Minimal effects of E. coli and Erwinia asparaginase on the coagulation system in childhood acute lymphoblastic leukemia: A randomized study

Abstract

A randomized study was done in twenty newly diagnosed children with acute lymphoblastic leukemia. Ten children were treated with Escherichia coli L-asparaginase, and ten with Erwinia chrysanthemi L-asparaginase. L-asparaginase (ASP) treatment started halfway during ALL-induction treatment with vincristine, prednisone, daunorubicin and intrathecal methotrexate. The mean activated partial thromboplastin time (APTT) level in all children demonstrated a significant fall (P < 0.001) from 28.25 sec at diagnosis to 23.0 sec at the start of ASP treatment. In this same time interval, the mean fibrinogen level declined markedly from 3 g/l to 1.2 g/l (P < 0.001), probably due to prednisone therapy. The APTT stayed shortened during ASP therapy, whereas the hypofibrinogenemia recovered significantly faster in the Erwinia group (P < or = 0.01). Factors (F) II, V, VII and X stayed within the normal range, while F VIII and F IX were elevated. During the entire period of induction therapy, the ATIII activity remained within the normal range in both treatment groups. The protein C values, however, demonstrated a steady decline from 140% at start of ASP treatment to a mean of 81% and 93%, respectively, at the end of the ASP therapy in the E. coli and Erwinia group. Five of the ten children treated with E. coli ASP demonstrated protein C levels below 70% at the end of ASP therapy, opposed to none of the Erwinia treated patients (P = 0.03). We suggest that the effect of ASP resulting in decreased coagulation factor synthesis is in part counterbalanced by the effect of prednisone on the coagulation system, when ASP is administered at the end of ALL induction treatment. The overall effect of ASP either of E. coli or of Erwinia on the hemorrhagic system reveals a slight imbalance towards thrombosis, mainly because of a gradual decrease in protein C activity. This imbalance is less pronounced in the Erwinia group.

Comparison of Escherichia coli-asparaginase with Erwinia-asparaginase in the treatment of childhood lymphoid malignancies: results of a randomized European Organisation for Research and Treatment of Cancer---Children's Leukemia Group phase 3 trial

“…The most frequent side effects were coagulation abnormalities, which were more frequent in the E coli-asparaginase arm, as previously reported. 11,24,25 Our results confirm a trend toward more neurotoxicity and convulsions with E coli-asparaginase. 11 However, their frequency (2.5% grade 3 or 4 neurotoxicity, 1.7% convulsions) remained moderate compared to the rate of relapse and death.…”

Validation of a predictive model for identifying an increased risk for thromboembolism in children with acute lymphoblastic leukemia: results of a multicenter cohort study

“…Apart from leukemia induction therapy, the risk assessment score included also te presence of CVLs and thrombophilic genetic abnormalities. 2,[17][18][19][20] The parameters were shown in a risk assessment model ( Table 1) that allows treating physicians to classify VTE risk in children with ALL. In an independent pediatric patient cohort the model was validated.…”

L-Asparaginase and Venous Thromboembolism in Acute Lymphocytic Leukemia

“…However, in one study, the use of E. coli asparaginase was associated with a greater likelihood of coagulation abnormalities (defined as 'any clinical or biologic abnormality, e.g., hypofibrinogenemia requiring a modification of chemotherapy or supportive care') [25]. In another small study (n = 20), the use of E. coli asparaginase was associated with a higher risk of decline in protein C level below 70%, compared with Erwinia asparaginase (50 vs 0%; p = 0.03) [27]. The use of L-asparaginase encapsulated within erythrocytes, compared with the native form of the enzyme, is thought to allow gradual serum asparagine depletion with lower doses.…”