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C. Rizzari et al.
therefore the pharmacodynamic effect exerted by PEG- asparaginase on the CNS of children with ALL. The inter- est in this aspect derives from various studies showing that different degrees of asparagine depletion in the CSF may depend not only on the asparaginase product used4–9 but, apparently, also on the levels of asparaginase activity achieved in serum.26–28
In this study the administration of PEG-asparaginase in the induction phase of the ALL treatment adopted was associated with a significant, even if widely variable, reduction of CSF asparagine below the physiological lev- els. However, complete asparagine depletion was observed overall in only about 28% of the analyzed CSF samples. Considerable CSF asparagine levels, greater than 1 μmol/L, and thus higher than the LLOQ of the assay used, which is considered the threshold of complete asparagine depletion, were detected overall in 23% of the analyzed CSF samples, with this latter figure becoming 17-19% and 35-41% for samples taken 7 and 19 days,
respectively, after PEG-asparaginase administration (Table 2A,B).
The findings of the large therapeutic drug monitoring program regarding asparaginase activity levels in serum conducted in the frame of the AIEOP-BFM ALL 2009 study and here reported regard exclusively the subset of patients studied to evaluate asparagine depletion in the CSF. These data show that after a dose of 2,500 IU/m2, PEG-asparaginase activity levels much higher than 100 IU/L are achieved in induction in the vast majority of patients and are maintained both 7 and 14 days following a standard administration schedule including PEG- asparaginase, thus fully confirming the prolonged half-life of this product (Table 5A,B).
In the serum samples collected along with CSF samples, PEG-asparaginase activity less than 100 IU/L was only detected in around 5-6% of samples, when the samples were taken ≤19 days after administration of PEG-asparag- inase (Tables 3A,B and 5A,B). We can, therefore, assume
Table 4. Asparagine levels in cerebrospinal fluid sorted by asparaginase activity levels in serum, at scheduled cerebrospinal fluid punctures (days +33 and +45) in the (A) Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP) and (B) Berlin-Frankfurt-Münster (BFM) cohorts.
A
Gender Male Female
Age at diagnosis 1-9 years 10-17 years
WBC count at diagnosis <20 x 106/L
≥20 x 106/L
Immunophenotype B lineage
T ALL
B
Gender Male Female
Age at diagnosis 1-9 years 10-17 years
WBC count at diagnosis <20 x 106/L
≥20 x 106/L
Immunophenotype B lineage
T ALL
Asparagine levels in CSF (μmol/L)
Serum PEG-ASP activity 0 <100 IU/L
Serum PEG-ASP activity ≥100 IU/L
Total
Mean (SD)
4.0 (3.5) 2.6 (2.6)
3.3 (3.0)
3.4 (4.4)
3.5 (3.0) 3.1 (3.5)
2.7 (2.5)
6.5 (4.5)
Median (IQR)
3.0 (0.8-7.7) 1.7 (0.5-4.6)
2.1 (0.6-6.4)
1.4 (0.4-8.5)
2.8 (0.5-6.4) 1.4 (0.6-7.7)
2.0 (0.5-4.8)
8.5 (1.3-9.6)
Mean (SD)
0.7 (0.8) 0.4 (0.8)
0.6 (0.8)
0.5 (0.8)
0.5 (0.8) 0.6 (0.9)
0.6 (0.8)
0.6 (0.7)
Median (IQR)
0.4 (0.2-0.9) 0.2 (0-0.6)
0.4 (0-0.8)
0.3 (0-0.7)
0.3 (0-0.7) 0.4 (0-1.0)
0.3 (0-0.8)
0.3 (0-0.9)
Mean (SD)
0.9 (1.4) 0.6 (1.2)
0.8 (1.3)
0.7 (1.3)
0.7 (1.2) 0.8 (1.5)
0.7 (1.1)
1.2 (2.2)
Mean (SD)
0.6 (0.8) 0.6 (1.5)
0.7 (1.3)
0.5 (0.5)
0.7 (1.4) 0.6 (0.6)
0.6 (1.2)
0.6 (0.8)
Median (IQR)
0.4 (0.2-1.0) 0.3 (0-0.7)
0.4 (0-1.0)
0.3 (0-0.8)
0.4 (0-0.8) 0.4 (0-1.0)
0.4 (0-0.8)
0.4 (0-1.4)
Median (IQR)
0.4 (0.0-0.9) 0.4 (0.0-0.9)
0.4 (0.0-0.9)
0.4 (0.0-0.8)
0.4 (0.0-0.9) 0.4 (0.0-0.9)
0.4 (0.0-0.9)
0.4 (0.0-0.9)
Asparagine levels in CSF (μmol/L)
Serum PEG-ASP activity 0 <100 IU/L
≥100
0.4 (0.0-0.8)
0.4 (0.0-0.8)
0.4 (0.0-0.9)
0.4 (0.0-0.7)
0.4 (0.0-0.8) 0.4 (0.0-0.8)
0.4 (0.0-0.8)
0.4 (0.0-0.8)
Total
Serum PEG-ASP activity
Mean (SD)
1.7 (1.8) 1.1 (0.5)
1.7 (1.7)
0.8 (0.6)
1.8 (1.8) 1.0 (0.8)
1.4 (1.3)
1.9 (2.2)
Median (IQR)
1.3 (0.5-2.2) 0.9 (0.7-1.2)
1.3 (0.6-2.2)
0.9 (0.4-1.1)
1.3 (0.7-2.1) 1.0 (0.4-1.4)
1.0 (0.5-2.1)
1.3 (0.9-1.6)
Mean (SD)
0.5 (0.6) 0.6 (1.6)
0.6 (1.3)
0.5 (0.5)
0.6 (1.4) 0.5 (0.5)
0.6 (1.2)
0.5 (0.5)
Median (IQR)
CSF: cerebrospinal fluid; PEG-ASP: pegylated asparaginase; SD: standard deviation; IQR: interquartile range; WBC: white blood cell; ALL: acute lymphoblastic leukemia.
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haematologica | 2019; 104(9)