Pharmacokinetics of native Escherichia coli asparaginase (Asparaginase medac) and hypersensitivity reactions in ALL‐BFM 95 reinduction treatment

Abstract

Summary. Repeated asparaginase treatment has been associated with hypersensitivity reactions against the bacterial macromolecule in a considerable number of patients. Immunological reactions may range from anaphylaxis without impairment of serum asparaginase activity to a very fast decline in enzyme activity without any clinical symptoms. Previous investigations on a limited number of patients have shown high interindividual variability of asparaginase activity time courses and hypersensitivity reactions in about 30% of patients during reinduction treatment. Therefore, monitoring of reinduction treatment was performed prospectively in 76 children with newly diagnosed acute lymphoblastic leukaemia (ALL). According to the ALL-Berlin±Frankfurt±Mu È nster (BFM) 95 protocol, 10 000 U/m 2 body surface area of native Escherichia coli asparaginase (Asparaginase medac) was given on d 8, 11, 15 and 18. In 45/76 children, trough and peak activities were determined with every dose, and also on d 4 and d 11 after the last administration. Data on asparaginase activity were not available from the remaining 31 patients, but information with regard to hypersensitivity reactions only was given. Eighteen out of 76 patients (24%) suffered a clinical hypersensitivity reaction; however, no silent inactivation was observed. Activity in the therapeutic range of greater than 100 U/l for at least 14 d was determined in 43 of the 45 patients who were analysed for enzyme activity.

Consensus expert recommendations for identification and management of asparaginase hypersensitivity and silent inactivation

“…3,5,6 Indeed, a major limitation in the capacity to deliver the intended up-front asparaginase therapy is the high rate of occurrence of hypersensitivity reactions, frequently reported in as many as 30% of patients receiving E. coliderived asparaginase, but with reported rates as high as 70%. 1,3,[7][8][9] Allergic reaction symptoms range from local reactions at the site of intramuscular injection to severe systemic reactions including anaphylaxis, which can occur with intramuscular or intravenous administration. Also demonstrated has been the phenomenon of "silent inactivation," with the formation of neutralizing antibodies and reduced asparaginase activity in the absence of a clinically evident allergic reaction.…”

A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug l-asparaginase

“…Why this happens is not well understood. Florid hypersensitivity reactions can occur, necessitating withdrawal of the drug, though not all patients with hypersensitivity develop neutralizing antibodies and not all patients who develop neutralizing antibodies exhibit hypersensitivity (12,13). Again, the reason why some patients develop allergy to l-asparaginase remains unknown.…”

Upregulation of asparagine synthetase fails to avert cell cycle arrest induced by L-asparaginase in TEL/AML1-positive leukaemic cells

“…We have grown cells in RPMI 1640 medium with L-asparaginase at concentrations 0.4 and 4 U/ml, chosen according to the serum concentration measured in pharmacokinetics studies. 30 During the first part of the experiment (lasting 9 days), cells at the concentration of 0.3 Â 10 5 /ml were cultured in medium supplemented with L-asparaginase. Control samples were cultured without drug for 9 days of experiments.…”