Venetoclax (Venclexta) plus rituximab (Rituxan)—a non–chemotherapy-containing regimen—was superior to standard-of-care bendamustine plus rituximab for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to a final analysis of the phase III MURANO study reported at the 2017 American Society of Hematology (ASH) Annual Meeting & Exposition.1
Median progression-free survival was not yet reached in the venetoclax-plus-rituximab arm vs 17 months in the bendamustine-plus-rituximab arm at a median follow-up of 23.8 months, representing an 83% reduced risk for disease progression favoring the experimental arm (hazard ratio = 0.17; P < .0001). Overall survival is still immature but trended higher for the venetoclax/rituximab arm. Progression-free survival results were consistent across subgroups, with responses seen in patients with poor-risk fluorescence in situ hybridization and molecular testing results as well as those who were at good or intermediate risk.
“This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach,” said lead author John F. Seymour, MBBS, PhD, Director of the Haematology Department, Peter MacCallum Cancer Center and Royal Melbourne Hospital, Melbourne.
“These findings suggest that venetoclax/rituximab could be a standard option for relapsed/refractory CLL. There is also evidence of eradication of detectable disease, which opens the prospect of time-limited therapy in this setting,” Dr. Seymour continued.
This is the first randomized trial comparing any of the new agents targeted to treat CLL against a standard chemoimmunotherapy program, and it has proved the superiority of the chemotherapy-free approach.— John F. Seymour, MBBS, PhD
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In the relapsed or refractory setting, CLL cells accumulate adverse biologic features, leading to a suboptimal response to conventional chemotherapy. With standard bendamustine/rituximab, previous studies had reported an objective response rate of 59% and a median progression-free survival of 15.2 months, Dr. Seymour explained.
Venetoclax, an orally administered, highly selective, potent BCL-2 inhibitor, is known to have excellent activity and safety as a single agent, demonstrating high complete response rates and minimum residual disease (MRD)-negativity. Some patients have shown durable disease control after stopping venetoclax-based treatment in a marrow MRD-negative state, Dr. Seymour said.
These observations led to the open-label, randomized phase III MURANO trial, designed to evaluate the safety and efficacy of time-limited venetoclax/rituximab vs bendamustine/rituximab in the relapsed or refractory setting. A total of 389 patients were randomized 1:1 to receive venetoclax at 400 mg orally once daily, given until progressive disease or unacceptable toxicity for a maximum of 2 years, plus rituximab for 6 cycles vs 6 cycles of bendamustine/rituximab. In the venetoclax arm, the dose was gradually ramped up to 400 mg/d over 4 to 5 weeks to reduce the likelihood of tumor-lysis syndrome.
Patients in both groups were well matched for baseline demographic and disease characteristics. Median age was about 65 years. All had received one to three prior lines of therapy, and 60% had received one prior line of therapy, 74% including fludarabine. About 27% in both arms had del(17p), an adverse risk factor. About 68% had unmutated IGHV, and about 25% had mutated TP53.
“A profound, clear superiority in progression-free survival was observed with venetoclax/rituximab,” Dr. Seymour said.
At 2 years of follow-up, median progression-free survival was not yet reached in the venetoclax/rituximab arm vs 17 months for bendamustine/rituximab. The 1-year progression-free survival rate was 92.7% vs 72.5%, respectively, and 2-year progression-free survival was 84.9% vs 36.3%. These findings were confirmed in an independent review. Progression-free survival was consistent across subgroups for clinical and biologic features.
Secondary endpoints, including overall survival, favored venetoclax/rituximab. Patients treated with venetoclax/rituximab had a 52% reduced risk of death. Median overall survival was not reached in either arm at 2 years of follow-up but trended higher for the venetoclax/rituximab arm (92% vs 87%, P = .0186).
Objective response rates were higher in the experimental arm as well: The overall response rate was 93.3%, compared with 67.7% for bendamustine/rituximab. Investigator-assessed complete response rates were three times higher with the new combination: Complete response or complete response with incomplete platelet recovery was 26.8%, compared with 8.2% for bendamustine/rituximab.
“MRD negativity [defined as < 1 CLL cell in 10,000 leukocytes] was much higher with venetoclax/rituximab at every time point,” Dr. Seymour told listeners. The overall rate of peripheral blood MRD negativity at any time on study was 83.5% with -venetoclax/rituximab vs 23.1% with bendamustine/rituximab.
No new safety signals emerged for any of the drugs. Almost all patients in both arms experienced at least one adverse event. Serious adverse events were reported in 46% of the venetoclax/rituximab arm vs 43% of the bendamustine/rituximab arm. Grade 3/4 adverse events were reported in 82% and 70%, respectively. Causes of death were balanced between the two arms.
Grade 3/4 neutropenia was more common in the venetoclax/ ritux-imab arm: 58% vs 39%. Infections were relatively infrequent. Tumor-lysis syndrome occurred in 3% vs 1%.
“Most of the toxicities seen with the venetoclax/rituximab combination occurred before obtaining disease control,” Dr. Seymour said.
Dr. Seymour said that further follow-up is needed to determine the durability of the benefit seen with venetoclax after treatment cessation. ■
DISCLOSURE: Dr. Seymour has received honoraria from AbbVie, Celgene, Roche, Janssen, MorphoSys, Gilead, Sunesis, and Takeda and research funding from AbbVie, Roche, and Janssen; is a member of the Board of Directors or advisory committees for AbbVie, Celgene, Roche, Janssen, MorphoSys, Gilead, Sunesis, and Takeda; and is a member of the speakers bureaus for AbbVie, Roche, Janssen, and Gilead.
1. Seymour JF, Kipps T, Eichhorst B, et al: Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia. 2017 ASH Annual Meeting. Abstract LBA-2. Presented December 12, 2017.
Robert Brodsky, MD
“Several new drugs that have been approved for the treatment of chronic lymphocytic leukemia (CLL) are changing the landscape of this disease. CLL is associated with a long survival, so we will need longer follow-up to see how deep the responses are,” said Robert...!-->!-->