The phase 3 MURANO study compared fixed-duration venetoclax (Ven), a BCL-2 inhibitor, combined with rituximab (VenR) versus standard bendamustine + rituximab (BR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). The VenR combination demonstrated superior progression-free survival (PFS) versus BR in the first preplanned analysis. At the ASH 2019 Annual Meeting, researchers presented the results of a 48-month updated analysis and previously unreported findings of response data from patients who underwent follow-up therapy.
Eligible patients were randomized to 6 cycles of VenR (Ven 400 mg once daily + rituximab, 375 mg/m2 day 1 cycle 1; 500 mg/m2 day 1 cycles 2-6), and then Ven 400 mg once daily for a total of 2 years, or 6 cycles of BR (bendamustine, 70 mg/m2 day 1 cycle 1 + rituximab, 375 mg/m2 day 1 cycle 1; 500 mg/m2 day 1 cycles 2-6). Central analysis of minimal residual disease (MRD) status in peripheral blood was performed at cycle 4, at the end of combination treatment, and then every 3 to 6 months thereafter. Patients were categorized as undetectable MRD (u-MRD; 10-4), low-MRD (10-4-10-2), or high-MRD (>10-2).
A total of 389 patients were enrolled; 194 received VenR and 195 received BR. With a median follow-up period of 22 months since Ven completion, the PFS benefit of VenR versus BR was sustained 2 years after end of therapy (EOT), and 4-year PFS estimates were 57.3% (95% confidence interval [CI], 49.4-65.3) versus 4.6% (95% CI, 0.1-9.2), respectively (hazard ratio [HR], 0.19; P <.0001).
In total, 130 of 194 patients completed 2 years of Ven therapy. Thirty-five patients had developed progressive disease after completion of Ven. Similarly, sustained overall survival (OS) benefit was demonstrated with VenR over BR, with a 4-year rate of 85.3% (VenR) versus 66.8% (BR). This OS benefit was seen despite 79% of BR patients receiving treatment after progression, mostly with novel targeted agents, indicating the value of early application of Ven therapy. The overall response rate to subsequent therapy was 77.3% in the BR arm versus 64.3% with VenR.
In both treatment arms, the previously reported association between u-MRD in peripheral blood at the end of combination treatment was maintained with extended follow-up. Among 130 patients who completed Ven monotherapy, u-MRD was 83% at EOT. In the VenR arm, PFS was longest in patients who were u-MRD at EOT (u-MRD vs low-MRD+: HR, 0.25; u-MRD vs high-MRD+: HR, 0.03). Among VenR patients who had detectable MRD at the end of the combination treatment response visit and at the end of treatment, low-MRD patients continued to show improved PFS versus high-MRD patients.
No new safety signals emerged during the 4-year follow-up period. Excluding nonmelanoma skin malignancies, 3 second primary malignancies were detected (1 who received BR [melanoma] and 2 who received VenR [melanoma and breast cancer]) since the previous update. No new events of Richter transformation were reported.
The researchers concluded that the time-limited combination of VenR yielded sustained PFS and OS benefits versus BR, and further support the use of this regimen in patients with R/R CLL.
Seymour JF, et al. ASH Abstract 355. Session 642.