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]
1. Lifelong Awareness of the Incidence of Inhibitors and Risk Factors
2. Early Recognition and accurate diagnosis
3. Organisation of Care and Communication Between All Stakeholders
4. Inhibitor eradication by Immune Tolerance Induction Therapy
5. Hemostatic Treatment with Bypassing Agents
6. Access to and Optimal Preparation for Surgery and Invasive Procedures
7. Delivery of Specialist Nursing Care
8. Provision of Tailored Physiotherapy Care
9. Access to Psychosocial Support
10. Involvement in the Research and Innovation
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 [8–10] 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 [15–17].
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.