Keywords Emicizumab - haemophilia A - inhibitors - prophylaxis
Schlüsselwörter Emicizumab - Haemophilia A - Inhibitoren - Prophylaxe
Introduction
Emicizumab is a recombinant bispecific antibody with humanised binding sites to activated
factor IX (FIXa) and factor X (FX), designed to mimic cofactor activity of factor
VIII (FVIII).[1 ] It was developed for bleeding prophylaxis in patients with haemophilia A (PWHAs)
with and without inhibitors.[2 ]
For full haemostatic activity, Emicizumab needs phosphatidylserine-exposed phospholipids
at the site of injury.[1 ] The route of administration is subcutaneous, and the half-life is approximately
4 to 5 weeks.[3 ] Pivotal clinical studies have been published in 2017 and 2018[4 ]
[5 ] leading to licensure of Emicizumab for bleeding prophylaxis in PWHAs with inhibitors
in November 2017 by the U.S. Food and Drug Administration (FDA) and in February 2018
by the European Medicines Agency (EMA), and for PWHAs without inhibitors in October
2018 by FDA and in March 2019 by EMA.
The mode of action, laboratory testing, potential interactions and adverse events
are substantially different from FVIII and require an adaption of management of bleeds/surgery
and laboratory monitoring.[4 ]
[6 ] Therefore, the ‘Ständige Kommission Hämophilie’ of the German, Austrian, Swiss Society
for Thrombosis and Haemostasis Research (GTH) decided to develop a practical guidance
document with recommendations and precautions for the use of Emicizumab in PWHAs.
Methods
A literature search in PubMed last updated on October 16, 2019, according to the PRISMA
guidelines,[7 ] was performed using the search terms ‘haemophilia’ and ‘Emicizumab’, revealing 108
publications. Additionally, congress abstracts of American Society of Haematology,
International Society on Thrombosis and Haemostasis and European Association of Haemophilia
and Allied Disorders congresses were screened. The search history is shown in [Fig. 1 ]. A final selection of 31 papers, focusing on treatment with Emicizumab, efficacy,
safety and laboratory testing, was included into the literature review. The recommendations
were drafted by the authors and presented at the meeting of the GTH-Haemophilia Board
‘Ständige Kommission Hämophilie’ at the annual congress of GTH in February 2019. Critical
points were discussed extensively among the active members of the board. A revised
draft of recommendations was discussed among the authors in a telephone conference
as well as few statements, in which complete consensus was not reached, decided by
using an electronic survey. A final set of recommendations was circulated to all 13
authors for approval via an online survey analogous to the Delphi method with a 5-point
Likert scale with rating as follows: strong agreement, agreement, limited agreement,
concern, and no agreement. Consensus was determined if a statement reached >80% responses
indicating ‘strong agreement’ or ‘agreement’ according to one suggested threshold
for the Delphi method.[8 ] All 13 authors responded to the survey. In [Table 1 ] the final recommendations and the proportion of agreement are displayed. The final
version of the revised manuscript was circulated and approved by all authors.
Fig. 1 Search history for the systematic literature review following PRISMA guidelines.
Table 1
Summary of recommendations and level of agreement after Delphi survey
Statement
Agreement[a ]
N = 13
General aspects
1.
Treatment with Emicizumab should be supervised by experienced haemophilia centres.
100% agreement
Patient education
2.
Patients have to be educated before start of therapy with Emicizumab (mode of action/impact
on routine coagulation tests, route of administration and dosing, storage, treatment
strategies in case of breakthrough bleeds or surgery)
100% agreement
3.
An informative emergency card has to be issued to every patient on Emicizumab
100% agreement
4.
Every single administration of Emicizumab should be documented in a patient diary
100% agreement
Management of breakthrough bleeds and surgery
5.
Each patient should have an emergency stock of FVIII or bypassing agents at home for
treatment of breakthrough bleeds
92.3% agreement
7.7% limited agreement
6.
Bleeding treatment in PWHA with or without inhibitors should be administered in relevant
bleeds or significant injury
92.3% agreement
7.7% limited agreement
7.
Not all non-severe bleeds need to be treated in patients receiving Emicizumab prophylaxis.
92.3% agreement
7.7% limited agreement
8.
