NPM1, IDH1/2 and DNAH11 Gene Mutations Can Improve a Prognostic Stratification of Acute Myeloid Leukemia Patients with Normal Karyotype but Not Harboring FLT3/ITD Mutation.
Notice bibliographique
Résumé
Abstract Abstract 2534 Background: Acute myeloid leukemia with normal karyotype (AML-NK) is known to be heterogeneous in the molecular level. Accordingly, it has become more critical to dissect this group of patients according to their prognosis using a molecular genetic technology. We attempted to analyze the incidence and prognostic implication of genetic abnormalities on survival in 426 adult patients with AML-NK. Methods: A total of 67 AML-NK patients achieved complete remission (CR), candidate mutations in 21 genes were identified by whole exome sequencing which has 41–89× coverage and by single-nucleotide polymorphism array analysis using marrow mononuclear cells at diagnosis of AML-NK. Subsequently, mutation analysis of 11 genes (i.e. FLT3/ITD, NPM1, DNMT3a, IDH1, IDH2, TET2, NRAS, WT1, DNAH11, SF3B1, and PHF6) which are known to be involved in the pathogenesis of hematologic diseases, were performed using Sanger sequencing in another subset of 359 AML-NK patients as a validation cohort. Results: Of 426 patients in total (median age: 51, ranges: 15–85), FLT3/ITD, NPM1, and DNMT3a mutations were associated with higher leukocytes counts at presentation of AML-NK. In 284 patients who received standard remission induction (RI) chemotherapy (excluding 119 patients with conservative treatment and 22 early death/1 follow-up loss after RI chemotherapy), those with FLT3/ITD mutation were significantly associated with a higher risk of relapse (p=0.02), a shorter leukemic-free survival duration (LFS)(p<0.01) or overall survival (OS) (p=0.01). Accordingly, we divided the patients into FLT3/ITD+ and FLT3/ITD− population, and analyzed their treatment outcomes according to the other mutations. In the FLT3/ITD− group (n=200), those with NPM1 mutation showed a higher CR rates after one or two cycles of RI chemotherapy (p<0.01) and a longer OS duration (p<0.01), hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.25–0.73, adjusted by other clinical variables including age, leukocyte counts at diagnosis, and transplantation (Figure 1). In the FLT3/ITD+ patients (n=84), NPM1 mutation was found to be a favorable prognostic factor showing a lower relapse rate (p=0.00), a longer LFS duration (p<0.01, HR 0.35, 95% CI 0.18–0.70), and OS duration (p=0.04, HR 0.55, 95% CI 0.31–0.98) in NPM1 mutated patients. In addition, OS was significantly different in favor of those with IDH2, especially R140Q IDH2 mutation, (p=0.04, HR 0.30, 95% CI 0.09–0.99), whereas DNAH11 mutation was associated with inferior OS (p<0.01, HR 5.78, 95% CI 1.65–20.25). Accordingly, we stratified the FLT3/ITD+ patients into three subgroups according to the NPM1, IDH1/2 and DNAH11 mutation status, Group 1: NPM1 mutation and IDH1 or 2 mutations (n=16), Group 2: isolated DNAH11 mutation (n=4) and Group 3: all mutations were negative (n=64). The group 1 showed significantly better OS than group 2 (p<0.01, HR 16.90, 95% CI 3.48–82.15) or group 3 (p<0.01, HR 3.40, 95% CI 1.20–9.55) (Figure 2). In a subgroup analysis of younger patients less than 60 years of age, similar outcomes were also observed in favor of group 1 in terms of OS (data not shown). Conclusion: Our study confirmed that NPM1 mutation is an independent prognostic factor in adult patients with AML-NK not harboring FLT3/ITD mutation. In addition, several other genetic markers were identified as prognostic including IDH1/2 or DNAH11 mutations as well as NPM1 mutation in a subgroup of AML-NK patients with FLT3/ITD mutation. Disclosures: No relevant conflicts of interest to declare.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
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 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 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 ».