2002 - Final 7-year Follow Up and Retreatment Substudy Analysis of MURANO: Venetoclax-Rituximab-Treated Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia

Introduction: The Phase 3 MURANO trial (NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with fixed-duration venetoclax-rituximab (VenR) vs bendamustine (B)R in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL). At the 5-year update, the median 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 patients treated with VenR vs BR, respectively (Seymour et al. Blood 2022). We report the final analyses of MURANO, with 7 years median follow up: specifically, updated PFS and OS, with minimal residual disease (MRD) evaluation, in patients treated in the main study, as well as in VenR-retreated patients in the substudy.

Methods: Patients with R/R CLL were randomized to VenR (Ven 400 mg daily for 2 years + monthly R for the first 6 months) or BR (6 months). In the substudy (from 2018 onwards), patients with progressive disease (PD) received VenR (to the same schedule as main study) as either retreatment 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 undetectable (u)MRD defined as < 1 CLL cell/10,000 leukocytes.

Results: Baseline characteristics are presented in the Table. At final data cutoff (3 August 2022), VenR-treated patients (n = 194) had a median PFS (95% confidence interval [CI]) of 54.7 months (52.3, 59.9) vs 17.0 months (15.5, 21.7) for BR-treated patients (n = 195; hazard ratio [HR] 0.25). Seven-year PFS rates (95% CI) were 23.0% (16.1, 29.9) with VenR, while no patients 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 patients have not received subsequent anti-CLL treatment.

Among VenR-treated patients who had uMRD at end of treatment (EOT) without PD (n = 83/118; 70.3%), median PFS (95% CI) from EOT was 52.5 months (44.5, 61.5) vs 18.0 months (8.5, 29.3; P < 0.0001) in patients who were MRD+ at EOT (n = 35; 29.7%). Fourteen (16.9%) patients had no PD nor confirmed MRD conversion at the 7-year update; in the 63 (75.9%) patients who had MRD conversion, median time to conversion (95% CI) was 19.4 months (8.7, 28.0). Among 63 patients 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 patients received VenR retreatment (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%) patients achieved uMRD at EOT in the main study. Best overall response rate (ORR) to retreatment was 72.0% and median PFS (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%) patients achieved uMRD at the retreatment end of combination treatment; however, no patients retained their uMRD status at the retreatment EOT.

No new safety findings were observed since the 5-year data cut.

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 patients 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 retreatment with VenR is a viable option for pretreated patients.