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

Treatment of haemophilia A with FVIII replacement has evolved over the past decades to adapt to the needs of patients. octanate®, a plasma-derived, double virus-inactivated, von Willebrand factor (VWF)-containing FVIII concentrate, has been used in clinics worldwide for over 20 years. First licensed in 1998 in Germany, octanate® is approved in over 80 countries for the prevention and treatment of bleeding and for surgical prophylaxis in patients with haemophilia A, and in over 40 countries for immune tolerance induction (ITI). The manufacturing process for octanate® was developed to ensure high viral safety and effectively eliminates both enveloped and nonenveloped viruses. Over the past 20 years, the excellent safety and efficacy of octanate® have been demonstrated in pivotal clinical trials in adult and paediatric previously treated patients (PTPs) for on-demand treatment, prophylaxis and as surgical cover. Importantly, octanate® has displayed low immunogenicity in previously untreated patients (PUPs), with only 9.8% of PUPs developing FVIII inhibitors. octanate® has also shown to be highly effective in inhibitor elimination when used as ITI therapy. In a population of patients with high risk of ITI failure, success was achieved in 79.2% of patients (70.8% complete success), even when using exceptionally stringent success criteria. No relapses were observed. Here we present an overview of the clinical data with octanate® that support its use in a range of patient populations and clinical indications.

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Immune tolerance induction with high von Willebrand factor/factor VIII content ratio concentrate in children with haemophilia A and high-responding inhibitor

Haemophilia ◽

10.1111/j.1365-2516.2008.01965.x ◽

2009 ◽

Vol 15 (2) ◽

pp. 617-619 ◽

Cited By ~ 3

Author(s):

H. PLATOKOUKI ◽

H. PERGANTOU ◽

P. XAFAKI ◽

A. KOMITOPOULOU ◽

S. ARONIS

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Immune Tolerance ◽

Tolerance Induction ◽

Haemophilia A ◽

Immune Tolerance Induction ◽

Content Ratio ◽

Von Willebrand ◽

Willebrand Factor

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Von Willebrand factor-containing factor VIII concentrates and inhibitors in haemophilia A

Thrombosis and Haemostasis ◽

10.1160/th10-03-0151 ◽

2010 ◽

Vol 104 (11) ◽

pp. 931-940 ◽

Cited By ~ 28

Author(s):

Giuseppe Lippi ◽

Massimo Franchini

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Immune Tolerance ◽

High Titer ◽

Tolerance Induction ◽

Haemophilia A ◽

Immune Tolerance Induction ◽

Bleeding Episodes ◽

Von Willebrand ◽

Willebrand Factor

SummaryThe development of inhibitors that neutralise the function of factor VIII (FVIII) is currently not only the most challenging complication associated with the treatment of haemophilia A but it also increases the disease-related morbidity as bleeding episodes do not respond to standard therapy. The main short-term goal of the treatment of inhibitor patients is to control bleeding episodes while the long-term one is to permanently eradicate the inhibitor by immune tolerance induction, particularly in the case of high-titer antibodies. Due to some in vitro studies and clinical observations, some investigators have suggested that FVIII concentrates containing von Willebrand factor (VWF) may be less immunogenic than high-purity or recombinant FVIII products. It has also been suggested that success rates for immune tolerance induction are higher when plasma-derived FVIII products are used. The currently available data from laboratory and clinical studies on the role of VWF in inhibitor development and eradication in haemophilia A is critically analysed in this review. As a result, we have not found definitive evidence supporting a role for product type on inhibitor incidence and inhibitor eradication in haemophilia A patients.

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Immune tolerance therapy utilizing factor VIII/von Willebrand factor concentrate in haemophilia A patients with high titre factor VIII inhibitors

Haemophilia ◽

10.1111/j.1365-2516.2007.01560.x ◽

2007 ◽

Vol 0 (0) ◽

pp. 071018054549002-???

Author(s):

M. A. H. KURTH ◽

D. DIMICHELE ◽

C. SEXAUER ◽

J. M. SANDERS ◽

M. TORRES ◽

...

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Immune Tolerance ◽

High Titre ◽

Haemophilia A ◽

Factor Concentrate ◽

Von Willebrand ◽

Willebrand Factor

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Risk Factors for the Progression from Low to High Titres in 260 Children with Severe Haemophilia A and Newly Developed Inhibitors

Thrombosis and Haemostasis ◽

10.1160/th17-01-0059 ◽

2017 ◽

Vol 117 (12) ◽

pp. 2274-2282 ◽

Cited By ~ 5

Author(s):

Maria Elisa Mancuso ◽

Kathelijn Fischer ◽

Elena Santagostino ◽

Johannes Oldenburg ◽

Helen Platokouki ◽

...

Keyword(s):

Risk Factors ◽

Immune Tolerance ◽

Laboratory Data ◽

Tolerance Induction ◽

High Titre ◽

High Dose ◽

Haemophilia A ◽

Severe Haemophilia ◽

Immune Tolerance Induction ◽

Potential Risk Factors

AbstractIn children with severe haemophilia A, inhibitors to factor VIII (FVIII) usually develop during the first 50 treatment exposure days and are classified as low or high titre depending on the peak inhibitor titre being greater or less than 5 Bethesda units/mL (BU/mL). Classification of the inhibitor may change with time, as some low-titre inhibitors progress to high titre following re-exposure to FVIII concentrate. The aim of this study was to investigate potential risk factors for such a progression in children with severe haemophilia A and newly diagnosed inhibitors. This study was a follow-up study of the PedNet Registry and included 260 children with severe haemophilia A and inhibitors born between 1990 and 2009 and recruited consecutively from 31 haemophilia centres. Clinical and laboratory data were collected from the date of each child's first positive inhibitor test for at least 3 years. At the time of first positive inhibitor test, 49% (n = 127) had low-titre inhibitors, with 50% of them progressing to high titre and only 25% maintaining low titres. The FVIII gene (F8) mutation type was known in 247 patients (95%), and included 202 (82%) null mutations. The progression to high-titre inhibitors was associated with null F8 mutations (odds ratio [OR]: 2.6; 95% confidence interval [CI]: 1.0–6.5), family history of inhibitors (OR: 7.2; 95% CI: 1.8–28.4) and the use of high-dose immune tolerance induction, defined as ≥100 IU FVIII concentrate/kg/d (OR: 3.9; 95% CI: 1.5–10.0). These results suggest that high-dose immune tolerance induction should be avoided as the initial strategy in patients who develop low-titre FVIII inhibitors.

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