Enduring undetectable MRD and updated outcomes in relapsed/refractory CLL after fixed-duration venetoclax-rituximab

Abstract

Kater and colleagues report on 5-year outcomes for patients with relapsed or refractory chronic lymphocytic leukemia (CLL) when treated with fixed-duration venetoclax-rituximab (VenR) in a pivotal randomized trial. Over 50% of patients who completed a 3-year VenR treatment have not progressed, and median time to next treatment is 58 months. Of 43% of patients with no measurable residual disease (MRD) at completion of VenR, 39% remained MRD-negative 3 years later, emphasizing the durability of the benefits for many patients.

Key Points

• Two-year fixed-duration VenR offers sustained PFS, OS, and MRD benefits over BR in R/R CLL, regardless of presence of high-risk biomarkers.

• Median MRD doubling time post-VenR EOT was 93 days, with 19 months from uMRD to MRD conversion and another 25 months from conversion to PD.

Visual Abstract

Abstract

The MURANO trial (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia [CLL]; ClinicalTrials.gov identifier #NCT02005471) reported superior progression-free survival (PFS) and overall survival (OS) with venetoclax-rituximab (VenR) vs bendamustine-rituximab (BR) in relapsed/refractory (R/R) CLL. Patients were randomized to 2 years of VenR (n = 194; rituximab for the first 6 months) or 6 months of BR (n = 195). Although undetectable minimal residual disease (uMRD) was achieved more often with VenR, the long-term implications of uMRD with this fixed-duration, chemotherapy-free regimen have not been explored. We report MRD kinetics and updated outcomes with 5 years’ follow-up. Survival benefits with VenR vs BR were sustained (median PFS [95% confidence interval]: 53.6 [48.4, 57.0] vs 17.0 [15.5, 21.7] months, respectively, P < .0001; 5-year OS [95% confidence interval]: 82.1% [76.4, 87.8] vs 62.2% [54.8, 69.6], P < .0001). VenR was superior to BR, regardless of cytogenetic category. VenR-treated patients with uMRD at end of treatment (EOT; n = 83) had superior OS vs those with high-MRD+ (n = 12): 3-year post-EOT survival rates were 95.3% vs 72.9% ( P = .039). In those with uMRD at EOT, median time to MRD conversion was 19.4 months. Of 47 patients with documented MRD conversion, 19 developed progressive disease (PD); median time from conversion to PD was 25.2 months. A population-based logistic growth model indicated slower MRD median doubling time post-EOT with VenR (93 days) vs BR (53 days; P = 1.2 × 10 ⁻⁷). No new safety signals were identified. Sustained survival, uMRD benefits, and durable responses support 2-year fixed-duration VenR treatment in R/R CLL.