For PWHA without inhibitors, clinically relevant breakthrough bleeds should be treated
with FVIII
100% agreement
9.
For PWHA and inhibitors, rFVIIa should be first-line treatment for clinically relevant breakthrough bleeds.
The use of aPCC in doses > 100 U/kg for more than 24 hours was associated with a risk
of thrombotic/TMA events.
92.3% agreement
7.7% limited agreement
10.
For surgery in PWHA without inhibitors, the necessity, dose and duration of FVIII
replacement should be adapted to the surgical procedure and the post-operative course.
100% agreement
11.
For surgery in PWHA with inhibitors, first-line additional haemostatic treatment is rFVIIa. The need for additional treatment,
dose and duration of rFVIIa replacement should be adapted to the surgical procedure
and the post-operative course.
100% agreement
Immune tolerance induction (ITI)
12.
In case of newly developed FVIII-inhibitors, ITI should be considered
100% agreement
13.
ITI protocols combining FVIII to induce immune tolerance and Emicizumab for prophylaxis
have only been used in case series, therefore no recommendation concerning indication,
dose and duration of ITI combined with Emicizumab prophylaxis can be made.
92.3% agreement
7.7% limited agreement
Previously untreated patients (PUPs)
14.
Emicizumab is licensed for all age groups; however, licensure for children is based
on limited data. The decision to use Emicizumab in small children, especially PUPs,
has to be made on an individual base.
92.3% agreement
7.7% limited agreement
Elderly patients
15.
There are no general concerns to use Emicizumab in elderly patients with HA. Individual
risk factors and comorbidities must be taken into account
100% agreement
Laboratory tests
16.
Emicizumab affects intrinsic pathway clotting-based laboratory assays occurring after
the first dose of Emicizumab and lasting up to 6 months after the last dose
100% agreement
17.
Tests to monitor FVIII replacement and FVIIIinhibitors as well as Emicizumab concentration
should be available
100% agreement
Abbreviations: aPCC, activated prothrombin complex concentrate; FVIII, factor VIII;
PWHA, patients with haemophilia A; TMA, thrombotic microangiopathy.
a ‘Strong agreement’ and ‘agreement’ are summarized as ‘agreement’.
General Aspects
EmicizumabIs Licensed for Prophylactic Treatment in Patients with Severe Haemophilia
A with and without Inhibitors of all Ages
The decision to use Emicizumab as a prophylactic approach in PWHAs has to be made
on an individual basis, considering the individual situation of the patient (e.g.,
patients with persistent FVIII inhibitors, venous access, bleeding phenotype) and
risk factors.
There is limited experience concerning the use of Emicizumab in PWHAs after successful
immune tolerance induction (ITI) in PUPs, small children, particularly newborns, children
<2 years and elderly patients >65 years of age.
After a loading dose of Emicizumab of 3 mg/kg subcutaneous (sc) per week for 4 weeks,
a maintenance dose of 1.5 mg/kg sc once weekly (qw), 3 mg/kg sc once every 2 weeks
(q2w) or 6 mg/kg sc once every 4 weeks (q4w) is approved.[4 ]
[5 ]
[9 ]
The choice of the dosing regimen can be based on clinical criteria, patient's preference
and vial size.
Recommendations
1.Treatment with Emicizumab should be supervised by experienced Haemophilia centres.
The medical staff should be experienced in diagnosis and treatment of PWHAs with and
without inhibitors.
The medical staff has to be educated in mode of action, risks and potential side effects
of Emicizumab.
24-hour emergency cover and access to adequate laboratory tests to monitor patients
under Emicizumab as well as rescue therapies have to be provided.
Other health care professionals (e.g., general practitioner, physical therapist, dentist)
involved in the patients' treatment have to be informed, e.g., by a discharge letter
and the Emicizumab emergency card.
