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

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.

Graphical abstract

Figure 1.

Kaplan-Meier estimates of investigator-assessed PFS in the overall intention-to-treat population (A) and according to IGHV mutation status (B), del(17p) and/or TP53 mutation status (C), and GC status (D). P values are descriptive only. *Stratified analysis; unstratified HR, 0.21 (95% CI, 0.16, 0.27). ^†Unstratified analysis. +, censored.

Figure 2.

Kaplan-Meier estimates of OS in the overall intention-to-treat population (A) and according to IGHV mutation status (B), del(17p) and/or TP53 mutation status (C), and GC status (D). P values are descriptive only. *Stratified analysis; unstratified HR, 0.42 (95% CI 0.27, 0.64). ^†Unstratified analysis. +, censored.

Figure 3.

Kaplan-Meier estimates of landmark PFS (A) and OS (B) according to PB MRD level at EOT in patients who completed 2 years of Ven treatment without prior PD. *Stratified. +, censored.

Figure 4.

Kaplan-Meier estimates of time from EOT to MRD conversion (A) and time from MRD* conversion to PD† (B) in VenR-treated patients (n = 83) who had uMRD at EOT. *MRD conversion was defined as 2 consecutive assays detecting MRD at ≥10⁻⁴ or PD according to iwCLL criteria in patients who previously had uMRD. †Investigators assessed PD by using iwCLL criteria. uMRD, <1 CLL cell/10 000 leukocytes. +, censored.

Figure 5.

MRD level at EOT according to treatment arm (A) and MRD doubling time according to treatment arm (B). Analysis was unadjusted for covariates.