B127
A PK/PD study on two clinical trials with E. coli and pegylated L-asparaginase focussing on the effects on L-Glutamine
Nick Coe1, Alan McGown1, Eddy Estlin2, Tim Eden3
1University of Salford, UK, 2Royal Manchester Children's Hospital, Manchester, UK, 3University of Manchester, UK
Background
L-Asparaginase plays an important part in the front line treatment of acute lymphoblastic leukaemia (ALL). However the anti-leukaemic properties of this enzyme are still not fully understood as the enzyme can hydrolyse both L-asparagine and L-glutamine. This study has been undertaken to investigate depletion of L-asparagine and L-glutamine in blood samples of patients following treatment with L-asparaginase.
Method
A group of patients (n=17) < 18 years of age with newly diagnosed childhood ALL received 6,000 U/m2 E.coli L-asparaginase intramuscularly three times per week for nine doses. In a separate study, the UKALL R3 trial focussed on children under 17 years receiving PEG- L-asparaginase at 1000 U/m2 on a fortnightly basis. Plasma samples were taken and assayed for enzyme activity and L-asparagine and L-glutamine levels throughout treatment.
Results
Trough activities levels for E. coli L-asparaginase showed a wide variation between 78 and 1400 U/L during remission induction. Mean L-glutamine levels fell 51% throughout trough sampling (range 7 439 μM) with L-asparagine being depleted to levels below the LOD over this period. Over the induction phase in the UKALL trial (n=64), mean activity was 331 U/L (range 30 856 U/L). Analysis of samples and a study of the relationship between enzyme activity and depletion of L-glutamine and L-asparagine is ongoing.
Conclusion
L-Asparaginase treatment reduces Asparagine to below the LOD in most patients. Glutamine reduction is significant in many patients. The large inter-patient variability in L-glutamine reduction may be important in patient treatment outcome and work is ongoing to relate these changes to clinical outcome.
