Rare Disease Report

CLL Therapy, Venetoclax/Rituximab, Shows Reduced Risk of Disease Progression

DECEMBER 02, 2018
Krista Rossi
Full results from AbbVie’s phase 3 MURANO trial investigating venetoclax/rituximab combination for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) were presented at the 60th ASH Annual Meeting & Exposition in San Diego, California. Among the results, a reduced risk in disease progression and 87.9% overall survival in treated patients stood out.

“Combinations of different agents are really allowing us to achieve responses and outcomes that are superior to chemotherapy, without the side effects of chemotherapy,” said Rod Humerickhouse, MD, PhD, asset strategy leader of AbbVie to Rare Disease Report®. “When venetoclax is part of those combinations, we can achieve deep responses, complete responses, and minimal residual disease (MRD)-negative responses, which really justify and support the stopping of treatment and enabling patients to have treatment-free remissions.”

The international, multicenter, open-label, randomized, phase 3 trial included 389 R/R CLL patients who were administered at least 1 prior therapy. Sixty-five years (range: 22 to 85) composed the median age of patients.

Evaluation of the efficacy and safety of venetoclax in combination with rituximab (N=194) in comparison to bendamustine in combination with rituximab (N=195) served as the basis behind the trial design.

Investigator-assessed progression-free survival (PFS) served as the primary efficacy endpoint.

Independent review committee (IRC)-assessed PFS, investigator - and IRC-assessed overall response rate (defined as complete response plus complete response with incomplete marrow recovery plus partial response plus nodular partial response), overall survival, and rates of minimal residual disease (MRD)-negativity included additional efficacy endpoints.

At the median follow-up of 36 months after all patients completed the fixed duration of therapy and stopped treatment, R/R CLL patients treated with the combination therapy did not experience disease progression or death (PFS) in comparison to patients treated with a standard of care regimen, bendamustine plus rituximab.

Also at 36 months, patients treated with venetoclax/rituximab had an estimated PFS rate of 71.4% (95% confidence interval [CI]: .64, .78) compared to patients treated with a standard of care combination of bendamustine/rituximab. (hazard ratio [HR]: .16; 95% CI: .12, .23), who had an estimated PFS of 15.2% (95% CI: .09, .21).

Six- and 12-month PFS estimates were 92% (95% CI: .87, .96) and 87% (95% CI: .81, .93) for the 130 patients who completed the 2-year treatment course of venetoclax and remained off therapy for a median of 9.9 months (range: 1.4 to 22.5).

At 3 years, the overall survival benefit was estimated to be 10% higher in the venetoclax/rituximab arm (87.9%) than in the bendamustine plus rituximab arm (79.5%) (HR: .50; 95% CI: .30, .85).
 
Minimal residual disease (MRD)-negativity in peripheral blood was also demonstrated by 78% of patients who completed the 2-year treatment course of venetoclax/rituximab without disease progression (N=114).

An objective measure defined as the presence of less than 1 CLL cell in 10,000 white blood cells remaining in the blood or bone marrow following treatment, MRD-negativity (undetectable MRD) is a secondary endpoint that was assessed at the end of combination therapy (9-month assessment).

An association between MRD-negativity achievement and improved clinical outcomes have been previously shown in earlier prospective clinical trials in CLL patients.

Safety profiles correlated with those each medicine independently. In the venetoclax single-agent treatment phase (N=171), 10% of patients experienced an adverse event (AE) resulting in drug withdrawal; 4% had an AE leading to dose reduction; 26% had an AE leading to dose interruption; and 4% had a fatal AE (4 other cancers, 2 cardiac, and 1 pneumonia).

Thirty-five patients experienced Grade 3/4 AEs, which included neutropenia (12%), anemia (3%) and thrombocytopenia (2%). During the single-agent phase, 7% of patients had a Grade 3/4 infection.

Study authors also noted that patients treated with venetoclax/rituximab did not reach median PFS compared with 17 months for bendamustine in combination with rituximab (HR: .17; 95% CI: .11, .25; P<.0001). The median follow-up for PFS was 23.8 months (range: 0.0 to 37.4) in the primary efficacy analysis.

“With targeted agents—with chemotherapy-free [treatments]—we don’t see patients losing their hair, we don’t see patients at significant risk for life-threatening infections,” said Dr. Humerickhouse. “Overall, other side effects, such as nausea, etc. are significantly reduced. The ability to tolerate the treatment as its being given has improved greatly. Also, not having to remain on therapy for extended periods of time is an improvement as well.”

“The treatment of CLL has advanced tremendously over the last 5 years,” he closed. “CLL was previously thought to be an incurable disease. While we don’t have proof of a cure, but we have significant for a cure hope today.”

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