Schrezenmeier.qxp 11/8/09 10:20 am Page 17
The Management of Paroxysmal Nocturnal Haemoglobinuria
treatment experienced significant improvements in quality of life patients who received primary warfarin prophylaxis, whereas the
and fatigue.
73
This provides further evidence that the diminished 10-year risk of thrombosis was 36.5% in patients without prophylaxis.
quality of life in PNH is also due to intravascular haemolysis and
does not just reflect the severity of anaemia. To study the impact of long-term eculizumab treatment on
thromboembolism, the event rate in the clinical trials including the
In general, eculizumab was safe and well tolerated.
70,74
The most open-label extension trials was compared with the pre-treatment rate
common adverse events reported in the eculizumab-treated in the same patients.
73
The event rate of venous or arterial
patients were headache, nasopharyngitis, back pain and nausea. thromboses prior to eculizumab was 7.37 events/100 patient-years.
The headaches occurred within the first 24 hours after The most common sites were lower-extremity deep veins (18.5%),
administration of the first two doses of eculizumab. Headache
decreased after the first two doses of eculizumab. The
The approval of eculizumab made a
headache after start of treatment may be related to a sudden
increase of NO due to effective blockade of intravascular
targeted, disease-modifying treatment
haemolysis and therefore cessation of NO scavenging by free
available that is well-tolerated and
haemoglobin. The decrease in headache after the first two doses
may indicate a return of NO to physiological levels.
70,74
reduces haemolysis, transfusion
requirements and risk for thrombosis and
Recently, a desquamating rash and hyperammonemia was reported
in a patient following the first administration of eculizumab;
77
the
improves anaemia and quality of life.
causality in this case is not clear and a drug–drug interaction with
trimethprim–sulfamethoxazole was assumed.
77
As the experience mesenteric/splenic veins (16.9%) and hepatic/portal veins (16.9%).
so far with eculizumab in this rare disease is limited, physicians With eculizumab treatment, the event rate dropped significantly to
must be vigilant for unexpected adverse events. It is known that 1.07 events/100 patient-years (p<0.001).
73
In the subgroup of patients
individuals with inherited terminal complement deficiency have an who had received antithrombotic treatment, the thromboembolic
increased risk of meningococcal infections. In eculizumab-treated event rate was 10.6 per 100 patient-years before eculizumab and was
patients, three cases of Neisseria meningitis infections have been reduced to 0.62 events per 100 patient-years in the same patients
reported.
78
Across all PNH studies, infections did not seem to be during eculizumab treatment.
73
Therefore, long-term administration of
more frequent in patients with eculizumab treatment compared eculizumab reduces the risk of thrombosis in PNH.
73
with patients who received placebo.
70,74
In acute thrombotic events, immediate anticoagulation with heparin
Eculizumab is administered in between 25 and 45 minutes as should be started. Successful local or systemic thrombolytic therapy
an intravenous infusion according to the following dosing schedule: an or radiological intervention has been reported in patients with acute
induction dose of 600mg every seven (±2) days for four weeks followed onset of Budd-Chiari syndrome.
79–82
After a thrombotic event, patients
one week later by a 900mg dose and then 900mg every 14 (±2) should be anticoagulated indefinitely.
1
days.
70–73,75
A reduction in the dosing interval from 14 to 12 days was
sufficient to maintain the levels of eculizumab necessary to completely Currently, it is controversial how the results on eculizumab will
block intravascular haemolysis in patients who experienced change the recommendations for anticoagulant treatment in PNH.
breakthrough haemolysis in the last days of the dosing interval.
75
All Further studies are needed to clarify whether eculizumab can replace
patients due to receive eculizumab must receive N. meningitidis primary or even secondary prophlyaxis. For decision-making
vaccine at least two weeks prior to commencement of eculizumab. on primary prophylaxis, all factors such as symptoms, size of PNH
Quadrivalent, conjugated meningococcal vaccines are strongly clone, other thrombophilic risk factors, treatment for PNH (in
recommended. Patients must be informed about the early clinical signs particular eculizumab) and other concomitant medication, platelet
of meningococcal infections and must be closely monitored. count, age, activity level, compliance and patient preference have to
be taken into consideration.
Given the impact of thrombosis on
Given the impact of thrombosis on mortality due to PNH,
9,13
one could
mortality due to paroxysmal nocturnal
expect that eculizumab treatment, by decreasing the risk of
haemoglobinuria, one could expect that
thrombosis, might increase the life expectancy of these patients.
eculizumab treatment, by decreasing the
Conclusion
risk of thrombosis, might increase the life
Recent developments have raised expectations for patients
with PNH, and recent results on stem cell transplantation
expectancy of these patients.
are encouraging. The approval of eculizumab made a targeted,
disease-modifying treatment available that is well-tolerated and
Prevention and Treatment of Thrombosis reduces haemolysis, transfusion requirements and risk of thrombosis
The most feared complications in PNH and the leading cause of and improves anaemia and quality of life.
disease-related death are thromboembolic events.
9,13
Based on
retrospective analysis, it was recommended to use primary The availability of eculizumab raises a lot of new questions. Does
prophylactic oral anticoagulation in patients with a large PNH cell eculizumab change the indication for allogeneic stem cell
population.
16
In this study, no thromboembolic event occurred in transplantation, and if so how? Does eculizumab treatment prior to
EUROPEAN HAEMATOLOGY 17
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