Initiation Of Immune Tolerance Induction Research Articles

Defining the impact of immune tolerance induction on clinically relevant outcomes in a US cohort of severe hemophilia A

AbstractAlthough the near-term benefit of immune tolerance induction (ITI) for the treatment of people with severe hemophilia A with inhibitor is apparent, the magnitude of the longer-term impact of ITI on clinical outcomes remains undefined. We examined the association between receiving ITI and the success of ITI on clinical outcomes including (1) clinical events, (2) health care use, (3) quality of life/function, (4) socioeconomic status, and (5) death, using the Community Counts (CC) registry of US Hemophilia Treatment Centers between 2013 and 2017. Multivariate logistic regression, negative binomial, and Poisson models were used. Included in this study were 3659 people with severe hemophilia A with median age of 21 years when entering the CC registry. Among 576 participants with inhibitors, 485 had received ITI (84%). ITI was successful in 299 (61.7%) and partially successful or failed in 95 (19.5%) or 91 (18.7%), respectively. Those that received ITI had fewer treated bleeds, less chronic pain, better function, and higher educational attainment than those not receiving ITI. Successful vs partially successful and failed ITI was associated with fewer treated bleeds, less health care use, less chronic pain, better function, and fewer missed days of school or work. Mortality was not associated with ITI, regardless of its success. Those with successful ITI had similar rates of treated bleeds, chronic pain, and health care use as those with no inhibitors. Undergoing ITI, particularly if successful, improved clinical outcomes but not mortality. These findings support decision making regarding initiation of ITI and inform future clinical trials.

Factor VIII inhibitors in hemophilia A treated with emicizumab: longitudinal follow-up of outcomes

BackgroundUsing emicizumab in lieu of immune tolerance induction (ITI) for patients with hemophilia A (HA) and factor (F)VIII inhibitors has been well described. However, decisions regarding ITI initiation, regimen, and preservation of tolerance remain to be elucidated. ObjectivesTo study the course of FVIII inhibitors in patients with HA and a history of FVIII inhibitors receiving emicizumab prophylaxis. MethodsPatients with HA, with and without FVIII inhibitors, initiating emicizumab prophylaxis were prospectively followed up in our center. All patients with current or previous inhibitors were included in this analysis. Plasma samples for FVIII inhibitor assays were obtained every 3 to 6 months or following FVIII exposure. Patients documented annual bleeding rate and any FVIII exposure days (EDs). ResultsOf 162 emicizumab-treated participants, 51 met the inclusion criteria. A decrease in annual bleeding rate was observed in all 51 participants followed up for a median of 3.3 years, with 31 breakthrough bleeding episodes reported in 22 of 51 participants. FVIII inhibitor level transiently increased following FVIII exposures in 5 of 15 failed ITI participants. Eight of 21 participants who did not undergo ITI were exposed to FVIII (1-2 EDs)), and 1 of these 8 participants demonstrated increased FVIII inhibitor levels after head trauma (following 1 ED). Among participants who underwent successful ITI, 8 of 15 patients were exposed to FVIII over a total of 13 EDs (1-2 ED(s) each) for traumatic breakthrough bleeds. In all these participants, inhibitor levels remained zero, indicating successful tolerance maintenance. ConclusionOur longitudinal follow-up of emicizumab-treated patients with HA and FVIII inhibitors shows that occasional exposure to FVIII may induce a transient anamnestic response. Nonetheless, no FVIII inhibitor recurrence was noted following FVIII exposures in patients who underwent successful ITI.

Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Rurioctocog Alfa Pegol Use in Immune Tolerance Induction: Interim Results from an Open-Label Multicenter Clinical Trial in Previously Untreated Patients with Severe Hemophilia a

Immune Tolerance Induction (ITI) with a Plasma-Derived Factor VIII for Patients with Hemophilia a and Inhibitors: A Retrospective Study

