Venetoclax plus rituximab increases progression-free survival in relapsed chronic lymphocytic leukemia

1. Patients with relapsed or remitting chronic lymphocytic leukemia (CLL) treated with venetoclax-rituximab had a greater 2-year progression-free survival rate compared to bendamustine-rituximab treated patients.

2. Progression-free survival rates were greater for venetoclax-rituximab patients in almost all subgroup analysis, including patients with chromosome 17p deletion.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Curative treatment of relapsed or remitting CLL is rare. Previously treated CLL cells are often resistant to cellular mechanisms employed in initial treatment, thus alternative cellular mechanisms are needed for treating relapsed or remitting CLL. The antiapoptotic protein BCL2 is overexpressed in CLL, and venetoclax is a highly selective BCL2 inhibitor previously shown to be effective in CLL treatment when combined with the CD20 antibody rituximab. This phase 3 randomized controlled trial sought to compare venetoclax plus rituximab to a standard chemotherapy regimen in patients with relapsed or remitting CLL. With a median follow-up of 23.8 months, progression-free was higher in venetoclax-rituximab treated patients than those treated with bendamustine-rituximab. Patients with or without at chromosome 17p deletion experienced greater progression-free survival with venetoclax-rituximab.

Strengths of this trial included its multicenter design intention-to-treat analysis, while limitations include lack of statistical power to show greater efficacy data for overall survival data.

Click to read the study in NEJM

Relevant Reading: Venetoclax adds a new arrow targeting relapsed CLL to the quiver

In-Depth [randomized controlled trial]: This international, randomized, open label phase 3 trial enrolled patients between 2014 and 2015. Eligible patients had relapsed or refractory CLL, has undergone 1 to 3 prior treatments, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were assigned to either a venetoclax-rituximab (n=194) or bendamustine-rituximab (n=195) groups, with drugs administered according to a standard regimen. The primary outcome was progression-free survival, with notable secondary outcomes including progression-free survival in chromosome p17 deletion patients and overall response. Patients were assessed at baseline and at follow-up times consistent with 2008 International Workshop on Chronic Lymphoid Leukemia guidelines. At a median follow-up time of 23.8 months, 2-year progression-free survival was significantly greater in the venetoclax-rituximab group (84.9%) compared to the bendamustine-rituximab group (34.3%; hazard ratio for progression or death [HR], 0.17; 95% confidence interval [CI], 0.11 to 0.25; P<0.001). Progression-free survival benefit to venetoclax-rituximab was observed in almost all subgroups analyzed, including patients with (HR, 0.19; 95% CI, 0.12 to 0.32) and without chromosome p17 (HR, 0.13; 95% CI, 0.05 to 0.29) deletions. Overall response rate was higher in the venetoclax-rituximab group. Almost all patients in both groups had an adverse response to treatment. Grade 3 or 4 adverse events occurred in 82.0% of the venetoclax-rituximab group and 70.2% of the bendamustine-rituximab group.

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