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Cost-minimisation of PEG-L-asparaginase versus native L-asparaginase for

the treatment of children with acute lymphoblastic leukemia in Belgium

Article · January 2013

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Tiene G M Bauters Veerle Mondelaers

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Pharmacotherapy 4
Cost-minimisation analysis of
PEG-L-Asparaginase versus native
L-Asparaginase for the treatment
of children with acute lymphoblastic
leukaemia in Belgium
T. Bauters, PharmD, PhD1, V. Mondelaers, MD2, B. De Moerloose, MD, PhD2, H. Robays, PharmD1,
Y. Benoit, MD, PhD2

PEG-L-Asparaginase (Oncaspar ®) is a major compound of antineoplastic combination therapy for rein-

duction in acute lymphoblastic leukaemia in children and adults with known hypersensitivity. In the United
States, it has been approved for many years as first-line treatment of children with acute lymphoblastic
leukaemia. Its clinical benefits have been extensively described. In this report, a cost-minimisation analysis
comparing the direct cost of PEG-L-asparaginase with that of native E. coli and Erwinia L-asparaginase
treatment is described.
(Belg J Hematol 2013;4(4):144-147)

Introduction The sources of asparaginase for hospital use are bacterial

Acute lymphoblastic leukaemia (ALL) is the most com-
mon childhood cancer, accounting for approximately
one quarter of new cancer diagnoses in children. The
combination of Escherichia coli L-asparaginase, vin-
cristine and prednisone treatment has increased the
remission induction rate to more than 95% in patients
with standard risk ALL. L-asparaginase (further referred
to as Asparaginase) has been shown to be a crucial
chemotherapeutic agent in ALL treatment.1-4
Asparaginase is an enzyme that catalyses the hydroly-
sis of extracellular asparagine to ammonia and aspartic
acid in the bloodstream and the extracellular space.
Normal cells are capable of synthesising asparagine,
which is essential for cell survival. Certain malignant
cells, especially leukemic lymphoblasts, however are
not and depend on extracellular sources of asparagines
for protein synthesis.5
in origin, mainly Escherichia coli (E. coli) and Erwinia
chrysanthemi. Native asparaginase is commercially avail-
able in two forms: E. coli (Paronal®, Nycomed) and Er-
winia (Erwinase®, Eusapharma, Jazz Pharmaceuticals).
The frequency of hypersensitivity reactions to E. coli is
rather variable (~40%) but ranges from 0 to 75% de-
pending on the publication.6,7 In case of hypersensitivity
reactions (i.e. generalised reaction including pain, ery-
thema, pruritus, angioedema, fever, respiratory distress
or a localised reaction or a combination of both), dis-
continuation of E. coli asparaginase and substitution
with Erwinia- or polyethylene glycol (PEG)-asparaginase
(Oncaspar®, Sigma-Tau) is preferred.
In Belgium, E. coli asparaginase (Paronal®) is available
and reimbursed in first-line treatment. Both Erwinia
asparaginase (Erwinia®) and PEG-asparaginase (Oncas-
par®) are not licensed in Belgium. They are reimbursed

Department of Pharmacy, Ghent University Hospital, Ghent, Belgium 2Department of Paediatric Hemato-Oncology and Stem Cell Transplantation,
1

Ghent University Hospital, Ghent, Belgium.

Please send all correspondence to: T. Bauters, PharmD, PhD, Ghent University Hospital, Department of Pharmacy, -1 K12, De Pintelaan 185,
B-9000 Ghent, Belgium, tel: +32 9 332 50 56, fax: +32 9 332 49 74, email: tiene.bauters@uzgent.be.
Conflict of interest: The authors have nothing to disclose and indicate no potential conflict of interest.
Key words: acute lymphoblastic leukaemia, cost-minimisation analysis, paediatrics, PEG-L-Asparaginase.

