Subscribe to RSS
DOI: 10.1055/s-2005-872516
© Georg Thieme Verlag Stuttgart · New York
Asparagine Concentration in Plasma After 2 500 IU/m² PEG-Asparaginase i.v. in Children With Acute Lymphoblastic Leukemia
Asparaginkonzentration im Serum nach Gabe von 2 500 IE/m² PEG-Asparaginase i. v. bei Kindern mit akuter lymphatischer LeukämiePublication History
Publication Date:
24 November 2005 (online)
![](https://www.thieme-connect.de/media/klinpaed/200506/lookinside/thumbnails/10.1055-s-2005-872516-1.jpg)
Abstract
Polyethylene glycol conjugated asparaginase (PEG-ASNase) can be substituted in cases of hypersensitivity to native Escherichia coli asparaginase. We measured asparagine (asn) levels in plasma after a single dose of 2 500 IU/m² i.v. PEG-ASNase (Oncaspar®) in consolidation treatment of ALL and compared those with data from the previous protocol COALL-05-92. This protocol was similar to COALL-06-97, except that children had been given 45 000 IU/m² C-ASNase instead of PEG-ASNase. Patients and Methods: Between May 2000 and December 2001 seventy-one children (38 boys, 33 girls) with newly diagnosed ALL treated according to the multicenter protocol COALL-06-97 were investigated in this study. Four hundred and seventy-four plasma samples (71 patients) were analysed by ion exchange chromatography after column derivatization with o-phthaldialdehyde. For comparison data (350 plasma samples) from 51 patients treated according to the protocol COALL-05-92 were available. The same method for detection of asn in plasma was used. Results: The median asparagine level in plasma after 2 500 IU/m² PEG-ASNase i.v. was below the limit of detection for at least 5 weeks in 81 % of the patients. When divided into high risk (HR) and low risk (LR) group, HR patients who had previously received one dose more of C-ASNase showed a markedly shorter depletion than the LR patients compatible with a higher risk of antibody formation and consequent silent inactivation after a higher number of exposures to ASNase. In the previous protocol COALL-05-92 median asn levels in plasma after 45 000 IU/m² native C-ASNase i.v. were below the limit of detection for at least 5 weeks in 65 % of the patients. Conclusions: 2 500 IU/m² PEG-ASNase led to an equally long depletion of asn in plasma as did 45 000 IU/m² native C-ASNase i.v. used in COALL-05-92.
Zusammenfassung
Polyethylenglykol-konjugierte Asparaginase (PEG-ASNase) kann im Falle von Hypersensitivitätsreaktionen auf native Escherichia-coli-Asparaginase eingesetzt werden. Wir haben Asparaginspiegel (Asn) im Plasma nach einer einzelnen Gabe von 2 500 IE/m² i. v. PEG-ASNase (Oncaspar®) während der Konsolidierungstherapie der ALL gemessen und diese mit Daten aus dem vorausgegangenen Therapieprotokoll COALL-05-92 verglichen. Dieses Protokoll entsprach dem Protokoll COALL-06-97, mit der Ausnahme, dass statt PEG-Asparaginase 45 000 IE/m² C-ASNase gegeben wurden. Patienten und Methoden: Zwischen Mai 2000 und Dezember 2001 wurden einundsiebzig Kinder (38 Jungen, 33 Mädchen) mit einer neu diagnostizierten ALL, die nach dem multizentrischen Therapieprotokoll COALL-06-97 behandelt wurden, in dieser Studie untersucht. Vierhundertundsiebzig Serumproben (71 Patienten) wurden per