HIGHER MUTATIONAL BURDEN BUT DOES NOT IMPACT TREATMENT EFFICACY IN FOLLICULAR LYMPHOMA
Notice bibliographique
Résumé
Introduction: Higher age is associated with shorter overall survival (OS) in patients (pts) with follicular lymphoma (FL), and age > 60 years is a component of the FL International Prognostic Index (FLIPI). However, it is unclear whether higher age directly impacts disease biology or treatment efficacy in FL. Methods: We analyzed 755 pts from the GLSG2000 trial who received R-CHOP for symptomatic, advanced stage FL. Pts who received consolidative autologous stem cell transplantation were censored at time of transplant. Progression of disease (POD) included progressive, relapsed or refractory disease (<PR). Failure-free survival (FFS) events consisted of POD or death. OS and FFS were calculated from treatment initiation. We used Kaplan-Meier curves and Cox proportional hazards regression for survival analyses. We performed competing risk analysis using cumulative incidences of POD and death without prior POD. DNA sequencing data from diagnostic FL biopsies were available from 151 R-CHOP treated pts, and another 107 pts from BCCA who received R-CVP for symptomatic advanced FL. We analyzed mutations in the coding regions of 74 targeted genes. Results: We categorized GLSG2000 pts into 5 distinct age groups: 65 pts (9%) were 18-40 years (yrs), 163 (22%) >40-50 yrs, 261 (35%) >50-60 yrs, 208 (28%) >60-70 yrs, and 58 (8%) >70 yrs. 5-year OS rates were 97%, 91%, 90%, 85%, and 53% (Figure A); 5-year FFS rates were 82%, 62%, 63%, 55%, and 42% (Figure B), respectively. We used the cohort >50-60 yrs as a reference. Older pts had inferior OS (>60-70 yrs: HR 1.90, 95%-CI [1.15; 3.13], p = 0.012; >70 yrs: HR 7.31, 95%-CI [4.25; 12.59], p < 0.0001). Significantly inferior FFS was only seen in pts >70 yrs (HR 2.17, 95%-CI [1.45; 3.25], p = 0.00016). Competing risk analysis revealed that inferior FFS of pts >70 yrs did not result from increased POD (HR 1.20, 95%-CI [0.75; 1.91], p = 0.45), but from higher incidence of death without prior POD (HR 24.81, 95%-CI [5.38; 114.44], p < 0.0001; Figure C). Sequencing data of diagnostic FL biopsies from 258 pts showed that the number of gene mutations increased with age (RR 1.14/decade, 95%-CI [1.09; 1.20], p < 0.0001). This increase was however caused by silent mutations and mutations predicted to have low functional impact (each p < 0.0001), whereas disruptive mutations or mutations predicted to have high functional impact did not significantly increase with age (p = 0.27 and p = 0.16, respectively). Similarly, the number of mutated genes increased with age (RR 1.12/decade, 95%-CI [1.07; 1.18], p < 0.0001), but the fraction of significantly mutated genes (by MutSigCV) decreased from 89% (range 40-100%) in young adults (18-40 yrs) to 74% (range 0-100%, p = 0.01) in the oldest cohort (>70 yrs). No single gene mutation was found to be associated with older age after correction for multiple testing. Keywords: follicular lymphoma (FL); molecular genetics; R-CHOP.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| 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 | 0,000 | 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 tête enseignante, 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 ».