The combination of rituximab and the BCL2 inhibitor venetoclax significantly lengthened PFS among CLL patients in the phase III MURANO trial.
The combination of rituximab plus the venetoclax, a small-molecule oral inhibitor of the antiapoptotic protein BCL2, significantly lengthened progression-free survival (PFS) compared with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to results from the phase III MURANO trial.
In addition, patients assigned to venetoclax and rituximab maintained a higher rate of minimal residual disease (MRD) clearance over time, according to John Seymour, PhD, of Peter MacCallum Cancer Center, Australia, and colleagues, who published the trial results in The New England Journal of Medicine.
The study included 389 patients, half of whom were randomly assigned to a regimen of six monthly doses of venetoclax plus rituximab. The remaining patients received 6 cycles of bendamustine plus rituximab.Patients in the venetoclax arm of the trial continued to use venetoclax alone for 2 years or until their leukemia returned.
With a median follow-up of about 2 years, PFS was significantly longer in patients assigned to venetoclax plus rituximab compared with the bendamustine combination (hazard ratio [HR], 0.17; 95% CI, 0.11–0.25; P < .001). Two-year PFS was 84.9% for the venetoclax group compared with 36.3% in the bendamustine group.
The improvement in PFS occurred across all of the clinical and biologic subgroups examined in the study. For example, patients with chromosome 17p deletion who were assigned to venetoclax plus rituximab had a 2-year PFS rate of 81.5%, compared with 27.8% in those randomized to bendamustine plus rituximab (HR, 0.13; 95% CI, 0.05–0.29). Similarly, 2-year PFS in patients without this deletion who received venetoclax was 85.9% compared with 41.0% for those treated with bendamustine (HR, 0.19; 95% CI, 0.12–0.32).
The majority (91.4%) of patients were assessed for MRD clearance using peripheral-blood samples, and an additional 29.6% had MRD assessed using bone marrow aspirate. At 9 months, MRD using peripheral blood was higher in patients who received venetoclax (62.4% vs 13.3% with bendamustine). At any time point during the trial, MRD clearance was higher in patients treated with the venetoclax combination, the researchers noted.
“The high rates of clearance of minimal residual disease that were observed in the venetoclax–rituximab group exceed those previously attained with other agents and combinations of agents in trials of relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma, findings that suggest that greater efficacy results can be attained by replacing chemotherapy with venetoclax than by adding other targeted agents to chemoimmunotherapy,” the researchers wrote.
Patients assigned to treatment with venetoclax plus rituximab had higher rates of grade 3/4 neutropenia compared with the bendamustine-plus-rituximab group; however, venetoclax was associated with lower rates of grade 3/4 febrile neutropenia and infections or infestations compared with bendamustine.
“Prespecified secondary efficacy measures, including the complete response rate, the overall response rate, and overall survival, also showed consistent patterns of clinically meaningful benefit with venetoclax plus rituximab,” the researchers wrote. “The substantial rate of clearance of minimal residual disease in the venetoclax–rituximab group may indicate improved disease control over a longer term, even when therapy is discontinued. Additional follow-up will be needed to assess the durability of such responses,” according to the researchers.