Results of a recently published study suggest a change to the standard treatment of relapsed or refractory chronic lymphocytic leukemia (CLL). Australian researchers are reporting that venetoclax plus rituximab may result in significantly higher rates of progression-free survival (PFS) than bendamustine plus rituximab in patients with relapsed or refractory CLL. In their study, published in The New England Journal of Medicine, they report that a substantial rate of clearance of minimal residual disease (MRD) was seen in the venetoclax–rituximab arm, suggesting improved disease control over a longer term even when therapy is discontinued.

“The consistency of these improvements across all clinical and biological subsets of patients, and the favorable toxicity profile do appear to be sufficient to justify a change in standard therapy, and the regulatory submissions necessary to enable this have been made based on this dataset,” said John F. Seymour, MB, BS, PhD, of the Department of Haematology at the Peter MacCallum Cancer Centre, Melbourne, Australia, and lead author of the study.

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The team investigated venetoclax because it inhibits BCL2, a pathologically overexpressed protein that is pivotal to the survival of CLL cells. The researchers analyzed the efficacy of venetoclax in combination with rituximab in the randomized, open-label, phase 3 MURANO trial. In this study, 389 patients were randomly assigned to receive venetoclax for up to 2 years plus rituximab for the first 6 months (n = 194) or bendamustine plus rituximab for 6 months (n = 195). Patients were enrolled at 109 sites in 20 countries. The median age across the 2 treatment groups was 65 years (range, 22 to 85 years) and 73.8% of the patients were men.


The study showed that PFS was significantly higher in the venetoclax–rituximab arm with 32 events of progression or death in 194 patients at a median follow-up period of 23.8 months. In the bendamustine–rituximab arm, there were 114 events in 195 patients. “The major findings of this study were the profound and consistent superiority of the venetoclax combination therapy over the conventional chemo-immunotherapy as shown by the more than doubling of progression free survival (2 year rates of 85% vs 36%; HR, 0.17),” Dr Seymour told Oncology Nurse Advisor.

He said the overall response rate was 93% for the venetoclax–rituximab arm compared with only 68% for the bendamustine-rituximab arm (by investigator). Dr Seymour said attainment of high quality responses as shown by peripheral blood MRD-negativity rate in the peripheral blood were impressive (84% vs 23%). There was a trend for better overall survival (OS) with a rate of 92% for the venetoclax–rituximab arm vs 87% for the bendamustine-rituximab arm. However, the follow-up has only been 2 years.

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Overall, 379 patients (99.2%) experienced at least one adverse event. The most common adverse event of anygrade in both treatment arms was neutropenia, occurring in 60.8% of patients in the venetoclax–rituximab arm and 44.1% of patients in the bendamustine–rituximab arm. However, the rates of grade 3 or 4 febrile neutropenia and infections were lower in the venetoclax-rituximab arm. Grade 3 or 4 tumor lysis syndrome (TLS) developed in 3.1% of the patients in venetoclax–rituximab arm (6 of 194 patients).