Conference Coverage

Venetoclax/rituximab boosts PFS in relapsed/refractory CLL


Key clinical point: Compared with bendamustine/rituximab, venetoclax/rituximab was associated with significantly superior progression-free survival of relapsed/refractory chronic lymphocytic leukemia.

Major finding: The hazard ratio for PFS with venetoclax/rituximab was 0.17 (P less than .001).

Data source: A randomized phase 3, open-label trial in 389 patients with relapsed/refractory CLL.

Disclosures: The MURANO trial was funded by AbbVie and Genetech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.

Source: Seymour J et al. ASH 2017 LBA-2.



– In patients with relapsed/refractory chronic lymphocytic leukemia (CLL), a combination of venetoclax (Venclexta) and rituximab was superior to bendamustine (Treanda) and rituximab for prolonging progression-free survival (PFS), with effects consistent across subgroups, regardless of mutational status, and a clinically meaningful improvement in overall survival.

An interim analysis from the phase 3 MURANO trial showed that after a median follow-up of 23.8 months, the median PFS for patients randomized to venetoclax/rituximab had not been reached, compared with 17 months for patients assigned to bendamustine/rituximab, reported John F. Seymour, MBBS, PhD, of the Peter MacCallum Cancer Centre at the University of Melbourne.

Dr. John F. Seymour of Australia

Dr. John F. Seymour

“I believe that venetoclax/rituximab should be considered as a suitable standard therapeutic option in patients with relapsed CLL,” he said in a late-breaking abstracts session at the annual meeting of the American Society of Hematology.

Relapsed/refractory CLL often has a suboptimal response to conventional chemotherapy because of adverse biological features that can accumulate in cells, he said.

The combination of bendamustine and rituximab has been associated with about 60% overall responses rates, a median PFS of approximately 15 months, and overall survival of nearly 3 years in patients with CLL, he noted.

The rationale for pairing venetoclax with rituximab in this population comes from evidence showing efficacy of the monoclonal antibody, an oral B-cell lymphoma–2 (BCL-2) inhibitor, as monotherapy in patients with relapsed/refractory CLL, including those with poor prognostic features such as the 17p deletion (del17p).

Dr. Seymour and his colleagues recently published results from a phase 1b trial of venetoclax/rituximab in patients with relapsed/refractory CLL. The combination was associated with a 51% complete ­response rate, and a 28% rate of negative marrow minimal residual disease (MRD) (Lancet Oncol. 2017 Feb;18[2]:230-40)

In the MURANO study (NCT02005471), the investigators evaluated whether time-limited therapy with venetoclax/rituximab could improve PFS over bendamustine/rituximab.

Patients 18 and older with CLL who had been treated with one to three prior lines of therapy, including at least one chemotherapy-containing regimen, were enrolled. Prior treatment with bendamustine was allowed only if patients had had a duration of response of at least 24 months.

After stratification by del17p status, responsiveness to prior therapy, and geographic region, 389 patients were randomly assigned to receive rituximab 375 mg/m2 on day 1 of cycle 1 and 500 mg/m2 on day 1 of cycles 2 through 6, plus either bendamustine 70 mg/m2 on days 1 and 2 of each of six cycles, or venetoclax 400 mg orally once daily until disease progression, cessation for toxicity, or up to a maximum of 2 years starting from day 1 of cycle 1.

As noted, investigator-assessed PFS, the primary endpoint, was significantly better with venetoclax, with a hazard ratio of 0.17 (P less than .001).

The respective 1- and 2-year PFS rates with venetoclax were 91.2% and 82.8%, compared with 74.1% and 37.4% with bendamustine.

The venetoclax/rituximab combination was also significantly superior across all subgroups, regardless of the number of prior therapies, refractory vs. relapsed after most recent prior therapy, del17p status, TP53 mutational status, or baseline immunoglobulin heavy chain variable (IGHV) mutated or unmutated status

Response rates assessed by both investigators and independent reviewers were also better with venetoclax. The investigator-assessed overall response rate (ORR) was 93.3%, compared with 67.7% for bendamustine/rituximab, including 26.8% complete responses (CR), compared with 8.2%. Independent reviewers decreed an ORR of 92.3% for venentoclax, vs. 72.3% for bendamustine, including respective CR rates of 8.2% and 3.6%.

The investigators also found that the percentage of MRD negativity was higher with venetoclax/rituximab, with 62% of patients in this group being MRD negative at 9 months. This rate remained fairly constant at 12-, 15- and 18-month follow-ups (60%, 57%, and 60%, respectively).

In contrast, 13% of patients treated with bendamustine were MRD negative at 9 months, and the rates gradually declined over time to 10%, 9%, and 5%.

Investigators also saw a clinically meaningful improvement in overall survival with the venetoclax/rituximab duo, although survival data are still not mature in this ongoing trial. The median OS had not been reached in either group at the time of data cutoff.

Respective 1- and 2-year OS rates with venetoclax were 95.9% and 91.9%, and with bendamustine were 91.1% and 86.6%.

At the time of this interim analysis, the hazard ratio favoring venetoclax/rituximab was 0.48 (P = .0186).

Drug discontinuation was more frequent with venetoclax/rituximab (25% vs, 17%), with disease progression and adverse events without progression being the most frequent reasons for stopping in each arm.

Serious adverse events occurred in 46% of patients on venetoclax/rituximab and 43% on bendamustine/rituximab. A higher percentage of patients on venetoclax/rituximab had grade 3 or 4 adverse events (82% vs, 70%). Ten patients (5%) in the venetoclax/rituximab arm died, and 11 patients (6%) on bendamustine/rituximab died.

Events with a greater than 2% difference included more frequent neutropenia, tumor lysis syndrome, hyperglycemia and hypogammaglobulinema with venetoclax/rituximab, and more frequent anemia, thrombocytopenia, febrile neutropenia, pneumonia, infusion-related reactions, and hypotension with bendamustine/rituximab.

In the question-and-response portion following Dr. Seymour’s presentation, an audience member commented that the continuation of venetoclax/rituximab beyond the initial treatment cycles amounted to a maintenance strategy, and that patients in the experimental arm were in treatment longer, which likely influenced the results.

“You’re absolutely correct that the treatment duration differed, although, of course, the capacity to deliver more than six cycles of bendamustine/rituximab would have been problematic,” Dr. Seymour replied.

“There are some data that antibody treatment may prolong progression-free survival. However, when this study was designed in 2013 that data was certainly not available, and I believe currently even maintenance antibodies are not an accepted standard of treatment,” he added.

The MURANO trial was funded by AbbVie and Genentech. Dr. Seymour disclosed honoraria, speakers bureau, research funding, and advisory activities with AbbVie and other companies.

SOURCE: Seymour J et al. ASH 2017 LBA-2.

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