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European principles of inhibitor management in patients with haemophilia: implications of new treatment options

In light of the rapidly changing landscape of haemophilia treatment, the authors of the position paper on the European Principles of Inhibitor Management” published in 2018 (Table 1) [1] now provide an update on the major impact of novel therapies that bypass and/or substitute clotting factor VIII (FVIII) and IX (FIX) in the care of haemophilia patients with FVIII- or FIX-neutralizing allo-inhibitory antibodies (inhibitors).

Table 1 European principles of inhibitor management in patients with haemophilia [1]

The most advanced novel agent is undoubtedly emicizumab (Hemlibra®, Roche), a bispecific antibody that mimics the function of FVIII and facilitates the coagulation cascade in haemophilia A patients both with and without inhibitors as it is not recognized by FVIII-neutralizing allo-inhibitory antibodies. Phase III clinical trials in adults (HAVEN 1) and children (HAVEN 2) have shown significant overall bleed reduction compared to prophylaxis with classical bypassing agents such as recombinant activated factor VII (rFVIIa) or activated prothrombin complex concentrate (aPCC) in patients with haemophilia A and inhibitors [2, 3]. This molecule is administered subcutaneously, once a week or less frequently, greatly alleviating the burden of intravenous injections, especially in paediatric patients with inhibitors. Emicizumab is currently the only novel marketed agent and is increasingly accessible for people with haemophilia A with and without inhibitors [4]. In many developed countries, emicizumab has become the prophylactic agent of choice for patients with persistent inhibitors against FVIII with major reported benefits [5].

Several other novel agents are in different stages of development and will probably also have a major impact on the care of haemophilia patients. A new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions (marzeptacog alfa (activated) (MarzAA)), has increased catalytic activity and prolonged half-life which allows subcutaneous dosing [6]. Other new agents which downregulate natural anticoagulants, thereby rebalancing haemostasis, are currently under study in patients with haemophilia A and B. These agents work either by blocking tissue factor pathway inhibitor (TFPI) using subcutaneous monoclonal antibodies (concizumab, NovoNordisk; marstacimab, Pfizer) or knocking down antithrombin synthesis through a subcutaneous double-stranded small interfering RNA (Alnylam) [7]. Haemophilia B patients with inhibitors, who have been clinically the most underserved subpopulation, may benefit the most from these new agents.

Emicizumab and the other agents described above will certainly have a major impact, as described below, in the care of patients with inhibitors. This is summarized in the 10 revised principles of inhibitor management originally proposed in 2018.

Awareness of the incidence of inhibitors and risk factors throughout life

The bispecific antibody, emicizumab, has the potential to modify the natural history of inhibitor development in some patients, especially in previously untreated patients (PUPs) treated with this agent early in life to avoid exposure to exogenous FVIII. More data shall become available about the role, safety and efficacy of emicizumab in PUPs [8,9,10] as well as in Previously Treated Patients (PTPs).

Early recognition and accurate diagnosis

The importance of early recognition and accurate diagnosis of patients developing inhibitors remains of high importance, regardless of the availability of these new agents. It is recommended for patients with inhibitors to have their inhibitor titre checked regularly, at least once per year and, most importantly, before any invasive procedure. Appropriate assays for inhibitor detection and quantification should be used in patients treated with emicizumab [11].

Optimal organization of care and communication between all stakeholders

Availability of a bispecific antibody and other novel agents will most likely impact significantly on how care of inhibitor patients is organised. As stated jointly by the European Haemophilia Consortium (EHC) and European Association for Haemophilia and Allied Disorders (EAHAD), supervision of patients on novel treatment products should be exclusively conducted in European Haemophilia Comprehensive Care Centres (EHCCCs) or European Haemophilia Treatment Centres (EHTCs), thus increasing the necessity of good communication between healthcare professionals involved. The frequency of visits of inhibitor patients to their treating specialists will probably diminish due to the less intensive treatment regimens and subcutaneous administration of the novel products. Measures should be taken to avoid negative impact of changes related to these treatment innovations on the patient-doctor relationships, in particular regular multidisciplinary follow-up by the EHCCCs with the crucial support and involvement of patients’ organisations. A major responsibility for these expert centers will also be to carefully monitor potential adverse events which may be different from those seen with rFVIIa and aPCC (such as arterial or venous thrombotic events or thrombotic microangiopathy).

