Primary Immune Tolerance Induction Research Articles

Immune Tolerance Induction (ITI) with a pdFVIII/VWF Concentrate (octanate) in 100 Patients in the Observational ITI (ObsITI) Study.

Background Immune tolerance induction (ITI) with repeated factor VIII (FVIII) administration is the only strategy proven to eradicate inhibitors. The observational ITI study is evaluating ITI with a range of FVIII products. Methods This subgroup analysis reports prospective interim data for patients treated with a plasma-derived, von Willebrand factor-stabilized FVIII concentrate (pdFVIII/VWF, octanate). Complete success (CS) of ITI required achievement of three criteria: inhibitor titer < 0.6 BU/mL; FVIII recovery ≥ 66%; FVIII half-life ≥6 hours. Partial success (PS) required achievement of two criteria and partial response (PR) one. ITI success was defined as CS or PS. Data were analyzed for patients who achieved CS, had 36 months' observation, or failed ITI. Results One-hundred prospectively enrolled patients were included in the analysis; 91 had poor prognosis factors for ITI success. The mean (standard deviation) daily ITI dose was 116.4 (61.1) IU FVIII/kg in 14 low responders (< 5 BU/mL) and 173.7 (112.0) IU FVIII/kg in 86 high responders (≥ 5 BU/mL). Inhibitor titers < 0.6 BU/mL were achieved in 71% of patients in a median of 4.01 months, accompanied by a 93% reduction in bleeding rate. ITI success was achieved by 70% of patients and 56 of 72 (78%) primary (first-line) ITI patients. PR was achieved by 5 patients; ITI failed in 25 patients. PS and CS were achieved in a median of 5.55 and 11.25 months, respectively. Conclusions ITI with pdFVIII/VWF led to rapid eradication of FVIII inhibitors, normalization of FVIII pharmacokinetics in the majority of patients, and a significant reduction in bleeding rates.

Immune Tolerance Induction Experience from a Single Institute in the United Arab Emirates

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

Predictors of inhibitor eradication by primary immune tolerance induction in severe haemophilia A with high responding inhibitors.

Immune tolerance induction (ITI) is the only proven strategy to eradicate factor VIII inhibitors in patients with haemophilia A (HA). To identify patients and treatment options with the highest chance of inhibitor eradication by primary ITI. In the frame of the Italian ITI Registry, carried out from 1995 to 2015 (last follow-up 2018), 137 primary ITI courses in severe HA patients (90/137 with poor prognosis) were analysed for predictors of outcome (complete/partial response or failure). Sixty-six of them (48%) were prospectively evaluated. ITI was successful in 91/137 patients (66.4%) and 70 (51.1%) achieved complete response within 11 months (median). Historical peak titres ≤200 BU/ml (P=.033), inhibitor titres ≤5 BU/ml at ITI start (P=.001), peak titres ≤100 BU/ml during ITI (P<.001) and missense mutations and small insertions/deletions of FVIII gene (P=.027) predicted complete inhibitor eradication. A score that considers the cumulative number of these variables predicted complete response with positive predictive values up to .81 at ITI start and .91 during ITI, respectively. Patients who had no bleeding (OR, 3.45, 95% CI: 1.4-8.6) nor other adverse events (OR 2.6, 95%CI: 1.3-5.3) during ITI had higher chances of complete response. During the 120-month follow-up (median), 2/70 patients who had achieved complete response relapsed (2.9%). This Registry, with a centralized review of outcomes, homogeneous data collection (half of which prospective) and long-term follow-up, provides insights for optimizing ITI, with a rationale for further studies in the currently evolving scenario of inhibitor management in HA patients.

Results of a prospective observation on the use of a coagulation factor concentrate VIII concentrate (Octanate®) for the induction of immunological tolerance in patients with an inhibitory form of hemophilia A

