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

Department of Pediatrics, Children's Hospitals and Clinics of Minnesota, Minneapolis, MN 55404, USA.
Journal of Thrombosis and Haemostasis (Impact Factor: 5.72). 08/2011; 9(11):2229-34. DOI: 10.1111/j.1538-7836.2011.04493.x
Source: PubMed


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.

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Available from: Brian Wicklund, Jun 09, 2015
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    • "Similar to this study, these are predominantly small retrospective chart reviews, and include patients with a range of risk profiles receiving both primary and salvage ITI. The largest of these cohorts (Kurth et al) was a multicentre US study that included 33 patients (8 primary ITI) and reported overall response rates of 75% and 52% for primary and secondary ITI, respectively [21]. In addition, Gringeri et al reported results from a prospective study of ITI outcomes using a FVIII/VWF concentrate in 17 high-risk patients, in which CR (53%) or PR (41%) was achieved in all but one patient, including all 4 patients who had previously failed attempted ITI using a non-VWF containing FVIII concentrate [13]. "
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    ABSTRACT: Introduction It 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 methods We 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 33 months and at completion of ITI. Fifteen male patients with SHA were included in the analysis. Results BIOSTATE was used for primary ITI in 8 patients (2 years, range 1.1–11.5 years) and for salvage ITI in 7 patients (9.9 years, 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 21 months (range 5–85 months); 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 18 months of ITI and another in whom a partial response had not been achieved after 22 months of ITI. Conclusion BIOSTATE 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.
    Full-text · Article · Sep 2014 · Thrombosis Research
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    • "Thirteen studies were included in the meta-analysis as the remaining 13 studies did not comply with the inclusion criteria for the meta-analysis. Three studies reported on exclusive use of VWF-containing concentrates (Greninger et al, 2008; Bidlingmaier et al, 2011; Kurth et al, 2011), another three studies exclusively used concentrates devoid of VWF (Batlle et al, 1999; Rocino et al, 2006; Lin et al, 2011) and in the remaining seven studies, both types of concentrates had been used or type of concentrate was not further specified ('mixed') (Smith et al, 1999; Lenk, 2000; Unuvar et al, 2000; Barnes et al, 2006; ter Avest et al, 2010; Callaghan et al, 2011; Hay & Dimichele, 2012). We did not have enough information at patient level about product type to make a comparison between the subjects within the mixed studies that used VWF-containing products and those that were treated with products devoid of VWF. "
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    ABSTRACT: This systematic review was designed to summarize the reported valid quantitative evidence on the association between use of von Willebrand factor (VWF)-containing Factor VIII (FVIII) concentrates and successful immune tolerance induction (ITI) in patients with severe haemophilia A. The primary outcome was successful ITI; secondary outcomes were time to success, complications of the inhibitor or ITI and relapse of the inhibitor. A systematic literature search identified 26 randomized controlled trials, registries and cohort studies, evaluating a total of 1284 patients. For a pooled meta-analysis, 13 studies evaluating 382 patients were included. Due to incomplete data we were not able to assign pre-ITI risk categories to all patients for risk factor analysis. The meta-analysis did not demonstrate a difference in the proportion of patients with successful inhibitor eradication between those treated with VWF-containing products and those treated with FVIII concentrates devoid of VWF (relative risk [RR] 0·70 (95% confidence interval [CI] 0·52-0·89) and 0·84 (95% CI 0·75-0·93) respectively). Bleeding rate during ITI ranged from 0·00 to 0·85 bleeding episodes per year. The proportion of patients with a relapse of the inhibitor (range 0-20%) was mentioned in four studies that were included in the meta-analysis. The results of this systematic review do not support the idea of a positive effect of VWF-containing products in ITI.
    Full-text · Article · May 2014 · British Journal of Haematology
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    ABSTRACT: For hemophilia patients with inhibitors, immune tolerance induction (ITI) may help to restore clinical response to factor (F) VIII or FIX concentrates. Several ITI regimens and protocols exist; however, despite 30 yr of progressive investigation, the ITI evidence base relies mainly on observational data. Expert opinion, experience, and interpretation of the available evidence are therefore valuable to support clinical decision-making. At the Sixth Zürich Haemophilia Forum, an expert panel considered recent data and consensus to distill key practice points relating to ITI. The panel supported current recommendations that, where feasible, ITI should be offered early to children and adults (ideally ≤ 5 yr of inhibitor detection) when inhibitor titers are <10 Bethesda units (BU) and should be stopped when successful tolerance is achieved. For hemophilia A inhibitor patients, ITI can be founded on recombinant FVIII at high doses. The panel considered that patients with a high bleeding frequency should be offered additional prophylaxis with a bypassing agent. For patients with hemophilia B, there may be a benefit of genetic testing to indicate the risk for inhibitors. ITI is often less effective and associated with a greater risk of side effects in these patients. For high-titer inhibitor (≥ 5 BU) hemophilia B patients, the panel advised that bypassing agents could be offered on demand in addition to ITI. Within future ITI regimens, there may be a role for additional immunosuppressant therapies. Participants agreed that research is needed to find alternatives to ITI therapy that offer durable and sustained effects and reduced rates of complications.
    Full-text · Article · Jan 2012 · European Journal Of Haematology
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