Background
MURANO was a phase III randomized open-label trial evaluating fixed-duration venetoclax plus rituximab (VenR, 2 years total) versus bendamustine plus rituximab (BR, 6 cycles) in patients with relapsed/refractory CLL after 1–3 prior lines. At the time, BR was a standard salvage regimen and venetoclax monotherapy had shown activity in R/R CLL. MURANO tested whether BCL-2 inhibition combined with anti-CD20 antibody could achieve superior, durable disease control with a finite treatment duration.
Interventions and follow up
Arm A: Bendamustine 70 mg/m² days 1–2 + rituximab 375–500 mg/m² ×6 cycles (BR) (n=195)
Arm B: Venetoclax (5-week ramp-up to 400 mg daily, 2 years total) + rituximab 375–500 mg/m² ×6 cycles (months 2–7) [VenR] (n=194)
Primary endpoint: Investigator-assessed PFS; secondary: OS, ORR, MRD, safety
mFollow up: 59.2 months (5-year update)
Arm B: Venetoclax (5-week ramp-up to 400 mg daily, 2 years total) + rituximab 375–500 mg/m² ×6 cycles (months 2–7) [VenR] (n=194)
Primary endpoint: Investigator-assessed PFS; secondary: OS, ORR, MRD, safety
mFollow up: 59.2 months (5-year update)
Results
5-yr PFS: 37.8% (VenR) vs 4.6% (BR), HR 0.19, 95% CI 0.14–0.25, P<.001
mPFS: 53.6 vs 17.0 months
5-yr OS: 82.1% vs 62.2%, HR 0.40, 95% CI 0.26–0.62
Bone marrow MRD negativity post-treatment: 62.4% vs 13.3%
del17p subgroup mPFS: shorter but favoring VenR over BR
mPFS: 53.6 vs 17.0 months
5-yr OS: 82.1% vs 62.2%, HR 0.40, 95% CI 0.26–0.62
Bone marrow MRD negativity post-treatment: 62.4% vs 13.3%
del17p subgroup mPFS: shorter but favoring VenR over BR
Adverse events
Hematologic (Grade ≥3, VenR vs BR): neutropenia 57.7% vs 38.8%; thrombocytopenia 5.7% vs 10.3%
Infections: Grade ≥3 infections 17.5% vs 21.4%
Other: tumor lysis syndrome Grade ≥3 ~3% (venetoclax ramp-up); second primary malignancies; Richter transformation in a minority of patients
Infections: Grade ≥3 infections 17.5% vs 21.4%
Other: tumor lysis syndrome Grade ≥3 ~3% (venetoclax ramp-up); second primary malignancies; Richter transformation in a minority of patients
Conclusions
Fixed-duration venetoclax plus rituximab (24 months total) achieved dramatically superior 5-year PFS (38% vs 5%, HR 0.19) and significantly improved OS (HR 0.40) versus BR in R/R CLL, establishing VenR as a standard of care in the relapsed/refractory setting and demonstrating that deep MRD-negative remissions from time-limited BCL-2 inhibitor-based therapy translate into prolonged treatment-free intervals and survival benefit.
Key Limitations
BR comparator now largely supplanted by BTKi-based therapy (ibrutinib, acalabrutinib, zanubrutinib) as preferred salvage; del17p/TP53-mutant patients had inferior outcomes despite benefit; rituximab contribution difficult to isolate from venetoclax; dose interruptions for cytopenias common; most contemporary R/R CLL patients have prior BTKi exposure, potentially altering venetoclax response kinetics; no BTKi-refractory subgroup specified at trial design (the BTKi era largely predated MURANO enrollment).
Clinical Context
MURANO led to FDA approval of venetoclax + rituximab for R/R CLL in June 2018. The 5-year OS benefit (HR 0.40) cemented VenR as a clinically meaningful R/R option. In the BTKi-pretreated R/R CLL landscape, venetoclax-based salvage (± obinutuzumab or rituximab) remains the preferred approach for patients failing continuous BTKi therapy, with CLL2-BAAG and others exploring post-BTKi venetoclax combinations. MURANO's fixed-duration principle (vs continuous BTKi) is attractive for patients wishing to avoid indefinite oral therapy. The ALPINE trial (zanubrutinib vs ibrutinib, NEJM 2023) represents the head-to-head BTKi evolution in the same R/R space.