Introduction: A serious complication in hemophilia A is the formation of inhibitors to clotting factors. The primary means for eradicating inhibitors is immune tolerance induction (ITI) therapy. Antihemophilic factor (human) (Koate®-DVI) is a purified dried concentrate indicated for the treatment of hemophilia A with insufficient activity of Factor VIII (FVIII). Although other plasma-derived concentrates containing von Willebrand factor have been utilized successfully for ITI, studies evaluating this product for ITI therapy have not been published. An evaluation of patient- and treatment-related factors associated with outcomes following primary or rescue ITI with antihemophilic factor (human) in patients with hemophilia A and inhibitors was conducted in this retrospective multicenter chart review project. Methods: An evaluation of medical records of 13 inhibitor patients treated with antihemophilic factor (human) for primary or rescue ITI therapy between January 1, 2012, and July 31, 2017, was conducted in five US hemophilia treatment centers. To be eligible for inclusion, patients were required to have a diagnosis of hemophilia A of any severity level, inhibitor to FVIII at the time of treatment initiation with antihemophilic factor (human), and ongoing treatment with antihemophilic factor (human) for primary or rescue ITI. Data were de-identified and analyzed descriptively. Outcome measures were defined, per the International Immune Tolerance consensus recommendations, as "complete success" (inhibitor titer <0.6 Bethesda Units [BU] at 33 months of ITI, FVIII recovery ≥66% and half-life ≥6 hours), "partial success" (a reduction in inhibitor titer to <5 BU mL with FVIII recovery <66% and/or FVIII half-life <6 hours associated with clinical response to FVIII therapy not followed by a treatment-limiting anamnestic rise in inhibitors to >5 BU mL), or "failure" (neither complete nor partial success). Results: All (N=13) patients who met the inclusion criteria were males with severe hemophilia, with the exception of one with moderate hemophilia. Six patients were African American, four were Hispanic, two Caucasian, and one was Asian. They were diagnosed with inhibitors between the ages of 8 months and 39 years and were 5 to 53 years old upon ITI with antihemophilic factor (human). Ten of 13 patients (76.9%) had successful ITI; seven with complete success and three with partial success (Table). Three patients failed ITI. As primary therapy, complete success was obtained with all but one of the six patients treated with antihemophilic factor (human). These six patients were all older than 7 at the initiation of ITI, a risk factor for poor ITI. Seven of the 13 total patients had a combined previous 12 attempts at ITI with other products (plasma derived and/or recombinant). Of these seven rescue patients, ITI with antihemophilic factor (human) was completely successful in two and partially successful in three. Adverse events reported once in separate patients during treatment with antihemophilic factor (human) included catheter infection, portal infection, bacteremia, peritonitis due to a ruptured appendix, and complications in treatment. One patient had several adverse events, including cellulitis at the port site, abdominal wall hematoma, right thumb fracture and hematoma, and left shoulder hemarthrosis. Conclusions: While retrospective data has limitations, real-world evidence demonstrates that ITI with antihemophilic factor (human) concentrate can be successful or partially successful in diverse populations of moderately complex patients with hemophilia A and inhibitors. The data suggest that antihemophilic factor (human) may be most appropriate for patients when used as primary ITI, as even patients older than 7 years achieved complete success. Additional patients need to be evaluated to make a definitive conclusion regarding the impact of age on success of ITI therapy in addition to other risk factors. Disclosures Escobar: Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; National Hemophilia Foundation: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees. Rajan:Bayer, Octapharma: Consultancy, Honoraria, Research Funding, Speakers Bureau. Amega:Kedrion Biopharma: Employment. OffLabel Disclosure: Koate is not approved to treat vWD, nor, cTTP however, based on some published reports using kotae for these indications, we are anticipating those type of off label inquiries. I will clearly disclose to the participants that these are off label indications.

Outcome of Immune Tolerance Induction Using an Extended Half-Life Clotting Factor Concentrate — Recombinant Factor VIII Fc (Eloctate™) — a Report from India

The development of inhibitors is the most serious adverse effect of replacement theray with clotting factor concentrates (CFC) in hemophilia. Its eradication is also difficult, usually requiring months of frequent exposure to high doses of the CFC - immune tolerance induction (ITI). There is limited data on use of extended half-life (EHL) CFC for ITI. A limited program of ITI was made possible in India with some of the rFVIIIFc (Eloctate™) provided through the humanitarian aid program of the World Federation of Hemophilia. This report summarizes the interim outcome of ITI in these patients treated at three centers participating in this program.ITI with rFVIIIFc was offered to patients with hemophilia A and significant inhibitors. The CFC dose used ranged from 50 IU/kg, 3x/week, to 200 IU/kg per day, depending on the weight, convenience and early response as well as availability of rFVIIIFc. All patients completing at least 10 weeks of ITI are included in this analysis. Bethesda assay was done every 2-4 weeks. Successful ITI was defined as a negative Bethesda assay with a FVIII recovery of >60%. Patients received either FEIBA or rVIIa for breakthrough bleeds.Thirty eight patients were included in this analysis. The median age at initiation of ITI was 15 years (range:2 -39). Nine (24%) patients had a family history of inhibitors. The median age at which inhibitors developed was 11 years (range:0.6 -38). Nine (24%) patients had history of surgery prior to onset of inhibitor. Ten patients (26%) had exposure to only plasma derived factors. All patients were on episodic CFC replacement therapy except two (5%) who were receiving low-dose prophylaxis prior to inhibitor development. The median exposures to FVIII was 20 (range:2-80) and duration of inhibitors prior to ITI was 2 years (range:0.1 - 20). The median highest inhibitor titre recorded prior to ITI was 19 BU (range:4-1177). Only 3 patients had their maximum inhibitor titer below 5BU. The median inhibitor titre at the time of starting ITI was 10.4 BU (range: 0.6-1177). The median peak inhibitor titer after starting ITI was 40.4 BU (range:3.5-13933). Out of the 38, 17 (45%) patients achieved a negative inhibitor status after ITI for a median duration of 23 weeks (range: 10-64). Among the 17 patients who had successful ITI, the median duration of ITI required to achieve negative inhibitor status was 20 weeks (range:10-60). Among the other 21 patients who had persistence of inhibitors, 4 were included in other clinical trials, 3 discontinued due to personal reasons while the other 14 are continuing ITI based on availability of appropriate EHL CFC. Among these patients with persistence of inhibitors, the last inhibitor titer was 6.4 BU (range:0.9-9240) after a median of 26 weeks of ITI (range:11-64). The median number of breakthrough bleeds during ITI was 1 (range:0-12), being 1 (range:0-6) among responders and 1 (range:0-12) among those with persistence of inhibitors. A comparison of the group which responded within this duration of ITI and those who did not respond is shown in the table. Older age and the peak inhibitor titer prior to ITI were the two significant variables which affected early outcome of ITI.These data show that EHL rFVIIIFc can be effective in ITI with nearly 45% of patients achieving a negative inhibitor titer within 1 year and with responses starting as early as 1 month and nearly half of them within 4 months. There was also a relatively low median annualized bleed rate during ITI. More patients need to be treated with different doses of rFVIIIFc to assess its potential in ITI and to determine the optimal protocols but the initial data is promising. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

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.

