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Klin Padiatr 2003; 215(6): 321-326
DOI: 10.1055/s-2003-45497
Therapiebegleitende Maßnahmen
Originalarbeit
© Georg Thieme Verlag Stuttgart · New York

Effects of Dose-Reduced Medac® L-Asparaginase on Coagulation in Trial ALL-BFM 2000

Gerinnungsveränderungen unter Dosis-reduzierter Medac® L-Asparaginase in der Studie ALL-BFM 2000A.  Attarbaschi1 , G.  Mann1 , M.  Kronberger1 , V.  Witt1 , H.  Gadner1 , M.  Dworzak1
  • 1St. Anna Children’s Hospital, Vienna, Austria
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Publication History

Publication Date:
15 December 2003 (online)

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Zusammenfassung

Hintergrund: Glukokortikoide und L-Asparaginase (L-ASP) sind essenzielle Komponenten von derzeitigen, modernen Chemotherapie-Protokollen der kindlichen akuten lymphoblastischen Leukämie (ALL). Beide Zytostatika verursachen jedoch signifikante Veränderungen im Gerinnungssystem, im Speziellen betreffend die Gerinnungsinhibitoren Antithrombin III (AT III), Protein C und Protein S. Patienten und Methoden: Das Ziel dieser prospektiven Studie war es, den Verlauf und das Ausmaß der Veränderungen verschiedener Gerinnungsproteine während der Induktionstherapie von 16 Patienten, die gemäß dem Protokoll ALL-BFM 2000 behandelt wurden, zu untersuchen. Das Induktionsprotokoll besteht aus einer 7-tägigen Monotherapie mit Glukokortikoiden und 4 weiteren Wochen mit zusätzlichem Vincristin, Daunorubicin und E. coli L-ASP (Medac®), die in einer Dosis von 5000 IE/m2 8-mal in 3-Tages-Intervallen verabreicht wird. Ergebnisse und Schlussfolgerungen: Diese Studie zeigt erstmalig, dass die Medac® L-ASP in einer Dosis von 5000 IE/m2 zu einer zeitlich minder ausgeprägten Reduktion des AT III- und Fibrinogen-Serumspiegels in der Induktionstherapie führt (nach der 5. L-ASP Dosis), im Vergleich zu vorherigen BFM-Protokollen, in welchen die Medac® L-ASP in einer Dosis von 10 000 IE/m2 verabreicht worden ist. Unsere Ergebnisse bestätigen auch, dass eine Monotherapie mit Glukokortikoiden zu einem Anstieg des AT III, Protein C und Protein S wie auch zu einem Abfall des Fibrinogen-Serumspiegels führt. Aufgrund der Tatsache, dass die Konzentration der D-Dimere während der 3 Wochen Kombinationstherapie mit L-ASP im Normbereich verblieb und es bei keinem der Patienten zu einer Thromboembolie kam, kann angenommen werden, dass trotz des signifikanten Abfalls der antithrombotischen Proteine ein Gleichgewicht zwischen Gerinnungsaktivierung und Fibrinolyse besteht. Aus diesem Grund kann möglicherweise die Bestimmung der D-Dimere als hilfreicher Indikator zu therapeutischen Interventionen verwendet werden.

Abstract

Background: Glucocorticoids and L-asparaginase (L-ASP) are essential elements of contemporary chemotherapy of childhood acute lymphoblastic leukemia (ALL). Both cytotoxic drugs are well-known to induce significant alterations in hemostasis, especially affecting the inhibitors of coagulation including antithrombin III (AT III), protein C and protein S. Patients and Methods: The objectives of the present prospective study were to analyze the course and degree of the changes of several coagulation proteins during induction therapy of 16 patients treated according to the Berlin-Frankfurt-Münster (BFM) ALL protocol 2000. The induction protocol included a 7-day mono-therapy with glucocorticoids followed by 4 weeks with additional vincristine, daunorubicin and E. coli L-ASP (Medac®) which was administered at a dosage of 5000 IU/m2 8-times at 3-day intervals. Results and Conclusions: This analysis is the first to show that 5000 IU/m2 of the Medac® L-ASP leads to a less pronounced decrease of the plasma AT III and fibrinogen concentrations during induction therapy (after the 5th L-ASP dose), as compared to previous BFM protocols which used the Medac® L-ASP in a dosage of 10 000 IU/m2. Our results confirmed that following a mono-therapy with glucocorticoids the AT III, protein C and protein S levels increased while the fibrinogen level decreased. As the D-Dimers remained within the normal range during the 3 weeks of L-ASP combination chemotherapy and none of the patients suffered a thromboembolic event, we also concluded that despite of the significant decrease of anticoagulant proteins, there might be a balance between coagulation and fibrinolysis; thus the D-Dimers may eventually serve as a helpful indicator for therapeutic interventions.

Schlüsselwörter

L-Asparaginase - Glukokortikoide - Gerinnung

Key words

L-asparaginase - glucocorticoids - coagulation

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Michael Dworzak, MD 

St. Anna Children’s Hospital

Kinderspitalgasse 6

1090 Vienna . Austria

Fax: +43-1-40170 70

Phone: +43-1-40170 250

Email: Dworzak@ccri.univie.ac.at

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