DOSE REDUCTION OF ASPARAGINASE UNDER PHARMACOKINETIC AND PHARMACODYNAMIC CONTROL DURING INDUCTION THERAPY IN CHILDREN WITH ACUTE LYMPHOBLASTIC-LEUKEMIA

The enzyme asparaginase is an important element in the therapy of acut e lymphoblastic leukaemia (ALL), The usual asparaginase dose as prescr ibed in the ALL-BFM-86/90 treatment protocol for the therapy of ALL is 10 000 IU/m(2) at 3 d intervals and had been developed on the basis o f the E. coli asparaginase preparation Crasnitin(TM) from the Bayer co mpany. Using the described schedule the E. coli asparaginase preparati on from the Medac company shows significantly higher biological activi ty than the Payer preparation. These findings prompted an attempt to r educe the dose of the Asparaginase medac(TM) under careful pharmacokin etic and pharmacodynamic monitoring. At the first step of dose reducti on in ALL treatment protocol I, 11 children received 5000 IU/m(2) of A sparaginase medac(TM) Another 15 children were given 2500 IU/m(2) of t he enzyme at the second step of dose reduction. Prior to each asparagi nase dose, blood samples were taken to determine amino acids and troug h enzyme activity. Concurrent with the asparaginase monitoring, the co agulation parameters were measured, 96% of samples from the first step of dose reduction (5000 IU/m(2) every third day) showed complete L-as paragine depletion (<0.1 mu M), the median trough enzyme activity was 265 IU/l. At the second step of dose reduction (2500 IU/m(2)) complete L-asparagine depletion was seen in 97% of samples, and the median tro ugh enzyme activity was 102 IU/l, Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Aspar aginase medac(TM) dose reduced from the usual 10000 IU/m(2) down to 50 00 IU/m(2) or 2500 IU/m(2), applied at 3 d intervals, was sufficient t o achieve complete L-asparagine depletion in serum. Changes of the fib rinogen levels was significantly less pronounced in the group on 2500 IU.