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C. Rizzari et al.
Nevertheless, it has been postulated that this activity
never exceeds 0.2% of that present in serum.11 Conversely,
this may not be possible for PEG-asparaginase, mainly
because of its tertiary structure.16,32,33 However, so far there
is no clear proof that any asparaginase product determines
any degree of CSF asparagine depletion in humans by
directly penetrating the CSF. To contribute to this issue a
preclinical study was recently conducted to evaluate
whether the three commercially available asparaginase
formulations have different abilities to enter the CSF and
reduce local asparagine levels. Even with the limitations of
the model used in that preclinical experience, the enzy-
matic activity measured in CSF demonstrated that
asparaginase products, in particular both the native forms
derived from Erwinia chrysanthemi and E. coli, may tran-
siently penetrate the CNS when administered at high
doses, whereas the PEG-asparaginase product does not,
most probably because of the differences in molecular weight.16,34,35
To conclude, the findings of the therapeutic drug moni- toring performed in our study and reported here indicate that: (i) the administration of PEG-asparaginase was able to cause a broad reduction of physiological CSF asparagine levels (normally 4-10 μmol/L) but complete asparagine depletion was observed overall in only about 28% of the analyzed CSF samples; (ii) CSF asparagine levels greater than 1 μmol/L (thus higher than the LLOQ of the assay adopted) were detectable in 23% of the analyzed samples; (iii) at serum asparaginase activity levels less than 100 IU/L only 6.5% of the CSF samples had asparagine levels below
the LLOQ; and (iv) at serum asparaginase activity levels of 100 IU/L and higher, up to 1,500 IU/L and beyond, CSF asparagine levels were lower than the LLOQ in only about 33-37% of the samples. Thus, a further increase of the PEG-asparaginase dose would not help to obtain complete CSF asparagine depletion.
The consistent results found in the two independent data sets presented here strengthen the observations inferred from this study.
Acknowledgments
The authors thank the patients and families who participated in this trial, the physicians and nurses of all hospitals for their contribution in performing this study, and the members of the AIEOP-BFM ALL 2009 Asparaginase Working Party for pro- ductive discussions during the development and progress of the study. They also thank the partners in the reference laboratories and all the technicians for their expert work in cytology, genetics, and MRD diagnostics; and the data managers for their careful study conduction.
Funding
This study was supported by Comitato M. L. Verga and Fondazione Tettamanti (Monza) and by Stiftung Deutsche Krebshilfe (Bonn).
The TDM program performed in the international AIEOP- BFM ALL 2009 study has been supported by an unrestricted grant from the Shire company (and previously from medac GmBH, Sigma-Tau, Baxalta, which marketed the drug during the period of the present study).
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