Although there have been major advancements in the treatment of hematologic malignancies in recent years, according to Richard Pazdur, MD, Director, FDA’s Oncology Center of Excellence, the number of agents [ Read More ]
April 2018 VOL 9, NO 4
Venetoclax plus Rituximab New Chemotherapy-Free Standard for Chronic Lymphocytic Leukemia
Venetoclax (Venclexta) plus rituximab (Rituxan) achieved superior progression-free survival (PFS) and overall survival (OS) compared with standard-of-care bendamustine (Treanda/Bendeka) plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). PFS improved by 81% and OS by 52% with venetoclax plus rituximab versus bendamustine plus rituximab, and the depth of response with venetoclax plus rituximab was impressive—complete response and complete response with incomplete platelet recovery was achieved in 26.8% of patients, and minimal residual disease (MRD) negativity in peripheral blood was seen in 83.5% of patients.
These findings from an interim analysis of the phase 3 clinical trial MURANO were reported at ASH 2017.
“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 investigator John F. Seymour, MBBS, PhD, FRACP, Director, Haematology Department, Peter MacCallum Cancer Centre, Melbourne, Australia.
“These findings suggest that venetoclax plus rituximab could be a standard option for relapsed or refractory CLL. There is also evidence of eradication of detectable disease that opens the prospect of time-limited therapy in this setting,” Dr Seymour continued.
The open-label, randomized MURANO study was designed to evaluate the safety and efficacy of a time-limited combination of venetoclax plus rituximab versus bendamustine plus rituximab in the relapsed or refractory setting. A total of 389 patients were randomized to oral venetoclax 400 mg once daily, given until disease progression or unacceptable toxicity, for a maximum of 2 years, plus rituximab for 6 cycles versus 6 cycles of bendamustine plus rituximab. In the venetoclax arm, the dose was gradually increased to 400 mg daily over 4 to 5 weeks to reduce the likelihood of tumor lysis syndrome.
The 2 treatment arms were well matched at baseline. All patients had 1 to 3 previous lines of therapy. Approximately 27% of patients in both arms had deletion 17p, which was an adverse risk factor.
The median PFS was not yet reached in the venetoclax arm versus 17 months in the bendamustine arm at a median follow-up of 23.8 months, representing an 83% risk reduction for disease progression favoring the experimental arm (P <.0001). The PFS results were consistent across subgroups, with responses seen in patients with poor-risk cytogenetics, as well as in those with good- or intermediate-risk.
The secondary end points favored the venetoclax arm, including OS. Patients who received venetoclax plus rituximab had a 52% reduced mortality risk. At 2 years of follow-up, the median OS was not reached in either arm but was numerically higher in the venetoclax arm.
The rate of MRD negativity at any time was higher with venetoclax plus rituximab than in the bendamustine arm (83.5% vs 23.1%, respectively).
Serious adverse events were reported in 46% of patients receiving venetoclax plus rituximab versus in 43% of those receiving bendamustine plus rituximab. Grade 3/4 adverse events were reported in 82% and 70% of patients, respectively. The causes of death were balanced between the 2 arms.
Grade 3/4 neutropenia was more common in the venetoclax arm than in the bendamustine arm (58% vs 39%, respectively). Infections were relatively infrequent. Tumor lysis syndrome occurred in 3% of patients in the venetoclax arm versus 1% of patients in the bendamustine arm.
Longer follow-up is needed to determine the durability of venetoclax benefit after treatment cessation.
“Today’s phase 3 MURANO study suggests that venetoclax/rituximab will be practice-changing. We are getting away from chemotherapy and avoiding alkylating agents,” said ASH Secretary Robert Brodsky, MD, Director, Division of Hematology, Johns Hopkins School of Medicine, Baltimore, MD, who moderated the press briefing.
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