Ionenaustauschchromatographie nach Post-column-Derivatisierung mit ortho-Phthaldialdehyd analysiert. Es standen Daten (350 Serumproben) von 51 Patienten, die entsprechend dem Therapieprotokoll COALL-05-92 behandelt wurden, zum Vergleich zur Verfügung. Es wurde dieselbe Methode zur Detektion von Asparagin im Serum verwendet. Ergebnisse: Der mediane Asparaginspiegel im Serum lag bei 81 % der Patienten mindestens 5 Wochen nach Gabe von 2 500 IE/m² PEG-ASNase i. v. unterhalb Nachweisgrenze für Asn. Betrachtet man High-risk(HR)- und Low-risk(LR)-Gruppe getrennt, fällt auf, dass HR-Patienten, die vorher eine Gabe C-ASNase mehr erhalten hatten, eine deutlich kürzere Depletion zeigten als LR-Patienten. Dies könnte auf ein höheres Risiko der Antikörperbildung und demzufolge einer stillen Inaktivierung nach häufigerer Exposition gegenüber ASNase zurückzuführen sein. In dem vorausgegangenen Protokoll COALL-05-92 lag der mediane Asn-Spiegel im Serum bei 65 % Patienten mindestens 5 Wochen nach Gabe von 45 000 IE/m² nativer C-ASNase i. v unterhalb der Nachweisgrenze. Schlussfolgerung: 2 500 IE/m² PEG-ASNase führt zu einer gleich langen Depletion im Serum wie 45 000 IE/m² native C-ASNase i. v., wie es im COALL-05-92 verwendet wurde.
Key words
asparaginase - aspraragine - PEG - acute lymphoblastic leukemia
Schlüsselwörter
Asparaginase - Asparagin - PEG - akute lymphoblastische Leukämie
References
- 1 Appel I M, Pinheiro J P, Den Boer M L, Lanvers C, Reniers N C, Boos J, Pieters R. Lack of asparagine depletion in the cerebrospinal fluid after one intravenous dose of PEG-asparaginase: a window study at initial diagnosis of childhood ALL. Leukemia. 2003; 17 2254-2256
- 2 Asselin B L, Whitin J C, Coppola D J, Rupp I P, Sallan S E, Cohen H J. Comperative pharmacokinetic studies of three asparaginase preparations. J Clin Oncol. 1993; 11 1780-1786
- 3 Asselin B L, Gelber R, Sallan S. Relative toxicity of E.coli L-asparaginase (ASP) and PEGasparaginase (PEG) in newly diagnosed childhood acute lymphoblastic leukemia (ALL). Med Pediatr Oncol. 1993; 21 556
- 4 Attarbaschi A, Mann G, Kronberger M, Witt V, Gadner H, Dworzak M. Effects of dose-reduced medac®L-asparaginase on coagulation in trial ALL-BFM 2000. Klin Pädiatr. 2003; 215 321-326
- 5 Becker E E, Broome J D. L-asparagine: inhibition of endogenous RNA polymerase activity in regenerating liver. Arch Biochem Biophys. 1969; 130 332-336
- 6 Billett A L, Carls A, Gelber R D, Sallan S E. Allergic reactions to Erwinia asparaginase in children with acute lymphoblastic leukemia who had previous allergic reactions to Escherichia coli asparaginase. Cancer. 1992; 70 201-206
- 7 Boos J, Nowak-Göttl U, Jürgens H, Fleischhack G, Bode U. Loss of activity of Erwinia asparaginase on repeat applications. J Clin Oncol. 1995; 13 2474-2475
- 8 Broome J D. Evidence that the L-asparaginase of guinea pig serum is responsible for its antilymphoma effects. J Exp Med. 1963; 118 121-147
- 9 Broome J D. L-asparaginase: discovery and development as a tumor-inhibitory agent. Cancer Treat Rep. 1981; 65 111-114
- 10 Dorr R T, Hoff D D. Drug monographs - asparaginase. In: Dorr RT, Hoff DD von (eds). Cancer chemotherapy handbook. Appleton and Lange, Norwalk, CT 1994; 201-209
