WT1 snp rs16754 Genotype Predicts Treatment Related Mortality (TRM) in African-American and Asian Pediatric AML Patients: A Report From the Children's Oncology Group
Notice bibliographique
Résumé
Abstract Abstract 1385 Background: Successful treatment of childhood acute myeloid leukemia (AML) requires multi-agent chemotherapy, beginning with intensive induction regimens. Treatment-related mortality (TRM) remains a significant concern, and may be influenced by patient-specific factors. Outcomes in adult and pediatric AML differ among ethnicities. We reported that the minor (G) allele of the WT1 synonymous SNP rs16754 is associated with improved outcome. Racial frequencies of SNP rs16754 vary significantly. Here we explore rs16754 genotype and 5-year rates of overall survival (OS), complete remission (CR), relapse risk (RR) and TRM in the Children's Cancer Group trial CCG-2961, in the context of ethnicity. Methods: To assess SNP rs16754 genotype, we directly sequenced WT1 exon 7 on available diagnostic specimens (N=492) from pediatric AML patients enrolled on CCG-2961. Patients with at least one minor (G) allele were considered SNP+, while patients homozygous for the major (A) allele were considered SNP−. We stratified SNP genotype by ethnicity and analyzed outcomes. In the 2961 trial, Induction Course 1 consisted of an intensively-timed hybrid regimen (Ida-DCTER: idarubicin/daunorubicin, dexamethasone, cytarabine, thioguanine, and etoposide). Patients with at least partial remission (<30% marrow blasts) were randomized to receive Induction Course 2 consisting of either a repeat course of Ida-DCTER (Regimen A) or Ida-FLAG (idarubicin, fludarabine, cytarabine; Regimen B). As most TRM events occurred within the first two cycles of chemotherapy, TRM was further examined separately on each of these two study arms. Results: Twenty-eight percent of patients were SNP+; SNP positivity correlated with improved overall survival (5 year OS, 61% vs. 44%, p=0.009), although other outcome measures (CR, RR, DFS) were not significantly different between SNP+ and SNP− groups in the 2961 study. Prevalence of the SNP G allele varied significantly across ethnic groups (p=0.034): Asian (n=8/15, 53%), Hispanic (n=28/82, 34%), Caucasian (n=81/322, 25%), and African-American (n=10/47, 21%). When examining rs16754 genotype within ethnic subgroups, SNP+ patients had higher 5 year OS in each population (Hispanic: 49% vs. 37%, p=0.433; African-American: 56% vs. 30%, p=0.207; Asian: 88% vs. 29%, p=0.037; and Caucasian: 65% vs. 48%, p =0.051); statistical significance was approached in the Caucasian group and was achieved only in the Asian group. When patients of all ethnicities were considered together, TRM rates did not vary by rs16754 genotype. However, TRM rate was significantly lower in SNP+ African-American and Asian patients taken together compared to their SNP− counterparts (p=0.020) with a trend to significance taken individually (Asian: 0% vs. 43%, p=0.063; African-American: 0% vs. 25%, p=0.105). Further, for patients who survived Induction 1 and underwent Induction 2 randomization, SNP− Asian and African-American patients experienced higher rates of TRM from randomization disproportionately on Arm B (p=0.107), where TRM in SNP+ vs. SNP− patients was 0% vs 60% in Asian patients (Arm B n=9, p=0.110) and 0% vs. 14% in African-American patients (Arm B n=21, p=0.305). Conclusions: As CCG-2961 comprised blocks of intensive inpatient therapy, this clinical trial provides a setting in which to study the effects of ethnicity on outcome while minimizing confounding non-biologic factors. African-American and Asian patients who were negative for SNP rs16754 experienced disproportionate TRM, particularly on experimental Arm B, which tested the then-novel agent fludarabine; conversely, the TRM rate was 0% for SNP+ patients of these two ethnicities. The biologic mechanism for this observation bears further study, as biomarkers predictive of drug-specific toxicity may inform treatment decisions in certain ethnic populations. 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 | 0,001 | 0,002 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,001 |
| 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 | 0,000 |
| 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 ».