March 21, 2018
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Venetoclax-rituximab combination improves PFS in refractory chronic lymphocytic leukemia

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John F. Seymour

The combination of venetoclax plus rituximab improved PFS 2 years after treatment compared with bendamustine plus rituximab among patients with relapsed or refractory chronic lymphocytic leukemia, according to results of a phase 3 clinical trial.

“The substantial rate of clearance of minimal residual disease in the venetoclax-rituximab group may indicate improved disease control over a longer term even when therapy is discontinued,” John F. Seymour, MD, director of Peter MacCallum Cancer Centre in Melbourne, Australia, and colleagues wrote.

Venetoclax (Venclexta; AbbVie, Genentech) — an orally administered selective inhibitor of BCL-2 — has demonstrated strong clinical activity as a single agent, including among patients with poor prognostic factors.

A previous phase 1 study showed safety and promising efficacy from the addition of rituximab (Rituxan; Genentech, Biogen) to venetoclax. The study showed improved complete remission rates, with high-quality remissions and no detectable leukemia. Based on those findings, researchers sought to compare that combination with the combination of rituximab and bendamustine.

The analysis included 389 patients who had received one to three prior therapies, including at least one with chemotherapy.

Researchers randomly assigned patients 1:1 to rituximab plus venetoclax (n = 194; median age, 64.5 years) or rituximab plus bendamustine (n = 195; median age, 66 years). Treatment continued for six 28-day cycles.

Patients assigned venetoclax underwent a 5-week schedule of gradual dose increase from 20 mg to 400 mg daily.

After the dose ramp-up period, daily administration of venetoclax continued at 400 mg per day for 2 years, or until disease progression or unacceptable toxicity. Rituximab was administered at a dose of 375 mg/m2 on day 1 of the first cycle, followed by 500 mg/m2 on day 1 of cycles two through six.

Patients assigned the other regimen received 70 mg/m2 IV bendamustine on days 1 and 2 of each 28-day cycle, plus rituximab on the same dosing schedule.

Investigator-assessed PFS served as the primary endpoint. Secondary endpoints included independent review committee-assessed PFS, PFS among patients with chromosome 17p deletion, best overall response, OS, EFS, duration of response, time to next anti-CLL treatment and achievement of minimal residual disease negativity.

Median follow-up was 23.8 months (range, 0-37.4).

At data cutoff in May 2017, 78 patients in the venetoclax group remained on venetoclax monotherapy and 154 patients in the bendamustine group had completed all six cycles of therapy.

Median PFS was not reached in the venetoclax group and 17 months in the bendamustine group. Two-year PFS assessed by investigators was 84.9% in the venetoclax group and 36.3% in the bendamustine group (HR for progression or death = 0.17; 95% CI, 0.11-0.25). Results appeared consistent across all clinical and biological subsets, including among patients with the 17p deletion (HR = 0.13; 95% CI, 0.05-0.29) and without 17p deletion (HR = 0.19; 95% CI, 0.12-0.32).

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Overall response rate assessed by independent review committee was 92.3% in the venetoclax group and 72.3% in the bendamustine group (difference, 20%; 95% CI, 12.4-27.6). In addition, 26.8% of patients who received venetoclax achieved complete response compared with 8.2% of patients who received bendamustine.

ORR assessed by investigators was 93.3% in the venetoclax group and 67.7% in the bendamustine group.

A higher percentage of patients assigned venetoclax achieved 2-year OS (91.9% vs. 86.6%; HR = 0.48; 95% CI, 0.25-0.9).

No new unexpected adverse events occurred.

Neutropenia was the most common grade 3 or grade 4 adverse event (60.8% in the venetoclax group vs. 44.1% in the bendamustine group).

“Neutropenia is a known on-target effect of venetoclax, and the higher rates of grade 3 or 4 events that were observed in the venetoclax-rituximab group as compared with the bendamustine-rituximab group were not unexpected, especially given the longer duration of treatment with venetoclax,” Seymour and colleagues wrote. “Nonetheless, infections and infestations in the venetoclax-rituximab group were uncommon.”

Additional follow-up is needed to measure durability of these responses, the researchers wrote. – by Melinda Stevens

Disclosures: Seymour reports financial relationships with AbbVie, Celgene, Gilead, Janssen, Morphosys, Roche, Sunesis and Takeda. Please see the full study for a list of all other authors’ relevant financial disclosures.