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

Durability of ITI Utilizing Rfviiifc

Introduction: The eradication of inhibitors using immune tolerance induction (ITI) remains the mainstay of therapy in patients with severe hemophilia A who develop inhibitors. The long-acting recombinant factor VIII Fc fusion protein, rFVIIIFc (Eloctate™), which is safe and effective in the prevention and treatment of bleeding events, may promote tolerance to FVIII as shown in preclinical animal models and an inhibitor prone child, as Fc suppresses immunoregulatory Tcells to proteins to which Fc is attached. We therefore previously hypothesized rFVIIIFc would provide effective ITI, specifically shortening and simplifying ITI, and have previously described successful inhibitor eradication in three patients. Long-term follow-up data after successful ITI in patients with severe hemophilia remains limited. In the International Immune Tolerance Induction study, at 1-year follow-up, 6 of 66 subjects who had achieved tolerance demonstrated evidence of relapse at a median of 9.5 months. Of these 6 subjects, 1 had a measurable inhibitor titer and 5 had reduced FVIII recovery. We aim to provide follow-up data on our cohort of patients who had successful inhibitor eradication utilizing rFVIIIFc for ITI. Methods: Immune tolerance induction was initiated in three patients with severe hemophilia A and anti-VIII >5 B.U., in two as initial ITI (Pt. 1, 3), and one as salvage (Pt. 2) after failing to achieve ITI with standard rFVIII due to poor compliance. Follow-up was scheduled every 6-8 weeks, with planned determination of FVIII half-life once the anti-FVIII fell to <0.6 B.U. Tolerance was a priori defined as achieving anti-FVIII <0.6 B.U., FVIII recovery of at least 60%, and half-life (t½) >6 hours. Once a t½ >6 hours was documented, incremental reduction to rFVIIIFc occurred. Patients continued to be followed by their local HTC as per standard of care. Results: ITI was initiated with rFVIIIFc at a dose of 100-200 IU/kg rFVIIIFc every other day or three times weekly per MD discretion. The time to initial anti-FVIII <0.6 B.U. was 4-12 weeks. Patient 1 and 2 were able to achieve tolerance, with a FVIII recovery of at least 60%, and half-life (t½) >6 hours, at weeks 18 and 17, respectively, after initiation of ITI. Patient 3 has improved but is not yet fully tolerized, as evidenced by 57% recovery and a t½ of approximately 7 hours. Anti-VIII inhibitor titers remain negative at 15, 16 and 15 months, from the initiation of ITI in patients 1, 2, and 3 respectively. Patients 1 and 2 have been able to decrease their post ITI prophylaxis dosing regimen to 80 IU/kg and 65 IU/kg three times a week while maintaining a FVIII trough of >1%. No patients were maintained on bypassing prophylaxis during ITI and no patients have experienced hemarthroses or other major bleeding event since the initiation of ITI. Discussion: Immune tolerance induction was successful in three children with inhibitors using rFVIIIFc, including a child previously failing rFVIII ITI. The time to anti-FVIII=0 was 4-12 weeks, significantly shorter than with current rFVIII ITI. At a mean duration of follow up of 15.3 months, all patients achieved an anti-VIII inhibitor titer of 0 B.U. Repeat pharmacokinetics studies will be available at planned subsequent follow-up visit. To date, these data indicate that rFVIIIFc safely and effectively induced immune tolerance to FVIII in three children with inhibitors, and has provided durable and continuing immune tolerance to FVIII. Whether rFVIIIFc ITI will be successful and durable in a larger cohort of children with severe hemophilia A will require prospective studies. A prospective observational study of rFVIIIFc ITI pre- and post-ITI T cell responses in children with hemophilia and inhibitors, the Hemophilia Inhibitor Response to Eloctate (HIRE) Study, has begun recruitment. Disclosures Ragni: SPARK: Research Funding; Shire: Consultancy; Novo Nordisk: Research Funding; Genentech: Research Funding; CSL Behring: Research Funding; Biomarin: Consultancy; Biogen: Consultancy, Research Funding; Baxalta: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Tacere Benitec: Consultancy; Vascular Medicine Institute: Research Funding; OPKO: Research Funding. Malec:Vascular Medicine Institute: Research Funding; Biogen: Research Funding; Baxalta: Research Funding; Biogen: Consultancy. Journeycake:CSL: Consultancy; Biogen: Consultancy; Baxalta/Shire: Consultancy.

