S201: FINAL 7-YEAR FOLLOW UP AND RETREATMENT SUBSTUDY ANALYSIS OF MURANO: VENETOCLAX-RITUXIMAB (VENR)-TREATED PATIENTS WITH RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA (R/R CLL)
Bibliographic record
Abstract
Background: The Phase 3 MURANO trial (NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with fixed-duration VenR vs bendamustine (B)R in patients (pts) with R/R CLL. At the 5-year update, the median (m)PFS was 53.6 vs 17.0 months (P<0.0001), and 5-year OS rates were 82.1% vs 62.2% (P<0.0001) in pts treated with VenR vs BR, respectively (Seymour et al. Blood 2022). Aims: We report the final analyses of MURANO, with 7 years median follow-up (FU): specifically, updated PFS and OS, with minimal residual disease (MRD) evaluation, in pts treated in the main study, as well as in VenR-retreated pts in the substudy. Methods: Pts with R/R CLL were randomized to VenR (Ven 400mg daily for 2 years + monthly R for the first 6 months) or BR (6 months). In the substudy (2018 onwards), pts with progressive disease (PD) received VenR (same schedule as main study) as either re-treatment or as crossover from BR. PFS data are by investigator assessment. Peripheral blood MRD was measured centrally by allele-specific oligonucleotide-PCR and/or flow cytometry, with a <10–4 threshold for undetectable (u)MRD. Results: Baseline characteristics are presented in the Table. At final data cutoff (3 August 2022), VenR-treated pts (n=194) had a mPFS (95% confidence interval [CI]) of 54.7 months (52.3, 59.9) vs 17.0 months (15.5, 21.7) for BR-treated pts (n=195; hazard ratio [HR] 0.25). Seven-year PFS rates (95% CI) were 23.0% (16.1, 29.9) with VenR, while no pts treated with BR remained progression-free at this time point; 7-year OS rates (95% CI) were 69.6% (62.8, 76.5) with VenR and 51.0% (43.3, 58.7) with BR (HR 0.53). Median time to next treatment with VenR was 63.0 months vs 24.0 months with BR (HR 0.30); 37.1% of VenR-treated pts have not received subsequent anti-CLL treatment. Among VenR-treated pts who had uMRD at end of treatment (EOT) without PD (n=83/118; 70.3%), mPFS (95% CI) from EOT was 52.5 months (44.5, 61.5) vs 18.0 months (8.5, 29.3; p<0.0001) in pts who were MRD+ at EOT (n=35; 29.7%). Fourteen (16.9%) pts had no PD nor confirmed MRD conversion at the 7-year update; in the 63 (75.9%) pts who had MRD conversion, median time to conversion (95% CI) was 19.4 months (8.7, 28.0). Among 63 pts who converted, 39 subsequently had PD or died; median time from conversion to PD (95% CI) was 28.3 months (23.2, 35.0). In the substudy (n=34), 25 pts received VenR re-treatment (Table), 92.0% of whom had at least one of the following high-risk features: IGHV-unmutated disease, genomic complexity, or del(17p) and/or TP53 mutations (Wu et al. EHA 2021); despite this, 14/25 (56.0%) achieved uMRD at EOT in the main study. Best overall response rate (ORR) to re-treatment was 72.0% and mPFS (95% CI) was 23.3 months (15.6, 24.3). Median (range) time between the last Ven dose in the main study and Ven ramp-up in the substudy was 2.3 (1.2–3.1) years. Eight (32.0%) pts achieved uMRD at the re-treatment end of combination treatment; however, no pts retained their uMRD status at the re-treatment EOT. No new safety findings were observed since the 5-year data cut. Summary/Conclusion: In this final long-term analysis of the MURANO trial, PFS and OS benefits for VenR over BR were sustained. Furthermore, achievement of uMRD was associated with prolonged PFS. In VenR-treated pts in the substudy, ORR was high and uMRD was still attainable in this high-risk population. Overall, these data continue to support the use of fixed-duration VenR in R/R CLL, and suggest that re-treatment with VenR is a viable option for pre-treated pts.Keywords: Retreatment, Chronic lymphocytic leukemia, Minimal residual disease (MRD), Venetoclax
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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 | 0.003 |
| 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".