Overall survival by <i>IDH2</i> mutant allele (R140 or R172) in patients with late-stage mutant-<i>IDH2</i> relapsed or refractory acute myeloid leukemia treated with enasidenib or conventional care regimens in the phase 3 IDHENTIFY trial.
Notice bibliographique
Résumé
7005 Background: IDH2 gene mutations (m IDH2) occur in up to ̃20% of patients (pts) with acute myeloid leukemia (AML), most commonly as R140Q (in ̃75% of cases) or R172K (̃25%) point mutations. The functional effects and prognostic relevance of m IDH2-R140 and m IDH2-R172 can vary (Papaemmanuil 2016). In the randomized, phase 3 IDHENTIFY trial, enasidenib (ENA), an oral mIDH2 inhibitor, did not significantly improve overall survival (OS) vs conventional care regimens (CCR) as salvage treatment (Tx) for older pts with m IDH2 relapsed/refractory (R/R) AML in ITT analysis, but a trend for improved OS with ENA was detected in pts with IDH2-R172 mutations. We further investigated OS and correlative biomarkers in IDHENTIFY pt subgroups defined by m IDH2 variant (R140/R172). Methods: This open-label trial (NCT02577406) enrolled pts ≥ 60 years of age who had received 2 or 3 prior AML Tx. Pts were preselected to a CCR (azacitidine, intermediate- or low-dose Ara-C, or supportive care), and were then randomized 1:1 to ENA 100 mg/d or CCR in 28d cycles. Co-occurring gene mutations were identified by targeted next-generation sequencing (37-gene panel) of bone marrow mononuclear cell (BMMC) DNA. Total 2-HG levels were determined by LC/MS. Results: Of 319 pts enrolled, 88 pts (28%; 43 ENA, 45 CCR) had m IDH2-R172 and 229 (72%; 115 ENA, 114 CCR) had m IDH2-R140. Median baseline (BL) 2-HG levels were similar between Tx arms and m IDH2 variant subgroups, as were IDH2 variant allele frequencies. Pts with m IDH2-R172 had fewer median BL co-mutations (4 [range 2–8]) than did pts with m IDH2-R140 (5 [1–11]) ( P < 0.0001). The most frequently co-occurring mutations were SRSF2 and RUNX1 in the R140 cohort (59% each) and DNMT3A in the R172 cohort (57%). Compared with the R172 cohort, the R140 group was enriched with SRSF2, FLT3 (-ITD/-TKD), NPM1, RUNX1, and JAK2 mutations, whereas DNMT3A and TP53 mutations were more common in the R172 group. In Cox multivariate analysis including m IDH2 variant (R140/R172), DNMT3A mutation status, and number of gene mutations at BL, m IDH2-R172 was significantly ( P = 0.04) correlated with improved OS (vs. R140) in the ENA arm, whereas the number of BL gene mutations was significantly ( P < 0.01) associated with OS in the CCR arm. Median OS in the R172 subgroup was 14.6 mo with ENA vs 7.8 mo with CCR (HR, 0.59 [95%CI 0.35-0.98]; P = 0.039) and 1-yr survival rates were 62% and 30%, respectively. In m IDH2-R140 pts, median OS was 5.7 mo in both Tx arms (0.93 [0.70-1.24]; P = 0.61), and 1-year survival rates were 29% and 25% with ENA and CCR, respectively. Conclusions: Mutational burden and co-mutational profiles differed between pts with m IDH2-R140 and m IDH2-R172 R/R AML. ENA improved survival outcomes for pts with IDH2-R172 mutations, with median OS and 1-year survival rate approximately double those in the CCR arm. Clinical trial information: NCT02577406.
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 | 0,001 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,000 | 0,000 |
| 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 | 0,002 |
| 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 ».