Prevalence and Clinical Implications of N-RAS Mutations in Childhood AML – A Report From the Children's Oncology Group.
Notice bibliographique
Résumé
Abstract Abstract 3115 Poster Board III-52 Mutations in the RAS proto-oncogenes are frequent in acute myeloid leukemia (AML) and serve as prototypic Class I lesions, initiating key downstream hyper-proliferative signal transduction pathways. N-RAS mutations (N-RASmut) are common in AML, occurring in 10-20% of adult and pediatric AML patients; however their prognostic significance in both adults and children remains disputed. Due to a frequent association with a normal karyotype, delineating the impact of these mutations on outcome may enable appropriate risk-adapted therapeutic approaches. Here, we report on the incidence and prognostic significance of N-RASmut in a cohort of 825 pediatric AML patients treated on 2 recent co-operative group studies, CCG-2961 and COG AAML03P1. In total, of the 825 children with de novo AML who underwent N-RAS mutational analysis, 86 (10%) were positive. Gender, age, race, presence of hepatosplenomegaly and FAB subtype were comparable between patients with and without N-RASmut. There was no statistically significant difference between those with and without N-RASmut with respect to specific chromosome class. FLT3/Internal tandem duplications (FLT3/ITD) were less common in those with N-RASmut (2% vs. 9%, p=0.03). In contrast, nucleophosmin (NPM) mutations were more common in those with N-RASmut (13% vs. 5%, p=0.02). Overall, N-RASmut showed a significant correlation with low risk AML (CBF, CEBPαa, or NPM, p=0.04) and an inverse relationship with high risk disease (-5/5q- or -7, FLT3/ITD/high allelic ratio, p=0.007). Patients with N-RASmut had similar complete remission (CR) rates following two courses of induction chemotherapy compared with non-mutated patients (79% vs. 79%, p=0.92). Those in CR had a similar relapse rate regardless of the presence of N-RASmut (RR 39% vs. 36%, p=0.97). Five year event free survival (EFS) and overall survival (OS) from study entry were also comparable, however N-RASmut patients demonstrated a marked increase in overall treatment related mortality (TRM) (21% vs. 14%, p=0.03), which was maintained when high and low risk patients were excluded (22% vs. 11%, p=0.05). Evaluation of TRM in CCG-2961 compared with COG AAML03P1 demonstrated that increased TRM in N-RASmut was only seen in patients treated on CCG-2961 and TRM was primarily due to invasive fungal and gram negative infections. Interestingly, for patients treated on CCG-2961, who received interval compressed intensive induction therapy, this increase in TRM correlated with a decrease in both OS and disease free survival from CR. Remission specimens from patients with N-RASmut were negative for the mutation, demonstrating that an increased infectious risk could not be attributed to a host polymorphism. We found N-RASmut did not contribute to increased disease recurrence in pediatric AML. Our findings indicate that N-RAS mutations do not identify a high risk population, however, as such mutations lead to downstream activation of signal transduction pathways, they may identify a target for directed therapy. 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) | 0,000 | 0,000 |
| Bibliométrie | 0,002 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 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 ».