Final analyses of the MURANO trial consolidate efficacy of venetoclax-rituximab in patients with relapsed/refractory chronic lymphocytic leukaemia

In the final and long-term analyses of the phase III MURANO trial, progression-free survival (PFS) and overall survival benefits for venetoclax-rituximab (VenR) over bendamustine-rituximab were sustained. Furthermore, achievement of undetectable minimal residual disease (uMRD) was associated with prolonged PFS. In VenR-treated patients in the substudy, the objective response rate was high and uMRD was still attainable in this high-risk population.

Previously, the phase III MURANO trial reported superior progression-free survival (PFS) and overall survival (OS) with fixed-duration venetoclax-rituximab (VenR) as compared to bendamustine-rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukaemia (R/R CLL). At EHA 2023, the final analyses of MURANO, with 7 years of follow-up were presented. Prof. Arnon Kater gave an overview of 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.

Study design

Patients with R/R CLL were randomised to VenR (Ven 400 mg daily for 2 years plus monthly R for the first 6 months) or BR (6 months). In the substudy (2018 onwards), patients with progressive disease 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

Median follow-up for efficacy was 86.8 months for VenR and 84.4 months for BR. No new safety signals were identified since the 5-year data cut-off. Median PFS was 54.7 months for patients receiving VenR and 17.0 months for patients in the BR arm, resulting in a decrease in the risk of disease progression or death by 77% (HR[95%CI]: 0.23[0.18-0.29], p< 0.0001). The 7-year PFS rate was 23.0% for patients in the VenR arm, while no patients treated with BR remained progression-free at this time point. Median OS was not estimable and 87.8 months for VenR and BR, respectively (HR[95%CI]: 0.53[0.37-0.74], p< 0.0002). The 7-year OS rates were respectively 69.6% and 51.0% for VenR and BR. Overall, 49.0% of VenR-treated patients and 67.2% of BR-treated patients received subsequent anti-leukaemic treatment. Median time to next treatment (TTNT) was 63.0 months for VenR and 24.0 months for BR (HR[95%CI]: 0.30[0.23-0.39], p< 0.0001). The achievement of uMRD at end of treatment was associated with prolonged PFS in VenR-treated patients (uMRD, median PFS: 52.5 months, low MRD, median PFS: 29.3 months, high MRD, median PFS 4.6 months). Most patients who received the full two years of VenR treatment had uMRD at end of treatment. Generally, MRD conversion with subsequent disease progression did not occur until approximately four years after end of treatment. Of note, favourable baseline characteristics were over-represented among patients with enduring uMRD. In this, among the 14 patients with sustained uMRD and EOT, median number of prior therapies was only 1 (range 1-3).

Out of the 34 patients with disease progression who entered the substudy, 25 were retreated with VenR. Median time from the final study drug dose in the main study to VenR retreatment in the substudy was 2.3 years. Most of the patients who received VenR retreatment were classified as high risk. Interestingly, VenR retreatment resulted in high response rates, which translated to meaningful PFS (median 23.3 months) amongst retreated patients. The best objective response rate was high at 72%, with 24% of patients achieving complete response. Median OS was not reached. Although uMRD status was attainable upon retreatment with VenR (32% of patients), it was not sustained for the duration of treatment.

Conclusion

In this final long-term analysis of the MURANO trial, PFS and OS benefit for two-year fixed treatment with VenR over BR were sustained. In addition, a longer TTNT with VenR was observed vs. BR. In patients retreated with VenR in the substudy, best ORR was high and uMRD was still attainable in this high-risk population. Retreatment with VenR is a viable option for pretreated patients, based on ORR and uMRD findings. Overall, these data continue to support the use of fixed-duration VenR in R/R CLL.

Reference

Kater A, et al. 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). Presented at EHA 2023; Abstract S201.