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Venetoclax-rituximab maintains efficacy in chronic lymphocytic leukemia 1-year posttreatment
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SAN DIEGO — Venetoclax plus rituximab was superior to bendamustine plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia, prolonging PFS and achieving “clinically meaningful OS benefits” 3 years after treatment initiation, according to new data from the MURANO trial presented at the ASH Annual Meeting and Exposition.
The analysis provides an additional 12 months of follow-up to the primary MURANO analysis comparing the addition of venetoclax (Venclexta; AbbVie, Genentech) vs. bendamustine to rituximab (Rituxan; Genentech, Biogen). All patients in this follow-up analysis have since completed therapy.
“The primary analysis was presented at last year’s ASH when the majority of patients were still on treatment, with a median follow-up of just under 24 months,” John F. Seymour, MD, director of Peter MacCallum Cancer Centre in Melbourne, Australia, said. “That showed a profound improvement in PFS with venetoclax combination.”
Findings from the primary MURANO analysis led to the FDA approval of venetoclax in June.
For the trial, researchers randomly assigned 389 patients with relapsed or refractory CLL to receive rituximab plus venetoclax (Venclexta; AbbVie, Genentech; n = 194) or bendamustine (n = 195). Patients assigned to the venetoclax combination regimen initially received a 20-mg dose of venetoclax, which increased over a 5-week ramp-up period until the target dose of 400 mg daily was met. At 6 weeks, patients received IV rituximab monthly for six 28-day cycles (375 mg/m2 at first dose, 500 mg/m2 thereafter). Patients remained on venetoclax for a maximum of 2 years or until disease progression.
Meanwhile, patients assigned to bendamustine received 70 mg/m2 on days 1 and 2 of each of the six 28-day cycles in combination with rituximab using the same dosing schedule.
The primary endpoint was investigator-assessed PFS. A key secondary endpoint was the rate of undetectable minimal residual disease (MRD), which was assessed in peripheral blood samples every 3 months for the first 3 years, then every 6 months until disease progression.
As previously reported, the 2-year PFS was 84.9% in the venetoclax arm and 36.3% in the bendamustine arm (HR for progression or death = 0.17; 95% CI, 0.11-0.25).
In the additional 12-month follow-up period, patients were off therapy for a median of 9.9 months. PFS remained significantly prolonged with venetoclax combination therapy compared with bendamustine combination therapy. Overall, the 3-year PFS rate was 71.4% in the venetoclax arm vs. 15.2% in the bendamustine arm.
“The magnitude of this therapeutic effect was comparable and showed no evidence of statistical heterogeneity by all of the biologic subtypes analyzed, including 17p deletion and TP53 mutation,” Seymour said.
The results further showed that venetoclax plus rituximab achieved a “clinically meaningful improvement” in OS compared with bendamustine plus rituximab, according to Seymour. The 3-year OS rate was 88% vs. 80%, respectively.
The researchers conducted a subanalysis evaluating disease progression in 130 patients in the venetoclax arm whose disease did not progress during the 2-year treatment period. They observed a “modest” rate of disease progression (12.3%) in the first 12 months after completing therapy. The 12-month estimate of PFS was 87.4%.
MRD status was a strong predictor of disease progression (P < .0001). Patients who had high MRD (n = 14) upon treatment completion were more likely to have disease progression than patients with low (n = 23) or undetectable (n = 83) MRD (78.6% vs. 13% and 2.4%).
In a safety analysis, Seymour said venetoclax combination therapy was “very well-tolerated,” with no new safety signals. The rate of neutropenia was higher in the venetoclax arm. However, the clinical complications of neutropenia, such as febrile neutropenia or infection, were infrequent and less common than in the bendamustine arm, according to Seymour.
“In earlier studies, there had been concern about the rate of Richter’s transformation,” he said. “In this randomized study, there was no difference in the number of Richter’s transformation between venetoclax-treated patients and bendamustine-treated patients.”
Seven cases of Richter’s transformation were identified in the venetoclax arm and six in the bendamustine arm.
“Overall, these data establish the feasibility and support the clinical utilization of fixed-duration venetoclax-rituximab for the majority of patients with relapsed or refractory CLL,” Seymour concluded. – by Stephanie Viguers
Reference:
Seymour JF, et al. Abstract 184. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.
Disclosure: Seymour reports receiving consultancy fees from AbbVie, Celgene, Genentech and Roche; honoraria fees from AbbVie, Janssen and Roche; research funding from AbbVie, Genentech and Janssen; and severing on boards or advisory committees for Genentech and Roche.