Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach

Abstract

To cite this article: DiMichele D. Immune tolerance therapy for factor VIII inhibitors: moving from empiricism to an evidence-based approach. Summary. Currently, the only proven strategy for achieving antigen-specific tolerance to factor VIII (FVIII) is immune tolerance induction (ITI) therapy. This paper discusses our current knowledge of the host and treatment factors, as well as supportive care initiatives, known or suspected to influence the outcome of ITI in the treatment of inhibitors arising in patients with severe hemophilia A. Among these, questions surrounding the choice of therapeutic product and/or dosing regimen generate the most controversy, given the lack of a definitive evidence-based approach to either. Furthermore, the potential for central venous access device (CVAD) and intercurrent bleeding complications to impact the ultimate success of ITI remains unclear. The ongoing clinical trials designed to further clarify several of these polarizing issues are reviewed. This paper also explores the current and future role of immune modulation in possible salvage, ancillary or primary alternative tolerance induction strategies. The special cases of low titer/ responding inhibitors and inhibitors developing in mild hemophilia A patients are considered. Finally, this paper summarizes the currently recommended approach to ITI and makes the case for a move from empiric therapeutics to a risk-stratified evidencebased approach to FVIII inhibitor eradication.

AAV liver expression of FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in hemophilia B dogs and mice

“…Systemic complications associated with inhibitory antibodies to FIX include anaphylactic reaction and nephrotic syndrome. 30,31 Importantly, Wiley showed no evidence of abnormal kidney function or urinary protein loss (data not shown). To confirm the eradication of inhibitory antibody to cFIX and immune tolerance induction, Wiley was challenged with 0.5 mg cFIX-WT protein concentrate 2.3 years after vector injection.…”

Adjuvant facilitates tolerance induction to factor VIII in hemophilic mice through a Foxp3-independent mechanism that relies on IL-10

“…This has led to an increasing interest in developing new protocols for the induction of tolerance to therapeutically administered clotting factors. 3 Recent clinical trials have explored the putative higher tolerogenicity of factor VIII (FVIII) coupled with von Willebrand factor or B-cell depletion with the anti-CD20 monoclonal antibody (mAb) rituximab. 4,5 The outcome of those trials has shown, at the most, a modest improvement in ITI efficacy.…”

The History and Evolution of the Clinical Effectiveness of Haemophilia Type A Treatment: A Systematic Review

“…Several factors have been related to the development of inhibitors, the most strongly associated is a type of genetic mutation of FVIII, as well as the type of Human Leucocitary Antigen (HLA) and the polymorphisms in the genes codified for cytokines (African or Hispanic background) of each individual [34], as well as the type of replacement therapy used and the age of starting up. In a study by Santagostino and Mancuso [20], 25 out of 108 children with haemophilia received prophylaxis and had a lower inhibitor risk than those treated on-demand (adjusted OR 0.2; CI: 0.06-0.9), suggesting a protective effect of prophylaxis from inhibitor development.…”