Patients with relapsed or refractory chronic lymphocytic leukemia (CLL) treated with the combination of fixed-duration venetoclax/rituximab had a longer overall survival and progression-free survival at 5 years compared with those treated with bendamustine/rituximab, according to a 5-year analysis of the MURANO trial reported at the 2020 American Society of Hematology (ASH) Annual Meeting & Exposition.¹ All patients had completed treatment at the end of 2 years.

The median 5-year progression-free survival was 53.6 months for those treated with fixed-duration venetoclax/rituximab vs 17 months for those given bendamustine/rituximab after 3 years or more off treatment (P < .0001). Median overall survival was not reached in either arm; the estimated 5-year overall survival was 82.1% vs 62.2%, respectively—a 60% improvement with venetoclax/rituximab.

Arnon P. Kater, MD, PhD

“Overall, sustained undetectable (minimal residual disease), progression-free survival and overall survival benefits, even after the end of treatment, provide further support for the use of a fixed duration of venetoclax/rituximab in patients with relapsed or refractory CLL,” said lead author Arnon P. Kater, MD, PhD, Leader of Tumor Immunology at the Cancer Center Amsterdam, The Netherlands.

Study Details

The international, multicenter, open-label, randomized phase III MURANO trial was designed to evaluate the efficacy and safety of fixed-duration treatment with venetoclax/rituximab compared with a standard of care, bendamustine/rituximab. The study enrolled 389 patients with relapsed or refractory CLL who had received at least one prior therapy who were randomly assigned 1:1 to venetoclax/rituximab (2 years of venetoclax, 6 months of rituximab) vs bendamustine/rituximab for 6 months.

The study met its primary endpoint of investigator-assessed progression-free survival. In the primary analysis, the median follow-up was 23.8 months, at which time median progression-free survival was not reached with venetoclax/rituximab vs 17 months for bendamustine/rituximab (P < .0001).

Focus on MRD

The primary analysis of MURANO also showed that patients who achieved minimal residual disease (MRD; also known as measurable residual disease) negativity without disease progression at the end of treatment (n = 83) had improved progression-free survival and overall survival compared with patients who had detectable MRD (n = 35). The 3-year progression-free survival was 61.3% for those with undetectable MRD and 40.7% for those with detectable MRD. An estimated 3-year survival after the end of treatment was 95.3% for those with undetectable MRD and 85% for those with detectable MRD.

Among 83 patients with undetectable MRD at 3 years after end of therapy with venetoclax and rituximab, 32 did not have disease progression and continued to have undetectable MRD out to 5 years. The median time from end of treatment to MRD conversion was 19.4 months, and of the 47 patients who became MRD-positive, 19 developed disease progression at a median time of 25.2 months.

“Most patients who completed venetoclax monotherapy had undetectable MRD at the end of treatment, and MRD status continued to be a robust predictor of outcomes. Undetectable MRD continued to be associated with improved survival. The longer undetectable MRD is maintained, the likelihood of conversion to MRD positivity is diminished,” Dr. Kater told listeners.

Several high-risk factors were associated with an increased risk of disease progression in patients with undetectable MRD at the end of treatment, including chromosome 17p deletion, genomic complexity (three or more subtle genetic abnormalities), and unmutated immunoglobulin heavy chain variable region (IGVH). Patients without these factors “were more likely to maintain undetectable MRD or experience MRD conversion without progressive disease at this follow-up,” Dr. Kater noted.

“These findings suggested slower kinetics, so we then analyzed MRD growth rates,” he explained. “Faster clonal growth rate indicated shorter MRD doubling time.”

The venetoclax/rituximab group (102 patients) had a longer mean doubling time for MRD compared with the bendamustine/rituximab group (104 patients, 72 days vs 52 days). Faster MRD doubling times after the end of treatment were observed in patients with three risk factors vs those without them: 17p deletion (44.9 days vs 85.6 days); genetic complexity (61.6 days vs 96.4 days); and unmutated IGVH (60.2 days vs 120.3 days).

Safety Profile

The safety profile of the venetoclax/rituximab combination is consistent with the known safety profile of each therapy alone. No new serious safety concerns emerged in the 5-year updated analysis of MURANO. Two second primary cancers, excluding nonmelanoma skin cancers (acute myeloid leukemia and multiple myeloma) were reported since the previous update. Both arms had comparable rates of Richter’s transformation (seven for venetoclax/rituximab, six for bendamustine/rituximab). 

DISCLOSURE: Dr. Kater has served as a consultant or advisor to AbbVie/Genentech, AstraZeneca, and Janssen Oncology; has received research funding from AbbVie/Genentech, Celgene, Gilead Sciences, Janssen Oncology, Roche/Genentech, and Sanofi; and has been reimbursed for travel, accommodations, or other expenses by Acerta Pharma/AstraZeneca and Roche/Genentech.

REFERENCE

1. Kater AP, Kipps TJ, Eichhorst, B, et al: Five-year analysis of Murano study demonstrates enduring undetectable minimal residual disease (uMRD) in a subset of relapsed/refractory chronic lymphocytic leukemia patients following fixed-duration venetoclax-rituximab therapy. 2020 ASH Annual Meeting & Exposition. Abstract 125. Presented December 5, 2020.