Antithrombin and fibrinogen levels as predictors for plasma L-asparaginase activity in children with acute lymphoblastic leukemia

Background: L-asparaginase is a cornerstone treatment for children with acute lymphoblastic leukemia (ALL). However, immune reaction to the drug may increase the clearance or impair the function of L-asparaginase and reduces its therapeutic efficacy. The objective of this study was to identify potential plasma proteins that could be used as proxies for L-asparaginase activity.

Methods: Fibrinogen, von Willebrand factor antigen (VWF:Ag), total protein, and albumin levels as well as antithrombin (AT) and L-asparaginase activities were measured in 97 children with ALL treated for prolonged period of time with L-asparaginase. Binary logistic regression and a receiver operating characteristic (ROC) curve analysis were performed to evaluate the predictive value of plasma proteins for L-asparaginase activity.

Results: Median E. coli L-asparaginase activity was 220 IU/L (range, 0-1308) throughout the treatment period. L-asparaginase activity was below 100 IU/L in 23% of measured samples. L-asparaginase activity was inversely associated with AT activity, fibrinogen, total protein, and albumin levels (r = -0.63, -0.62, -0.57, and -0.45, respectively; P < 0.0001), but not with VWF:Ag. ROC curve analyses showed an intermediate accuracy of AT activity (area under the ROC curve [AUC] = 0.77) to detect specimens with subtherapeutic level of L-asparaginase. An optimal accuracy was found when AT and fibrinogen were combined (AUC = 0.82; sensitivity = 75%; specificity = 82%; positive predictive value = 55%; negative predictive value = 92%) with cutoff values of 0.73 IU/mL and 1.85 g/L, respectively.

Conclusions: AT combined with fibrinogen levels could be used as a proxy to identify patients with therapeutic level of L-asparaginase activity in the absence of real-time asparaginase measurement during prolonged exposure to L-asparaginase.