BACKGROUND: Therapeutic drug monitoring (TDM) can identify patients with subtherapeutic asparaginase (ASNase) activity [silent inactivation (SI)] and prospectively guide therapeutic adaptation. However, limited intra-individual variability is a precondition for targeted dosing and the diagnosis of SI. METHODS: In the AIEOP-BFM acute lymphoblastic leukemia (ALL) 2009 trial, 2771 children with ALL were included and underwent ASNase-TDM in a central laboratory in Münster. Two biweekly administrations of pegylated ASNase during induction and a third dose during reinduction or the high-risk block, which was administered several weeks later, were monitored. We calculated (1) the incidence of SI; and (2) the predictivity of SI for SI after the subsequent administration. ASNase activities monitored during induction were categorized into percentiles at the respective sampling time points. These percentiles were used to calculate the intra-individual range of percentiles as a surrogate for intrapatient variability and to evaluate the predictivity of ASNase activity for the subsequent administration. RESULTS: The overall incidence of SI was low (4.9%). The positive predictive value of SI identified by one sample was ≤21%. Confirmation of SI by a second sample indicated a high positive predictive value of 100% for biweekly administrations, but not for administration more than 17 weeks later. Sampling and/or documentation errors were risks for misdiagnosis of SI. High intra-individual variability in ASNase activities, with ranges of percentiles over more than 2 quartiles and low predictivity, was observed in approximately 25% of the patients. These patients were likely to fail dose individualization based on TDM data. CONCLUSIONS: To use TDM as a basis for clinical decisions, standardized clinical procedures are required and high intra-individual variability should be taken into account. Details of the treatment are available in the European Clinical Trials Database at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004270-43/DE.
- MeSH
- akutní lymfatická leukemie farmakoterapie MeSH
- asparagin krev MeSH
- asparaginasa aplikace a dávkování krev terapeutické užití MeSH
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- metabolická inaktivace fyziologie MeSH
- mladiství MeSH
- monitorování léčiv metody MeSH
- polyethylenglykoly aplikace a dávkování terapeutické užití MeSH
- předškolní dítě MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: In the international AIEOP-BFM ALL 2009 trial, asparaginase (ASE) activity was monitored after each dose of pegylated Escherichia coli ASE (PEG-ASE). Two methods were used: the aspartic acid β-hydroxamate (AHA) test and medac asparaginase activity test (MAAT). As the latter method overestimates PEG-ASE activity because it calibrates using E. coli ASE, method comparison was performed using samples from the AIEOP-BFM ALL 2009 trial. METHODS: PEG-ASE activities were determined using MAAT and AHA test in 2 sets of samples (first set: 630 samples and second set: 91 samples). Bland-Altman analysis was performed on ratios between MAAT and AHA tests. The mean difference between both methods, limits of agreement, and 95% confidence intervals were calculated and compared for all samples and samples grouped according to the calibration ranges of the MAAT and the AHA test. RESULTS: PEG-ASE activity determined using the MAAT was significantly higher than when determined using the AHA test (P < 0.001; Wilcoxon signed-rank test). Within the calibration range of the MAAT (30-600 U/L), PEG-ASE activities determined using the MAAT were on average 23% higher than PEG-ASE activities determined using the AHA test. This complies with the mean difference reported in the MAAT manual. With PEG-ASE activities >600 U/L, the discrepancies between MAAT and AHA test increased. Above the calibration range of the MAAT (>600 U/L) and the AHA test (>1000 U/L), a mean difference of 42% was determined. Because more than 70% of samples had PEG-ASE activities >600 U/L and required additional sample dilution, an overall mean difference of 37% was calculated for all samples (37% for the first and 34% for the second set). CONCLUSIONS: Comparison of the MAAT and AHA test for PEG-ASE activity confirmed a mean difference of 23% between MAAT and AHA test for PEG-ASE activities between 30 and 600 U/L. The discrepancy increased in samples with >600 U/L PEG-ASE activity, which will be especially relevant when evaluating high PEG-ASE activities in relation to toxicity, efficacy, and population pharmacokinetics.
- MeSH
- antitumorózní látky krev MeSH
- asparaginasa krev MeSH
- enzymatické testy metody MeSH
- lidé MeSH
- monitorování léčiv metody MeSH
- polyethylenglykoly MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- Klíčová slova
- KIDROLASA,
- MeSH
- akutní lymfatická leukemie farmakoterapie MeSH
- asparagin krev MeSH
- asparaginasa aplikace a dávkování krev metabolismus MeSH
- Dickeya chrysanthemi MeSH
- dítě MeSH
- Escherichia coli MeSH
- lidé MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- alkalická fosfatasa izolace a purifikace krev MeSH
- asparaginasa * izolace a purifikace krev účinky léků MeSH
- chlorid uhličitý krev metabolismus škodlivé účinky MeSH
- experimenty na zvířatech * MeSH
- játra * účinky léků zranění MeSH
- králíci MeSH
- proteiny izolace a purifikace MeSH
- statistika jako téma MeSH
- transaminasy izolace a purifikace krev MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- MeSH
- alkalická fosfatasa izolace a purifikace krev MeSH
- asparaginasa * izolace a purifikace krev účinky léků MeSH
- chlorid uhličitý krev metabolismus škodlivé účinky MeSH
- experimenty na zvířatech MeSH
- játra * účinky léků zranění MeSH
- morčata * krev zranění MeSH
- proteiny izolace a purifikace MeSH
- statistika jako téma MeSH
- transaminasy izolace a purifikace krev MeSH
- zvířata MeSH
- Check Tag
- morčata * krev zranění MeSH
- zvířata MeSH
