What is the role of an extended half-life product in immune tolerance induction in a patient with severe hemophilia A and high-titer inhibitors?

Hemophilia A is an X-linked recessive disease characterized by decreased levels of factor VIII (FVIII) that predispose to bleeding, and especially spontaneous bleeding, in patients with severe disease where FVIII levels are <1% (0.01 IU/mL). Up to 30% of patients with severe hemophilia develop inhibitors or alloantibodies that neutralize the activity of FVIII, resulting in difficult-to-control bleeding.¹  The current management of these patients is to treat acute bleeding with agents that bypass the need for FVIII, activated prothrombin complex concentrate, or activated recombinant factor FVII, along with immune tolerance induction (ITI) in order to eradicate the inhibitor. Several protocols of ITI have been published worldwide with approximately a 70% overall success rate.²  Although different factors were studied as possible predictors of ITI success,³  we will focus here on the type of FVIII product and the role of extended half-life product (EHL), especially rFVIIIFc in ITI.

We conducted a search in Embase and Medline, using as keywords “immune tolerance induction in hemophilia” (791 and 416, respectively) and “recombinant FVIIIFc” (112 and 32, respectively). We found a total of 4 articles combined, from which 1 additional reference, covering immunogenicity of EHLs, was taken from the bibliography⁴ : 1 was cited as an abstract with no available full article, 2 were series of case reports, and 1 focused on immunogenicity in hemophilia A mice.

The development of alloantibodies or inhibitors in patients with hemophilia receiving FVIII products is a very complex process. It involves several components of the immune system as well as the FVIII molecule itself and its immunogenicity. What is well known is that T cells drive the inhibitor development that is secreted by B cells as FVIII-specific alloantibodies. ITI with regular prolonged exposure to clotting factor concentrate is the mainstay of treatment of patients with inhibitors in order to induce tolerance and therefore eradicate the alloantibodies. The choice of the product to be used remains challenging with conflicting data about superiority of plasma-derived products over recombinant products. A meta-analysis of 13 studies failed to clarify this matter as most of these studies did not control for other confounding factors, especially pre-ITI risk.⁵  We are left with the lack of randomized trials comparing these 2 classes of products and the emergence of the new EHLs that offer a prolonged half-life of FVIII in the blood along with speculative theories about reduced immunogenicity.

Coupling FVIII with the human Fc fragments confers a prolonged stability and availability of FVIII in the circulation, through the interaction of the Fc domain with neonatal Fc receptors, a mechanism that is well known to protect immunoglobulin G from catabolism.⁶  At the immunogenicity level, so far, available data from clinical trials that were conducted in previously treated patients suggest that FVIIIFc is a safe molecule, as no inhibitors have been reported in these patients.^7,8  Awaiting more clinical data in previously untreated patients and in ITI, the rationale of safely using FVIIIFc products is well supported by published bench work. The Fc fragment of immunoglobulin G contains regulatory T-cell (Treg) epitopes, designated as Tregitopes. These Tregitopes protect the FVIIIFc molecules from the deleterious anti-FVIII immune response by inducing the expansion of Tregs.⁹  Krishnamoorthy et al showed, in FVIII-deficient mice, a decreased immune response to FVIIIFc products.¹⁰ 

As this is a fairly newly approved product, we do not have enough clinical data or randomized trials on its use in ITI. Groomes et al and Malec et al published a series of case reports describing the successful treatment of 4 children with severe hemophilia A and high-titer inhibitor using different doses of rFVIIIFc ITI ranging from 50 to 200 IU/kg per dose.^11,12  Taking into account the very small numbers, and in comparison with historical controls treated on varying protocols, patients treated with rFVIIIFc appeared to achieve recovery at a faster rate than is seen with standard factors.

Based on these considerations, we can conclude that the use of rFVIIIFc in ITI can be considered (grade 2C). This recommendation is based on case reports and strong laboratory data. Randomized controlled trials are needed to better evaluate the efficacy of rFVIIIFc in ITI. While more data accumulate on the role of EHL in ITI, we would encourage consideration of the use of rFVIIIFc to eradicate inhibitors, particularly in refractory patients and those with a high-risk profile (such as those with a family history of failure of ITI with standard factors or history of a high-peak inhibitor).

Maissaa Janbain, 1430 Tulane Ave 8078, New Orleans, LA 70001; e-mail: mjanbain@tulane.edu.