Belgian Journal of Hematology Volume 4, Issue 4, December 2013

14 4
Pharmacotherapy
ASPARAGINASE (E.Coli)
→ Hospitalization
→ Day-clinic
No
E. Coli asparaginase
→ Day-clinic: 4 x 2 vials*
Figure 1. Algorithm for treatment with E. coli asparaginase (* = mean number of vials).
in second-line, i.e. after hypersensitivity reaction to E. coli
asparaginase.
Oncaspar® is indicated as a component of antineoplastic
combination therapy for reinduction in ALL in children
and adults with known hypersensitivity. In the US,
PEG-asparaginase has been approved for many years
as first-line treatment of children with ALL.5-8
The clinical benefits of the pegylated formulation (sig-
nificantly longer half-life and therefore fewer adminis-
trations) have been extensively described, just as pharma-
coeconomic analyses of PEG-asparaginase versus native
E. coli asparaginase, in favour of PEG-asparaginase.3,9-11
We conducted a cost-minimisation analysis for the
Belgian National Institute for Health and Disability In-
surance (NIHDI/RIZIV/INAMI) to compare the direct
cost of PEG-asparaginase with that of native E. coli
and Erwinia asparaginase.
Methods
To obtain valuable parameters for the cost-minimisation
analysis, a review of all patients treated with Paronal®
and Erwinase® at the Ghent University Hospital ( Janu-
ary to December 2011, i.e. 12 months) was performed.
This enabled us to obtain an objective estimation of
the mean number of vials used per patient. These data
were only generated as basis for further comparisons.
The total cost was presented as direct drug cost (per
vial) plus hospital cost per day-clinic visit (maxiforfait)
Belgian Journal of Hematology Volume 4, Issue 4, December 2013
14 5
INDUCTION
2 administrations = 2 x 2 vials *
6 administrations = 6 x 2 vials *
RE-INDUCTION
Allergic reaction?
Yes (~ 40% of patients) (6,7)
→ switch to Erwinia Asparaginase
Erwinia asparaginase
→ Day-clinic: 6 x 3 vials*
or daily hospital cost (100%). Other costs (personnel,
laboratory tests, charges for premedication, etcetera)
and indirect costs (i.e. absenteeism from school or work,
follow-up visits, long-term morbidity, etcetera) were
not included in the current simulation.
Direct drug costs (per vial) were based on official prices,
i.e. €58 (Paronal®, 10000 IU/flacon), €846 (Erwinase®,
10000 IU/flacon) and €1,249 (Oncaspar®, 3750 IU/
flacon).
Taking into account all Belgian paediatric hemato-on-
cology centres, the average maxiforfait cost for admin-
istration in day-clinic was €193 and €582 for daily
hospital cost (100%) (data obtained from NIHDI dd.
01/01/2012).
The standard treatment was performed according to the
European Organisation for Research and Treatment of
Cancer (EORTC) 58081 protocol.12 For the simulation
of the switch from Paronal® or Oncaspar® to Erwinase®
(in case of hypersensitivity), the switch to Erwinase® was
integrated from the reinduction phase on. An overview
of this treatment flow is given in Figure 1.
Results
During a twelve-month period, 28 patients were treated
with Paronal® and nine with Erwinase®. These data were
used to calculate the mean number of vials per admin-
istration, i.e., two for Paronal® and three for Erwinase®.
Based on these data and taken into account the mean
 4
PEG-ASPARAGINASE

INDUCTION

→ Hospitalization 1 administration = 1 x 1 vial *

→ Day-clinic 1 administration = 1 x 1 vial *

RE-INDUCTION

Allergic reaction?
Yes (~10% of patients) (7)
No
→ switch to Erwinia asparaginase

PEG-Asparaginase Erwinia Asparaginase

→ Day-clinic: 1 x 1 vials* → Day-clinic: 6 x 3 vials*

Figure 2. Algorithm for treatment with PEG-asparaginase (* = mean number of vials).

