Patients with hemophilia A and inhibitors: prevention and evolving treatment paradigms

ABSTRACT

Introduction: Novel non-replacement therapies (e.g. emicizumab) have improved the management of patients with hemophilia A with and without inhibitors while introducing new challenges and increasing the complexity of clinical decision-making.

Areas covered: Use of emicizumab can substantially delay initial exposure to FVIII thereby altering the natural history of inhibitor development, but it remains unclear whether later exposure to FVIII might modify the incidence of inhibitor development. Moreover, decisions regarding initiation of immune tolerance induction (ITI) therapy in patients with newly diagnosed inhibitors have become more complicated since emicizumab was introduced. Using emicizumab in lieu of ITI has implications such as precluding the use of FVIII for breakthrough bleeds and surgery, and possibly impacting on patients’ future ability to receive gene therapy. Although bypassing agents are the mainstay of managing acute bleeds and surgery in inhibitor patients, their concomitant use with novel therapies can be difficult to manage/monitor. Evidence from the HAVEN clinical trials program suggests that minor surgeries in inhibitor patients can be performed with emicizumab alone, whereas major surgeries require the use of perioperative bypassing agents.

Expert opinion: Until the long-term effects of non-replacement therapies become known, patients who develop inhibitors should continue to receive ITI.

KEYWORDS:

• Hemophilia A
• inhibitors
• bypassing agents
• factor VIII
• emicizumab
• fitusiran

Acknowledgments

This manuscript was developed from the proceedings of a Grifols-sponsored symposium held at the ISTH 2019 Congress in Melbourne, Australia. Evidence presented at the symposium is supplemented by other literature known to the authors. Writing assistance for this article was provided by Kerry Dechant and Rob Furlong on behalf of Content Ed Net (Madrid, Spain) with funding from Grifols (Barcelona, Spain), a manufacturer of pdFVIII.

Article Highlights Box

• The current treatment paradigm for hemophilia is shifting towards use of novel therapies that can increase thrombin generation without replacing deficient coagulation factor.

• Emicizumab was the first non-replacement therapy to be approved for clinical use in hemophilia patients with or without inhibitors.

• Emicizumab prophylaxis offers several benefits over replacement therapy but, since clinical experience is limited, long-term outcomes are not yet clear.

• In new inhibitor patients, a low-dose immune tolerance induction regimen (FVIII 50 IU/kg 3 times weekly) plus emicizumab is emerging as recommended treatment.

• The role of emicizumab in managing inhibitor patients who require surgery is becoming clearer.

• Given the myriad of new and novel options on the horizon for hemophilia management, a certainty in upcoming years will be uncertainty.

Declaration of interest

D Lillicrap has received research support from Bayer, Biomarin, Bioverativ/Sanofi, CSL Behring, and Octapharma; has served in an advisory role for Bioverativ/Sanofi, CSL Behring, Octapharma, and Roche. The institution of K Fijnvandraat has received unrestricted research grants from CSL Behring and NovoNordisk; and has received consultancy fees from Grifols, Novo Nordisk, Roche and Takeda. G Young has received honoraria and consulting fees from Bioverativ/Sanofi, CSL Behring, Freeline, Genentech/Roche, Grifols, Kedrion, Novo Nordisk, Spark, Takeda, and UniQure. ME Mancuso has received speaker’s bureau from Bayer, Biotest, CSL Behring, Grifols, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and Sobi; has served as consultant or advisory board member for Bayer, Bioverativ, Catalyst, CSL Behring, Grifols, Kedrion, Novo Nordisk, Octapharma, Pfizer, Roche, Shire, and Sobi. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.