Combination of Dexamethasone and Asparaginase Induces Prothrombotic State in Children Receiving Multiagent Chemotherapy for Acute Lymphoblastic Leukemia
Bibliographic record
Abstract
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. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".