Relevance. Immune tolerance induction (ITI) is the only approach proven to eradicate inhibitors in hemophilia A patients. ITI with Octanate® (human VWF-stabilized FVIII) has been shown to be effective at eradicating inhibitors, even in poor-prognosis patients. Here we report interim data from two observational, prospective studies on the use of Octanate® for ITI in patients in Russia.Purposes of research. The primary objective was to assess the efficacy of ITI. Secondary objectives included assessment of time to ITI success and inhibitor eradication.Patients and methods. Patients of any age with any severity of hemophilia A and a FVIII inhibitor  0.6 BU/mL were eligible. The ITI regimen was at the discretion of the treating physician.Results. The analysis included 73 patients. ITI outcomes were assessed in 63 patients who had completed the study, of whom 56 (89 %) had  1 poor prognostic factors. Inhibitor eradication was achieved by 77.1 % (37/48) of primary ITI patients and 71.4 % (45/63) of all patients, in a median of 2.4 months (range – 0.0–27.4) for both groups. Complete success was achieved by 72.9 % (35/48) of primary ITI patients in a median of 8.9 months (range – 2.4–28.0) and 66.7 % (42/63) of all patients in a median of 10.5 months (range – 2.4–28.0). No relapses were reported after complete or partial ITI success. Of the patients with  1 poor prognostic factors, 67.9 % achieved inhibitor eradication and 62.5 % complete success.Conclusions. ITI with Octanate® in a real-world setting showed rapid and sustained success, even in patients with poor prognostic factors.

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 &lt;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 &lt;5 BU mL with FVIII recovery &lt;66% and/or FVIII half-life &lt;6 hours associated with clinical response to FVIII therapy not followed by a treatment-limiting anamnestic rise in inhibitors to &gt;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.

Long-Term Follow-up of Hemophilia a Patients Who Previously Showed Complete or Partial Success in Immune Tolerance Induction Therapy with a Single Plasma-Derived FVIII/VWF Product: Long-Term ITI Study

IntroductionInhibitor development against infused FVIII is a serious complication in hemophilia A that greatly increases the risk of developing major bleeding episodes. Immune tolerance induction (ITI) is the standard therapy for the management and eradication of inhibitors and return to effective FVIII therapy. Little evidence exists on the long-term status of patients who eradicated the inhibitor totally or partially by ITI. Therefore, the aim of this study is to investigate the clinical status and sustainability of tolerance in patients who succeeded on ITI therapy.MethodsThe Long-term ITI study was an international, multicenter, observational, retrospective study performed on hemophilia A patients who received primary or rescue ITI therapy using a single pdFVIII/VWF concentrate (Fanhdi®, Grifols, Spain) and who showed partial or total success in the Grifols-ITI study (Oldenburg J et al. Haemophilia 2014;20:83, Rangarajan S et al. J Thromb Haemost 2013;11 suppl 2;1081). In the G-ITI study, 60 patients from Germany, Italy and Spain showed a success rate of 85% and nine other G-ITI patients from UK obtained a 78% of ITI success. Demographics and clinical data relevant for the Long-term ITI study were extracted from the medical records of eligible patients. Primary endpoints were to describe the long-term status and post-ITI outcomes (including comorbidities, joint status, bleeding episodes, inhibitor relapses, venous access complications, hospitalizations and surgeries). Secondary endpoints included regular hemophilia therapy as well adjuvant and concomitant therapy used. Statistical analysis performed was descriptive.ResultsForty-four out of the 57 eligible patients signed the informed consent and were included in the study. The mean follow up period after ITI success was 9.3 ±3.3 years (range: 2.1-17.7). At least one co-morbidity was reported in 17 (38.6%) patients, which included liver and lung cancer, hypertension, liver disease, hepatitis C and HIV infection. Twenty-one (47.7%) patients had a total of 37 affected -joints of which 5 patients had 2 affected joints, 1 patient had 3 affected joints and 3 patients had 4 affected joints. In 38 (86.4%) patients at least 1 bleeding episode was reported (mean annual bleeding rate: 1.0±1.2; range 0.1-3.9). A total of 330 bleeding episodes were described, of which 271 were treated with Fanhdi. Four (9.0%) patients had inhibitor relapse. Of those, 2 patients did not attempt rescue ITI because in one case the inhibitor (0.5 BU) disappeared after the next infusion with Fanhdi, and the other was considered of low titer (3.5 BU). The 2 patients who attempted rescue ITI (one under prophylaxis with Kogenate and the other treated on demand with Emoclot at the time of inhibitor relapse) were both successfully tolerized, one completely after 3.9 months of ITI with Fanhdi and the other partially after 9.1 months of ITI with Haemate P. Twenty venous access complications were reported in 10 (22.7%) patients. Thirty-nine surgical/invasive procedures were reported in 22 (50.0%) patients, 37 procedures requiring extra treatment with FVIII (Fanhdi), 25 of them for more than 3 days and 14 for more than 5 days. Hospitalizations reported were 79, 17 of them due to bleeding, 18 due to venous access complications, 33 due to surgical/invasive procedures, and 11 due to other reasons. Treatment product for hemophilia after ITI success was always Fanhdi in 29 (65.9%) patients, while 13 (29.5%) other patients were first treated with Fanhdi and then switched to other FVIII products, and 2 patients were immediately switched post-ITI to other FVIII products. The most common regimen used was prophylaxis (42 patients, 95.4%), and the most common treatment frequency was every 48 hours (16 patients, 36.4%). The FVIII dose ranged from 20 to 85 IU/Kg. Use of NSAIDs was reported for 6 patients and immunesuppressors for 5 patients.ConclusionsAfter an average of more than 9 years of post-ITI success follow up of patients participating in the G-ITI Study, all of them continue with regular FVIII treatment for hemophilia. The few inhibitor relapses were successfully overcome. DisclosuresJiménez-Yuste:Baxter, Bayer, CSL-Behring, Grifols, Novo Nordisk, Octapharma and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Oldenburg:Baxter, Bayer, Biogen Idec, Biotest, CSL-Behring, Grifols, Novo Nordisk, Octapharma, Swedish Orphan Biovitrum and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Rangarajan:Baxter, Grifols, Biotest and Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau. Peiró:Grifols: Employment. Santagostino:Bayer, Baxter, Pfizer, CSL Behring, Novo-Nordisk, Sobi/Biogen, Octapharma, Kedrion, Roche and Grifols: Consultancy, Honoraria, Research Funding, Speakers Bureau.

