The combination of bendamustine and rituximab is a standard of care for patients with relapsed/refractory chronic lymphocytic leukemia. While this combination is associated with high initial responses, the majority of patients relapse within 2 years. In a phase Ib study, combination of the BCL-2 inhibitor venetoclax with rituximab showed promising activity, including an overall response rate (ORR) of 86%, including durable deep responses. Also in other trials, venetoclax has been shown to induce minimal residual disease (MRD) negativity, an increasingly important treatment goal to achieve best long-term outcomes.
Results from the phase III MURANO study (N = 389), which compared venetoclax plus rituximab to bendamustine plus rituximab in patients with relapsed/refractory CLL, were presented at the 2017 American Society of Hematology Annual Meeting by John Seymour, MBBS, PhD (Peter MacCallum Cancer Centre, Melbourne, Australia). Venetoclax/rituximab was associated with a significant improvement in progression-free survival (PFS) compared to bendamustine/rituximab (not reached vs 18.1 months; HR 0.19, P<.0001). The 2-year estimated PFS was 82.8% with venetoclax/rituximab, compared to 37.4% with bendamustine/rituximab. The treatment effect was consistent across all prespecified patient subgroups, including patients with deletion 17p (HR 0.13).
The overall response rate (ORR) was also significantly higher in patients receiving venetoclax/rituximab (92.3% vs 72.3%; P<.0001). Two-year OS rate was improved with venetoclax/rituximab compared to bendamustine/rituximab (91.9% vs 86.6%). This is probably a reflection of the depth of remissions. MRD negativity at the end of combination treatment period was achieved in a 62% of patients receiving venetoclax/rituximab, compared to only 13% of patients receiving bendamustine/rituximab.
There were not new safety signals of concern in patients receiving venetoclax/rituximab. The most common grade 3/4 adverse events (AEs) occurring in ³10% of patients were neutropenia (58% vs 39%), anemia (11% vs 14%), thrombocytopenia (6% vs 10%), and febrile neutropenia (4% vs 10%). Tumor lysis syndrome (TLS), a potentially life-threatening AE sometimes associated with venetoclax treatment, occurred in 3% of patients.
Dr Seymour concluded that these results support the superiority of nonchemotherapy combination of venetoclax plus rituximab to standard therapy bendamustine plus rituximab, and that this combination should be considered as a standard treatment option for relapsed/refractory CLL.
Studies examining venetoclax in combination with other agents in CLL are also ongoing. The combination of venetoclax plus ibrutinib demonstrated promising activity, including MRD eradication, in the TAP CLARITY trial, indicating potential synergy between venetoclax and ibrutinib. For more information on these trials, please see the prIME Oncology Clinical Spotlight in Chronic Lymphocytic Leukemia.