Figure 3. Total price per treatment per patient for a whole cycle
without hypersensitivity (theoretically).
maxiforfait for day hospitalisation and/or hospitalisa-
tion cost (100%), cost-simulations were performed.
If a patient were to be treated exclusively with one prod-
uct, the cost per patient per treatment would theoreti-
cally be €4,487 (Paronal®), €50,326 (Erwinase®) and
€4,717 (Oncaspar®). An overview of the direct cost-
minimisation analysis per patient per treatment without
hypersensitivity (theoretically) is presented in Figure 3.
However, as most of the treatments involve a switch due
to hypersensitivity reactions, alternative treatment reg-
imens were calculated. From literature data, it is clear
that ~40% of patients treated with Paronal® and 10%
Figure 4. Annual estimated cost for the Belgian paediatric
population with de novo ALL treated with Paronal® or Oncaspar®
regimens (taken into account a hypersensitivity reaction chance
of 40% for Paronal® and 10% for Oncaspar® with subsequent
switch to Erwinase® treatment).
of patients with Oncaspar®, are switched to Erwinase®
as a result of hypersensitivity reaction. Therefore, a switch
from Paronal® or Oncaspar® to Erwinase® (product of
choice in case of hypersensitivity) was taken into con-
sideration in the reinduction phase (IIA).
In Belgium, an average of 70 paediatric patients are
diagnosed with de novo ALL per year, therefore a
simulation for the Belgian population was performed.
Estimating that 40% of patients treated with Paronal®

Belgian Journal of Hematology Volume 4, Issue 4, December 2013

14 6
 Pharmacotherapy
Key messages for clinical practice
• The pharmacologic profile and the cost-minimisation analysis of PEG-asparaginase justify its
use in certain paediatric populations.
• Apart from the cost of fewer hospitalisations and a lower use of Erwinia-asparaginase, fewer
days spent in hospital and less traveling time to physicians offer additional benefits to the patient.
and 10% of patients with Oncaspar®, have a hypersen-
sitivity reaction and assuming that both groups are
switched to Erwinase®, the total cost for the Belgian
population is estimated at €738 269 for patients start-
ed on Paronal® and €434 801 for patients treated with
Oncaspar® in first-line (Figure 4).6,7
The mean cost per individual patient would be €10,547
(treatment with Paronal®) in first-line and €6,211 (treat-
ment with Oncaspar®), indicating a cost reduction of 40%.
Discussion
The question that guided this analysis was to estimate
the cost of Oncaspar® treatment compared to the cost
of the current first-line reimbursed treatment with
Paronal® (from the perspective of NIHDI). Only the
cost for the hospital and the direct drug cost were taken
into account for the simulation.
Although Oncaspar® is more expensive per single-dose
vial (€1,249 versus €58), simulation data revealed that
complete standard therapy with Oncaspar® is less ex-
pensive than treatment with Paronal®. The use of Oncas-
par® requires lower doses with less frequent injections
and less hypersensitivity reactions with concurrent
switch to the expensive Erwinase®.
The results of this simulation suggest that Oncaspar®
should not be restricted from a treatment protocol solely
because of the high direct drug cost.
Apart from the bulk-saving cost from fewer hospitalisa-
tions and a lower use of Erwinase®, there are additional
benefits for the patients. Fewer days spent in hospital
or traveling time to physicians should also offer a posi-
tive psychological benefit to the patient.
It must be mentioned that in this cost-minimisation
analysis, the time spent and the devices used by phar-
macists, nurses and physicians for the safe preparation,
manipulation and administration of the products would
be remarkably higher for Paronal® and Erwinase® com-
pared to Oncaspar®.
An identical cost calculation can be performed for non-
Hodgkin T-cell or precursor B-cell lymphoblastic lym-
phoma.
Belgian Journal of Hematology Volume 4, Issue 4, December 2013
147
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Conclusion
Based on the pharmacologic profile and this cost-min-
imisation analysis, it would be appropriate for clinicians
to investigate using PEG-asparaginase earlier in certain
paediatric populations.
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