If applicable, patients should be included into clinical trials (interventional trial,
observational studies or registries)
Supporting Data
Efficacy and Safety
The phase 3 HAVEN study program evaluated efficacy and safety in PWHAs with and without
inhibitors.[4 ]
[5 ]
[9 ]
[10 ] For PWHAs with inhibitors aged 12 years or older (HAVEN 1), the annualised rate
of treated bleeds (ABR) was 2.9 (95% confidence interval [CI]: 1.7–5.0) in the group
randomly assigned to Emicizumab prophylaxis (n = 35) compared with 23.3 (95% CI: 12.3–43.9) in those assigned to on-demand treatment
(n = 18), p < 0.001. In total, 63% of patients with Emicizumab prophylaxis experienced no bleeds
compared with 6% of patients without prophylaxis. An updated analysis revealed further
reduction of ABR in the second and third 24-week observation periods and a further
increase in proportion of patients without any treated bleeds.[11 ] Most frequent side effects were injection-site skin reactions in 15 to 22% of participants.
These were usually mild and self-limiting. Thrombotic microangiopathy (TMA) and thrombosis
were reported in two cases each in the primary analysis and another case of TMA after
data cut-off for primary analysis. These events occurred in patients receiving multiple
dosing of activated prothrombin complex concentrate (aPCC) for breakthrough bleeding
(>100 IU/kg for >24 hours).[4 ]
Another case of TMA with concomitant use of aPCC was reported post-marketing, so as
of September 30, four TMA cases were reported out of >5,400 patients treated. In addition
to the two cases in HAVEN 1, seven more cases of thrombotic events (without TMA) were
reported, all seven occurred with aPCC< 100 U/kg/24h or with Emicizumab alone, but
patients had underlying risk factors like previous pulmonary embolism or arterial
hypertension. Up to September 30, 2019, 17 fatalities were reported in clinical trials,
compassionate use, expanded and post-marketing access, but none was judged to be related
to Emicizumab.[12 ] No data on mortality rate of PWHAs with inhibitors without Emicizumab prophylaxis
are available for comparison. There were no safety concerns with the use of recombinant
activated FVII (rFVIIa) at doses/intervals as described in the product information.[13 ]
In HAVEN3, PWHAs without inhibitors aged 12 years or older on previous episodic treatment
were randomly assigned to receive a subcutaneous maintenance dose of Emicizumab 1.5 mg/kg
qw (n = 36) or 3.0 mg/kg q2w (n = 35) or no prophylaxis (n = 18). The ABR was 1.5 (95% CI: 0.9–2.5), 1.3 (95% CI: 0.8–2.3) and 38.2 (95% CI:
22.9–63.8) in the three groups, respectively (p < 0.001). The proportion of patients with no bleeds was 56 and 60% in patients on
Emicizumab prophylaxis versus 0% in patients without prophylaxis. In an intraindividual
comparison of 48 patients who received previous FVIII prophylaxis, a reduction of
ABR of 68% was observed on Emicizumab prophylaxis (p < 0.001), suggesting a lower bleeding rate compared with their previous FVIII prophylactic
regimen. Patients could continue on FVIII prophylaxis until the second loading dose.
No thrombotic/TMA events occurred with concomitant FVIII treatment; most common adverse
events were again, similar to older patients, injection-site reactions.[5 ]
A dosing regimen with a maintenance dose of 6 mg/kg q4w in PWHAs with and without
inhibitors showed similar efficacy with a low rate of treated bleeds (ABR: 2.4; 95%
CI: 1.4–4.3), and 56% of 41 patients reported no treated bleeds.[9 ] Regimens have not been compared directly, but the mean ABR seems to be slightly
higher in the q4w regimen compared with q1w and q2w, maybe due to one outlier with
a high bleeding rate (ABR: 32.07).
In HAVEN2, 88 PWHAs with inhibitors aged <12 years (or 12–17 years with <40 kg body
weight) with or without previous prophylactic bypassing agents (BPAs) were enrolled
to receive Emicizumab prophylaxis with a maintenance dose of 1.5 mg/kg qw (n = 68), 3 mg/kg 2qw (n = 10) or 6 mg/kg q4w (n = 10). In total, 18 patients were ≤2 years old. The primary analysis revealed an
ABR of 0.3 (95% CI: 0.17–0.50), 0.2 (95% CI: 0.03–1.72) and 2.2 (95% CI: 0.69–6.81)
in the groups treated qw, q2w and q4w, respectively. In the q4w group, one patient
developed neutralising anti-drug antibodies (ADA). Zero treated bleeds were reported
in 76.9, 90 and 60% of patients, respectively.[10 ] An interim analysis of 88 patients with inhibitors in the STASEY trial reported
comparable bleeding rates and no further thrombotic events or other safety signals.[14 ]
Patient Education
2. Patients have to be educated before starting therapy with Emicizumab (mode of action/impact
on routine coagulation tests, route of administration and dosing, storage, treatment
strategies in case of breakthrough bleeds or surgery).
