Blood, 1 September 2002, Vol. 100, No. 5, pp. 1923-1925
CORRESPONDENCE
To the editor:
Pharmacology of PEG-asparaginase in childhood acute
lymphoblastic leukemia (ALL)
Asparaginase (ASNase) has long been considered to be an
important element in the management of childhood ALL. Its antileukemic effect is thought to be related to a metabolic deficiency reflected by
the blasts' incapability to synthesize asparagine (ASN) from aspartic
acid. Treatment with ASNase aims therefore at depleting the blood of
ASN in order to exhaust the substrate supply that became selectively
essential to the malignant cells. Highly interesting findings
on PEG-ASNase, which is a polyethylene glycol (PEG) conjugate of an
ASNase derived from Escherichia coli, have recently been reported by Avramis et al.1 In the context of a
randomized trial, the authors evaluated several important
pharmacologic parameters after a single intramuscular (IM)
administration of 2500 IU/m2 PEG-ASNase in children with
newly diagnosed ALL.
The pharmacokinetic results show that the mean ASNase serum activity
peaked on day 5 after the first IM dose at an average of 1000 U/L and
was quantifiable within the therapeutic range of above 100 U/L over a
period of about 28 days. Elimination from the serum was described by a
single exponential function.1 Remarkably, the presented
findings contrast in every aspect with results observed after the
intravenous use of the identical dose of PEG-ASNase within the ALL
protocols of the Berlin-Frankfurt-Münster (BFM) study
group.2 Using a well-established drug monitoring program
at our own institution, we have been able to identify peak ASNase serum
activities ranging around 2500 U/L immediately after administration,
but the time period with activity values above 100 U/L, which was
usually 3 weeks, was significantly shorter than the one reported by
Avramis et al.1 Comparison of these data with intravenous
results after 1000 IU/m2 (Müller et al3)
have also shown that a substantial increase of the PEG-ASNase dose
neither translated into a prolongation of time with activities above
100 U/L nor influenced the rate of patients with early ASNase
inactivation. For these reasons and with regard to the predictive use
of pharmacokinetic (PK) modeling, we conclude that the
elimination of PEG-ASNase from the serum cannot generally be
characterized using the linear model as proposed by the authors. Due to
the effects of the IM route of administration on the distribution of
the ASNase activities, the suggested method might, however, in their
study have served as the most appropriate approach to describe
PEG-ASNase elimination.
ASN concentrations in the serum and cerebrospinal fluid (CSF) that
allow a more accurate estimate of an effect caused by ASNase have also
been measured in the study performed by Avramis et al.1 The authors state that ASN was depleted rapidly from serum and CSF
after administration of PEG-ASNase. This is somewhat confusing because,
in contrast to the authors' conclusion, ASN is represented in
considerable amounts in every figure illustrating the amino acid
results. Independent of the applied ASNase or the activity measured at
the same time, the lowest mean ASN concentrations are
depicted in a range of about 1 µM. In view of in vitro findings demonstrating ongoing leukemic blasts' growth in medium
containing comparable amounts of ASN,4 as well as
findings from other working groups showing complete depletion at a
level of 0.2 µM after administration of different schedules
using native ASNase preparations,5-7 a clarification
of the outlined discrepancy would be desirable for an adequate estimate
of the treatment intensity achieved with the schedules presented in the
paper. Under methodologic aspects, giving a clear definition of ASN
depletion or a description of the preanalytic sample preparation might
be helpful since hemolysis of blood after withdrawal is eg
known to influence ASN concentrations leading to false high values.
Joao Paulo Vieira Pinheiro, Claudia Lanvers, Gudrun Würthwein, and Joachim Boos
Correspondence: Joachim Boos, University Children's Hospital
Muenster, Department of Pediatric Hematology and Oncology,
Albert-Schweitzer-Strasse 33, 48129 Münster, Germany; e-mail:
onkpharm{at}uni-muenster.de
References
1.
Avramis VI, Sencer S, Periclou AP, et al.
A randomized comparison of native Escherichia coli asparaginase and polyethylene glycol conjugated asparaginase for treatment of children with newly diagnosed standard-risk acute lymphoblastic leukemia: a Children's Cancer Group study.
Blood.
2002;99:1986-1994[Abstract/Free Full Text].
2.
Müller HJ, Beier R, Casimiro da Palma J, et al.
PEG-asparaginase (Oncaspar) 2500 IU/m2 BSA in reinduction and relapse treatment in the ALL/NHL-BFM protocols.
Cancer Chemother Pharmacol.
2002;49:149-154[CrossRef][Medline]
[Order article via Infotrieve].
3.
Müller HJ, Löning L, Horn A, et al.
Pegylated asparaginase (Oncaspar) in children with ALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols.
Br J Haematol.
2000;110:379-384[CrossRef][Medline]
[Order article via Infotrieve].
4.