Access to haemostatic agents

While inhibitors can be eradicated in patients who have access and a positive response to immune tolerance induction therapy, the inhibitors persist in many patients. These patients standardly require regular treatment with bypassing agents, ideally administered prophylactically. The bispecific antibody and other novel agents should be readily available, when licensed, especially for patients with persistent inhibitors. Clear protocols should be put in place for the management of breakthrough bleeds, as well as for the co-administration of clotting factor concentrates or bypassing agents in case of invasive procedures [12, 13].

Inhibitor eradication by immune tolerance induction (ITI) therapy

Inhibitor eradication by immune tolerance induction (ITI) remains the best option for patients with inhibitors [14]. Treatment with the bispecific antibody or other novel agents should be considered if ITI cannot be conducted or was not successful. Studies are currently ongoing to evaluate the impact of these new agents on ITI indications and modalities [15,16,17].

Access to, and optimal preparation for, surgery and other invasive procedures

Availability of the bispecific antibody and other novel therapies currently evaluated in trials has a substantial impact on access and modalities of invasive procedures and surgery for people with inhibitors. Minor invasive procedures, e.g. dental extraction or central venous access device insertion, can be successfully performed with the bispecific antibody without FVIII and tranexamic acid, given that there is a close collaboration between the haematologist and the specialist performing the procedure. Careful planning and timing of major elective surgery is mandatory, along with well-designed protocols for co-administration of bypassing agent(s) during surgery [12;13]. The current inhibitor titre at the time of surgery should be properly determined in order to evaluate whether replacement therapy with FVIII or FIX concentrates represents an alternative to the use of bypassing agents.

Provision of specialist nursing care

It is crucial to provide nurses with continuous and practical education about the bispecific antibody and other emerging therapies, including awareness and understanding of their respective mode of action, the precautions of use, situations requiring co-treatments with factor concentrates or bypassing agents, skills for intravenous and subcutaneous infusions …

Provision of tailored physiotherapy care and monitoring

The use of the bispecific antibody allows inhibitor patients to engage in various types of physical activities and for those already disabled has the potential to convert them into ambulatory patients, as reported previously with aPCC given prophylactically and combined with active physiotherapy [18]. Regular musculoskeletal assessment and physical coaching by experts in physiotherapy attached to EHCCCs or EHTCS should be provided to patients switched to new agents in order to prepare them physically and mentally for this important transition. However, permanent irreversible joint damage and chronic pain remain challenges that require continued tailored physiotherapy care and monitoring in the era of new therapies.

Access to psychosocial support

The new perspectives opened by a life with much fewer bleeds and less treatment burden require major individual mental, physical and social adaptation that could benefit from the support of psychosocial experts within the multidisciplinary team.

Involvement in research and innovation

Clinical data on the use of the bispecific antibody and other novel products in the real life remain scarce, especially in the cohort of inhibitor patients. Thus, it is essential to collect treatment and outcome data regularly in the frame of international registries and/or pharmacovigilance programs. Further international, multicentric and collaborative studies and research initiatives exploring the impact and modalities of use of the novel therapies in patients with inhibitor should be encouraged and promoted.

Conclusion

As described above, adoption of novel non-replacement therapies for haemophilia will have a major impact on each of the 10 principles of inhibitor management published in 2018. This amendment of the 10 principles appears as a very important advocacy tool and framework in order to promote access and proper use of these revolutionary therapies for all stakeholders actively involved in the care of patients with inhibitors.

Availability of data and materials

Not applicable.