Patients should be trained in subcutaneous injection.
Patients or caregivers should regularly be trained in intravenous injection for emergency
treatment with FVIII or BPAs.
Inhibitor patients should be informed about the risk for developing thrombotic events
or TMA when using aPCC in the presence of Emicizumab.
Patients need to be informed about treatment strategies in case of bleeds or surgery.
Patients should contact the treatment centre in case of bleeds to agree on treatment.
3. An informative emergency card has to be issued to every patient on Emicizumab.
Contact details of the centre and the treatment strategy in case of bleeds/surgery
have to be provided.
In inhibitor patients the last inhibitor titre should be documented. Inhibitor testing
should be performed at least every 6 months or according to clinical demands/before
surgical interventions.
Information on Emicizumab interference with standard coagulation tests and precautions
should be included.
4. Every single administration of Emicizumab should be documented in a patient diary.
Additional treatment with clotting factor concentrates has to be documented.
Data should be captured in registries, such as the German/Austrian/Swiss Haemophilia
Registry or German Pediatric Haemophilia Research Database (GEPHARD), PedNet, etc.
Management of Breakthrough Bleeds and Surgery
Management of Breakthrough Bleeds and Surgery
5. Each patient should have an emergency stock of FVIII or BPAs at home for treatment
of breakthrough bleeds.
Patients should be provided with at least one to two doses of bleeding treatment medication,
a bigger amount can be considered depending on the distance to the centre, travel
activities or bleeding phenotype.
6. Bleeding treatment in PWHAs with and without inhibitors should be administered in
relevant bleeds or significant injury.
Joint bleeds, defined by pain, acute swelling and/or decreased range of motion.
Muscle bleeds/intracranial haemorrhage/retroperitoneal bleed/GI-bleed, etc.
7. Not all non-severe bleeds need to be treated in patients receiving Emicizumab prophylaxis.
Minor bleeds or injuries (e.g., subcutaneous haematoma, nose bleeds, mucosal bleeds,
small wounds) need individual evaluation.
Tranexamic acid can be used locally or systemically.
8. For PWHAs without inhibitors, clinically relevant breakthrough bleeds should be treated
with FVIII.
Standard FVIII regimens according to bleeding type have been used without complications.
The basal haemostatic activity of Emicizumab should be considered when treatment duration
with additional FVIII is determined.
If necessary, FVIII replacement can be monitored using a bovine chromogenic FVIII
assay.
After intensive treatment with FVIII, inhibitor testing should be performed using
a chromogenic bovine Bethesda assay.
9. For PWHAs with inhibitors, rFVIIa should be first-line treatment for clinically relevant
breakthrough bleeds. The use of aPCC in doses >100 U/kg for more than 24 hours was
associated with a risk of thrombotic/TMA events.
Bleeding treatment with rFVIIa dosed according to prescription information was safe
and clinically effective.
In case of poor clinical response to rFVIIa, FVIII can be used in patients with low
FVIII inhibitor activity.
Recombinant porcine FVIII may be an option, however not licensed for patients with
congenital haemophilia and inhibitors.
aPCC should only be used if no other treatment options are available or effective.
An initial aPCC dose of maximum 50 U/kg should not be exceeded. Lower doses (15–25
U/kg) have been described to be effective and safe in single cases.
If a second dose of aPCC is required, the patient should be admitted to a hospital
for surveillance (e.g., TMA, thrombotic events, control of bleed)
10. For surgery in PWHAs without inhibitors, the necessity, dose and duration of FVIII
replacement should be adapted to the surgical procedure and the post-operative course.
For minor surgery, additional FVIII treatment is not always necessary, but patients
should be clinically monitored for occurrence of abnormal bleeding.
Standard FVIII regimens according to bleeding risk of surgery have been used without
complications.
The basal haemostatic activity of Emicizumab should be considered when treatment duration
with additional FVIII is determined.
