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 CrasnitinTM 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 medacTM 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 medacTM. 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 μM), the median trough enzyme acitivity 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 acitivity was 102 IU/l. Cerebrospinal fluid (CSF) depletion was complete in all samples tested (11/11). We concluded that an Asparaginase medacTM 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.

Asparaginase pharmacodynamics differ by formulation among children with newly diagnosed acute lymphoblastic leukemia

“…3,17 Modest differences in scheduling or preparations of asparaginase have been associated with significant differences in cure rates and toxicity. 3,18,19 Native E. coli preparations have been the most commonly used form of the drug in newly diagnosed patients with ALL; however, when these patients develop hypersensitivity, the relative efficacy of PEG, Erwinia, or native E. coli asparaginase in depleting asparagine is not known. In this study, our aim was to assess serially whether asparagine depletion varied with anti-asparaginase antibody status during treatment with three different asparaginase preparations.…”

Long-term results of five consecutive trials in childhood acute lymphoblastic leukemia performed by the ALL-BFM study group from 1981 to 2000

“…17 Since ALL-BFM 95, the E. coli L-ASP dose has been reduced to 5000 IU/m 2 in Protocol I because of the higher activity and toxicity compared with the formerly applied preparation from Bayer. 21,34,35 Methotrexate. ID-MTX IV (0.5 g/m 2 Â 4, 24-h infusion) was introduced as part of the extracompartment therapy ( Figure 1) in study ALL-BFM 81 for the randomized study in SR patients ( Figure 5a) and was subsequently used in all strata of study ALL-BFM 83.…”

Anti-asparaginase antibodies following E. coli asparaginase therapy in pediatric acute lymphoblastic leukemia

“…One difficulty in interpreting incidences of reactions is that a number of preparations of E. coli asparaginase prepared by different manufacturers have been used by various treatment groups. Because native E. coli asparaginase prepared by different manufacturers may vary markedly in their pharmacokinetic and pharmacodynamic properties, 18 it is important to indicate the specific commerical product used in clinical trials, which has not been done uniformly in the past.…”