The Expert Committee recommended the addition of pegaspargase to the
complementary list of the EML and EMLc for use in the treatment of acute
lymphoblastic leukaemia. The listing should indicate that quality-assured
biosimilars of pegaspargase should also be considered as essential.
The Committee noted pegaspargase was associated with less
immunogenicity and development of neutralizing antibodies than native
asparaginase, which may offer advantages in terms of improved patient adherence
enabling completion of treatment, thereby reducing the risk of relapse.
The application requested the addition of pegaspargase (PEGylated Escherichia
coli asparaginase) to the EML and EMLc for use in the treatment of acute
lymphoblastic leukaemia (ALL).
Pegaspargase had not previously been considered by the Expert Committee for
addition to the EML. Native E. coli asparaginase is currently included on the EML
and EMLc for treatment of ALL.
Asparaginases represent a therapeutic group including native E. coli
asparaginase, PEGylated E. coli asparaginase, Erwinia asparaginase, and
biosimilars. When asparaginases are used at the recommended dose and schedule,
and when use is not limited by hypersensitivity or neutralizing antibodies, any
of these three asparaginases effectively treat ALL.
Public health relevance
Acute lymphoblastic leukaemia (ALL) is a rare haematological malignancy.
Globally, from 2003 to 2007, the age-standardized incidence rate of ALL ranged
from 1.08 to 2.12 per 100 000 person-years. ALL accounts for approximately 25%
of all cancers (80% of leukaemias) in children. The disease is far less common in
adults (<1% of all cancers) where is associated with much lower cure rate that
that achievable for children (1).
Allergic reactions to native E. coli asparaginase occur in 20% to 42% of
patients with ALL, and silent (asymptomatic) neutralizing antibody formation
in another 30 to 40%, such that around two thirds of patients do not complete
all their required asparaginase unless they have access to a second asparaginase
product, usually Erwinia asparaginase (2–10).
Hypersensitivity or silent antibody formation necessitate a change to
another form of asparaginase. The supply of Erwinia asparaginase has been
limited to high-income countries, and supply is often insufficient to meet the
needs of patients who react to first-line native E. coli asparaginase.
When no second product is available (or an allergy occurs to the alternate
asparaginase), the inability to complete asparaginase treatment increases the
risk of relapse, which is associated with poor prognosis, with survival after
relapse ranging from 20% to 50% (11). Furthermore, relapse therapy entails
intense salvage chemotherapy followed by allogeneic stem cell transplantation,
which greatly increases treatment costs (9). Minimization of allergic reactions to
the initial form of asparaginase improves outcomes and reduces costs.
PEGylation of E. coli asparaginase to create pegaspargase increases the half-life
of asparaginase and decreases immunogenicity and allergic reactions/antibody
formation from 20–42% to 2–11% (12).
The UKALL 2003 trial used pegaspargase in a schedule that included
several days of glucocorticoids prior to each dose of pegaspargase in low- and
intermediate-risk patients. Glucocorticoid pre-treated patients had a 1% rate of
allergic reaction and five-year event-free survival of around 95% (13).
Patients in the high-risk arm received several doses of pegaspargase
without preceding glucocorticoids and had a reaction rate of 6%, such that in the
whole study the reaction rate was 2% (13, 14). These findings led to a change in
clinical practice, and modification of existing ALL treatment protocols to include
glucocorticoid pre-treatment before each pegaspargase dose, to reduce the
incidence of allergic reactions, thus allowing patients to complete asparaginase
therapy and reducing the need for a second-line asparaginase (e.g. Erwinia).
Asparaginase products have different molecular structures, different
half-lives, and different clinical activities per unit. Pegaspargase is six to nine
times more potent than native E. coli asparaginase and each dose lasts 2–3 weeks
instead of 2–3 days. Modern ALL protocols require lower doses and fewer doses
of pegaspargase to provide the asparaginase needed for patients.
Treatment strategies using pegaspargase as initial therapy are more
effective because they reduce the rates of hypersensitivity and neutralizing
antibodies from a total of 50–65% (including both) to 10–15% (including both)
and thus allow more patients to continue first-line asparaginase and complete all
doses of the treatment protocol. Completion of all doses of first-line asparaginase
reduces the risk of relapse and thus reduces costs associated with salvage therapy
(15). It also reduces the need for second-line Erwinia asparaginase, which is not
available in many countries (especially LMICs) and which has suffered from
recurrent shortages and stock-outs even in high-income countries (HICs).
No data were presented in the application in relation to the comparative safety
A randomized, open-label Phase III trial compared the relative toxicity and
efficacy of intravenous (IV) pegaspargase and intramuscular (IM) native E coli
asparaginase in 463 children with newly diagnosed ALL who had achieved
complete remission following induction therapy (16). Five-year disease-free
survival was similar between treatment groups: 90% vs 89% for IV pegaspargase
and IM native E coli asparaginase treated patients, respectively (p=0.58). There
was no significant difference in the frequency of asparaginase-related toxicities
(allergy, pancreatitis or thrombotic or bleeding adverse events) between the
treatment groups: 28% vs 26% in the pegaspargase and native E. coli asparaginase
groups, respectively (p=0.60). Pegaspargase was associated with less anxiety
than native E. coli asparaginase. The most common adverse events of Grade 3 or
higher were infections (bacterial or fungal) and occurred at a similar rate in both
A retrospective study compared the efficacy and safety of pegaspargase
and native E. coli asparaginase in 122 adolescents and adults with newly diagnosed
ALL (17). Both treatments demonstrated comparable complete remission rates
(95.65 vs 90.79%), median overall survival (14.07 vs 16.29 months) and median
relapse-free survival (10.00 vs 8.57 months). Pegaspargase-treated patients aged
less than 35 years had a higher median relapse-free survival time compared
with E. coli asparaginase-treated patients (10.93 vs 8.97 months; p=0.037). Both
treatments were found to be acceptably tolerable and demonstrated similar
incidences of allergy, hepatic toxicity, pancreatic lesions, and bleeding and
In patients with relapsed ALL, and with hypersensitivity to native E. coli
asparaginase, pegaspargase treatment was associated with similar tolerability as
in newly diagnosed patients (18).
Cost / cost effectiveness
The application estimated that, on average, the ratio of the number of vials of
E. coli asparaginase needed versus vials of pegaspargase was 10.3 (assuming
no obesity and no vial sharing between patients) meaning that a per-vial price
of pegaspargase that is 10.3 times greater than that of a vial of native E. coli
asparaginase would be cost-neutral, without considering differences in efficacy.
Costs for native E. coli asparaginase were reported as between US$ 150–
177 per vial, compared to US$ 1300–1400 per vial for pegaspargase in Europe
and Latin America.
Pegaspargase is marketed by Servier Pharmaceuticals. Biosimilars of pegaspargase
are in development in some jurisdictions.
The risk of allergic hypersensitivity reactions to asparaginase therapy increases
with the number of doses and up to one third of patients experience a reaction by
the fourth dose. This is one of the highest reported sensitivity reactions reported
from chemotherapy drugs. Approximately 10% of reactions are life-threatening.
Reactions involving the formation of silent neutralizing antibodies
result in inactivation of asparaginase and reduced serum asparaginase activity
levels. This results in a low therapeutic threshold of the drug. For these patients,
therapeutic drug monitoring is essential, but not generally available in LMICs.
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