FVIII replacement should be monitored using a bovine chromogenic FVIII assay.
After intensive treatment with FVIII, inhibitor testing should be performed using
a chromogenic bovine Bethesda assay.
Currently, there is little experience with major surgery in PWHAs without inhibitors
using Emicizumab prophylaxis.
11. For surgery in PWHAs with inhibitors, the first-line additional haemostatic treatment
is rFVIIa. The need for additional treatment, dose and duration of rFVIIa replacement
should be adapted to the surgical procedure and the post-operative course.
For minor surgery, not always additional BPA treatment is necessary, but patients
should be clinically monitored for occurrence of abnormal bleeding.
In major surgery, preventive treatment with rFVIIa should be used according to bleeding
risk of surgery and clinical course.
Inhibitor testing should be done before surgery to explore the possibility to treat
the patient with FVIII in case of low or negative inhibitory activity.
In case of inadequate efficacy of rFVIIa, recommendations for second-line treatment
correspond to bleeding treatment [see point 10(a–f)].
If the use of aPCC at standard doses is planned to cover major surgery, Emicizumab
has to be stopped for approximately 6 months upfront. Because of the long half-life
of Emicizumab (4–5 weeks), interactions are expected for up to 6 months.
Supporting Data
PWHAs without Inhibitors
In PWHAs without inhibitors , additional FVIII replacement has been successfully used for treatment of breakthrough
bleeds or surgery. The efficacy of FVIII replacement despite presence of Emicizumab
is due to the lower binding affinity of Emicizumab to FIXa and FX with the effect
that higher FVIII concentrations displace Emicizumab from binding sites.[6 ] A non-additive effect of FVIII in combination with Emicizumab has also been shown
in thrombin generation assays.[15 ] No thrombotic/TMA events occurred with additional FVIII replacement,[5 ] therefore there are no safety concerns for the use of FVIII in standard dosing regimens.
Not all bleeds occurring under Emicizumab prophylaxis need to be treated. In HAVEN3,
a total ABR of 2.5 (95% CI: 1.6–3.9) in patients treated with 1.5 mg/kg qw and 2.6
(95% CI: 1.6–4.3) in the group treated with 3 mg/kg q2w was reported with only 1.5
(95%CI: 0.9–2.5) and 1.3 (95% CI: 0.8–2.3) treated bleeds, respectively.[5 ]
For minor surgical procedures, additional FVIII replacement is not always necessary.
In HAVEN3, 50 procedures in 30 patients have been performed, of those 46 were minor
surgeries, including dental (n = 17), oesophagogastroduodenoscopy or colonoscopy (n = 14), and orthopaedic (n = 10) procedures. In total, 28 (61%) of these procedures were performed without additional
preventive FVIII replacement with only one bleed in a patient with tooth extraction.
A total of 18 patients received preventive FVIII replacement, 14 for less than 24 hours.
Overall, three patients experienced bleeds; however, no patient required treatment
for >72 hours. Four patients with major orthopaedic surgery received preventive FVIII
infusions for 14 to 18 days without bleeding complications. No thrombotic event and
no de novo inhibitors occurred.[16 ]
PWHAs with Inhibitors
In HAVEN1, two thrombotic and three TMA events occurred in patients treated with additional
aPCC> 100 U/kg for >24 hours.[4 ] An additional TMA was reported post-marketing.[12 ] Interaction of aPCC with Emicizumab leads to excessive thrombin generation (synergistic
effect), because aPCC contains FIXa and FX, the substrate for Emicizumab.[17 ] Lower doses of aPCC (15–25 U/kg) have been shown to be effective in vitro and in
vivo in a patient with a spontaneous psoas bleed.[18 ] In vitro measurements of ROTEM and thrombin generation assays suggest that even
lower doses of aPCC can be effective in PWHAs with inhibitors under Emicizumab, which
has been shown by spiking experiments, showing similar effect of aPCC 10 U/kg in Emicizumab-treated
haemophilia A (HA) as 100 U/kg in Emicizumab-untreated HA.[19 ] In the HAVEN study program, 210 bleeds have been treated with rFVIIa with no occurrence
of thrombosis or TMA, also at high doses.[13 ]
Not all bleeds in PWHAs with inhibitors under Emicizumab prophylaxis need to be treated
with additional BPA. In HAVEN1, the total ABR was 5.5 (95% CI: 3.6–8.6) and 2.9 (95%CI:
1.7–5.0) in treated bleeds. In total, 47% of bleeds could be treated with a single
rFVIIa treatment.[4 ] If rFVIIa is not effective for bleeding treatment or surgery, in PWHAs with low-titre
FVIII inhibitors, FVIII has been used successfully for up to 6 days.[20 ] Theoretically, also recombinant porcine FVIII could be an option in refractory bleeding;
however, it is only licensed for acquired HA.[21 ]
In HAVEN1 and 2, 19 minor surgeries [13 central venous access devices (CVADs), 6 tooth
extractions, 9 and 4 without additional BPA treatment, respectively] have been reported.
