Abstract

Abstract 3536

Background:

Concomitant administration of asparaginase (ASP) and steroids, backbone of front line acute lymphoblastic leukemia (ALL) therapy, are shown to increase the risk of thromboembolism (TE). On Dana-Farber Cancer Institute (DFCI) ALL Consortium studies occurrence of TE is frequent during ASP intensification phase where pulse steroids are administered for 5 days at the start of a 3-week multiagent chemotherapy cycle (Grace et al, 2011). The DFCI ALL 05–001 trial randomized children to PEG ASP (2500IU/m2 intravenous every 14 days) or E. coli ASP (25000 IU/m2 intramuscular every 7 days) for 30 weeks.

Aims:

We undertook an exploratory study to investigate changes in hemostatic factors from baseline to after administration of ASP with and without dexamethasone (Dex) (standard risk: 6mg/m 2/day, high risk: 18mg/m 2/day × 5 days), and the influence of type of ASP, if any, in children receiving consolidation II therapy on the 05–001 protocol.

Methods:

Children (>1 to ≤18 years of age) in remission following consolidation I therapy, with no history of TE or allergy to ASP, were eligible to participate. Blood samples were collected at 3 time points: prior to the first post-induction dose of ASP (“baseline”), at a week 2 (effects of ASP and Dex therapy) and prior to subsequent week 1 (effect of ASP only). Samples were analyzed for procoagulant factors [F VIII:C, vonWillebrand Factor (vWF) antigen], markers of natural anticoagulant factors [antithrombin (AT), protein C (PC), free protein S (PS)], fibrinolytic proteins [plasminogen, tissue plasminogen activator antigen (tPA-Ag), plasminogen activator inhibitor-1antigen (PAI-1Ag), D-Dimer] and endogenous thrombin generation [prothrombin activation fragment (F1.2)]. Baseline parameters were compared to parameters after ASP and Dex therapy, and after ASP only therapy, using paired t-tests. Change in parameters were also compared for patients receiving PEG versus E coli ASP using Student's t-test.

Results:

Of the 20 participants (mean age of 5.8 years; 11 male; 5 high risk), 10 were randomized to PEG ASP. Although significant reduction in AT and PS occurred following ASP alone therapy, the values were within normal range. Type of ASP had no effect on hemostatic parameters except protein S (significant reduction) and PAI-1 Ag (significant increase) in patients treated with PEG ASP compared to E. coli ASP. Compared to baseline FVIII and vWF were significantly increased only after ASP-Dex therapy (Table 1). D-dimer and plasminogen decreased with ASP-Dex and ASP only therapy. There was significant increase in F1.2 following ASP therapy, but more so after ASP-Dex therapy.

Limitations:

Small sample size and exploratory, single institution study, undertaken within the context of multi-agent chemotherapy, are limitations of this study.

Conclusion:

Concomitant Dex and ASP, administered in conjunction with multiagent chemotherapy, induces prothrombotic state compared to baseline or that following ASP alone, with resultant increases in procoagulant factors (FVIII, vWF), reduction in fibrinolytic potential as indicated by decrease in plasminogen and D-Dimer, and increase in endogenous thrombin generation reflected by increase in F1.2. This may explain clinical observations of increased prevalence of TE in patients receiving concomitant ASP and steroids.

Table 1.

Change in hemostatic parameters from baseline to after administration of ASP with and without DEX

Asparaginase + DexamethasoneAsparaginase
ParametersPre (Mean)Post (Mean)% Change*Significance (<0.05) (2-tailed)Pre (Mean)Post (Mean)% Change*Significance (<0.05) (2-tailed)
FVIII 1.04 1.70 + 63 <0.001 1.05 1.07 + 29 0.591 
vWF 1.23 1.65 + 34 0.005 1.26 1.20 − 4 0.482 
AT 1.16 1.03 − 11 0.071 1.03 0.77 −33 <0.001 
Protein C 0.87 1.20 + 37 0.015 0.87 0.73 − 16 0.056 
Protein S 0.89 0.81 − 9 0.303 0.92 0.74 −20 0.004 
tPA Ag 7.59 10.13 + 33 0.001 8.31 10.79 + 30 0.072 
PAI-1 Ag 25.69 29.98 + 17 0.532 27.63 36.25 + 31 0.254 
Plasminogen 0.84 0.62 −26 <0.001 0.85 0.49 −44 <0.001 
D-Dimer 551.06 399.44 −28 0.015 570.94 367.69 −36 0.003 
F1.2 106.45 165.38 + 55 0.003 105.17 141.04 + 34 0.012 
Asparaginase + DexamethasoneAsparaginase
ParametersPre (Mean)Post (Mean)% Change*Significance (<0.05) (2-tailed)Pre (Mean)Post (Mean)% Change*Significance (<0.05) (2-tailed)
FVIII 1.04 1.70 + 63 <0.001 1.05 1.07 + 29 0.591 
vWF 1.23 1.65 + 34 0.005 1.26 1.20 − 4 0.482 
AT 1.16 1.03 − 11 0.071 1.03 0.77 −33 <0.001 
Protein C 0.87 1.20 + 37 0.015 0.87 0.73 − 16 0.056 
Protein S 0.89 0.81 − 9 0.303 0.92 0.74 −20 0.004 
tPA Ag 7.59 10.13 + 33 0.001 8.31 10.79 + 30 0.072 
PAI-1 Ag 25.69 29.98 + 17 0.532 27.63 36.25 + 31 0.254 
Plasminogen 0.84 0.62 −26 <0.001 0.85 0.49 −44 <0.001 
D-Dimer 551.06 399.44 −28 0.015 570.94 367.69 −36 0.003 
F1.2 106.45 165.38 + 55 0.003 105.17 141.04 + 34 0.012 
*

(+) = % Increase or (-) = % Decrease from baseline

Disclosures:

No relevant conflicts of interest to declare.

Reference:

Reference:

Author notes

*

Asterisk with author names denotes non-ASH members.