Abbreviations

aPCC:

Activated prothrombin complex concentrate

EAHAD:

European Association for Haemophilia and Allied Disorders

EHC:

European Haemophilia Consortium

EHCCC:

European Haemophilia Comprehensive Care Centre

EHTC:

European Haemophilia Treatment Centre

FVIII:

Factor VIII

FIX:

Factor IX

ITI:

Immune tolerance induction

PTP:

Previously treated patient

PUP:

Previously untreated patient

rFVIIa:

Activated recombinant FVIIa

References

  1. 1.

    PLF G, Hermans C, O’Mahony B, de KP BM, Batorova A, et al. European principles of inhibitor management in patients with haemophilia. Orphanet J Rare Dis. 2018;13(1):66.

    Article  Google Scholar 

  2. 2.

    Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, et al. Emicizumab prophylaxis in hemophilia a with inhibitors. N Engl J Med. 2017;377(9):809–18.

    CAS  Article  Google Scholar 

  3. 3.

    Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jimenez-Yuste V, et al. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia a with inhibitors. Blood. 2019;134(24):2127–38.

    CAS  Article  Google Scholar 

  4. 4.

    Ebbert PT, Xavier F, Seaman CD, Ragni MV. Emicizumab prophylaxis in patients with haemophilia a with and without inhibitors. Haemophilia. 2020;26(1):41–6.

    CAS  Article  Google Scholar 

  5. 5.

    Page D. Parent testimonial: a caregiver whose son with inhibitors has been receiving emicizumab. Transfus Apher Sci. 2019;58:5.

    Article  Google Scholar 

  6. 6.

    Gruppo RA, Malan D, Kapocsi J, Nemes L, Hay CRM, Boggio L, et al. Phase 1, single-dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia. J Thromb Haemost. 2018;16(10):1984–93.

    CAS  Article  Google Scholar 

  7. 7.

    Butterfield JSS, Hege KM, Herzog RW, Kaczmarek R. A molecular revolution in the treatment of hemophilia. Mol Ther. 2019;28(4):997.

    Article  Google Scholar 

  8. 8.

    The Hemophilia Inhibitor Prevention Trial. https://www.clinicaltrials.gov/ct2/show/NCT04303559. 22-7-2020.

  9. 9.

    A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Subcutaneous Emicizumab in Participants From Birth to 12 Months of Age With Hemophilia A Without Inhibitors (HAVEN 7). https://www.clinicaltrials.gov/ct2/show/NCT04431726?term=emicizumab&draw=2&rank=6 . 22-7-0020.

  10. 10.

    Pierce GF, Hart DP, Kaczmarek R. Safety and efficacy of emicizumab and other novel agents in newborns and infants. Haemophilia. 2019;25(5):e334–5.

    Article  Google Scholar 

  11. 11.

    Jenkins PV, Bowyer A, Burgess C, Gray E, Kitchen S, Murphy P et al. Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline. Haemophilia 2019; ;26(1):151.

    Google Scholar 

  12. 12.

    Susen S, Gruel Y, Godier A, Harroche A, Chambost H, Lasne D, et al. Management of bleeding and invasive procedures in haemophilia a patients with inhibitor treated with emicizumab (Hemlibra((R)) ): proposals from the French network on inherited bleeding disorders (MHEMO), the French reference Centre on Haemophilia, in collaboration with the French working group on perioperative Haemostasis (GIHP). Haemophilia. 2019;25(5):731–7.

    Article  Google Scholar 

  13. 13.

    Castaman G, Santoro C, Coppola A, Mancuso ME, Santoro RC, Bernardini S, et al. Emergency management in patients with haemophilia a and inhibitors on prophylaxis with emicizumab: AICE practical guidance in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET. Blood Transfus. 2019;18:1–8.

    Google Scholar 

  14. 14.

    Carcao M, Escuriola-Ettingshausen C, Santagostino E, Oldenburg J, Liesner R, Nolan B, et al. The changing face of immune tolerance induction in haemophilia a with the advent of emicizumab. Haemophilia. 2019;25(4):676–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Batsuli G, Zimowski KL, Tickle K, Meeks SL, Sidonio RF Jr. Immune tolerance induction in paediatric patients with haemophilia a and inhibitors receiving emicizumab prophylaxis. Haemophilia. 2019;25(5):789–96.

