Functional GSTA1 Haplotypes Affect Clearance and Toxicity of Busulfan When Administered in 16 Doses to Pediatric Patients Undergoing Hematopoietic Stem Cell Transplantation: A Multicenter Prospective Study on Behalf of the Pediatric Disease Working Party of the European Society for Blood and Marrow Transplantation (EBMT)
Notice bibliographique
Résumé
Abstract Busulfan (BU) dose adjustment following therapeutic drug monitoring (TDM) contributes to better outcome of hematopoietic stem cell transplantation (HSCT). The therapeutic target window can be reached in approximately 51% to 74% of pediatric cases and 45% to 64% of infants depending on the dosing guideline used. We hypothesize that a higher proportion of pediatric patients could achieve the target BU area-under-the-curve (AUC) of 900-1500 µM.min per dose in a four times dosing schedule through genotype-guided initial BU dosing. Previous investigations by our group and others showed association of glutathione -S- transferase alpha 1 (GSTA1) with reduced BU clearance (CL), likely due to altered expression of GSTA1 enzyme, principally involved in BU metabolism. To delineate and investigate the association of each GSTA1 haplotype with the CL of BU, promoter haplotypes of GSTA1 gene were assessed in vitro with reporter gene-assay and clinically in a pediatric multi-center study (N =138) through association with BU CL, AUC, dose change and clinical outcomes. All patients received BU based myeloablative conditioning regimen. BU PK parameters from 1st dose were estimated and further doses were adjusted to have a steady state concentrations of 600-900 ng/mL and GSTA1promoter SNPs at -69, -513, -631, -1142 positions were genotyped using allele specific oligo hybridization method. Reporter-gene assays confirmed significant differences between the haplotype subgroups and supported their importance in capturing PK variability. Four GSTA1 diplotype groups (I-IV) that significantly correlated with CL (p=0.009) were distinguished. GSTA1 diplotypes (group I) underlying fast metabolizing capacity (*A2*A2&*A2*A3) had lower cumulative AUC and a higher dose increase after TDM whereas those with slow metabolizing capacity (group IV, *B1a*B1a /*B1a*B1b /*B2*B1a / *A1*B1b)had highest AUC and least dose change (p=0.02). Multivariate linear model included GSTA1 diplotype groups and non-genetic factors such as age, gender, first BU dose in mg/kg and patients origin. Dose (p<0.0005), gender (p=0.05) and GSTA1 diplotypes (p=0.01) were retained in the final model that explained 34% of overall variability. Analysis with clinical outcomes indicated higher incidences of sinusoidal obstruction syndrome in Group IV diplotype carriers (HR=7.1; 95% CI: 2.5-20.4) compared to patients with other GSTA1diplotypes. A similar association was also seen with acute graft versus host disease (aGvHD grade I-4) and combined treatment-related toxicity (TRT) (p≤0.003). In conclusion, this study has replicated and provided additional evidence for the association of GSTA1 with BU PK and clinical outcomes of HSCT. GSTA1 diplotypes can explain in some models ~20% of the variability seen in BU CL and can contribute to HSCT-related complications acting within and beyond BU metabolism. Genotyping therefore may be helpful in deciding the first BU dose, thus decreasing consequences like TRT due to inaccurate first and subsequent dosing. This may be particularly important for GSTA1 diplotype Group IV carriers. Disclosures Bittencourt: Jazz Pharmaceuticals: Consultancy, Other: Educational Grant; Seattle Genetics: Consultancy.
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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) | 0,000 | 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 ».