Effect of Asparaginase and Dexamethasone on FVIIa-at Complex and F1.2 in Children with Acute Lymphoblastic Leukemia: Evidence of Hypercoagulable State
Notice bibliographique
Résumé
Abstract Purpose: Concomitant administration of asparaginase (ASP) and steroids, the 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 TE is frequent during ASP intensification phase (Consolidation II) where pulse steroids are administered for 5 days at commencement of 3-week multiagent chemotherapy cycles (Grace et al, 2011). These observations indicate that combination therapy with ASP and steroids leads to a hypercoagulable state. However, there are no in vivo or in vitro data to support these clinical observations. Hence we undertook a study to evaluate the impact of concomitant administration of ASP and steroids on markers of endogenous thrombin generation namely prothrombin activation fragment 1.2 (F1.2) and, activated coagulation factor VII (FVIIa) and antithrombin (AT) complex (FVIIa-AT). Hypothesis: ASP administered with steroids results in increased levels of endogenous thrombin generation when compared to baseline or with ASP only therapy. Methods: Children (>1 to ≤18 yrs. of age) treated according to DFCI ALL 05-001 therapy protocol who are in remission following consolidation I therapy, without prior TE or ASP allergy, were eligible. Blood samples collected at 3 time points: prior to the first post-induction dose of E. Coli ASP ("baseline"), prior to Week 2 therapy (effects of ASP and Dex therapy) and prior to subsequent Week 1 (effect of ASP only) of three week cycle of Consolidation II therapy, were analyzed for F1.2 and FVIIa-AT complex. F1.2 levels were estimated by enzyme-linked immunosorbent assay (ELISA). FVIIa-AT levels were analyzed using the Asserachrome FVIIa-AT ELISA kits (Diagnostica Stago). Baseline parameters [time point (TP) 1] were compared to parameters after ASP and Dex (TP2), and after ASP only (TP3) therapy, using paired t-tests. Pearson correlation was used to evaluate the relationship between FVIIa-AT complex and F1.2. Results: This exploratory study included 9 patients (7 boys; 2 with high-risk ALL). The average age was 4.7 yrs. (range 1 to 8 yrs.). All patients received weekly E. Coli ASP during Consolidation II phase. As shown in Table 1, compared to baseline both F1.2 and FVIIa-AT complex levels were significantly increased at TP2 (ASP and Dex) and TP3 (ASP alone). In all but one patient the FVIIa-AT levels were higher following Dex therapy (TP2) compared to ASP alone (TP3). However this difference was not statistically significant [mean difference 83.4 (SD152.1), 95% CI -33.5, 200.4; p=0.138]. Similarly F1.2 levels were higher at TP2 compared to TP3 in all but 2 patients, but the difference was not statistically significant [mean difference -5.9 (SD 38.2), 95% CI-35.2, 23.4; p=0.656]. Following ASP alone therapy F1.2 and FVIIa-AT were significantly correlated (Pearson correlation coefficient 0.716, p=0.046). Conclusions: E. Coli ASP and Dex therapy is associated with significantly increased levels of F1.2 and FVIIa-AT levels compared to baseline, indicating activation of the coagulation cascade with increased endogenous thrombin generation. In the majority of patients combination of ASP and Dex had increased levels of F1.2 and FVIIa-AT compared to ASP alone therapy. However as a group this comparison was statistically insignificant. This may explain the increased risk of TE with concomitant ASP and Dex therapy as in Consolidation II phase on DFCI ALL therapy protocol. Small sample size is a limitation of our study. Hence we recommend a larger study to confirm our findings. Table 1. Variable TP1 Mean(SD) TP2 Mean (SD) Mean Difference TP1/TP2 (SD)[95% CI] P value TP3 Mean (SD) Mean Difference TP1/TP3 (SD)[95% CI] P value FVIIa-AT (pmol/L) 77.4 (25.7) 296.4 (132.3) -291.0 (133.9)[-322.0,-116.0] 0.001 213.0 (131.4) -135.6 (117.6)[-226.0, -45.1] 0.009 F1.2 (nmol/L) 110.7 (45.9) 153.0 (78.8) -42.3 (50.4) [-81.1,-3.6] 0.036 158.9 (80.4) -48.2 (61.3)[-95.3,-1.1] 0.046 Disclosures No relevant conflicts of interest to declare.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».