Pharmacokinetic, pharmacodynamic and intracellular effects of PEG-asparaginase in newly diagnosed childhood acute lymphoblastic leukemia: results from a single agent window study

Abstract

L-asparaginase is an effective drug for treatment of children with acute lymphoblastic leukemia (ALL). The effectiveness is thought to result from depletion of asparagine in serum and cells. We investigated the clinical response in vivo of 1000 IU/m 2 pegylated (PEG)-asparaginase and its pharmacokinetic, pharmacodynamic and intracellular effects in children with newly diagnosed ALL before start of combination chemotherapy. The in vivo window response was significantly related to immunophenotype and genotype: 26/38 common/pre B-ALL cases, especially those with hyperdiploidy and TELAML1 rearrangement, demonstrated a good clinical response compared to 8/17 T-ALL (P ¼ 0.01) and BCRABL-positive ALL (P ¼ 0.04). A poor in vivo clinical window response was related to in vitro resistance to L-asparaginase (P ¼ 0.02) and both were prognostic factors for long-term event-free survival (hazard ratio 6.4, P ¼ 0.004; hazard ratio 3.7, P ¼ 0.01). After administration of one in vivo dose of PEG-asparaginase no changes in apoptotic parameters or in intracellular levels of twenty amino acids in leukemic cells could be measured, in contradiction to the changes found after in vitro exposure. This may be explained by the rapid removal of apoptotic cells from the circulation in vivo. One additional dose of PEG-asparaginase upfront ALL treatment did not lead to other severe toxicities.

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.…”

“…18 This cut-off of ≥ 0.1 IU/mL has been confirmed and used in many clinical trials. 9,19,[22][23][24] The question arises whether a lower threshold, for example of 0.05 IU/mL, also leads to complete asparagine depletion. 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.…”

Long-term results of Dutch Childhood Oncology Group studies for children with acute lymphoblastic leukemia from 1984 to 2004

“…23 Results of the pharmacokinetic and dynamic studies of vincristine and PEG-asparaginase given upfront before start of the combination chemotherapy are published elsewhere. 14,15,16 Treatment results according to presenting features Tables 3-6 show the outcomes per study according to the NCI criteria. 20 In the BFM-based protocols ALL-7 and ALL-8, a poor outcome is related to NCI HR criteria, male gender (only ALL-8 study), T-lineage ALL and a high WBC.…”

“…Part of the patients were included in research projects that studied pharmacokinetics andFdynamics of one additional dose of vincristine 14 or PEG-asparaginase before start of therapy. 15,16 The treatment protocol for NHR patients was identical to the ALL-6. HR patients received several intensification elements on top of the NHR schedule: (a) Daunorubicin was added to the 3 drug induction.…”

Five‐year single‐center study of asparaginase therapy within the ALL‐BFM 2000 trial

“…Previous studies have proposed that enzyme activities greater than 100 U/L ensure asparagine depletion in the serum and CSF [7,23,24]. An important prognostic milestone in ALL therapy is day of the end of induction therapy (day 33 on the BFM regimens) when the measurement of MRD (negative or not negative) and the randomization according to three different risk categories (SR, MR, HR) take place.…”