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Venetoclax Plus Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia

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Key Points

  • Venetoclax plus rituximab significantly improved progression-free survival vs bendamustine plus rituximab.
  • 2-year progression-free survival rates were 84.9% vs 36.3%.

In the phase III MURANO trial reported in The New England Journal of Medicine by Seymour et al, the combination of the BCL2 inhibitor venetoclax (Venclexta) with rituximab (Rituxan) markedly improved progression-free survival vs bendamustine plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia.

Study Details

In the open-label trial, 389 patients who had received 1 to 3 previous treatments including at least 1 chemotherapy regimen from 109 sites in 20 countries were randomized between March 2014 and September 2015 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).

Venetoclax was given in a 5-week ramp-up from 20 mg to 400 mg/d, with rituximab added after ramp-up at 375 mg/m2 for the first dose (day 1, cycle 1) and 500 mg/m2 thereafter on day 1 of 28-day cycles 2 to 6. Bendamustine at 70 mg/m2 was given on days 1 and 2 of each 28-day cycle for 6 cycles in combination with rituximab.

The primary endpoint was investigator-assessed progression-free survival. Crossover to treatment with venetoclax and rituximab after disease progression was not permitted.

Progression-Free Survival

Median follow-up was 23.8 months. Progression-free survival events occurred in 32 patients in the venetoclax-plus-rituximab group vs 114 in the bendamustine-plus-rituximab group. Median progression-free survival was not reached vs 17 months; 2-year progression-free survival was 84.9% vs 36.3% (hazard ratio [HR] = 0.17, P < .001).

The benefit of venetoclax plus rituximab was observed across all clinical and biologic subgroups. Two-year progression-free survival was 81.5% vs 27.8% (HR = 0.13, 95% confidence interval [CI] = 0.05­­–0.29) in the subgroup with chromosome 17p deletion and 85.9% vs 41.0% (HR = 0.19, 95% CI = 0.12–0.32) in the subgroup without chromosome 17p deletion.  

Investigator-assessed overall response rates were 93.3% vs 67.7%, including complete response or complete response with incomplete hematologic recovery in 26.8% vs 8.2%.

The benefit of venetoclax plus rituximab was confirmed in independent review committee assessment of progression-free survival and other efficacy endpoints.

Adverse Events

The most common adverse event of any grade in both groups was neutropenia, occurring in 60.8% of the venetoclax-plus-rituximab group and 44.1% of the bendamustine-plus-rituximab group. Grade 3 or 4 adverse events occurred in 82.0% vs 70.2%, with the most common being neutropenia (57.7% vs 38.8%); febrile neutropenia occurred in 3.6% vs 9.6% and infection/infestation in 17.5% vs 21.8%. The rate of grade 3 or 4 tumor lysis syndrome in the venetoclax-plus-rituximab group was 3.1%. Adverse events resulted in death in 5.2% vs 5.9% of patients (four fatal infections/infestations in each group).

The investigators concluded, “Among patients with relapsed or refractory chronic lymphocytic leukemia, venetoclax plus rituximab resulted in significantly higher rates of progression-free survival than bendamustine plus rituximab.”

The study was funded by Genentech and AbbVie. 

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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