In none of the CVAD procedures bleeding occurred, but in 50% of tooth extraction (in
one with and one without additional preventive BPA).[22 ] Further nine cases with surgical procedures experienced a low bleeding frequency
with one to six doses of rFVIIa (90 µg/kg) or FVIII (100 IU/kg, in the case of low-titre
inhibitor) or observation.[23 ] Altogether, within the HAVEN study program 215 minor surgeries have been performed
in 115 patients (64 dental, 34 CVADs, 30 endoscopic, 25 joint, and 62 other procedures).
Of the 141 (65.6%) minor surgeries/procedures managed without prophylactic coagulation
factor, 128/141 (90.8%) did not result in treated post-operative bleeds. In 14/64
dental procedures, treated post-operative bleeds were reported, in 9/42 (21.4%) in
patients without and 5/22 (2.7%) in patients with prophylactic coagulation factor
replacement.[24 ]
In addition, 19 major surgeries have been performed in 19 patients, of which 5 were
joint arthroplasties, 4 synovectomies and 9 other procedures. In 16/19 major surgeries,
prophylactic replacement of FVIII or rFVIIa was given resulting in 1 treated and 2
untreated post-operative bleeds. Three procedures were performed without prophylactic
replacement therapy without bleeding complications. No thromboembolic events occurred.[22 ]
[24 ] In one of the above patients with the treated post-operative bleed, a right-hip
replacement was performed with the coverage of rFVIIa and lacking response (developed
a right-thigh haematoma and experienced dropping haemoglobin levels). Since the inhibitor
titre was low, FVIII treatment could be safely used in this patient for several days
until anamnestic response occurred.[20 ] In two further cases of the HAVEN trials, major surgery was conducted with the use
of rFVIIa safely: a total hip arthroplasty[25 ] and knee replacement.[26 ]
Immune Tolerance Induction
Immune Tolerance Induction
12. In case of newly developed FVIII inhibitors, ITI should be considered.
Successful ITI offers the possibility to treat bleeds and to cover surgery and bleeds
with FVIII, as well as access to gene therapy.
Standard ITI protocols, e.g., Bonn protocol, have been proven to be effective (60–80%)
and safe.[27 ]
[28 ]
[29 ]
To prevent breakthrough bleeds, ITI should be started immediately after inhibitor
confirmation.
If the start of ITI has to be postponed, prophylactic treatment with Emicizumab can
be considered.
In patients on ITI experiencing frequent breakthrough bleeds, a prophylactic approach
using BPA or Emicizumab can be considered.
In patients having been treated with Emicizumab < 6 months, the use of aPCC as a prophylactic
agent during ITI has to be avoided.
13. ITI protocols combining FVIII to induce immune tolerance and Emicizumab for prophylaxis
have only been used in case series, therefore no recommendation concerning indication,
dose and duration of ITI combined with Emicizumab prophylaxis can be made.
No controlled study data are available yet on ITI with FVIII in combination with Emicizumab.
ITI courses combined with Emicizumab should be documented in studies or registries.
The peak inhibitor titre should be taken into consideration when choosing the FVIII
dose.
During ITI combined with Emicizumab prophylaxis, FVIII and FVIII inhibitors have to
be monitored using chromogenic bovine FVIII assays.
How to maintain FVIII tolerance after successful ITI is not clear. If patients remain
on Emicizumab, the necessity, amount and duration of additional FVIII application
is not known.
