Treatment of inhibitors

The development of anti-factor VIII (FVIII) antibodies (inhibitors) is the most serious treatment-related complication in patients with hemophilia A, rendering standard replacement therapy ineffective, heightening the risk for uncontrollable bleeding and morbidity, decreasing quality of life, and increasing healthcare costs.

Current management includes bypassing agents to treat and prevent bleeding and immune tolerance induction (ITI) to attempt inhibitor eradication. For those patients with low responding inhibitors treatment with high doses of FVIII is also an alternative.

Bypassing agents, aPCC and rFVII

  • aPCC is a pooled human plasma derivative that contains factors II, IX and X mainly in non-activated form as well as activated factor VII with approved indications* for:
    • Treatment , prophylaxis and surgical interventions of bleeding in haemophilia A and B patients with Factor VIII and FIX inhibitor.
    • Treatment and prophylaxis of bleeding in non haemophiliacs with acquired inhibitors to Factors VIII, IX, XI.
    • Other uses include patients with an inhibitor to von-Willebrand Factor, and the used in combination with Factor VIII concentrate for long-term therapy to avoid breakthrough bleeding during ITI.
  • rFVII Eptacog alfa (activated) is recombinant coagulation factor VIIa (rFVIIa). Indicated * for the treatment of bleeding episodes and for the prevention of bleeding in those undergoing surgery or invasive procedures in the following patient groups:
    • In patients with congenital haemophilia with inhibitors to coagulation factors VIII or IX > 5 Bethesda Units (BU).
    • In patients with congenital haemophilia who are expected to have a high anamnestic response to factor VIII or factor IX administration.
    • In patients with acquired haemophilia.
    • In patients with congenital FVII deficiency.
    • In patients with Glanzmann's thrombasthenia with antibodies to GP IIb - IIIa and/or HLA, and with past or present refractoriness to platelet transfusions.
Bypassing agents, aPCC and rFVII 1, 2

Immune Tolerance Induction: Eradication of Inhibitor

  • Immune tolerance induction (ITI) is the use of frequent exposure to FVIII until antigen acceptance is achieved and normal replacement FVIII kinetics are restored.
  • The goal of ITI is the permanent eradication of the inhibitor and the restoration of the clinical and biologic efficacy of FVIII concentrates.
  • The major complication experienced by patients with inhibitors is the difficulty to control bleeding, which often can be managed with bypass agents while waiting for immune tolerance to eradicate the inhibitor.
Immune Tolerance Induction: Eradication of Inhibitor

Immune tolerance induction –40 years of experience

  • Experience has shown success rates of between 60% and 80% for patients with hemophilia A administered ITI 1-3
  • Inhibitor eradication is required to ensure a more normal quality of life and reduced long-term morbidity.
Immune tolerance induction –40 years of experience

Classic Immune tolerance protocols

  • Summary of the main classic immune tolerance induction protocols 5

Actual treatments will vary from center to center and most protocols have been based on these classic protocols.

Classic Immune tolerance protocols

Predictors for ITI Success

  • There have been parameters identified retrospectively that can influence both time to successful ITI and success rate in severe hemophilia A patients with high titer inhibitors 6

Adapted from Di Michele DM. 6

Predictors for ITI Success

Effect of Product Type on ITI Success

Despite more than 35 years of clinical experience, the optimal ITI regimen, including the choice of FVIII product for immune tolerance, has not been established largely due to the lack of evidence from large-scale and methodologically rigorous trials 7

Several studies have reported success in patients with poor prognostic factors receiving ITI treatment with both pd FVIII/ VWF concentrates and rFVIII 8-20

Effect of Product Type on ITI Success

The role of VWF in immune tolerance induction with pdFVIII/FVW concentrates

  • There are hypothetical mechanisms that have been proposed to explain why the inclusion of VWF in FVIII concentrates may increase the efficacy of ITI: 21-22
    • FVIII/VWF complex may block anti-FVIII-antibody binding to epitopes located in the VWF-binding A3 and C2 domains of the FVIII light chains.
    • A prolonged FVIII presentation to the immune system.
    • Immunomodulatory effect of VWF.
  • There are several in vitro and in vivo observations in published studies:
    • The lower inhibitory activity against FVIII/FVW complex compared to recombinant FVIII in inhibitor plasmas with anti-C2-specifity 21-25
    • Higher recovery when the infused FVIII concentrate contained VWF during treatment of patients with hemophilia A and an inhibitor against the light chain of FVIII 23-26

"Native pdFVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors." Bravo MI. Haemophilia 2014 27

  • Objective: To test inhibitor reactivity in different combinations of VWF, FVIII concentrates (plasma-derived and recombinant) and inhibitors.
  • Results:
    • Inhibitor titers for plasma and pdFVIII/VWF complex were comparable at all time points.
    • Inhibitor titers for all concentrates of isolated FVIII were significantly higher than those for plasma or pdFVIII/VWF complex (1.4–1.9 fold) even after pre-incubation with VWF.

"Beneficial effect of VWF in FVIII recovery of different FVIII concentrates in a mouse model of severe hemophilia with high inhibitor titers" Bravo MI. J Thromb Haemost., 2015 28

  • Objective: To evaluate in a mouse model of severe hemophilia the differences of FVIII in vivo recovery between different FVIII concentrates –with and without VWF– in the presence of high inhibitor levels (>5BU).
  • Results:
    • In the presence of high titer inhibitors FVIII recovery was higher for native pdFVIII/VWF when compared to concentrates of isolated FVIII (20.8% vs. 5.4% for rFVIII and 1.2% for pdFVIII, respectively).
    • Similar results were achieved with low titer inhibitors: 71.1% vs. 31.4% for rFVIII and 25% for pdFVIII.
The role of VWF in immune tolerance induction with pdFVIII/FVW concentrates

Economics of ITI

Treating hemophilia patients with inhibitors is costly regardless of the preferred treatment approach. In particular, although ITI treatment is associated with a high cost, the overall lifetime treatment costs are substantially lower than treating prophylactically with bypassing agents 29

A cost analysis on factor VIII alloantibody inhibitors on immune tolerance induction vs. prophylaxis and on-demand with bypass treatment was recently published: 29

  • Compared to on-demand and prophylactic treatment with bypassing agents, ITI was found to be less expensive when considering lifetime costs.
  • Even though on demand treatment was not substantially more costly, it carries much more risk due to the occurrence of four times as many bleeding events.
  • As a result, ITI may be associated with lower lifetime costs than when treating on-demand or prophylactically with bypassing agents. The economic benefit of treating with ITI is best achieved the earlier one begins immune tolerance therapy in a patient with an inhibitor.
Economics of ITI

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It is important to note that treatment varies by patient. Be sure to consult a healthcare professional before making any treatment decisions and continue to remain informed to help facilitate care.

NEXT: RESOURCES FOR YOU 

It is important to note that treatment varies by patient. Be sure to consult a healthcare professional before making any treatment decisions and continue to remain informed to help facilitate care.

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