Pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant asparaginase preparation in children with previously untreated acute lymphoblastic leukemia: a randomized phase 2 clinical trial

Abstract

The pharmacokinetics, pharmacodynamics, efficacy, and safety of a new recombinant Escherichia coli-asparaginase preparation was compared with Asparaginase medac. Thirty-two children with acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5000 U/m 2 every 3 days, for a total of 8 doses during induction treatment. The serum activity-time profile after the first dose of recombinant asparaginase was similar to that of Asparaginase medac. The trough serum activities were greater than the desired threshold of 100 U/L in both treatment groups. Asparagine was completely depleted in serum and in cerebrospinal fluid, whereas glutamine levels were only moderately influenced. No significant difference between the 2 treatments regarding the degree of asparagine depletion, duration of depletion, complete remission rate, and minimal residual disease status at the end of induction, overall frequency or intensity of adverse events was seen. Observed adverse reactions are known as possible and la-

Pediatric Acute Lymphoblastic Leukemia: Efficacy and safety of recombinant E. coli-asparaginase in infants (less than one year of age) with acute lymphoblastic leukemia

“…Furthermore, this trial confirms data from another trial 4 that ASNase serum trough activity levels need not necessarily exceed the often cited cut-off level of 100 U/L to achieve complete asparagine depletion. Trough levels as low as 20 U/L seem to be sufficient for that purpose.…”

“…6 The observed ASNase activity serum levels 3 days after ASNase infusion were comparable with those recorded in older children (1 -14 years) with de novo ALL treated with 5 000 U/m² rASNase every third day during induction treatment of de novo ALL. 4 This means that rASNase doses between 5 000 and 10 000 U/m 2 will lead to comparable trough ASNase serum activity levels in children.…”

“…In a preceding trial, rASNase was shown to be pharmacokinetically bioequivalent to Asparaginase medac ® in pediatric patients aged 1-15 years and led to complete asparagine depletion in serum in all patients for the desired time period during remission induction treatment. 4 The aim of this trial was to show that the rASNase dose regimen used in the current INTERFANT-06 protocol is safe in infants, provides sufficient ASNase activity during induction treatment and leads to complete asparagine depletion in serum for the desired time period. This is the first prospective trial investigating the pharmacokinetics and pharmacodynamics of an ASNase preparation in infants with de novo ALL.…”

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

“…Rizzari and colleagues showed that trough asparaginase activity levels of < 0.05 IU/mL, obtained either with native E. Coli or Erwinia asparaginase, resulted in serum and CSF asparagine depletion in children with ALL. 25 In some studies activity levels as low as 0.02 IU/mL 26,27 or 0.03 IU/mL 21,28 resulted in sufficient depletion. In contrast, the only study indicating that higher activity levels are needed is a recent COG study of two pegylated E. coli asparaginase preparations, calaspargase pegol and pegaspargase, in which the plasma asparagine level began…”

Effect of combined arginase and nitric oxide donor treatment on normal and leukemic cells in vitro

“…Current clinical strategy against childhood acute leukemia often employs combination of standard anticancer agents with asparaginase as a second line therapy [21]. This is because certain type of leukemia and lymphoma are auxotrophic for asparagine and thus susceptible to the treatment with recombinant asparaginase [23].…”