A regimen of venetoclax plus rituximab (VR) resulted in significantly higher rates of progression-free survival (PFS) than bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). The benefit was observed in all subgroups analyzed, according to a study in The New England Journal of Medicine.
Despite advances in treatment, relapsed or refractory CLL remains incurable due to increasingly developed resistance after treatment with DNA-damaging agents.
The antiapoptotic protein BCL2 is a rational therapeutic target, as it is an important regulator of the intrinsic apoptotic pathway. Prior studies have shown that venetoclax, a highly selective, potent BCL2 inhibitor, is effective in CLL alone or in combination with rituximab, a CD20 antibody.
The study, dubbed the MURANO trial, was led by John F. Seymour, MBBS, FRACP, PhD, from the Royal Melbourne Hospital and the University of Melbourne in Australia. The investigators compared VR with BR, a standard chemoimmunotherapy regimen, in patients with relapsed or refractory CLL.
In the open-label, phase 3 trial, patients from 109 sites in 20 countries were randomly assigned to receive venetoclax for up to 2 years plus rituximab for the first 6 months (VR group) or bendamustine plus rituximab for 6 months (BR group). The primary endpoint was investigator-assessed PFS.
Patients 18 years of age or older were eligible if they had a diagnosis of relapsed or refractory CLL, had received one to three previous treatments, and had an ECOG score of 0 or 1.
In addition to investigator assessments, an independent review committee whose members were unaware of the treatment-group assignments assessed all patients for disease response and progression using clinical data, imaging, and bone marrow biopsies.
The VR group started oral venetoclax at 20 mg daily and gradually increased over five weeks to 400 mg per day. At that time, IV rituximab was added at 375 mg/m2 for the first dose, then 500 mg/m2 IV thereafter for six treatment cycles of 28 days each; oral venetoclax 400 mg daily was continued for two years.
In the BR group, IV bendamustine 70 mg/m2 was given on days 1 and 2 of each 28-day cycle for six cycles in combination with rituximab (same dosing schedule as in the VR group). Crossover to VR treatment after disease progression was not permitted.
The primary endpoint was investigator-assessed PFS, defined as the time from randomization to the first occurrence of disease progression, relapse, or death. Secondary efficacy endpoints included independent review committee-assessed PFS, as well as endpoints assessed by both investigators and the independent review committee.
A total of 389 patients were randomly assigned to receive VR or BR. The demographic and disease characteristics of the groups were similar at baseline, the median age was 65 years, and a majority of the patients (73.8%) were men. Of the 342 patients assessed for chromosome 17p deletion status, 26.9% had the deletion.
At the time of the data cutoff for the primary analysis, 78 of the patients in the VR group (40.2%) were still receiving venetoclax monotherapy; 154 patients (79.0%) in the BR group had completed all six cycles of treatment.
After a median follow-up period of 23.8 months, the median investigator-assessed PFS was significantly longer in the VR group than in the BR group; the median PFS was not reached in the VR group. It was 17 months in the BR group.
The 2-year rate of investigator-assessed PFS was 84.9% vs 36.3% in the VR and BR groups, respectively (hazard ratio [HR] for progression or death: 0.17, P < 0.001). This was similar to the results assessed by the independent review committee.
Consistent benefit in favor of the VR group was observed in subgroup analyses and across all sensitivity analyses of the primary endpoint, in which 2-year PFS rates ranged from 82.8% to 85.8% in the VR group and 36.6% to 39.4% in the BR group.
Among patients with chromosome 17p deletion, the 2-year rate of investigator-assessed PFS was higher in the VR group than in the BR group (81.5% vs 27.8%, HR: 0.13) and for patients without chromosome 17p deletion (85.9% vs 41.0%; HR: 0.19).
The ORRs were 92.3% and 93.3% in the VR groups and 72.3% and 67.7% in the BR groups assessed by the independent review committee and investigators, respectively.
The rate of CR or CR with incomplete hematologic recovery assessed by investigators was 26.8% vs 8.2% in the VR and BR groups, respectively. The independent review committee classified 50 patients as a partial response and one as stable disease.
The authors explained that the primary reason for the discordance between assessments was divergent interpretation of residual adenopathy on computed tomography of lesions measuring 30 mm or smaller, despite bone marrow clearance.
The rate of OS was higher in the VR group than in the BR group, with 24-month rates of 91.9% and 86.6%, respectively (HR: 0.48).
The 2-year PFS was longer in the VR group than in the BR group (84.9% vs 34.8%).
The time to the next treatment for CLL was also longer for those treated with VR than with BR; the proportion of those who had not received a next treatment for CLL at two years was 90.0% and 52.1%, respectively.
Almost all (99.2%) patients in both groups reported at least one adverse event (AE). The most common AE in both treatment groups was neutropenia (60.8% and 44.1% in VR and BR groups, respectively).
The duration of treatment was longer with venetoclax, which may explain why the rate of grade 3 or 4 neutropenia was higher in the VR group than for those treated with BR. Nonetheless, the rates of grade 3 or 4 febrile neutropenia and infections or infestations were lower with venetoclax than with bendamustine. The investigators believe that treatment with granulocyte colony-stimulating factor could diminished neutropenia.
Assessments of minimal residual disease (MRD) were available from peripheral-blood samples for 366 patients and from bone marrow aspirate in 115 patients. At 9 months, the rate of clearance of MRD based on peripheral-blood samples was higher in the VR group than in the BR group (62.4% vs 13.3%). The higher rate of clearance of MRD in the VR group was maintained over time.
Evaluation of bone marrow aspirates also indicated higher rates of clearance of MRD in those treated with VR compared to BR (27.3% vs 1.5%).
“Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax in combination with rituximab resulted in a markedly higher rate of progression-free survival than standard bendamustine in combination with rituximab,” the authors concluded. “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.”
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