with inhibitors. ObsITI satellite studies additionally look at other factors related to tolerisation.Methods and Materials:As of February 2018, 193 patients from 20 countries undergoing ITI have been recruited in ObsITI. 152 patients completed the study and 41 are ongoing. A subgroup of more than 80 prospective patients were treated exclusively during the complete ITI course with a single plasma-derived (pd) FVIII concentrate that contains von Willebrand factor (VWF) in a VWF/FVIII ratio of 0.4 (Octapharma AG). According to the recommended Bonn protocol, low responders at ITI start received 50-100 IU FVIII kg-1 daily, or every other day; high responders received 100 IU FVIII kg-1 every 12 hours.Results:In this ongoing study, the majority of patients treated with the pdFVIII/VWF product achieved a negative inhibitor titre. ITI outcome was significantly correlated with the bleeding rate during ITI, the peak titre during ITI, the inhibitor titre at start of ITI >10 BU, and the number of poor prognosis factors.Conclusion:Treatment with this particular pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in HA patients with inhibitors and corroborates previously published success rates (77.1% complete/partial success in 48 inhibitor patients undergoing ITI with the same product). DisclosuresEscuriola Ettingshausen:SOBI: Honoraria, Research Funding; Shire: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Octapharma: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Novo Nordisk: Honoraria; Roche: Honoraria; Grifols: Honoraria; Pfizer: Honoraria; LFB: Honoraria. Berntorp:Octapharma: Consultancy; CSL Behring: Consultancy; Shire: Consultancy, Other: honoraria for lecturing . Negrier:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Octapharma: Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; LFB: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi/Bioverativ: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta/Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Research Funding. Pavlova:Novo Nordisk: Honoraria; Octapharma: Honoraria. Oldenburg:Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees; Grifols: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biogen Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Swedish Orphan Biovitrum: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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

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.

The Japanese Immune Tolerance Induction (J-ITI) study in haemophilia patients with inhibitor: Outcomes and successful predictors of ITI treatment.

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

Risk Factors for the Development of High-Titer Inhibitors in 260 Children with Severe Hemophilia a Born Between 1990 and 2009: The Remain Study

▪The development of anti-FVIII antibodies (i.e., inhibitors) is the major side effect of severe hemophilia A treatment. Inhibitors mainly develop in children during the first 50 exposure days and are classified in low-and high-titer (i.e., peak titer < or > 5 UB/ml). High-titer inhibitors have the major clinical impact. At diagnosis however, the real nature of the antibody is not clear in all patients, since some low-titer inhibitors may progress to high-titer. The determinants of the evolution from low- to high-titer inhibitors are still unclear and the aim of the present study was to investigate potential risk factors associated with the progression from low- to high-titer inhibitors. This study is a follow-up study of the PedNet Registry and includes 260 children with severe hemophilia A and clinically relevant inhibitors, born between 1990 and 2009 and consecutively recruited from 31 hemophilia centers in 16 countries. Clinical and laboratory data were collected from the date of first positive inhibitor test and covered a minimum of 3-years follow-up. Factors potentially associated with progression from low- to high-titer inhibitor development were analyzed using univariate and multivariate logistic regression. F8 mutation type was known in 247 patients (95%), including 202 (82%) null mutations (i.e., large deletions, nonsense mutations and inversions). Positive family history of inhibitors was present in 37 of 99 (37%) with positive family history of hemophilia. At diagnosis 49% (n=127) had low-titer inhibitors, however, upon FVIII re-exposure, 50% of low-titer inhibitors progressed to high-titer and only 25% of patients (n=69) had persistent low-titer inhibitors. Within the first 3 years of follow-up, immune tolerance induction (ITI) was equally implemented in around 80% of low-and high-titer patients but it was started later in children with high-titers (median time to ITI start 4.5 vs 0.3 months; p<0.001) in whom daily regimens and high-dose FVIII were more frequently adopted (89, 67% vs 41, 50% and 98, 74% vs 35, 43%; p=0.01 and <0.001, respectively). Overall high-titer inhibitor development was associated with null F8 mutations (OR 2.8, 95%CI 1.4-5.5) and family history of inhibitors (OR 3.9, 95%CI 1.2-12.6). The progression from low- to high-titer inhibitors during follow up, was associated with the use of high-dose ITI regimens (i.e., >100 IU/kg/day) with an OR of 3.9 (95%CI 1.5-10.0), independent from the effects of F8 mutation type (adjusted OR 3.6, 95%CI 1.4-9.8) and family history of inhibitors (adjusted OR 6.7, 95%CI 1.1-42.6). No difference was found by comparing the use of daily versus non-daily ITI. In conclusion, in a cohort of 260 children with severe hemophilia A and inhibitors, 49% presented with low-titers at diagnosis and 46% of them progressed to high-titers during follow-up. Progression to high-titer inhibitors was associated with the use of high-dose ITI. These results suggest that intensive ITI should be avoided as initial strategy in low-titer inhibitor patients. DisclosuresMancuso:Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sobi/Biogen Idec: Consultancy, Speakers Bureau; Novo Nordisk: Consultancy, Speakers Bureau; CSL Behring: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Baxalta: Consultancy, Speakers Bureau; Bayer Healthcare: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kedrion: Consultancy. Fischer:Wyeth/Pfizer: Research Funding; Biogen: Consultancy; NovoNordisk: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Biotest Octapharma: Speakers Bureau; CSL Behring: Speakers Bureau; Baxter: Consultancy, Research Funding, Speakers Bureau; Freeline: Consultancy; Bayer: Consultancy, Research Funding, Speakers Bureau. Santagostino:Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Sobi: Consultancy; Biogen Idec: Consultancy; Roche: Consultancy; Grifols: Consultancy; Pfizer: Consultancy; Baxalta: Consultancy; CSL Behring: Consultancy; Bayer: Consultancy. Escuriola:Baxalta, now part of Shire: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Investigator Clinical Studies, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Biotest: Consultancy, Honoraria, Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Octapharma: Consultancy, Honoraria, Research Funding; NovoNordisk: Consultancy, Honoraria, Research Funding. Liesner:BPL: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Speakers Bureau; Cangene: Research Funding; CSL Behring: Consultancy, Honoraria, Research Funding; Baxalta Innovations GmbH, now a part of Shire: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; SOBI: Consultancy, Honoraria, Research Funding, Speakers Bureau; Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Biogen: Consultancy, Honoraria, Research Funding; Grifols: Consultancy, Honoraria. Nolan:Sobi: Research Funding; Biogen: Research Funding.

