Prolonged Survival in Bi-Allelic <i>TP53</i>-Mutated (<i>TP53</i>mut) MDS Subjects Treated with Oral Decitabine/Cedazuridine in the Ascertain Trial (ASTX727-02)
Notice bibliographique
Résumé
Introduction: TP53 mutations (TP53mut) in myelodysplastic syndrome (MDS) patients have been characterized as an independent prognostic factor for poor outcome. These patients may have similar response rates to hypomethylating agents (HMAs) but markedly diminished overall survival (OS) compared to those with wild-type (WT) TP53 status (9.4 vs. 20.7 months [mo.]; Takahashi, K, et al. Oncotarget. 2016). Further analyses have defined monoallelic (MA) and bi allelic (BA)/multi-hit TP53mut populations with very different survival outcomes (8.4 vs. 30 mo.; Bernard, et al. Nat Med. 2020). Oral decitabine/cedazuridine (ASTX727) is a fixed dose combination of decitabine (35 mg) and the cytidine deaminase inhibitor cedazuridine (100 mg) with pharmacokinetic (PK) exposure equivalent to the standard intravenous (IV) decitabine regimen of 20 mg/m2 daily X 5 days on a 28-day cycle. The ASCERTAIN study enrolled MDS and chronic myelomonocytic leukemia (CMML) subjects and the primary endpoint demonstrating PK (AUC) equivalence of oral decitabine/cedazuridine compared with IV decitabine was met (Garcia-Manero, ASH 2019); median overall survival (mOS) was 31.7 mo. (Savona, et al. MDS symposium 2021). Here we present preliminary analysis of the mutation profile of subjects enrolled on ASCERTAIN and evaluate the impact on overall and leukemia-free survival based on the NCCN MDS panel with a focus on the TP53 mutant population. Methods: 133 subjects with MDS/CMML were enrolled to ASCERTAIN and were randomly assigned either IV decitabine for cycle 1 and oral decitabine/cedazuridine for cycle 2 or the opposite treatment sequence. All subjects continuing beyond cycle 2 received oral decitabine/cedazuridine for all subsequent cycles until treatment discontinuation for disease progression, toxicity, patient's decision, or hematopoietic stem cell transplantation. Whole blood collected prior to treatment was used for DNA isolation and molecular abnormalities identified using next generation sequencing (NGS) hematologic malignancy panel of 179 genes including 30 genes from the NCCN MDS panel. Results: Of the 133 treated subjects, NGS analysis was available for 125 subjects. The percentage of subjects with mutations in the following genes were: TET2 (36.8%), TP53 (35.2%), ASXL1 (28%), DNMT3A (25.6%), SRSF2_MFSD11 (17.6%), SF3B1 (15.2%), STAG2 (12.8%), EZH2 (11.2%), RUNX1 (11.2%), U2AF1 (10.4%), BCOR (10.4%), CBL (8.8%). TP53, EZH2, RUNX1, CBL, DNMT3A, SF3B1, and ASXL1 were selected for further analysis based on their reported negative impact on OS and leukemia-free survival (LFS). TP53 and CBL mutations were closely associated with a worse OS (Hazard Ratio[HR] and 95% CI: 1.70 (1.00, 2.87) and 2.54 (1.19, 5.43), respectively) and LFS (HR and 95% CI: 1.63 (0.98, 2.72) and 2.01 (0.95, 4.26), respectively) compared with WT gene status, while subjects with DNMT3A mutation showed a trending advantageous relationship with OS and LFS over WT gene status. The TP53mut population (N=44) was characterized by median age 70.5 years, 63.6% M: 36.4% F, 91% MDS: 9% CMML, IPSS categories: 20% HR, 30% Int-2, 39% Int-1, 2% LR, 9% N/A, Cytogenetics: 27% Better-risk, 18% Intermediate risk, 48% Poor risk, 5% N/A, ECOG 0: 39%, 1: 61%, MA 68%, BA/multi-hit 32%. The median OS and LFS of the TP53mut population were 25.5 and 22.1 mo., respectively, compared to the TP53 WT group with mOS and LFS estimates 33.7 and 31.7 months, respectively (Figure 1). The TP53mut population was further characterized by allelic status and found to have 14 subjects with BA mutations and 30 subjects with MA TP53 mutations without other chromosomal deletions. The respective estimated mOS and 95% CI in the BA vs MA were 13.0 (5.3, 29.1) months vs. 29.2 (19.8, NE) mo. (Figure 2). Conclusion: The NGS mutational profile of MDS and CMML subjects in the ASCERTAIN trial included 35% with TP53mut and this group had a worse survival than those with WT TP53 apparently driven by the poor outcome of those with BA TP53mut. Further LOH studies will help refine this analysis, but in this conservative estimate, treatment with oral decitabine/cedazuridine in the ASCERTAIN study resulted in an estimated survival of 13 months for BA TP53mut which compares favorably with historical results. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal
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 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,000 |
| 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 | 0,001 |
| 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 ».