    CAS  Article  Google Scholar 

  16. 16.

    The Hemophilia Inhibitor Eradication Trial. https://clinicaltrials.gov/ct2/show/NCT04303572.

  17. 17.

    A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN 1). https://www.clinicaltrials.gov/ct2/show/NCT02622321.

  18. 18.

    Kajiwara M, Shima M, Yoshioka A. Two haemophilia patients with inhibitors who became ambulatory after physiotherapy under haemostatic cover with bypassing agents. Haemophilia. 2013;19(5):e301–4.

    CAS  Article  Google Scholar 

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Acknowledgements

The European Haemophilia Consortium (EHC) and European Association for Haemophilia and Allied Disorders (EAHAD) wish to acknowledge the contribution of the following health care professionals (in alphabetical order) to the development of this update of the guidelines:

J. Astermark (Centre for Thrombosis and Haemostasis, Skåne University Hospital, Malmö, Sweden); A. Bok (European Haemophilia Consortium, Brussels, Belgium); M. Crato (Portuguese Haemophilia Association, Lisbon, Portugal); R. d’Oiron (Hôpital Bicêtre AP-HP, Paris XI University, Le Kremlin-Bicêtre, France); A. Dougall (Dublin Dental University Hospital, Dublin, Ireland); K. Fijnvandraat (Department of Pediatric-Hematology, Emma Children’s Hospital, Academic Medical Centre (AMC), Amsterdam, The Netherlands); S. Grønhaug (Centre for Rare Disorders, Department of Rare Disorders and Disabilities, Oslo University Hospital, Rikshopitalet, Oslo, Norway); V. Jiménez-Yuste (Hospital Universitario La Paz, Unidad de Coagulopatías, Servicio de Hematología, Universidad Autonoma de Madrid, Madrid, Spain); M. Jokić (Serbian Haemophilia Society, Belgrade, Serbia); S. Lobet (Haemostasis and Thrombosis Unit, Division of Haematology, Haemophilia Clinic, Saint-Luc University Hospital, Brussels, Belgium); B. Nolan (Department of Haematology, Our Lady’s Children’s Hospital, Dublin, Ireland); F. Peyvandi (Angelo Bianchi Bonomi Hemophilia and Thrombosis Centre, Fondazione IRCCS Ca′ Granda Ospedale Maggiore Policlinico, Milan, Italy); A. Ryan (European Association for Haemophilia and Allied Disorders, Brussels, Belgium).

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CH, KJ and PG were responsible for drafting the final version of the manuscript, which was also reviewed and approved by all co-authors.

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Correspondence to C. Hermans.

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Competing interests

PG has received consultancy and/or lecture fees from CSL Behring, Novo Nordisk, and Pfizer within the last year. CH has received consultancy and/or lecture fees from Bayer, Takeda, Roche, CSL Behring, NovoNordisk, Pfizer, SOBI, LFB, OctaPharma within the last year. AB received a speaker fee from SOBI, Roche, Shire and Octapharma within last year. MB is currently a member of the Roche/Chugai Haemophilia A Advisory Board and is in receipt of funding from Pfizer for an investigator-initiated research study. JB has received speaker’s fees and/or served as a consultant for NovoNordisk, Shire/Takeda, Sobi, LFB, Pfizer and Roche within last year. BO’M, PdK and KJ state that they have no competing interests to report.

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Hermans, C., Giangrande, P.L.F., O’Mahony, B. et al. European principles of inhibitor management in patients with haemophilia: implications of new treatment options. Orphanet J Rare Dis 15, 219 (2020). https://doi.org/10.1186/s13023-020-01511-8

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Keywords

  • Haemophilia
  • Guidelines
  • Inhibitors
  • Factor VIII
  • Factor IX
  • Bypassing agents
  • Emicizumab
  • Immune tolerance