Immune tolerance induction in patients with haemophilia a and inhibitors: effectiveness and cost analysis in an European Cohort (The ITER Study).

Although immune tolerance induction (ITI) is considered the first choice treatment to eradicate inhibitors in haemophilia A patients, little is known about outcomes determinants and cost magnitude. A retrospective, multicentre study was conducted to assess the relationship between ITI outcome, clinical and treatment characteristics and cost of ITI treatment in haemophilia A patients. Data from 12 months before inhibitor diagnosis to 12 months after ITI completion were collected. Treatment cost was calculated in the third-party perspective and expressed as mean € per patient-month. Cox regression models were used to identify predictors of better outcome and the time taken to achieve tolerance. Seventy-one patients, aged 0.4-41 years (median: 3.8 years) at ITI start, were enrolled. Undetectable inhibitor was achieved in 84.5% of patients and inhibitor eradication with normal factor VIII (FVIII) pharmacokinetics in 74.2%. Median time to successful tolerance was 10.7 months (range 2.0-90.0 months). Peak inhibitor level on ITI was a significant predictor of ITI success. Breakthrough bleeding event incidence during ITI was associated with time to success. The mean cost of treatment for the time period between inhibitor diagnosis and ITI start was €3188 per patient-month (92.1% for bypassing agents), and €60 078 during ITI (76.8% for FVIII use in ITI). Immune tolerance induction in this patient cohort was successful in 84.5% of patients with a mean cost of €60 000 per patient-month. This high cost is dwarfed by comparison with the prospect of lifelong care of an inhibitor patient, in addition to gains in life expectancy and health-related quality of life.

Prompt immune tolerance induction at inhibitor diagnosis regardless of titre may increase overall success in haemophilia A complicated by inhibitors: experience of two US centres

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

Primary and rescue immune tolerance induction in children and adults: a multicentre international study with a VWF‐containing plasma‐derived FVIII concentrate

Most studies on immune tolerance induction (ITI) therapy in haemophilia A patients are focused on primary ITI in children. Here we report on the ITI outcome in a large retrospective cohort, including adults and patients with rescue ITI, treated with a pdFVIII/VWF concentrate. Retrospective data from haemophilic patients (FVIII< 2%) with inhibitors from 22 centres in Spain, Italy and Germany, who underwent primary or rescue ITI with pdFVIII/VWF concentrate, were collected. Complete success (CS), partial success (PS) and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. A total of 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults) were evaluated. Success (CS+PS) rate of 87% was achieved in primary ITI and 74% in the higher risk profile of rescue ITI. Eight of nine (85%) patients with poorest prognosis (three or more of the known risk factors of poor response to ITI) achieved success (CS+PS). CS of 100% was observed in eight primary ITI patients with titre at start of ITI ≤2.5 BU and inhibitor peak ≤25 BU. The favourable response rates in primary and rescue ITI in children and in adult patients, even in the presence of poor prognostic factors, should be encouraged for broadening the indication of immune tolerance therapy in haemophilia A patients with inhibitors.

