Immune tolerance induction in patients with severe hemophilia with inhibitors: expert panel views and recommendations for clinical practice

Abstract

Patients with congenital hemophilia require lifelong replacement therapy with a clotting factor concentrate: factor (F) VIII in hemophilia A and FIX in hemophilia B (1). However, patients can develop inhibitors to these exogenous factors, resulting in the most serious treatment related complication in hemophilia (2, 3). Once inhibitors have developed, it is more challenging to achieve hemostasis than in non-inhibitor patients. Furthermore , the presence of inhibitors has a major impact on patients' physical functioning, quality of life, morbidity , and mortality (4-6). In patients with high-titer inhibitors [ ‡5 Bethesda units (BU)], immune tolerance induction (ITI) aims to eradicate anamnestic inhibitors and restore normal responses to replacement therapy. The process of ITI involves regular infusion of FVIII or FIX concentrate with the goal 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 Zü rich 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.

Immune response to enzyme replacement therapies in lysosomal storage diseases and the role of immune tolerance induction

“…Intravenous immune globulin is sometimes included in these regimens as an additional immune modulating agent. Such immune tolerance regimens for patients with inhibitors to factor VIII are reported to have success rates of ranging 51-70% and have the advantage of being nonimmunosuppressive [58,59].…”

“…Hunter syndrome that could place him at an increased risk of bacterial colonization of the heart valves under T cell suppression, a non-cytotoxic target regimen was initiated, consisting of more frequent administration of ERT and IVIG [58]. The regimen was adapted from immune tolerance regimens used in…”

Spanish Consensus Guidelines on prophylaxis with bypassing agents in patients with haemophilia and inhibitors

“…Lack of experience and the absence of evidence-based clinical guidelines may also account for the limited uptake of this approach. To date, recommendations have been largely based on expert opinion (19,(21)(22)(23)(24)(25). However, consensus is still required with respect to key aspects of prophylaxis including the benefit of this approach in relation to ITI.…”

Stratification of Antibody-Positive Subjects by Antibody Level Reveals an Impact of Immunogenicity on Pharmacokinetics

“…Therefore, the inverse relationship between ADA incidence and dose level is probably not due to the interference of circulating drug with ADA detection. Instead, repeated dosing at higher levels may have induced immunological tolerance in the highest-dose group (22) or the drug's mechanism of action may have resulted in an attenuated immune response at the highest dose. Nevertheless, drug interference may have played a role in the observations related to antibody concentration.…”