New predictive approaches for ITI treatment

Abstract

Summary Immune tolerance induction (ITI) therapy in patients with haemophilia A and inhibitors constitutes a huge burden for affected patients and families and poses a large economic burden for a chronic disease. Concerted research efforts are attempting to optimize the therapeutic approach to the prevention and eradication of inhibitors. The Italian ITI Registry has provided data on 110 patients who completed ITI therapy as at July 2013. Analysis of independent predictors of success showed that, together with previously recognized factors – namely inhibitor titre prior to ITI, historical peak titre and peak titre on ITI – the type of causative FVIII gene mutation also contributes to the identification of patients with good prognosis and may be useful to optimize candidate selection and treatment regimens. Numerous studies have demonstrated that inhibitor reactivity against different FVIII products varies and is lower against concentrates containing von Willebrand factor (VWF). An Italian study compared inhibitor titres against a panel of FVIII concentrates in vitro and correlated titres with the capacity to inhibit maximum thrombin generation as measured by the thrombin generation assay (TGA). Observations led to the design of the PredictTGA study which aims to correlate TGA results with epitope specificity, inhibitor reactivity against different FVIII concentrates and clinical data in inhibitor patients receiving FVIII in the context of ITI or as prophylactic/on demand treatment. At the immunological level, it is known that T cells drive inhibitor development and that B cells secrete FVIII‐specific antibodies. As understanding increases about the immunological response in ITI, it is becoming apparent that modulation of T‐cell‐ and B‐cell‐mediated responses offers a range of potential new and specific approaches to prevent and eliminate inhibitors as well as individualize ITI therapy.

Distinguishing lupus anticoagulants from factor VIII inhibitors in haemophilic and non‐haemophilic patients

“…The two samples negative for anti‐FVIII IgG4 were the initial and final samples from a single patient (H8), who developed anti‐FVIII IgG4 (and was successfully tolerized) in the interim. It has been previously reported that anti‐FVIII IgG4 antibodies are typically observed only in samples with high‐titre inhibitors, whereas low‐titre inhibitors are predominantly anti‐FVIII IgG1‐positive . Our study using the FLI found the vast majority of low‐titre inhibitor samples to be both anti‐FVIII IgG1 and IgG4 positive .…”

“…antibodies are typically observed only in samples with high-titre inhibitors, whereas low-titre inhibitors are predominantly anti-FVIII IgG1-positive. 22,23 Our study using the FLI found the vast majority of low-titre inhibitor samples to be both anti-FVIII IgG1 and IgG4 positive. 3 Samples from subjects H9, H10 and H11 show the value of performing additional testing in questionable cases.…”

A longitudinal evaluation of anti‐FVIII antibodies demonstrated IgG4 subclass is mainly correlated with high‐titre inhibitor in haemophilia A patients

“…The correlation between inhibitor and IgG4 were r* 0.949, r* 0.803, r* 0.866, patients 2, 3 and 5 respectively (*Spearman correlation). discussion regarding the better success rates when FVIII concentrates containing VWF is used in ITI protocols [19,20].…”

Heat treatment of samples improve the performance of the Nijmegen–Bethesda assay in hemophilia A patients undergoing immune tolerance induction

“…However, ITI is a complex and often longlasting therapy, involving a fair amount of human and material resources. Inhibitor titers measured by the Nijmegen-Bethesda assay are the most important parameter for ITI management, thus, the accuracy of this assay can be regarded as a critical determinant of ITI success [6]. In this study, we demonstrated that heat treatment of plasma samples improved the sensitivity of the Nijmegen-Bethesda method, particularly in patients who were recently exposed to FVIII concentrates, as during ITI treatment.…”