A Case Series Evaluating the Use of a Von Willebrand Factor/Factor VIII Concentrate (Wilate®) for Immune Tolerance Induction (ITI) in Children with Severe Factor VIII Deficiency

Introduction: Development of circulating anti-factor VIII antibodies (inhbitors) is the most serious and challenging complication in the treatment of hemophilia A. Up to 38% of hemophilia patients develop inhibitors with recombinant FVIII (rFVIII) products (Gouw et al. N Engl J Med. 2013; 368:231-239). The presence of inhibitors leads to an increased risk of bleeding, poor physical functioning and quality of life (Benson et al., Eur. J. Haematol. 2012; 88:371-379). Immune tolerance induction (ITI) is the most common method for eliminating inhibitors, historically performed with high dose, and prolonged treatment with plasma-derived (pd), or recombinant FVIII (rFVIII) concentrates. Although ITI for the eradication of inhibitors has become standard of care for hemophilia patients the therapeutic superiority of a particular product type (rFVIII vs. pd-FVIII) has not yet been conclusively demonstrated. In accordance with its role in stabilizing FVIII, the presence of von Willebrand factor (VWF) in pd-FVIII concentrates has been shown to improve the outcome of ITI. Wilate® (Octapharma) is a high-purity human plasma derived complex containing two proteins (VWF and FVIII) in a 1:1 ratio. The aim of this study was to determine the effectiveness of Wilate for primary ITI therapy for six patients with severe hemophilia A.Patients and Methods: The case history for six pediatric hemophilia A patients prior to and during primary Wilate ITI was reviewed. For 5/6 patients, inhibitors developed during rFVIII factor replacement therapy. For the sixth patient, inhibitors were detected at the time of hemophilia diagnosis. ITI began once patients achieved an inhibitor titer of less than 10 BU/mL. The ITI dosing regimen ranged from 50-60 IU/Kg of Wilate three times per week to 200 IU/Kg once daily. Inhibitor titers were measured regularly, prior to and during ITI using the Nijmegen-Bethesda assay. The number of port-a-cath infections and bleeding episodes were also monitored. ITI success was defined as: an undetectable inhibitor level (<0.6 BU/mL), FVIII plasma recovery ≥ 66% of predicted, and FVIII half-life ≥6 hours.Results: Wilate ITI was well tolerated in all patients, with no product-related adverse events. All patients had a port-a-cath device inserted for Wilate injections. Two port-a-cath infections occurred during ITI. Five of six patients had poor prognostic factors for ITI outcome. These poor prognostic factors included a high-risk FVIII gene mutation, historical peak inhibitor titer greater than 50 BU/mL, age of ITI onset greater than 6 years, and ITI onset more than 12 months from inhibitor development. The frequency of these poor prognostic factors varied amongst the patients: 1 patient had 4, 1 patient had 2, and 3 patients presented with 1 poor prognostic factor. Despite the presence of these high-risk factors, Wilate was successful at reducing the inhibitor titers to undetectable levels in all patients. Furthermore, inhibitor titers have remained low or undetectable without significant spikes for the duration of treatment. Patient plasma recovery and FVIII half-life results have also indicated that patients are progressing towards successful ITI. Importantly, for 6/6 patients (including 3 patients who had previously been treated with Anti-Inhibitor Coagulant Complex (FEIBA) prophylaxis therapy) - Wilate therapy was successful at reducing the number of bleeding episodes allowing for the cessation of FEIBA prophylaxis. Since commencing Wilate ITI, 6/6 patients have not reported any major bleeding episodes. The improved clinical outcome was perceived by the patients as an improved well-being, and quality of life.Conclusion: Wilate ITI was found to be well tolerated, safe, and successful at reducing inhibitor levels to below the detectable range for six severe hemophilia A patients. Patients experienced no treatment related adverse events, had a low rate of port-a-cath infections, and did not present with any major bleeding episodes while on Wilate ITI. In light of the 3-5 fold increase in overall treatment costs of immune tolerance induction, careful consideration should be given to choice of product (rFVIII versus pd-FVIII) – especially for patients at high-risk of failure. (Dimichele et al. Haemophilia 2004: 10 Suppl 4;140-145). The present data suggest that Wilate, a pd-FVIII product, is effective in managing patients with inhibitors. DisclosuresBelletrutti:Baxter Canada: Honoraria, Membership on an entity’s Board of Directors or advisory committees; CSL Behring Canada: Honoraria.

