Pegylated asparaginase (Oncaspar^TM) in children with ALL: drug monitoring in reinduction according to the ALL/NHL‐BFM 95 protocols

Abstract

Hypersensitivity reactions are relevant adverse effects of asparaginase therapy. Therefore, children treated with native Escherichia coli asparaginase in induction therapy of acute lymphoblastic leukaemia (ALL) or non‐Hodgkin's lymphoma (NHL) were switched to the pegylated enzyme for reinduction under drug monitoring. Seventy children, including four patients with allergic reactions during induction, were given one dose of OncasparTM 1000 U/m2 intravenously. Activity was determined every third or fourth day until it dropped below the limit of quantification. In current reinduction protocols [ALL/NHL‐Berlin–Frankfurt–Münster (BFM) 95 trials], four doses of 10 000 U/m2E. coli asparaginase deplete asparagine for about 2–3 weeks, therefore activities of ≥ 100 U/l up to day 14 and ≥ 50 U/l up to day 21 were targeted. In 66 patients without an allergic reaction during induction, the mean activity was 606 ± 313 U/l, 232 ± 211 U/l and 44 ± 50 U/l after 1, 2 and 3 weeks respectively. In 44/66 patients, activity was ≥ 100 U/l after 14 d. A rapid decline in activity was seen in the remaining 22 patients, including 8/22 patients who showed no activity after 1 week. Toxicity was low and comparable to the native enzymes but, in contrast to about 30% of hypersensitivity reactions with conventional reinduction therapy, no allergic reaction was seen. Substituting 4 × 10 000 U/m2 asparaginase medac for one dose of 1000 U/m2 OncasparTM was safe and well tolerated. Comparable pharmacokinetic treatment intensity was achieved in about two‐thirds of patients.

Identification and Structural Analysis of an l-Asparaginase Enzyme from Guinea Pig with Putative Tumor Cell Killing Properties

“…A reduced but still present immune intolerance remains because of the foreign origin of these drugs. Furthermore, the enzyme can still be cleared from the blood and an immune reaction elicited because of antibody formation against PEG (11)(12)(13). This suggests that a more human-like enzyme, which would be less immunogenic, could be a superior replacement (14 -16).…”

PEGylated Biopharmaceuticals

“…Oncaspar is a bacterial enzyme covalently linked to multiple 5-kDa methoxy-PEG molecules that is used for the treatment of acute lymphoblastic leukemia in pediatric patients (Schrappe, Reiter, Ludwig, et al 2000;Schrappe, Reiter, Zimmermann, et al 2000;Schrappe, Camitta, et al 2000). Anti-PEG antibodies have been associated with rapid blood clearance and reduced treatment efficiency in up to one-third of patients treated with Oncaspar (Muller et al 2000;Armstrong et al 2007).…”

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

“…In the absence of asparagine, they undergo apoptosis (8). A plasma l-asparaginase level of more than 100 U/l appears to correlate with adequate systemic asparagine depletion (9). Patients, however, show a wide variation in plasma levels after exposure to the drug (7).…”