Dose reduction of asparaginase under pharmacokinetic and pharmacodynamic control during induction therapy in children with acute lymphoblastic leukaemia

Abstract

The enzyme asparaginase is an important element in the therapy of acute lymphoblastic leukaemia (ALL). The usual asparaginase dose as prescribed in the ALL-BFM-86/90 treatment protocol for the therapy of ALL is 10,000 IU/m2 at 3 d intervals and had been developed on the basis of the E. coli asparaginase preparation Crasnitin from the Bayer company. Using the described schedule the E. coli asparaginase preparation from the Medac company shows significantly higher biological activity than the Bayer preparation. These findings prompted an attempt to reduce the dose of the Asparaginase medac under careful pharmacokinetic and pharmacodynamic monitoring. At the first step of dose reduction in ALL treatment protocol I, 11 children received 5000 IU/m2 of Asparaginase medac. Another 15 children were given 2500 IU/m2 of the enzyme at the second step of dose reduction. Prior to each asparaginase dose, blood samples were taken to determine amino acids and trough enzyme activity. Concurrent with the asparaginase monitoring, the coagulation parameters were measured. 96% of samples from the first step of dose reduction (5000 IU/m2 every third day) showed complete L-asparagine depletion (< 0.1 microM), the median trough enzyme activity was 265 IU/l. At the second step of dose reduction (2500 IU/m2) complete L-asparagine depletion was seen in 97% of samples, and the median trough enzyme activity was 102 IU/l. Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Asparaginase medac dose reduced from the usual 10000 IU/m2 down to 5000 IU/ m2 or 2500 IU/m2, applied at 3 d intervals, was sufficient to achieve complete L-asparagine depletion in serum. Changes of the fibrinogen levels was significantly less pronounced in the group on 2500 IU.