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Effects of PEG-asparaginase on CSF asparagine levels
Discussion
Survival rates obtained with chemotherapy schedules applied over the last three decades in childhood ALL have increased progressively and currently approach 90%.3
Asparaginase has been shown to play a key role in obtaining such excellent results and for this reason the drug has been invariably included, since its introduction in clinical practice, in the polychemotherapy schedules designed for childhood ALL. The enzyme exerts its antileukemic activity by depleting the systemic pools of asparagine, an amino acid essential for the rapid prolifera- tion of malignant lymphoblasts.21–23
It is well known that the activity of any asparaginase product may be pharmacologically monitored by measur- ing serum asparaginase activity levels, which reflect the enzyme’s ability to deplete circulating asparagine pools and are considered a surrogate marker of its clinical effica- cy.1 There is currently a wide agreement that activity lev-
A
els of at least 0.1 IU/mL (i.e. 100 IU/L) should be achieved and maintained during the whole planned asparaginase treatment to ensure maximal asparagine depletion in serum (<0.2 μmol/L) and maximal therapeutic efficacy.9,21 Whether a similarly profound and prolonged asparagine depletion in the CSF is needed to prevent CNS relapses is not known; however, there are reports associating the two phenomena.4
The physiological concentration of asparagine in human CSF varies depending on the age of the patient. In children and adolescents its concentration ranges between 4 and 10 μmol/L.24 Although these values are lower than those found in serum (about 40-80 μmol/L), it has been reported that these levels ensure the growth of leukemic blasts.25 For this reason, in principle, it is reasonable to study asparagine depletion in CSF to evaluate its clinical rele- vance better and prospectively.
The main purpose of the study reported here was to evaluate the level of asparagine depletion in the CSF and
B
Figure 2. Effect of pegylated-asparaginase activity on asparagine level in the cerebrospinal fluid. Distribution of asparagine levels (μmol/L) detected in cere- brospinal (CSF) samples collected during puncture on days +33 (blue dots) and +45 (red dots) versus pegylated asparaginase (PEG-ASP) activity levels (IU/L) detect- ed in serum at the same sampling day (±1) in the (A) Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) and (B) Berlin-Frankfurt-Münster (BFM) cohorts.
A
B
Figure 3. Cerebrospinal fluid asparagine concentration at different levels of pegylated-asparaginase activity. Box plots of asparagine cerebrospinal fluid (CSF) con- centrations (μmol/L) versus categorized pegylated-asparaginase (PEG-ASP) activity levels (IU/L) in serum collected at the same sampling points (±1 day) in the (A) Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) and (B) Berlin-Frankfurt-Münster (BFM) cohorts.
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