Immune tolerance induction in the treatment of paediatric haemophilia A patients with factor VIII inhibitors

Abstract

The development of an inhibitor to transfused factor VIII (FVIII) is a serious treatment-related problem in haemophiliac children. The management of patients with high titre FVIII inhibitors is difficult, and immune tolerance induction (ITI) is the only method available for the eradication of these inhibitors. The results of the ITI regimen used at the Children's Hospital of Michigan Haemophilia Treatment Center are described and discussed. ITI was attempted in 14 children with severe haemophilia A (13 high responders, one low responder), with daily doses of FVIII alone. FVIII dosage was chosen according to the patient's historical peak inhibitor titre. ITI included three phases; induction phase, dose reduction phase and maintenance phase. During the first phase, the starting dose was 50 or 100 U kg-1 d-1; during the second phase the FVIII dosage was reduced gradually to 25 U kg-1 every other day according to the inhibitor titre, FVIII recovery and/or half-life study. In the third (maintenance) phase, the children received either prophylactic therapy or episodic therapy for 12 months. The inhibitor elimination was defined as the time taken to achieve a negative inhibitor assay with no anamnestic response and normal FVIII recovery and/or normal half-life. Immune tolerance was achieved in 11 of 14 patients (79%) patients within a median time of 6 months; two children are still on therapy, three failed ITI. We observed either failure or prolongation of immune tolerance if the historical peak titre or the maximum titre during ITI was >200 BU. The success rate of our low dose ITI regimen is not different from that reported by other investigators and the inhibitor elimination time is similar to some of the studies reported previously.

Optimizing management of immune tolerance induction in patients with severe haemophilia A and inhibitors: towards evidence‐based approaches

“…Relapse rates ranging from 3AE8% to 12AE5% have been reported in the small retrospective series (Mauser-Bunschoten et al, 1995;Batlle et al, 1999;Unuvar et al, 2000;Rocino et al, 2006) over variable follow-up periods (5-8AE5 years). In the IITR, six of 128 patients (4AE7%) who achieved the normalization of FVIII pharmacokinetics, relapsed 1-15 years after ITI success (Mariani & Kroner, 2001).…”

“…The original van Creveld Clinic protocol involved a neutralizing FVIII treatment during the first 1-2 weeks, followed by FVIII infusions on alternate days (van Leeuwen et al, 1986). In addition, a number of other low or intermediate FVIII dose regimens (£100 iu/kg/d) have been used (Ewing et al, 1988;Kucharski et al, 1996;Unuvar et al, 2000;Rocino et al, 2001) in the attempt to improve the costeffectiveness of ITI treatment (Table I). In some cases, the association of immune modulating agents was still proposed (Gruppo et al, 1992;Batlle et al, 1999).…”

Long-term induction of immune tolerance after blockade of CD40-CD40L interaction in a mouse model of hemophilia A

“…3,4 Patients with such antibodies require additional therapies to eliminate the undesired anti-fVIII immune response. The current strategy to induce immune tolerance is frequent infusions of high doses of fVIII, 5,6 and this is usually successful but very expensive. 7 In this study, we have used fVIII knockout mice generated by targeted disruption of exon 16 of the fVIII gene.…”

Syngeneic transplantation of hematopoietic stem cells that are genetically modified to express factor VIII in platelets restores hemostasis to hemophilia A mice with preexisting FVIII immunity

“…11 Induction of immune tolerance to the FVIII protein is a treatment option for the eradication of anti-FVIII inhibitors, but it is very expensive and may not always be effective. [12][13][14] Infusion of NovoSeven (FVIIa) may also restore hemostasis in patients with inhibitors, but it is more costly because of its short half life and may result in thrombotic complications. [15][16][17] Gene therapy could be an alternative treatment for hemophilia A.…”