Immune tolerance induction using a factor VIII/von Willebrand factor concentrate (BIOSTATE®), with or without immunosuppression, in Australian paediatric severe haemophilia A patients with high titre inhibitors: A multicentre, retrospective study

IntroductionIt has been postulated that factor VIII (FVIII) products containing von Willebrand factor (VWF) may improve immune tolerance induction (ITI) success rate in patients with haemophilia A and poor prognostic factors. Materials and methodsWe conducted a retrospective cohort analysis of a FVIII/VWF concentrate (BIOSTATE®) for ITI in paediatric patients with severe haemophilia A (SHA) and inhibitors, from January 2003 to December 2011 at 3 paediatric-only Haemophilia Treatment Centres in Australia. Response to ITI was assessed at or before 33months and at completion of ITI. Fifteen male patients with SHA were included in the analysis. ResultsBIOSTATE was used for primary ITI in 8 patients (2years, range 1.1–11.5years) and for salvage ITI in 7 patients (9.9years, range 1.1–15.4). At the end of the observation period there were 11 patients who achieved a complete response with BIOSTATE after a median duration of 21months (range 5–85months); a partial response was achieved in 2 patients in whom ITI is ongoing. Therefore, the overall response rate was 86.6%. Two patients were deemed treatment failures: one due to non-compliance after 18months of ITI and another in whom a partial response had not been achieved after 22months of ITI. ConclusionBIOSTATE was well-tolerated and effective when used for primary or salvage ITI in this cohort of paediatric patients with SHA and a high-level inhibitor.

ITI choice for the optimal management of inhibitor patients - from a clinical and pharmacoeconomic perspective.