Supporting Data
Eradication of inhibitors using ITI therapy is an effective, safe and proven strategy
to eradicate inhibitors in PWHAs.[27 ]
[28 ]
[29 ] The Bonn protocol[30 ] using FVIII at doses of 100 to 150 IU/kg twice daily and BPA prophylaxis in case
of breakthrough bleeds is standard of care in Germany. Even in the era of Emicizumab,
national guidelines and experts recommend the use of ITI.[31 ]
[32 ]
[33 ]
[34 ] Successful inhibitor eradication allows safer management of bleeds and surgery,
sustain patient's or parent's ability to infuse intravenous clotting factor and access
to future therapeutic options (e.g., gene therapy). The availability of Emicizumab
allows postponing ITI and offering effective bleeding prophylaxis during ITI. Experience
with ITI for inhibitor eradication and concomitant Emicizumab prophylaxis is limited.
Recently, the first report of seven paediatric inhibitor patients aged 21 months to
12 years undergoing the Atlanta protocol, i.e., 100 IU FVIII/kg threetimes per week
and Emicizumab prophylaxis, has been published. Inhibitor titres decreased in all
patients. Three of the seven patients achieved negative inhibitor titres [<0.6 chromogenic
Bethesda units (CBU)/mL] and two patients achieved a normal FVIII recovery (>66%).
There were nine bleeding episodes in four patients and no thrombotic events.[35 ] Complete success has not been published yet. To date, all patients still have been
on the ITI FVIII dose.
Questions remain on the optimal FVIII dose /ITI protocol, the approach for tapering
down FVIII ITI dosing and how to maintain tolerance after successful ITI.
ITI courses combined with Emicizumab and the treatment strategy should be documented
in studies or registries (MOTIVATE study, PedNet, ObsITI, etc.).
Previously Untreated Patients
Previously Untreated Patients
14. Emicizumab is licensed for all age groups; however, licensure for children is based
on limited data. The decision to use Emicizumab in small children, especially PUPs,
has to be made on an individual basis.
Supporting Data
There are no data on the efficacy, pharmacokinetic/pharmacodynamic and safety of Emicizumab
administration in newborns with HA so far. The equilibrium of the coagulation system
of the newborns (coagulation, anticoagulation, fibrinolysis) differs from older children.
Since haemostatic efficacy of Emicizumab is dependent on FIX activity, it is important
to consider that concentrations of FIX are reduced at birth and reach normal values
at the age of approximately 6 months. Even in older children, FIX levels might be
physiologically reduced. Whether prevention of intracerebral bleeds can be achieved
with Emicizumab prophylaxis started in early life needs to be explored in further
studies.
In the frame of the HAVEN2 trial, only five infants with severe HA and inhibitors
(1 month up to <2 years) have been included. Another three haemophilia patients without
inhibitors aged <3 years have been treated in the HOHOEMI study[36 ] without any safety concerns. In the frame of the HAVEN studies in children <12 years
of age, no differences of efficacy have been observed between the different age groups.
The steady state plasma trough concentrations of Emicizumab were comparable in adult
and paediatric patients older than 6 months. In addition, the adverse events were
similar in type to those observed in adult HA patients.[10 ]
A single-centre experience reported the prophylactic use of Emicizumab in 11children
with inhibitors (median age: 26 months). Prophylaxis was judged to prevent patients
from haemarthrosis and spontaneous bleeds. Four out of 11 patients were treated with
rFVIIa occasionally. Three minor surgeries were performed, one complicated by major
bleeding. The authors emphasize that bleeds occurred in those patients with the lowest
thrombin generation results.[37 ]
In general, there are no data available on the treatment strategy in PUPs (Emicizumab
stand-alone prophylaxis or Emicizumab prophylaxis combined with the episodic prophylactic
administration of FVIII). Studies are urgently needed and are currently planned (FREE-study,
Finding the Response to Early Emicizumab in PUPs <2 years of age). All PUP data should
be captured in the GEPHARD registry.
Elderly Patients
15. There are no general concerns to use Emicizumab in elderly patients with HA. Individual
risk factors and co-morbidities must be taken into account.
Supporting Data
The HAVEN study program also included elderly patients. Median age was 28 years (range:
12–75), 38 years (range: 13–77), 39 years (range:14–68) in HAVEN 1, 3 and 4, respectively.
