Background. Asn depletion in the serum during ASNase treatment (Tx) causes the death of lymphoblasts that lack ability to synthesize Asn. The Asn serum levels during treatment depend on ASNase activity, the rate of clearance of the enzyme and the input rate of Asn into circulation from the liver and other organs (Imax). We developed a population pharmacokinetic & pharmacodynamic (PK-PD) model in NONMEM to estimate the input rate in the standard risk ALL patients (pts) treated on CCG-1962.

Methods. We compared the Asn concentrations during induction determined by HPLC amino acid assay in 24 pts who subsequently relapsed and in all event-free (CCR) pts from CCG-1962 SR ALL study. A best fit population PK-PD model between ASNase and Asn concentrations was developed for each patient to estimate the maximum input rate, Imax, and its additive error correction factor. Six year event-free survival was correlated with Imax or additive error with Kaplan-Meier analyses.

Results. Patients received either 2500 IU/m2 PEG-ASNase once or 6000 IU/m2 native ASNase x 9, intramuscularly, during induction. The deaminated Asn serum levels were superimposable in patients randomized to native or PEG-ASNase arm. The mean and SDEV for Imax and the additive error are shown in Table 1 for each enzyme preparation for patients in CCR and for those who later developed BM, CNS, or testicular relapses. Imax was significantly greater in the relapsed than in the CCR patients, in the PEG-ASNase (p=0.002) and in the native ASNase (p=0.005) arms.

Table 1. Imax and additive error of Asn in relapsed and in continuous complete remission (CCR) patients - CCG-1962

CCG-1962 ArmsPEG-ASNase arm, n=56PEG-ASNase arm, n=56Native ASNase arm, n=57Native ASNase arm, n=57
* nmoles/ml/min, ** All values are mean ± SDEV 
PD Parameters Imax* Additive error* Imax* Additive error* 
CCR patients 9.93 E -6 ± 2.4 E -5** 1.51 E -6 ± 2.86 E -6 2.92 E -5 ± 1.52 E -4 2.52 E -6 ± 6.61 E -6 
N 46 46 43 43 
Relapsed 8.9 E -3 ± 6.0 E -3 2.87 E -6 ± 3.1 E -6 4.51 E -3 ± 4.94 E -3 1.05 E -5 ± 1.76 E -5 
N 10 10 14 14 
p, unequal variance t-test P=0.0021 p=0.25 p=0.0047 p=0.118 
CCG-1962 ArmsPEG-ASNase arm, n=56PEG-ASNase arm, n=56Native ASNase arm, n=57Native ASNase arm, n=57
* nmoles/ml/min, ** All values are mean ± SDEV 
PD Parameters Imax* Additive error* Imax* Additive error* 
CCR patients 9.93 E -6 ± 2.4 E -5** 1.51 E -6 ± 2.86 E -6 2.92 E -5 ± 1.52 E -4 2.52 E -6 ± 6.61 E -6 
N 46 46 43 43 
Relapsed 8.9 E -3 ± 6.0 E -3 2.87 E -6 ± 3.1 E -6 4.51 E -3 ± 4.94 E -3 1.05 E -5 ± 1.76 E -5 
N 10 10 14 14 
p, unequal variance t-test P=0.0021 p=0.25 p=0.0047 p=0.118 
View Large

Table 2 shows the summary of the Kaplan-Meier analyses in all patients. Both the Imax and additive factor significantly correlate with relapse.

Table 2. Summary of Kaplan - Meier analyses

PatientsPEG-ASNase arm, n=56PEG-ASNase arm, n=56Native E.Coli-ASNase arm, n=57Native E.Coli-ASNase arm, n=57
Parameter and cutoff Imax < 0.001 Imax > 0.001 Imax < 0.001 Imax > 0.001 
Events, Observed/Exp 2/8.59 8/1.41 3/6.14 11/7.86 
Total 45 11 26 31 
Log-rank p value 1.64 E -6  0.046  
Parameter and cutoff Add rate < 1E -6 Add rate > 1E -6 Add rate < 1E -6 Add rate > 1E -6 
Events, Observed/Exp 1/5.63 9/4.37 5/10.36 9/3.64 
Total 28 28 39 18 
Log-rank P value 0.002  0.0024  
PatientsPEG-ASNase arm, n=56PEG-ASNase arm, n=56Native E.Coli-ASNase arm, n=57Native E.Coli-ASNase arm, n=57
Parameter and cutoff Imax < 0.001 Imax > 0.001 Imax < 0.001 Imax > 0.001 
Events, Observed/Exp 2/8.59 8/1.41 3/6.14 11/7.86 
Total 45 11 26 31 
Log-rank p value 1.64 E -6  0.046  
Parameter and cutoff Add rate < 1E -6 Add rate > 1E -6 Add rate < 1E -6 Add rate > 1E -6 
Events, Observed/Exp 1/5.63 9/4.37 5/10.36 9/3.64 
Total 28 28 39 18 
Log-rank P value 0.002  0.0024  
View Large

Conclusions. The Asn levels after Tx are similar in both arms in pts with events and CCR. Nevertheless this PD model strongly suggests that the Imax of input of Asn in the circulation is faster in relapsed than in CCR patients. Furthermore, Imax and its additive rate are correlated with 6 year event free survival of SR ALL pts, independent of the ASNase formulation used in their Tx.

Topics:
acute lymphocytic leukemia, asparaginase, asparagine, pharmacodynamics, deamination, pediatrics, brachial plexus neuritis, enzymes, amino acids, complete remission

Author notes

Corresponding author

2005, The American Society of Hematology
2004
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