The development of alloantibody inhibitors against factor VIII (FVIII) represents the most significant complication of haemophilia care. Inhibitors tend to develop early in the course of treatment in about 20-30% of patients with severe haemophilia who receive on-demand or prophylactic FVIII therapy. Many factors are associated with inhibitor formation, including disease severity, major FVIII gene defects, family history and non-Caucasian race, as well as age at first treatment, intensity of early treatment, use of prophylaxis and product choice. As these latter treatment-related variables are modifiable, they provide opportunity to minimize inhibitor incidence at the clinical level. Data from the Bonn Centre in Germany have indicated an overall success rate of 78% for immune tolerance induction (ITI) therapy, with a failure rate of 15% and with some treatments either ongoing (3%) or withdrawn (4%). Similarly, data from the G-ITI study, the largest international multicentre ITI study using a single plasma-derived (pd) FVIII/von Willebrand factor (VWF) product, have demonstrated success rates (complete and partial) in primary and rescue ITI of 87% and 74%, respectively, with 85% of poor prognosis patients achieving success. Favourable clinical results based on success rates and time to tolerization continue to be reported for use of pdFVIII/VWF in ITI, with pdFVIII/VWF having a particular role in patients who require rescue ITI and those with a poor prognosis for success. Data from prospective, randomized, controlled clinical studies, such as RES.I.ST (Rescue Immune Tolerance Study), are eagerly awaited. Another factor to consider with ITI therapy is cost; preliminary data from an updated decision analytic model have provided early evidence that ITI has an economic advantage compared with on-demand or prophylactic therapy.

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.

Economic Comparison Of Treating Hemophilia Patients Who Have Developed Inhibitors Via Immune Tolerance Induction Versus Prophylaxis and On-Demand Treatment With Bypassing Agents

▪ ObjectiveThe most serious complication of treatment for patients with severe hemophilia A is the development of FVIII alloantibody inhibitors. Treating hemophilia is expensive at best; however, incurring an inhibitor substantially increases those costs. As a result, a cost-efficient strategy for treating patients with inhibitors is desirable. Three approaches have been used to treat patients with inhibitors: 1) administer bypassing agents such as activated prothrombin complex concentrate (aPCC) or activated recombinant factor VII (rFVIIa) only when a bleed occurs (on-demand); 2) administer bypassing agents prophylactically to prevent bleeds from occurring; or 3) initiate immune tolerance induction (ITI) with factor VIII (FVIII) concentrate in an attempt to eradicate the inhibitor and then long term follow up with a lower dose prophylaxis regimen to maintain the inhibitor free status. In this study, we compare the costs and outcomes of these treatment strategies in order to assist healthcare providers in making more informed treatment decisions. MethodsA decision-analytic model (Figure 1) was developed to compare commonly used treatment regimens for severe hemophilia A patients with inhibitors over the course of an average patient's lifetime. On-demand patients were treated for their acute bleeding events with a conventional dose of rFVIIa (based on the FENOC study, a mean of 105 µg/kg) administered every 2-3 hours until the bleed stopped. Patients treated prophylactically received 85 IU/kg of aPCC 3 times per week (from Pro-FEIBA study). The International Immune Tolerance Study compared ITI treatment with either a low dose (50 IU/kg 3 times a week) or a high-dose regimen (200 IU/kg daily) of FVIII concentrate. The high dose regimen was selected for inclusion in this decision-analytic model due to its more rapid induction of immune tolerance with fewer break-through bleeds. When ITI was successful, FVIII replacement dosing was resumed at a prophylactic level (30 IU/kg FVIII 3 times per week). Data from the International and North American ITI Registries were used to estimate the success of inhibitor eradication on ITI. Relapse of inhibitors was assumed to occur in 15% of patients 15 years after inhibitors had been eradicated. Patients who failed primary and secondary ITI or who succeeded and then relapsed were treated prophylactically with bypassing agents (85 IU/kg of aPCC 3 times per week). The rate of reduced bleeding events for patients on prophylaxis was derived from the results observed in previously published clinical studies. The lifetime projections of product dosing requirement considered changes in patient weight over time. Life expectancy was modeled via US life tables and an increased risk of death was ascribed to the presence of inhibitors (as per CDC data reported by Soucie). Costs were obtained from standard US costing sources and are reported in 2013 US dollars. Hemophilia-specific utility weights were estimated from the published literature. Costs and outcomes were discounted at 3% per annum. [Display omitted] ResultsTreating patients with inhibitors via an ITI approach can successfully eradicate the inhibitors 74% of the time. Based on the model, the estimated lifetime costs of treating patients with inhibitors was substantially lower for the ITI approach compared with either treating on-demand or prophylactically with bypassing agents (discounted costs of $22,201,832 versus $38,656,756 and $42,104,865, respectively). In addition, patients treated via ITI are projected to live longer (74.3 years versus 69.6 and 69.6 years, respectively) and have greater discounted quality-adjusted life years (25.1 versus 14.7 and 20.5, respectively). Patients treated via ITI or prophylactically with bypassing agents incur less than half the number of bleeding events over their lifetime compared to patients treated via on-demand therapy (801 and 694 versus 1,819 bleeding events). ConclusionTreating patients via ITI in an attempt to eradicate inhibitors results in lower lifetime costs and a greater number of life years and quality-adjusted life years than when treating on-demand or prophylactically with bypassing agents. Disclosures:Earnshaw:RTI Health Solutions: Employment, Grifols has contracted RTI-HS to do research Other, Research Funding. McDade:Grifols: Research Funding. Spears:Grifols Inc: Employment. Kessler:Baxter: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Grifols: Consultancy, Research Funding; Biogen-Idec: Consultancy; Octapharma: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy.

