HIGHER MUTATIONAL BURDEN BUT DOES NOT IMPACT TREATMENT EFFICACY IN FOLLICULAR LYMPHOMA
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".