Asparaginase administration in children suffering from acute lymphoblastic leukemia

Summary

Background: Previous studies focusing on asparaginase(ASP)-induced acquired alterations of the hemostatic system reported in childhood acute lymphoblastic leukemia (ALL) could not sufficiently explain the sporadic manifestations of thrombotic events in the studied populations, reported as between 0.8% and 11%. Therefore the present retrospective overview was conducted to unravel the possible interaction between prothrombotic risk factors, leukemia protocols and the concomitant use of different anti-leukemic agents with respect to the presence of symptomatic venous vascular accidents. Methods: Published reports on childhood leukemia and hemostatic alterations (no case-reports) obtained from a Medline-based search (1980-2000) were included in the present overview. Conclusions: Based on the data presented here, evidence is given that the wide range of thrombotic events reported is due mainly to different study designs, prospective versus retrospective data, E. coli ASP sources of different origin (Erwinia, E. coli A, E. coli B) and dosages, administered alone or in combination with steroids, as well as a variable number of patients included in the studies reported.

Zusammenfassung

Hintergrund: Zahlreiche Studien über Asparaginase (ASP)-induzierte Gerinnungsstörungen bei akuter lymphoblastischer Leukämie (ALL) im Kindesalter konnten die berichtete symptomatische Thromboserate zwischen 0.8% und 11% nicht hinreichend erklären. Daher haben wir hier die bisher publizierten pädiatrischen Daten in einer Übersicht zusammengestellt und versucht, eine mögliche Erklärung für die unterschiedlich berichteten Thromboseraten abzuleiten. Methoden: Arbeiten (keine Falldarstellungen) zwischen 1980 und 2000 (Medline) wurden berücksichtigt. Schlussfolgerungen: Auf Grund der hier zusammengefassten Daten postulieren wir, dass die unterschiedliche Thromboserate hauptsächlich durch die unterschiedlichen Studiendesigns, prospektive versus retrospektive Datenerhebung, unterschiedliche Asparaginasepräparate (Erwinia, E. coli A, E. coli B), alleine oder in Kombination mit Steroiden, und die unterschiedliche Anzahl der untersuchten Patienten begründet ist.

Keywords

Childhood ALL - symptomatic thrombosis - prothrombotic risk factors - asparaginase - steroids

Schlüsselwörter

Kinder und ALL - symptomatische Thrombose - genetische Thromboserisikofaktoren - Asparaginase - Steroide

• References

• 1 Ahlke E, Nowak-Göttl U, Schulze-Westhof P. et al. Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukemia. Br J Haematol 1997; 96: 675-81.
• 2 Capizzi RL, Holcenberg JS. Asparaginase. In: Holland JF, Frei III E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR. (eds). Cancer Medicine. Philadelphia, London: Lea & Febiger; 1993: 796-803.
• 3 Carlsson H, Stockelberg D, Tengborn L. et al. Effects of Erwinia-asparaginase on the coagulation system. Eur J Haematol 1995; 55: 289-93.
• 4 Chabner BA, Collins JM. Enzyme therapy: L-asparaginase. Cancer Chemotherapy: Principles and Practice. Philadelphia: Lippincott; 1990: 397-407.
• 5 Eckhof-Donovan S, Schwamborn D, Körholz D. et al. Thromboses in children with acute lymphoblastic leukemia treated by the COALL-protocol. Klin Pädiatr 1994; 206: 327-30.
• 6 Homans AC, Rybak ME, Baglini RL. et al. Effect of L-asparaginase administration on coagulation and platelet function in children with leukemia. J Clin Oncol 1987; 5: 811-7.
• 7 Kirschke R, Nürnberger W, Eckhof-Donovan S. et al. Coagulation and fibrinolysis in children with acute lymphoblastic leukemia treated according to the COALL-05-92-protocol. Klin Pädiatr 1998; 210: 285-90.
• 8 Kucuk O, Kwaan HC, Gunnar W. et al. Thromboembolic complications associated with L-asparaginase therapy. Cancer 1995; 55: 702-6.
• 9 Legnani C, Parlareti G, Pession A. et al. Intravascular coagulation phenomena associated with prevalent fall in fibrinogen and plasminogen during L-asparaginase treatment in leukemic children. Haemostasis 1988; 18: 179-86.
• 10 Mauz-Körholz C, Junker R, Göbel U, Nowak-Göttl U. Prothrombotic risk factors in children with acute lymphoblastic leukemia treated with delayed E. coli asparaginase (COALL-92 and 97 protocols). Thromb Haemost 2000; 83: 840-3.
• 11 Miniero R, Saracco P, Einaudi S. et al. L-asparaginase-induced coagulopathy in children with acute lymphoblastic leukemia. Drugs Exptl Clin Res 1987; 13: 377-9.
• 12 Mitchell L, Hoogendoorn H, Giles AR. et al. Increased endogenous thrombin generation in children with acute lymphoblastic leukemia: risk of thrombotic complications in L-asparaginase-induced antithrombin III deficiency. Blood 1994; 83: 386-91.
• 13 Nowak-Göttl U, Boos J, Wolff JEA. et al. Influence of two different E. coli asparaginase preparations on coagulation and fibrinolysis: a randomised trial. Fibrinolysis 1994; (S2); 8: S66-8.
• 14 Nowak-Göttl U, Ahlke E, Schulze-Westhoff P, Boos J. Changes in coagulation and fibrinolysis in childhood ALL: a two-step dose reduction of one E. coli asparaginase preparation. Br J Haematol 1996; 95: 123-7.
• 15 Nowak-Göttl U, Wermes C, Junker R. et al. Prospective evaluation of the thrombotic risk in children with acute lymphoblastic leukemia carrying the MTHFR TT677 genotype, the prothrombin G20210A variant, and further prothrombotic risk factors. Blood 1999; 93: 1595-9.
• 16 O’Meara Daly M, Hallinan FH. Increased antithrombin concentration in children with acute lymphoblastic leukemia receiving L-asparaginase therapy. Med Ped Oncol 1988; 16: 169-74.
• 17 Pui CH, Jackson CW, Chesney CM. et al. Involvement of von Willebrand factor in thrombosis following asparaginase-prednisone-vincristine therapy for leukemia. Am J Hematol 1987; 25: 291-8.
• 18 Pui CH, Chesney CM, Weed J. et al. Altered von Willebrand factor molecule in children with thrombosis following asparaginase-prednisone-vincristine therapy for leukemia. J Clin Oncol 1985; 3: 1266-72.
• 19 Risseuw-Appel IM, Dekker I, Hop WCJ. et al. Minimal effects of E. coli and Erwinia asparaginase on the coagulation system in childhood acute lymphoblastic leukemia: A randomised study. Med Ped Oncol 1994; 23: 335-43.
• 20 Semeraro N, Montemurro P, Giordano P. et al. Unbalanced coagulation - fibrinolysis potential during L-asparaginase therapy in children with acute lymphoblastic leukemia. Thromb Haemost 1990; 64: 38-40.
• 21 Shapiro AD, Clarke SL, Christian JM. et al. Thrombosis in children receiving L-asparaginase. Determining patients at risk. Am J Pediatr Hematol Oncol 1993; 15: 400-5.
• 22 Sutor AH, Mall V, Thomas KB. Bleeding and thrombosis in children with acute lymphoblastic leukemia treated according to the ALL-BFM-90 protocol. Klin Pädiatr 1992; 211: 201-4.
• 23 Zaunschirm A, Muntean W. Correction of hemostatic imbalance induced by L-asparaginase therapy in children with acute lymphoblastic leukemia. Ped Hematol Oncol 1989; 3: 19-25.