Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations

Boos, Joachim; Werber, G.; Ahlke, E.; Schulze-Westhoff, P.; Nowak‐Göttl, Ulrike; Würthwein, Gudrun; Verspohl, E. J.; Ritter, J.; Jürgens, H.

doi:10.1016/0959-8049(96)00131-1

Cited by 193 publications

(204 citation statements)

References 21 publications

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“…Our data are in correspondence with previous data observed in a larger group of patients treated with L-asparaginase and confirm that PEG-asparaginase will yield its pharmacodynamic effects for 2-4 weeks. 38 However, in vivo no changes were observed in the levels of intracellular amino acids (including asparagine, aspartic acid, glutamine and glutamic acid) directly after PEG-asparaginase administration nor on successive days thereafter, except for valine. So far, no explanation can be given for the high level of valine in the nonresponding group.…”

Section: L-asparaginase Activity In Serum and Intracellular Amino Acidsmentioning

confidence: 97%

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

et al. 2008

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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.

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Section: L-asparaginase Activity In Serum and Intracellular Amino Acidsmentioning

confidence: 97%

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

et al. 2008

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“…3,17 Modest differences in scheduling or preparations of asparaginase have been associated with significant differences in cure rates and toxicity. 3,18,19 Native E. coli preparations have been the most commonly used form of the drug in newly diagnosed patients with ALL; however, when these patients develop hypersensitivity, the relative efficacy of PEG, Erwinia, or native E. coli asparaginase in depleting asparagine is not known. In this study, our aim was to assess serially whether asparagine depletion varied with anti-asparaginase antibody status during treatment with three different asparaginase preparations.…”

Section: Discussionmentioning

confidence: 99%

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Chen

et al. 2004

Leukemia

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Polyethylene glycol-conjugated (PEG) asparaginase is approved for use in patients who develop allergy to other forms of asparaginase, although its ability to deplete asparagine systemically in patients with hypersensitivity has not been well elucidated. In 53 children with newly diagnosed acute lymphoblastic leukemia, we serially assessed asparagine concentrations in cerebrospinal fluid (CSF) and plasma as well as serum anti-asparaginase antibodies. All patients received native Escherichia coli (Elspar) asparaginase during induction therapy; patients received PEG asparaginase during reinductions when available, and those who developed allergy received Erwinia asparaginase. All eight patients who developed clinical evidence of allergy to asparaginase had anti-asparaginase antibodies. Among patients who had no antibodies, those who received E. coli had lower mean (7s.d.) CSF asparagine (0.2970.63, n ¼ 9) than those who received PEG (0.7770.82, n ¼ 4) (P ¼ 0.007). Results were similar for plasma asparagine. There was no situation where asparagine concentrations were more effectively depleted by PEG than by other preparations. None of the five patients who developed thrombosis had an allergy or antibodies to asparaginase at the time of the thrombosis. We conclude that asparagine concentrations were less effectively depleted by PEG than by E. coli asparaginase at the doses commonly used. The risk of thrombosis may be affected by the intensity of asparaginase exposure.

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“…The serum half life of E. coli asparaginase and the in vivo asparagine depletion induced by E. coli are significantly longer than that of Erwinia asparaginase. 24,25 Our data underline the importance of optimal asparaginase treatment in ALL trials and prompted us to investigate the benefit of prolonged asparaginase treatment in our current trial (58951). E. coli asparaginase is used in this study and, in case of toxicity to this drug, the switch to Erwinia asparaginase (at higher doses) is recommended.…”

Section: Figurementioning

confidence: 99%

Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report

Vilmer

Suciu

Ferster³

et al. 2000

Leukemia

193

142

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We present here the long-term results of three randomized clinical trials conducted on children with newly diagnosed acute lymphoblastic leukemia (ALL) between 1983 and 1998 by the Children Leukemia Cooperative Group (CLCG) from EORTC. In study 58831/32, the overall event-free survival (EFS) rates (± s.e.) at 6 and 10 years were 66% ± 1.8% and 65% ± 1.8%, respectively, and the risk of isolated central nervous system (CNS) relapse was 6% ± 1% and 7% ± 1%, respectively. In patients with a standard risk of relapse the omission of cyclophosphamide had no adverse effect on disease-free survival rates at 10 years (trial 58831). In medium-and high-risk patients the omission of radiotherapy did not increase the risk of CNS or systemic relapse (trial 58832). In study 58881 (1989-1998) the overall EFS rate at 8 years was 68.4% ± 1.2% and the risk of isolated CNS relapse was 4.2% ± 0.5%. In this trial which adressed three randomized questions, the following results were obtained: the combination of cytarabine at high doses with methotrexate at high doses during interval therapy did not improve prognosis. The addition of 6-mercaptopurine iv during maintenance increased the risk of late relapse. E. coli asparaginase was more toxic and has a higher efficacy than Erwinia asparaginase. Leukocyte counts Ͼ100 × 10 9 /l, specific genetic abnormalities, a poor initial response to steroids or a high level of minimal residual disease at early time points were consistently associated with an adverse prognosis in the 58881 trial.

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Monitoring of asparaginase activity and asparagine levels in children on different asparaginase preparations

Cited by 193 publications

References 21 publications

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

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

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

Long-term results of three randomized trials (58831, 58832, 58881) in childhood acute lymphoblastic leukemia: a CLCG-EORTC report

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