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

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

Outcome of the Japanese Immune Tolerance Induction (ITI) Registry and Predictors of Successful ITI

[Background] Immune tolerance induction (ITI) therapy is the only therapeutic approach that can eradicate factor (F)VIII and FIX inhibitors in patients with hemophilia A (HA) and B (HB), respectively. Although results of several retrospective cohort studies have been published, predictors of successful outcome are still debated. Nonetheless, little information is so far available in terms of large ITI cohort in non-Caucasian countries.[Aim] In this study, we performed a retrospective cohort study on ITI therapy carried out for Japanese hemophilia patients with inhibitors to understand the status of practice on this therapy in Japan and to study the predictors of successful outcome.[Methods] As of March 31, 2015, the registry of ITI therapy in Japanese hemophilia patients had received reports on 155 HA patients (140 severe type, high responder 69.1%) and 7 HB patients (7 severe type, high responder 42.5%) who have undergone this therapy from 45 hospitals including Hemophilia Treatment Centers since 2000. The ITI outcome was centrally reviewed. The success of ITI was defined as an undetectable inhibitor for 2 successive measurements, and the salvage ITI was defined as any rescue ITI regimen by using von Willebrand factor-containing FVIII concentrates.[Results] Among the completed ITI courses, the overall success rate of ITI therapy was 71.2% (94/132) and 83.3% (5/6) for HA and HB patients, respectively. Cumulated ITI success rates of 50% and 80% for HA patients were achieved at 1.6 and 4.3 years after the inhibitor diagnosis, and 0.6 and 2.3 years after the initiation of ITI, respectively. Significant predictors for success of ITI in HA were (i) low responding inhibitors (success 35/37 (94.5%)) compared to high responding inhibitors (59/93 (63.4%); p <0.0001), (ii) shorter intervals from inhibitor diagnosis to the initiation of ITI (success (S): 1.85±3.52 vs failure (F): 3.38±3.77 years; p =0.02), (iii) lower historical peak titers on pre-ITI (S: 24.9±55.2 vs F: 132±295 BU/ml; p =0.04), and (iv) lower peak inhibitor titers on-ITI (S: 72.4±231 vs F: 916±1,307 BU/ml; p <0.01). However, outcome was not significantly different (p =0.77) between high dose regimens (>90 IU/kg, 7 days/wk) and low dose regimens (<75 IU/kg, 3 days/wk). Also, either FVIII products (plasma-derived or recombinant) at the initiation or the insertion of central venous access devise (CVAD) did not affect the outcome (p =0.32 and 0.85). Although the outcome prediction was difficult for HB because of low number of the cases registered, success rate was much higher than those of previous reports. The success rate of salvage ITI was 50% (6/12) for HA. The significant predictive parameter for outcome was only the age at the initiation of salvage ITI (p =0.03). The inhibitor relapsed in 6 cases, and all cases were HA patients (4.5% 6/140). In 86 cases with insertion of CVAD, the catheter-related infection was complicated in 21 cases (12.9%).[Conclusion] This study underscores the importance of initiating the ITI as early as possible after the diagnosis of inhibitor and the low response of inhibitor titer before and during the ITI to maximize the success of the treatment for Japanese hemophilia patients. DisclosuresNogami:Chugai: Membership on an entity's Board of Directors or advisory committees; Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding. Taki:Biogen, Baxalta, Bayer, Novo, Pfizer: Honoraria; Biogen, Baxalta, NovoNordisk, CSL-Behring, Kaketsuken, Chugai: Research Funding. Matsushita:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CLS-Behling: Research Funding; Japan Blood Products Organization: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Octapharma AG: Honoraria; Sysmex: Speakers Bureau; Seamens: Speakers Bureau; Nihon Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Kaketsuken: Honoraria, Research Funding, Speakers Bureau; Asahi Kasei Pharma: Honoraria, Research Funding, Speakers Bureau; Eisai: Research Funding; Novartis Pharma: Honoraria, Speakers Bureau; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding. Hanabusa:Novo Nordisk, Baxalta, Bayer, Pfizer, Biogen, and KaketsuKen: Honoraria; Novo Nordisk, Baxalta, KaketsuKen, and Biogen: Membership on an entity's Board of Directors or advisory committees. Shima:Pfizer: Honoraria, Research Funding; Kaketsuken: Honoraria; Biogen: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding.

Anti‐A2 and anti‐A1 domain antibodies are potential predictors of immune tolerance induction outcome in children with hemophilia A

HemophiliaA (HA) is a congenital bleeding disorder resulting from factorVIII deficiency. The most serious complication of HA management is the appearance of inhibitory antibodies (Abs) against injected FVIII concentrates. To eradicate inhibitors, immune tolerance induction (ITI) is usually attempted, but it fails in up to 30% of cases. Currently, no undisputed predictive marker of ITI outcome is available to facilitate the clinical decision. To identify predictive markers of ITI efficacy. The isotypic and epitopic repertoires of inhibitory Abs were analyzed in plasma samples collected before ITI initiation from 15 children with severe HA and high-titer inhibitors, and their levels were compared in the two outcome groups (ITI success [n=7] and ITI failure [n=8]). The predictive value of these candidate biomarkers and of the currently used indicators (inhibitor titer and age at ITI initiation, highest inhibitor titer before ITI, and interval between inhibitor diagnosis and ITI initiation) was then compared by statistical analysis (Wilcoxon test and receiver receiver operating characteristic [ROC] curve analysis). Whereas current indicators seemed to fail in discriminating patients in the two outcome groups (ITI success or failure), anti-A1 and anti-A2 Ab levels before ITI initiation appeared to be good potential predictive markers of ITI outcome (P<0.018). ROC analysis showed that anti-A1 and anti-A2 Abs were the best at discriminating between outcome groups (area under the ROC curve of >0.875). Anti-A1 and anti-A2 Abs could represent new promising tools for the development of ITI outcome prediction tests for children with severe HA.