More than a decade of international experience with a pdFVIII/VWF concentrate in immune tolerance

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

Rescue and Primary ITI in Children and Adults with a Single FVIII/VWF Product

AbstractAbstract 1174 IntroductionInhibitors are the most serious complication of hemophilia A (HA) treatment. Current optimal intervention for inhibitor eradication is immune tolerance induction (ITI), the goal of which is for the patient to resume therapy with FVIII. Basic and clinical research have strongly supported that VWF containing FVIII concentrates may be less immunogenic and are effective in primary ITI as well as for rescue ITI for those who fail to develop tolerance with recombinant proteins. ObjectiveTo assess the outcome of rescue and primary ITI in children (<18 years old) and adults with a single FVIII/VWF product (Fanhdi®, Grifols, Barcelona, Spain). MethodsRetrospective data from HA patients (FVIII< 2%) with inhibitors from 22 centers in Spain, Italy and Germany, who underwent primary or rescue ITI with FVIII/VWF concentrate were evaluated. Success, partial success and failure were defined based on the criteria of the consensus recommendations of the 2006 International ITI Workshop. ResultsThe largest international multicenter study on ITI using a single product has evaluated 41 cases of primary ITI (32 children and 9 adults) and 19 cases of rescue ITI (17 children and 2 adults).Table 1illustrates the overall response rates for children and adults.Table 1Primary ITIRescue ITIChildren (n = 49)Complete Success = 21 (65%)Complete Success = 6 (35%)Primary ITI – n = 32 (65%)Partial Success = 7 (22%)Partial Success = 6 (35%)Rescue ITI – n = 17 (35%)Failure = 4 (13%)Failure = 5 (30%)Adults (n = 11)Complete Success = 5 (56%)Complete Success = 1 (50%)Primary ITI – n = 9 (82%)Partial Success = 3 (33%)Partial Success = 1 (50%)Rescue ITI – n = 2 (18%)Failure = 1 (11%)Failure = 0Table 2describes the rescue and primary ITI outcome for high risk patients. Risk factors for poor response include: failure of a previous ITI, inhibitor peak >200 BU, age at ITI start >7 years old, titer ≥ 10 BU at ITI start and >24 months between diagnosis and start of ITI.Table 2Number of risk factors012345Primary ITI (n=41)Complete success127*2410Partial success212310Failure04*2000Rescue ITI (n=19)Complete success000430Partial success0013*12Failure011111*Time from diagnosis to ITI start not available in 1 patient (this risk factor is not considered in that patient). ConclusionThe response rate of 87% (CS+PS) in primary ITI exceeds that previously reported with any product class. The response rate (CS+PS) of 74% in the higher risk profile of rescue ITI is what one might expect for primary ITI. These excellent results, using a single VWF containing FVIII product, should encourage the use of this class of product for immune tolerance. Acknowledgments:The authors acknowledge Grifols financial support of the study. The authors also acknowledge Drs Jeffrey Spears and Roser Peiro, Grifols, for their editorial assistance in preparation of the abstract. Disclosures:Aledort:Grifols: Advisory Board Other, Honoraria; Kedrion: Advisory Board, Advisory Board Other; Baxter: DSMB, DSMB Other; Octapharma: DSMB, DSMB Other. Off Label Use: This FVIII is not licensed for ITI - nor is any other product. Oldenburg:d and e: Baxter, Bayer, Biotest, CSL-Behring, Grifols, Inspiration, NovoNordisk, Octapharma, Pfizer e: Biogen IDec, Swedish Orphan Biovitrum: Honoraria, Research Funding. Santagostino:Bayer, Baxter, Pfizer, CSL Behring, Novo Nordisk, Biotest, Kedrion and Grifols: Speakers Bureau; Pfizer, Baxter, Bayer, CSL Behring, Kedrion, Grifols and Novo Nordisk: Consultancy; Novo Nordisk and Pfizer: Research Funding. Jimenez Yuste:Grifols, Baxter, Pfizer, NovoNordisk: Advisory Board Other, Consultancy.