Exact numbers of patients aged >65 years are not published.[4 ]
[5 ]
[9 ]
Altogether, at end of September 2019, more than 5,400 patients have been treated with
Emicizumab worldwide. Apart from the 4 cases of TMA in patients treated with additional
high doses of BPA, 9 thrombotic events (not TMAs) occurred, 2 in the HAVEN 1 study
with high doses of BPA and 7 without additional BPA or low doses. Most patients had
additional risk factors like arterial hypertension and previous venous thromboembolism.[12 ]
There is no evidence that age itself is a risk factor, but patients should be evaluated
for cardiovascular risk factors and decision to prescribe Emicizumab to patients with
risk factors should be based on individual benefit/risk evaluation.
Laboratory Tests
16. Emicizumab affects intrinsic pathway clotting based laboratory assays occurring after
the first dose of Emicizumab and lasting up to 6 months after the last dose.
Activated partial thromboplastin time (aPTT; shortened) and all aPTT-based one-stage
clotting assays (e.g., FVIII–XII, classical [Nijmegen modified] Bethesda assay, protein
C/protein S activity, activated protein Cresistance) are influenced by Emicizumab
and cannot be interpreted during the use and up to 6 months after discontinuation
of Emicizumab.[38 ]
[39 ]
The following tests are not influenced by Emicizumab: thrombin time, prothrombin time
based one-stage tests for single factor activity, chromogenic factor assays (except
for FVIII), chromogenic FVIII assay with bovine components, immune-based assays (ELISA;
turbidimetric methods) and Bethesda assay with the bovine chromogenic FVIII assay.
17. Tests to monitor FVIII replacement and FVIII inhibitors as well as Emicizumab concentration
should be available in centres treating PWHAs with Emicizumab.
For monitoring FVIII replacement in the presence of Emicizumab, a chromogenic test
with bovine components has to be used.
Inhibitor testing has to be performed with a bovine chromogenic test as well. Inhibitory
activity is expressed in CBU/mL.
Monitoring of Emicizumab concentration should be used with the aim to detect lacking
therapy adherence or neutralising ADAs. Fully neutralising ADAs are captured with
measuring a prolonged aPTT, but partially neutralising ADAs need more sensitive tests.
If aPCC at standard doses is intended to be used, sensitive tests to monitor Emicizumab
concentration can be useful to exclude relevant concentrations. Because of the long
half-life of Emicizumab, relevant concentrations can be expected for up to 6 months
after the last dose of Emicizumab.
Emicizumab concentration can be monitored using a chromogenic test with human components
or a diluted one-stage clotting assay calibrated against Emicizumab.
We recommend monitoring of Emicizumab concentration 1 week after the last loading
dose and then every 3 months for a year, then every 6 to 12 months or in case of lacking
efficacy. Expected trough levels in the steady state with the 1.5 mg/week dosing regimens
are 25 to 75µg/L.[40 ]
For monitoring FVIII replacement or for FVIII inhibitor testing in the presence of
Emicizumab, a chromogenic test with bovine components can be used.
Supporting Data
Development of ADAs against Emicizumab is rare. In the HAVEN study program, 14 out
of 398 patients were tested positive for ADA, in 7 of whom the antibodies were transient,
and 3 patients (0.75%) had neutralizing antibodies with reduction of efficacy including
one patient with a fully neutralizing ADA resulting in lacking efficacy including
repeated break-through bleeds.[41 ]
For monitoring Emicizumab concentration in plasma, a chromogenic test with human components
showed good linearity within the expected plasma concentrations (5–150 µg/mL). Also,
a one-stage clotting assay with diluted patient plasma (1:80) has been validated for
measuring Emicizumab concentration. For both tests, Emicizumab should be used as a
calibrator.[38 ]
[39 ]
[40 ] FVIII measurement is not influenced by Emicizumab if a chromogenic test with bovine
FIXa and FX as reagents is used.[38 ]
Conclusion
This studyis designed to support haemophilia physicians using Emicizumab in PWHA.
Deliberate education of patients and medical staff is required as well as adjusted
strategies in case of break-through bleeding and surgery. With emerging further experience
and clinical trials, these recommendations need to be updated at regular intervals.