Immune Tolerance Induction (ITI) in Adults with Congenital Hemophilia: A Multicenter Experience

AbstractAbstract 1123 IntroductionMost inhibitors developing in adulthood are low titer inhibitors [Eckhardt 2012], however high titer inhibitors have been described [Kruse-Jarres 2010, Hay 2011]. The role of ITI in the management of adult inhibitors has not been established. Two large registries have suggested that age at ITI initiation could be a predictor of success. The North American ITI registry showed a trend toward a younger age in the ITI success group [DiMichele 2002], while the International ITI group showed a more definitive difference, where patients receiving ITI at age > 20 years had a 40 % success rate compared to a much higher success rate of 70 t0 78% in younger individuals [Mariani 2001]. Prospective therapy trials in an adult congenital hemophilia inhibitor population are difficult to conduct, as the number of patients is limited. The aim of the this multicenter retrospective review was to document our experience in the management of adult hemophilia inhibitor patients with ITI MethodsTwelve hemophilia treatment centers which are part of the Globally Emerging Hemophilia Expert Panel (GEHEP) with centers in Canada, Europe, South Africa and the US, who collectively look after over 3000 hemophilia patients, participated in this study. Each center obtained ethics approval prior to data collection. Retrospective record review was undertaken at each center to identify congenital hemophilia patients treated with ITI as an adult (started at ≥ 17 years of age)and who completed the treatment course between 1980 and 2012. The treatment course was defined as any of the accepted ITI regimens. Treatment success was defined as inhibitor eradication or >66% factor recovery. ResultsOf 21 patients who received ITI as an adult, 71% had partial (<5BU and FVIII was able to be reinstated) or complete success. All patients had hemophilia A and most were severe (One patient in the ITI failure group had a level of 2% and in the success group, one had a level of 1% and on of 3%). Of the 13 patients achieving complete success, 38% relapsed (mean follow up of 9.4 years, range 3 months to 29 years). Age at start of ITI did not seem to be a predictor of success: mean age in the success group was 32.0 years (range 17 –55) and in the failure group was 33.5 years (range 22 – 57). All patients in the failure group were white, where 3 patients in the success group were non-white. The success group included one low responding inhibitor and had an overall lower peak inhibitors (mean 89.75 BU, range 3 – 270 BU) than the failure group (mean 353.8 BU, range 89–600 BU). Fifty percent of the failure patients had received a prior ITI attempt, where only 8% of the success group had. More patients in the failure group had received plasma derived factor VIII product for their ITI (83%) than in the success group (69%) but dosing was not significantly different (mean of 416 units/kg/week in failure group, 455 U/kg/week in success group). Overall, patient who failed stayed on ITI slightly longer (mean 20 months) than the patients who succeeded (mean 16 months). ConclusionIn this limited series of adult inhibitor hemophilia patients treated with ITI, the success rate was high and comparable to that obtained in the pediatric population. Age at start of ITI did not seem to be a predictor of success, but prior ITI and historical peak inhibitor were negative predictors. Prospective clinical studies are required to expand on these preliminary findings. Disclosures:Kruse-Jarres:Bayer: Administrative and meeting support Other, Honoraria, Research Funding.

Eradication of factor viii inhibitors in patients with mild and moderate hemophilia A

In hemophilia A, up to 25% of new antifactor VIII (FVIII) inhibitory antibodies (inhibitors) occur in patients with mild or moderate disease. Once the inhibitor develops, options for management include observation, immune modulation, and immune tolerance induction (ITI). Currently, there is little data to guide a clinician's management decisions. In a case series, eight of the 26 subjects with mild or moderate hemophilia complicated by an inhibitor underwent ITI; two were successful, two were unsuccessful, and four were partially successful. In a systematic review of the literature, 12 of the 16 patients with mild or moderate hemophilia responded to rituximab for treatment to eradicate the inhibitor. To increase our understanding of treatment options for inhibitor eradication in patients with mild or moderate hemophilia A complicated by an inhibitor, a secondary analysis of clinical and treatment characteristics in a cohort of 36 patients with mild or moderate hemophilia A and inhibitor was undertaken. In multivariate analyses, rituximab alone (n = 6) and other immune-modulating treatments alone (n = 2) were significantly associated with an increased likelihood of inhibitor clearance [hazard ratio (HR) = 4.4 (95% CI = 1.06–20.03) and 10.21 (95% CI = 1.17–78.28), respectively], whereas ITI alone (n = 9) was not [HR = 1.35 (95% CI = 0.44–4.07)].

