Abstract
Deamination of asparagine (Asn) and glutamine (Gln) by asparaginase (ASNase) induces apoptosis of ALL lymphoblasts, which lack ability to synthesize Asn de-novo. Early treatment intensification after Induction, including PEG-ASNase instead of native E.Coli-ASNase, in addition to more vincristine and intravenous methotrexate, improves outcome in pediatric ALL patients presenting with unfavorable features, who show rapid early response to Induction chemotherapy (
Seibel NL, et al., Blood, 2003;102:224a
). Erwinase was used for patients with overt clinical allergy to E.Coli-ASNase. We evaluated the population pharmacokinetics and pharmacodynamics (PK-PD) of the three ASNase formulations employed on CCG-1961. The PK-PD parameters of native and PEG-ASNase in this group of HR ALL patients were similar to those reported from SR ALL patients from CCG-1962 (Avramis VI, et al., Blood, 2002;99:1986–1994
). Population PK (NONMEM) showed the expected half-lives of native E.Coli-ASNase (6000 IU/m2): 1.3 days; PEG-ASNase (2500 IU/m2): 6.5 days; and Erwinase (6000 IU/m2): 0.8 days. Repeated doses resulted in an accumulation of activity with moderate prolongation of elimination half-lives for all formulations. PEG-ASNase provided > 0.3 IU/ml activity for > 21 days for most patients in Delayed Intensification. We measured simultaneous amino acid levels in 430 sera samples obtained from various phases of CCG-1961 from these 187 fully evaluable patients with detectable post-treatment ASNase activity. The averages of pre-treatment control serum levels for Asn and Gln were 44.8 ± 3.0 μM (mean ± SE) and 363.8 ± 23.9 μM, respectively. There were no statistical differences between the PD effects of ASNase formulations on serum Asn deamination, although the lowest Asn levels averaging 2.6 ± 0.4 μM were obtained on 11–14 days post-PEG-ASNase samples (n=14). Glutamine deamination enhanced Asn depletion, and deamination correlated with ASNase activity. At levels >0.4 IU/ml, PEG-ASNase and native ASNase provided 95 ± 8% and 85 ± 26% Gln deamination, respectively (p=0.04). Eleven to 14 days after PEG-ASNase, Gln levels averaged 13 ± 5 μM (n=14). In general, Erwinase provided greater Gln deamination (94 ± 5%, n=19) 2–3 days post administration, than either native or PEG-ASNases at comparable activity levels, which were 70–80% (p<0.001). Greater Gln deamination yielded lower Asn levels after Erwinase. These PD results provide insight into the benefit of PEG-ASNase intensification and possibly Erwinase substitution in the treatment of patients with high risk ALL treated with augmented BFM therapy and need to be further explored.Author notes
Corresponding author
2005, The American Society of Hematology
2004