Natural History Of Inhibitor Recurrence Following Successful Immune Tolerance Induction

Introduction The formation of Factor VIII (FVIII) inhibitory antibodies is a major complication of hemophilia A. Currently immune tolerance induction (ITI) is successful in up to 70% of patients. Outside of the International Immune Tolerance Registry, where 6 of 128 patients had a recurrent inhibitor between 1 and 6 years, little is known about the probability of inhibitor recurrence following successful ITI. Objective To determine the probability of inhibitor recurrence and the influence of adherence to post-ITI prophylaxis on inhibitor recurrence following successful ITI. Methods All persons with hemophilia A (FVIII level 6 hours and/or FVIII recovery > 66% in addition to inhibitor titer 80% of prescribed infusions vs. < 80% of prescribed infusions) and inhibitor recurrence was assessed using the chi-square test. Results Eighty-three male subjects were enrolled. The median age at start of ITI was 3.3 years (range: 0.08 - 39). The majority of the subjects were white (73%) and non-Hispanic (73.5%). Seventy-one (85.6%) had severe hemophilia. The median peak inhibitor titer was 8.5 BU/ml (range: 0.6 - 950). Four subjects (5%) had a prior unsuccessful course of ITI. FVIII alone was used in 85% of subjects. Sixty-seven (80.7%) met criteria for tolerance and 64 had follow-up data available, with a median follow up time of 3.4 years (range: 0.08-12.4). Forty-four subjects (68.7%) remained tolerant without a recurrent inhibitor titer after a median 4.7 years (range: 0.25-12.4) of follow-up. Twenty subjects (31.3%) had at least one inhibitor titer ≥ 0.6 BU/ml after a median of 1.6 years (range 0.08-5.7). The probability of recurrent inhibitor at 1 year is 0.15 (95% CI: [0.05, 0.20]); at 3 years is 0.30 (95% CI: [0.2, 0.4]) and 5 years is 0.35 (95% CI: [0.2, 0.5]) ([Figure 1][1]). Four subjects discontinued post-ITI prophylaxis anywhere from 6 months to greater than 6 years after tolerance was achieved, of whom 2 (50%) developed a recurrent inhibitor. Of those that remained on post-ITI prophylaxis, 41 subjects (64.1%) were adherent (took >80% of prescribed infusions) to their post-ITI prophylaxis regimen, of whom 13 (31.7%) developed a recurrent inhibitor. Twenty-three (35.9%) who were non-adherent (took <80% of the prescribed infusions) of which 7 (30.4%) subjects developed a recurrent inhibitor; no statistically significant association was found between adherence and inhibitor-free status (p=0.92). ![Figure 1][2] Figure 1 Conclusion ITI is currently the most effective treatment to eradicate FVIII inhibitors, however 5 years after completion, 30-35% of patients will have at least one inhibitor titer ≥ 0.6 BU/ml. A recurrent inhibitor is unlikely after 5 years. Adherence to post-ITI prophylaxis does not appear to be a major driver of inhibitor recurrence. It is imperative to elucidate the factors that influence the durability of successful ITI to improve quality of life and cost of treatment in these patients. Disclosures: Monahan: Baxter: Consultancy, Honoraria, Research Funding, travel support, travel support Other; Bayer: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novo Nordisk: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Prolor Biotech: Research Funding; Asklepios: Consultancy, Research Funding, travel support Other. Manco-Johnson: Eisai: Research Funding; Novo Nordisk: Membership on an entity’s Board of Directors or advisory committees; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees; Baxter BioScience: Membership on an entity’s Board of Directors or advisory committees; CSL Behring: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Bayer HealthCare: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Carpenter: Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Grifols: Honoraria, Research Funding. Kruse-Jarres: Bayer HealthCare: Consultancy; Biogen IDEC: Consultancy; Grifols: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy; Baxter Healthcare: Consultancy. Ragni: Novo Nordisk: Research Funding; Merck: Research Funding; CSL Behring: Research Funding; Bayer: Research Funding; Baxter: Research Funding; Tacere Benitec: Consultancy; Smith Kline Glaxo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Biogen Idec: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding. Kempton: Novo Nordisk: Research Funding; Baxter Healthcare: Membership on an entity’s Board of Directors or advisory committees. [1]: #F1 [2]: pending:yes

A review of immune tolerance induction with Haemate® P in haemophilia A

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