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)

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