Immunotolerance is still the goal of management of hemophilia A with inhibitor in the era of non-factor therapy

Inhibitors: Still a serious complication of hemophilia and how to manage it

The development of neutralizing antibodies (inhibitors) against administered factor VIII (FVIII) occurs in 25–40% of individuals with severe hemophilia A. Resistance to administered FVIII caused by the presence of a high-titre inhibitor renders FVIII administration entirely ineffective. This condition requires alternative methods to manage bleeding or ideally prevent it. The presence of an inhibitor is associated with increased morbidity and mortality in patients.

Historically, the only correct approach (the “gold standard”) in the presence of inhibitors has been considered to be the induction of immune tolerance, which leads to eradication of the inhibitor in the majority of patients.

Recently, however, new treatment methods have entered clinical practice, some of which are still being tested in clinical studies. In practice, the emicizumab antibody is available among these new approaches (also referred to as non-factor therapy for hemophilia A) for the prevention of bleeding in hemophiliacs. Since they stop bleeding through mechanisms different from FVIII, they can be used in patients who have developed an inhibitor as a complication of replacement therapy. However, they are not intended for use in acute bleeding or major surgical procedures.

It is also historically known that in the presence of an inhibitor, hemostasis needs to be achieved using another method – either high doses of FVIII in low-titre inhibitors or bypassing agents. However, their effectiveness is not as predictable or excellent compared to FVIII products in patients without inhibitors.

Consensus of the FIT expert panel

The conclusions of the recent expert discussion can be summarized as follows:

• Despite the undeniable success of emicizumab in treating hemophilia A patients, especially those with inhibitors, the expert group still considers the eradication of inhibitors to be very important. Therefore, ITI, at least one attempt to eradicate the inhibitor, should continue to be offered to every patient who develops one. There is no evidence, nor is it expected, that emicizumab alone would lead to inhibitor eradication. It can be assumed that without ITI, particularly in high-titre inhibitors, the inhibitor will remain for the rest of the patient's life.
• For patients who cannot use ITI for various reasons or need to delay it, monotherapy with emicizumab is now an option.
• Consideration is being given to the possibility of administering ITI simultaneously with preventive emicizumab treatment. It is expected that emicizumab will effectively prevent bleeding with lower-intensity and lower-dose ITI regimes alongside FVIII. However, no data on such an approach have been published so far.
• The likelihood of ITI success is primarily based on certain risk factors, such as the highest inhibitor titre before starting treatment or the maximum rise in titre during treatment. The ITI regimen should be chosen considering known risk factors associated with ITI success.
• Response monitoring for ITI should be done more frequently (e.g., monthly), and the dose/frequency of FVIII should be adjusted based on patient progress (changes in inhibitor titre or bleeding phenotype).
• With the availability of non-factor therapy, immunosuppressive treatment should not be provided to patients with inhibitors as part of second-line ITI.

Summary and Conclusion

The discussion of experts on the role and future of ITI in treating hemophilia A patients with inhibitors is very important. New drugs come with questions impacting everyday clinical practice. It is possible that study results, a uniform approach to these patients in clinical practice, and other factors will lead to a change in this recommendation in the future.

At this time, however, the effort to eradicate inhibitors remains the gold standard, and ITI should be recommended in at least one sufficiently prolonged course to every patient diagnosed with an inhibitor.

(eza)

Source: Carcao M., Escuriola-Ettingshausen C., Santagostino E. et al.; Future of Immunotolerance Treatment Group. The changing face of immune tolerance induction in haemophilia A with the advent of emicizumab. Haemophilia 2019 Jul; 25 (4): 676–684, doi: 10.1111/hae.13762.