The use of a single von Willebrand factor-containing, plasma-derived FVIII product in hemophilia A immune tolerance induction: the US experience.

Inhibitors are a serious complication for patients with severe hemophilia A. Immune tolerance induction (ITI) is the primary method for eradicating these inhibitors. The role of type of concentrate and in particular the use of von Willebrand factor-containing, plasma-derived factor VIII (VWF/pd-FVIII) concentrate in primary or rescue ITI remains unclear. To report retrospective collection of data on the use of a single VWF/pd-FVIII concentrate in primary and rescue ITI. Retrospective chart review of hemophilia A inhibitor patients at 11 US institutions who received VWF/pd-FVIII concentrate in primary or rescue ITI. Primary ITI was carried out in eight inhibitor patients with a 75% complete and partial success. Secondary ITI was carried out in 25 inhibitor patients, with 52% attaining complete or partial success. This report represents the largest group of primarily pediatric, high-titer inhibitor patients treated with a single VWF/pd-FVIII concentrate. It adds retrospective data to the use of VWF-containing plasma-derived factor VIII concentrate in primary and rescue ITI, particularly in those patients with characteristics of poor response to ITI.

The Impact of Factor VIII/von Willebrand Factor Concentrate in Inhibitor Development and Management of Patients with Hemophilia A with Inhibitors

The development of inhibitor antibodies that bind to active sites on the factor VIII (FVIII) molecule and neutralize its function and/or accelerate its clearance is the most serious adverse event and safety issue associated with the treatment of hemophilia A. Inhibitor development complicates hemostasis management and increases morbidity and the cost of treatment because bleeding episodes do not respond to standard replacement therapy. Risk factors for inhibitor development include genetic and non-genetic factors. Immunogenicity of the type of product used for replacement therapy may also play a role. Within the category of human-derived products, the presence of von Willebrand factor (vWF) bound to FVIII (vWF/FVIII products) may reduce its immunogenicity. The challenge for inhibitors is to reduce their incidence and, when present, to facilitate their eradication. Factor-bypassing agents have been used to treat acute bleeds in patients who have inhibitors. Immune tolerance induction (ITI) therapy is an alternative approach whose goal is to create tolerance to inhibitors and return patients to their native state. The use of ITI therapy has raised many questions, including the optimal regimen and cost. The basic science data on reduced immunogenicity of vWF/FVIII-containing products and their success in achieving ITI have given us an incentive to continue to explore this approach to both primary and secondary ITI.

The Impact of Factor VIII/von Willebrand Factor Concentrate in Inhibitor Development and Management of Patients with Hemophilia A with Inhibitors

The development of inhibitor antibodies that bind to active sites on the factor VIII (FVIII) molecule and neutralize its function and/or accelerate its clearance is the most serious adverse event and safety issue associated with the treatment of hemophilia A. Inhibitor development complicates hemostasis management and increases morbidity and the cost of treatment because bleeding episodes do not respond to standard replacement therapy. Risk factors for inhibitor development include genetic and non-genetic factors. Immunogenicity of the type of product used for replacement therapy may also play a role. Within the category of human-derived products, the presence of von Willebrand factor (vWF) bound to FVIII (vWF/FVIII products) may reduce its immunogenicity. The challenge for inhibitors is to reduce their incidence and, when present, to facilitate their eradication. Factor-bypassing agents have been used to treat acute bleeds in patients who have inhibitors. Immune tolerance induction (ITI) therapy is an alternative approach whose goal is to create tolerance to inhibitors and return patients to their native state. The use of ITI therapy has raised many questions, including the optimal regimen and cost. The basic science data on reduced immunogenicity of vWF/FVIII-containing products and their success in achieving ITI have given us an incentive to continue to explore this approach to both primary and secondary ITI.

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.