Prophylaxis in haemophilia with inhibitors: update from international experience

An antibody response to therapeutically administered factor VIII (FVIII) can occur in up to 30% of patients with haemophilia, resulting in the production of inhibitors that neutralize FVIII coagulant activity. Immune tolerance induction (ITI) therapy can be used to eradicate inhibitors in these patients, allowing them to continue with factor replacement therapy. Patients with inhibitors (prior to initiation of ITI, while on ITI or those who fail ITI) experience more difficulty in treating bleeds than those patients who do not develop inhibitors. Increasingly, prophylaxis with bypassing therapy is being employed in patients who develop inhibitors. Two bypassing agents, a plasma-derived activated prothrombin complex concentrate [aPCC (FEIBA; Baxter AG, Vienna, Austria)] and NovoSeven [recombinant factor VIIa (rFVIIa); NovoNordisk, Denmark] are potentially available for prophylaxis in patients with haemophilia who have developed inhibitors. Results from recent retrospective studies demonstrate the efficacy and safety of both aPCC and rFVIIa in decreasing the frequency of bleeding episodes in patients with haemophilia and inhibitors. In this article, we highlight a number of ongoing studies that aim to identify patients who should be placed on prophylaxis with bypassing agents.

Detection of Inhibitor Development in Hemophilia A Patients From the Time of First Exposure to Factor VIII: Performance of An ELISA-Based Factor VIII Antibody Screening Assay.

Abstract 3482Poster Board III-419About 25% of patients with severe hemophilia A develop neutralizing antibodies to factor VIII (FVIII), termed inhibitors, within a median of eleven exposure days to factor VIII containing therapeutic replacement products. Effective monitoring of inhibitor development in young hemophilic children is hampered by their frequently difficult venous access and their limitations on blood sample size, often making it a challenge to obtain samples suitable to carry out standard PTT based Bethesda assays. We evaluated the performance of the Factor VIII Antibody Screen (GTI Diagnostics, Waukesha, WI), an ELISA-based assay to detect FVIII antibodies in a cohort of hemophilia A patients as they were first exposed to FVIII replacement therapy for treatment of hemorrhages. FVIII antibodies were detected in the assay by incubation of duplicate patient samples and controls in microtiter wells coated with recombinant FVIII. After washing, bound FVIII antibody was detected with alkaline phosphatase conjugated goat anti-human IgG, and a colorimetric endpoint (optical density [OD] read at 405or 410 nm by spectrophotometry) determined in an ELISA plate-reader after incubation with p-nitrophenyl phosphate. Samples were considered positive if the average of the sample ODs was higher than the positive controls or negative if the average of the sample ODs was lower than the negative controls. Thirty consecutively identified patients with severe hemophilia A, who were enrolled in a longitudinal inhibitor study, and had samples of serum or plasma banked from the time of their first exposures to FVIII-containing therapeutic products were included. Patients were followed a median of 15.5 years (range 2 – 23 years). Nineteen (63%) of the patients never developed clinical or laboratory evidence of inhibitor development during follow-up. Eleven of the thirty (37%) developed an inhibitor during follow-up; one of these occurred in a 5 year-old after more than 650 exposure days to factor VIII concentrate. There were no differences in the time-to-first-exposure or pattern of hemorrhages in the two groups with the exception that all post-circumcision hemorrhages (N=6) occurred in the non-inhibitor group. In the non-inhibitor group, banked samples were selected corresponding to 0, 5, 10 and >50 factor VIII exposure-days; none of these samples had a positive result in the FVIII antibody screen ELISA. In the 11 inhibitor patients, banked samples were selected that corresponded with the earliest available sample, a sample obtained prior to the first positive Bethesda assay, the first Bethesda positive sample, a sample obtained at the initiation of immune tolerance induction (ITI), the peak Bethesda titer sample, the first negative Bethesda titer sample during ITI, and the most recent sample. All eleven of those who developed an inhibitor underwent successful immune-tolerance therapy with high dose (100 units/kg/day) factor VIII infusions. All Bethesda positive samples were positive by the FVIII antibody screen ELISA with one exception, a sample from one of the inhibitor patients just prior to development of a recurrent inhibitor. There were 5 Bethesda assay negative/FVIII antibody screen ELISA positive samples in the inhibitor patients; each of these samples had been obtained during ITI at 24-48 hours post factor VIII concentrate infusions, and were concordant with lower than expected factor VIII recoveries. We conclude that the ELISA-based FVIII antibody screen is sensitive and specific for the detection of factor VIII antibodies in patients with hemophilia A who develop inhibitors. Because it can be carried out with small serum as well as plasma samples, it provides a convenient method to obtain results in small patients with poor venous access, although quantification of the antibody titer in positive samples would require additional sample to carry out a PTT-based Bethesda assay. Unlike the Bethesda assay, this ELISA-based assay was able to detect antibodies in transfused patients undergoing ITI without the need for a prolonged washout period. Prospective studies to determine the utility and cost-effectiveness of this method are warranted. Disclosures:Gill:GTI Diagnositcs: Consultancy. Stapleton:GTI Diagnostics: Employment. Kern:GTI Diagnostics: Employment.

