A Pharmacokinetic Study of Native E.coli Asparaginase for Acute Lymphoblastic Leukemia Treated with ThaiPOG Protocol.

BACKGROUND: Asparaginase is one of the essential chemotherapies used to treat acute lymphoblastic leukemia (ALL). Asparaginase antibody production may cause a subtherapeutic level and result in an inferior outcome. The aim of this study was to prove the efficacy of current native E.coli asparaginase-based protocol. Moreover, does subtherapeutic result appeared in small group of the trial?. METHODS: A prospective study of asparaginase activity among patients who received native E.coli asparaginase 10,000 IU/m2 intramuscularly according to The Thai Pediatric Oncology Group (ThaiPOG) protocol was done. The plasma asparaginase activity was measured by the coupled enzymatic reaction. Pharmacokinetic data including peak activity (Cmax), time to maximum concentration (Tmax), area under the curve (AUC0-48h) being elucidated. RESULTS: Eight patients (five males and three females), median age 9.5 years, were enrolled. The median asparaginase activity of seven cases who were eligible for calculation reached Tmax within 24 hours (range 6-48 hours) with mean±SD of Cmax 3.60±0.34 (range 3.02-4.11) IU/ml. Mean±SD of AUC0-48h is 143.23±36.94 IU.h/mL (range 71.07 - 180.12 IU.h/mL). The post-48-hour activity showed a mean±SD of 3.19±0.24 IU/ml (range 2.77-3.51 IU/ml) which implied an adequacy of activity over 48 hours and proper for the 12-day period. One relapsed ALL patient showed an extremely low AUC of asparaginase activity which coincided with urticaria after asparaginase injection. Subsequently, the asparaginase antibody was demonstrated in this patient. CONCLUSION: Native E. coli asparaginase-based protocol provides a compelling pharmacokinetic effect. Asparaginase activity and/or antibody testing is recommended for all cases especially in a relapsed patient, history of high accumulative dose of asparaginase or suspected allergic reaction. Patients with low asparaginase activity or allergy may benefit from switching to an alternative form of asparaginase to maintain treatment efficacy.

Reference values for thrombotic markers in children.

Thromboembolic events are an increasingly common problem encountered in children. The laboratory diagnosis of thrombotic disorders in children differs from that in adults. To establish the normal reference of natural anticoagulant parameters in children of different age groups, plasma from healthy children between the ages of 2 months and 16 years (n = 127) and adults (n = 30) were assayed for a disintegrin-like and metalloprotease with thrombospondin type 1 domain 13 (ADAMTS-13), von Willebrand factor collagen-binding activity (vWF:CB), tissue factor pathway inhibitor (TFPI), homocyteine and natural anticoagulants. Children were divided into four age groups: less than 1 year, 1-5 years, 6-10 years, and 11-16 years. The reference values for ADAMTS 13, homocysteine, and protein C activity were significantly lower in children of all age groups compared with those in the adults. Similarly, those for protein C antigen, total protein S, free protein S and antithrombin III (AT III) for children less than 1 year were significantly lower than in the adults. On the contrary, TFPI levels were significantly higher in the children for all age groups when compared with the adults. vWF:CB levels were comparable across all groups. There are age-related physiologic differences in ADAMTS-13, TFPI, homocysteine and natural anticoagulants between children and adults. Our data will provide physicians with a useful reference guide in interpreting test results of inhibitors of hemostatic parameters in children suspected of thrombotic disorders.