- 11 Fabry U, Körholz D, Jürgens H, Göbel U, Wahn V. Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children - evidence of a complement-mediated mechanism. Pediatr Res. 1985; 19 400-408
- 12 Fumarola C, Zerbini A, Guidotti G G. Glutamine deprivation-mediated cell shrinkage induces ligand-independent CD95 receptor signaling and apoptosis. Cell Death Differ. 2001; 8 1004-1013
- 13 Haley E E, Fischer G A, Welch A D. The requirement for L-Asparagine of mouse leukaemia cells L5178Y in culture. Cancer Res. 1961; 21 532-536
- 14 Harms D, Janka-Schaub G E. Co-operative study group for childhood acute lymphoblastic leukaemia (COALL): long-term follow-up of trials 82, 85, 89 and 92. Leukemia. 2000; 14 2234-2239
- 15 Ho D, Thetford B, Carter C, Frei E. Clinical pharmacologic studies of L-asparaginase. Clin Pharmacol Therapeut. 1970; 11 408-417
- 16 Jürgens H, Schwamborn D, Körholz D, Wahn V, Göbel U. Clinical experience with polyethylene-glycol-l-asparaginase in patients with recurrent all. Klin Pädiatr. 1988; 200 184-189
- 17 Körholz D, Urbanek R, Nürnberger W, Jobke A, Göbel U, Wahn V. Development of specific IgG-Antibodies during l-Asparaginase treatment - distribution of IgG-subclasses. Monatsschr Kinderheilkd. 1987; 135 325-328
- 18 Körholz D, Wahn U, Jürgens H, Wahn V. Allergic reaction during treatment with L-asparaginase - role of specific IgE antibodies. Monatsschr Kinderheilkd. 1990; 138 23-25
- 19 Kurtzberg J, Asselin B L, Poplack D. Antibody response to Escherichia coli L-asparaginase. Prognostic significance and clinical utility of antibody measurement. Am J Pediatr Heamatol Oncol. 1993; 34 304
- 20 Kurtzberg J. A new look at PEG-L-asparaginase and other asparaginases in haematological malignancies. Cancer Invest. 1994; 12 (Suppl 1) 59-60
- 21 Müller H J, Boos J. Use of L-asparagine in childhood ALL. Crit Rev Oncol Haematol. 1998; 28 97-113
- 22 Müller H J, Löning L, Horn A, Schwabe D, Gunkel M, Schrappe M, Schütz V, Henze G, da Palma J C, Ritter J, Vieira Pinheiro J P, Winkelhorst M, Boos J. Pegylated asparaginase (Oncaspar®) in children with ALL: drug monitoring in reinduction according to the ALL/NHL-BFM 95 protocols. Br J Haematol. 2000; 110 379-483
- 23 Müller H J, Beier R, Casimiroda Palma J, Lanvers C, Ahlke E, Schütz V, Gunkel M, Horn A, Schrappe M, Henze G, Kranz K, Boos J. PEG-asparaginase (Oncaspar®) 2 500 U/m² BSA in reinduction and relapse treatment in the ALL/NHL-BFM protocols. Cancer Chemother Pharmacol. 2002; 49 149-154
- 24 Stams W A, den Boer M, Beverloo H B, Meijerink Jules P P, Stigter R L, Wering E R, Janka-Schaub G E, Slater R, Pieters R. Sensitivity to L-Asparaginase is not associated with expression levels of asparagine synthetase in t(12;21) positive pediatric ALL. Blood. 2003; 101 2743-2747
- 25 Vieira Pinheiro J P, Müller H J, Schwabe D, Gunkel M, da Palma J C, Henze G, Schütz V, Winkelhorst M, Würthwein G, Boos J. Drug monitoring of low dose PEG-asparaginase (Oncaspar®) in children with relapsed acute lymphoblastic leukaemia. Br J Haematol. 2001; 113 115-119
Prof. Dr. G. Janka-Schaub
University Children's Hospital of Hamburg · Department of Hematology and Oncology
Martinistr. 52
20246 Hamburg
Germany
Phone: +49/40/428 03 25 80
Fax: +49/40/428 03 46 01
Email: janka@uke.uni-hamburg.de