Use of Factor VIII/Von Willebrand Factor Complex for Inducing Immune Tolerance in Hemophilia a Patients Who Have Failed with Recombinant Fviii: Recent Canadian Experience

Immune tolerance induction (ITI) is effective in approximately 63–83% of hemophilia patients with inhibitors. Poor prognostic factors are age > 18 years, ITI started > 4 years after inhibitor development, inhibitor peaks > 200 BU, inhibitor titre > 10 BU at ITI initiation, and previously failed ITI. It has been reported that patients who have failed ITI with a recombinant FVIII concentrate achieved and maintained immune tolerance when VWF/FVIII complex concentrates were used. We present our Canadian experience with a factor VIII/von Willebrand factor concentrate (Humate-P) for inducing immune tolerance in patients who have previously failed ITI. A questionnaire was sent to all Hemophilia Treatment Centers of Canada. Data collected included baseline FVIII level, mutation, date at initial diagnosis of inhibitor, peak titer, concentrate associated with development of inhibitor, inhibitor titer at initiation of first ITI, concentrate and regimen used, and concentrate, dosing and outcome of secondary ITI with Humate-P. All Hemophilia Centers agreed to participate. 5 Centers submitted data about 8 patients. One patient resistant to initial ITI with Kogenate FS achieved good partial response with Humate-P, with titers going down from 40 to values between 0,6 and 4 BU. One patient who responded to initial ITI with Kogenate FS with peaking of inhibitor to 380 BU was remaining above 100 BU and lowered to 28 BU on Humate-P. In three patients, Humate-P induced an anamnestic response. Two of those patients had a concomitant line infection at time of switching to Humate-P. The third of those three patients had a transient anamnestic response after introduction of Humate-P. One patient had successfull induction of immune tolerance using multiple therapies (cyclophosphamide, Immunate, IVIG, Rituximab) and maintained remission under Humate-P. One patient was on ITI for 27 months using Recombinate and switched to Humate-P when Recombinate was withdrawn from the market. After 12 months, the inhibitor had gone from 12 to 7.3 BU. One patient attained complete remission during primary ITI using recombinant FVIII concentrate (Advate) and maintained remission when switched to Humate-P. In subjects failing ITI with recombinant factor VIII concentrates, Humate-P may be considered as a second line for inducing immune tolerance.

The use of factor VIII/von Willebrand factor concentrate for immune tolerance induction in haemophilia A patients with high‐titre inhibitors: association of clinical outcome with inhibitor epitope profile

A retrospective chart review of 11 subjects with severe haemophilia A and high-titre inhibitors who received a von Willebrand factor-containing FVIII concentrate (VWF/FVIII) for immune tolerance induction (ITI) was accompanied by B cell inhibitor epitope mapping during 10/11 treatment courses. ITI was successful or partially successful in all seven subjects who received VWF/FVIII for initial ITI, and failed in all four subjects whose ITI with this product was initiated following treatment failure using recombinant factor VIII. Variables including age at inhibitor development and age at ITI initiation, interval between inhibitor detection and ITI initiation, titre at start of ITI, and peak historical titres prior to and during ITI were not statistically significant outcome predictors in this cohort. However, the B cell epitope specificity in all four successful and in one of two partially successful ITI subjects for whom information was available included the C2 and excluded the A2 domains. Conversely, FVIII B cell epitopes in one partially successful ITI and in all three failed ITI subjects for whom data were available mapped to both the C2 and the A2 domains. The FVIII B cell epitope profile was associated with ITI outcome in this VWF/FVIII-treated cohort. Its role in predicting ITI outcome and guiding choice of FVIII product for ITI requires further study.

Novel Treatment Approaches in Combination with Rituximab for Immune Tolerance Induction in Severe Hemophilia B.