Cooney D, Handschuhmacher R.
L-asparaginase and L-asparagine metabolism.
Ann Rev Pharmacol.
1970;10:421-440.
5.
Ahlke E, Nowak-Göttl U, Schulze-Westhoff P, et al.
Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia.
Br J Haematol.
1997;96:675-681[CrossRef][Medline]
[Order article via Infotrieve].
6.
Woo MH, Hak LJ, Storm MC, et al.
Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase in children with acute lymphoblastic leukemia.
J Clin Oncol.
1999;17:1568-1573[Abstract/Free Full Text].
7.
Rizzari C, Zucchetti M, Conter V, et al.
L-asparagine depletion and L-asparaginase activity in children with acute lymphoblastic leukaemia receiving im or iv Erwinia C or E coli L-asparaginase as first exposure.
Ann Oncol.
2000;11:189-193[Abstract/Free Full Text].
Response:
PEG-asparaginase and deamination of serum asparagine
in children with standard-risk lymphoblastic leukemia (CCG-1962)
We are aware of Vieira Pinheiro et al's data
showing the rapid elimination of PEG-asparaginase at low serum
concentrations. We have not seen that late decay with a similar
formulation in our pediatric population. Our findings are consistent
with those reported by Asselin et al1 using the same
PEG-ASNase formulation as that used in the Children's Cancer Group
studies. The Europeans use a different form of pegylated native
Escherichia coli asparaginase produced in Japan and marketed
by Medac than that used in the United States. Dr Boos's group reported
that the native asparaginase marketed by Medac has different
pharmacokinetic properties than other native E coli
asparaginase preparations.2 The native E coli
asparaginase used in the United States is produced by Merck and is
pegylated by a different chemistry according to the manufacturer (Enzon, Bridgewater, NJ). This may have lead to a pegylated
product with different characteristics in drug disposition and
elimination. The rapid fall in asparaginase activity at late time
points suggests that their enzyme preparation may contain a mixture of
variously pegylated products with different half-lives.
The route of administration in our pediatric trial was intramuscular,
while the Boos group gives their drug intravenously. Our population
analyses estimated a long half-life of absorption from the injection
site of this drug. This could have lead to a depot effect that masked
any late decline in enzyme activity. Nevertheless, we also found a
first-order disappearance of PEG-asparaginase in 24 adult patients
treated intravenously.3 It should be added that neither
the native E coli asparaginase nor the PEG-asparaginase marketed by Medac are licensed in the United States. We would like to
conduct a randomized study between the 2 PEG-asparaginase formulations
if the Medac product becomes licensed for use in the United States.
We have consistently found low residual asparagine concentrations in
some patient samples with high levels of enzyme activity. We rapidly
chilled the samples to prevent continued ex vivo deamination of
asparagine, and we found that very few samples had visual signs of
hemolysis. Asselin et al have reported that asparagine concentrations return toward normal much faster when care is taken to inhibit ex vivo
enzyme activity.4 We sent a blinded set of our samples to
Dr Asselin, and she confirmed the asparagine values we reported. Liver
perfusion studies and modeling of asparaginase treatment suggest that
there is a high rate of asparagine input into the circulation from diet
and the tissues.5,6 An equilibrium between the rate of
asparagine input and the asparaginase activity can result in a low
(nonzero) steady-state asparagine concentration.
Vassilios I. Avramis and John S. Holcenberg
Correspondence: Vassilios I. Avramis, USC Keck School of
Medicine, Children's Hospital Los Angeles, Division of
Hematology/Oncology, 4650 Sunset Blvd, Los Angeles, CA 90027
References
1.
Asselin BL, Whitin JC, Coppola DL, et al.
Comparative pharmacokinetic studies of three asparaginase preparations.
J Clin Oncol.
1993;11:1780-1786[Abstract/Free Full Text].
2.
Boos J, Werber G, Ahlke E, et al.
Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations.
Eur J Cancer.
1996;32A:1544-1550[CrossRef][Medline]
[Order article via Infotrieve].
3.
Douer D, Cohen LJ, Periclou AP, et al.
PEG-Asparaginase (PEG-ASP) in a remission induction regimen for newly diagnosed acute lymphoblastic leukemia (ALL) adults.
Blood.
1998;92(suppl):400a.
4.
Asselin BL, Lorenson MY, Whitin JC, et al.
Measurement of serum L-asparagine in the presence of L-asparaginase requires the presence of an L-asparaginase inhibitor.
Cancer Res.
1991;51:6568-6573[Abstract/Free Full Text].
5.
Woods JA, Handschumacher RE.
Hepatic regulation of plasma L-asparagine.
Am J Physiol.
1973;224:740-745[Free Full Text].
6.
Holcenberg JS, Roberts J.
Enzymes as drugs.
Ann Rev Pharmacol Toxicol.
1977;17:97-116[Medline]
[Order article via Infotrieve].