Although only 4–5% of patients with severe Hemophilia B (HB) develop factor IX (FIX) antibodies that cause inactivation of transfused FIX concentrate (conc), about 1/3 of these are associated with life-threatening anaphylactic reactions; immune tolerance induction (ITI) with high-dose FIX conc is often unsuccessful. We present individualized novel approaches to ITI in 2 boys with severe HB and high-responding inhibitors. ELISA assays utilizing recombinant FIX (rFIX) to capture patient IgG followed by detection with subclass specific monoclonal antibodies were developed to evaluate the characteristics of the factor IX inhibitors before, during and following ITI. Patient 1, a 2 yo boy, presented with a subdural hemorrhage; his inhibitor titer was 14 BU. He was treated with recombinant VIIa (rVIIa), 200 mcg/kg followed by 100 mcg/kg q2 hours plus rFIX conc (BeneFix), 1000 U/kg prior to and post subdural hematoma evacuation; a continuous infusion, 40U/kg/hour rFIX conc was started. FIX:C was >100%, so rVIIa was discontinued and the rFIX infusion was continued to maintain FIX:C levels above 50%. Rituximab (375 mg/m2 q week x 4) was started. On the 6th day, he developed anamnesis; plasma FIX:C dropped to the 20% range in spite of increases in his rFIX conc drip to 68 u/kg/hour. Investigation of right leg edema revealed a large thrombus involving the popliteal, iliac and inferior vena cava with pulmonary embolism. In order to remove the inhibitor antibody and achieve plasma FIX levels that would allow safe anticoagulation with heparin, plasmapheresis with an immunoadsorption Protein A sepharose column (Fresenius) was undertaken. FIX:C levels were unexpectedly lower immediately following each cycle. Investigation of FIX: Ag and anti-FIX IgG, IgG1 and IgG4 by ELISA assays before and after each cycle revealed the presence of FIX: Ag and specific anti-FIX IgG in the column eluates. After the 5th cycle, increasing FIX:C levels allowed weaning of the rFIX conc; the thromboses completely resolved. The patient currently is on standard prophylactic doses of rFIX conc with expected recoveries with no evidence of inhibitor. Patient 2 was a 9 year old boy with a high responding anaphylactoid inhibitor; he had severe and frequent hemarthroses treated with rVIIa with variable success resulting in significant hemophilic arthropathy. He had previously received 2 courses of rituximab with recurrence of inhibitor 3 weeks post-therapy. Therefore, in order to suppress T-cell as well as B-cell immune responses, after desensitization with increasing infusions of rFIX conc, he was treated with cyclophosphamide (10 mg/kg IV on days 2, 3 and PO on days 4 and 5) a standard course of rituximab (375 mg/m2 on days 1, 8, 15, 22), IVIG (100 mg/kg on days 2–5) initially, and high dose rFIX conc, 100U/kg/day. He is now maintained on every-other monthly doses of rituximab and replacement doses of IVIG. As FIX levels rose during ITI, rFIX conc was weaned; eight months after initiation of ITI, he has expected recoveries of FIX: C on standard prophylactic doses of rFIX conc. Investigation of the nature of the patient's inhibitors revealed that both patients had high titer IgG1 and IgG 4 anti-factor IX antibodies that disappeared after ITI. Unlike the persistence of non-inhibitory IgG4 factor VIII antibodies reported in some patients with hemophilia A, in these two patients, there was no detectable FIX-specific pan-IgG, IgG1 or IgG4 following ITI. We conclude that novel approaches to ITI can be successfully undertaken in severe HB patients with high titer factor IX inhibitors.

Immune Tolerance Induction in 28 Children with Hemophilia Awith Inhibitors.

Aim: To study the characteristics, treatment, and outcome of patients with hemophilia with inhibitors who have undergone immune tolerance induction (ITI) at the Children's Hospital of Michigan over the past 14 years.Methods: In compliance with local IRB regulations, patient charts and laboratory databases were reviewed and salient data extracted. 28 boys underwent 29 attempts at immune tolerance induction.Results:Hemophilia A26 boys with severe hemophilia A with inhibitors underwent 27 trials of ITI. In this cohort of 26 patients the average age at which patients developed an inhibitor was 22 months and the average age at start of ITI was 5 years 4 months (range 2 months to 17 years 5 months). The average number of exposure days prior to inhibitor development was 10 (1–47). The average time between development of an inhibitor and initiation of ITI was 43 months, with no difference between those who successfully completed ITI and those who did not. Six patients had low titer inhibitors (0.8–6.5 BU) and successfully completed ITI using a modified low dose ITI regimen of factor infusions 3–7 times per week. 20 of the patients with high titer inhibitors (6.4–1280 BU) were treated with daily infusions of 50–200 units/kg/d of factor VIII (FVIII) products. For ITI, 4 patients received high purity plasma derived FVIII (PD-FVIII) and 21 received recombinant FVIII (rFVIII) and one received both. In patients who became tolerized to FVIII, the average time to achieve an inhibitor titer of 0 Bethesda Units (BU) was 211 days. In those who were unable to achieve tolerance, the average length of the trial was 263 days. 21 of the ITI trials employed a central venous catheter and in 5 patients ITI was stopped after removal of the line because of recurrent infections. 14 boys received FEIBA, rFVIIa, or porcine FVIII for bleeding episodes during ITI; 8 of them failed ITI and one is still on therapy. Seven trials of ITI were in Caucasian patients (26 %), 17 in African American (AA) (63 %), and 3 in Middle Eastern patients (11 %). 19 patients achieved complete tolerance (73 %), 6 patients failed (23 %), one failed twice, and one patient continues on therapy. All but 2 patients who successfully completed ITI went on prophylaxis with FVIII. All patients who successfully completed ITI have maintained tolerance with a mean follow-up of 101 months (range 7–168).Table I:Hemophilia AFailed ITISuccessful ITINumber of trials*7 (23 %)19 (73 %)African Americans7 (41 %)10 (59 %)Non-AA010 (100 %)Historical Peak Titer (mean)345 BU47 BUTiter at Start of ITI (mean)62 BU5 BUPeak Titer on ITI (mean)168 BU46 BUAge at inhibitor development (mean)26 months12 monthsITI with PD-FVIII14ITI with rFVIII715*One still ongoingHemophilia BDuring this time period, 2 boys with severe hemophilia B underwent ITI. Both had severe allergic reactions at the time of inhibitor development; both underwent desensitization successfully but both failed ITI. Both started ITI with plasma derived factor nine at age 15 months. One developed nephrotic syndrome while on ITI.Conclusions:Most patients with Hemophilia A were able to achieve and maintain tolerance (73%). Higher titer inhibitors, hemophilia B, younger age at development of inhibitor, AA race and treatment of bleeds with bypass agents or porcine factor while on ITI were risk factors for ITI failures. Loss of central venous access with recurrent infections was also a common reason for ITI failure.