The MURANO study evaluates the benefit of combination therapy with venetoclax and rituximab compared with treatment with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). Data from the first 48 months of the study demonstrated deep responses with superior progression-free survival (PFS) with venetoclax-rituximab combination therapy compared with bendamustine-rituximab.1 Researchers reported on long-term minimal residual disease (MRD) kinetics and updated efficacy outcomes, including 5-year follow-up data on patients with re-exposure to venetoclax-rituximab.
In the MURANO study, 389 patients were randomized to treatment with venetoclax-rituximab or bendamustine-rituximab with a median follow-up of 59.2 months.2 Treatment with venetoclax-rituximab demonstrated a sustained PFS benefit. Median PFS was 53.6 months for patients receiving venetoclax-rituximab compared with 17.0 months for bendamustine-rituximab. Overall survival (OS) benefit was maintained for patients treated with venetoclax-rituximab, with 5-year OS estimates of 82.1% compared with 62.2% for bendamustine-rituximab.
Of 118 patients treated with venetoclax-rituximab who reached the end of treatment without progressive disease, those with undetectable MRD (uMRD) (83/118) had a 3-year post–end-of-treatment survival estimate of 95.3% compared with 85.0% for patients with MRD (35/118). Among the 83 patients with uMRD at end of treatment, 32 had not shown progressive disease and remained with uMRD, 4 had progressive disease without prior confirmed MRD conversion, and 47 had MRD conversion. Median time to MRD conversion from end of treatment was 19.4 months.
Among patients with uMRD at the end of treatment, the baseline presence of 17p deletion, genomic complexity (GC), or unmutated immunoglobulin heavy chain gene (IGVH) was each associated with increased risk of MRD conversion and subsequent progressive disease after the end of treatment. Of the 4 patients with 17p deletion, all experienced MRD conversion and subsequent progressive disease. In addition, 44% of patients with GC converted to MRD and developed progressive disease, compared with 20% without GC. The rate of MRD conversion with eventual progressive disease was also higher in patients with unmutated IGVH (37%) than those without (4%). Patients without 17p deletion or GC, or with mutated IGVH, were more likely to maintain uMRD or experience MRD conversion without subsequent progressive disease at follow-up.
No new safety signals were identified. Since the previous update, 2 second primary malignancies were reported (acute myeloid leukemia and multiple myeloma), both occurring in the venetoclax-rituximab group. Rates of Richter transformation remained balanced between the 2 treatment groups.
A substudy was introduced in 2018 allowing patients who developed progressive disease following treatment with either regimen to receive the venetoclax-rituximab regimen. Following progression of disease in the main study, 34 patients were enrolled in the substudy. Of these, 25 received retreatment and 9 received crossover treatment. Median follow-up in the substudy was 12.1 months. Of the 34 patients enrolled in the substudy, 16 have completed retreatment. These patients were noted to have unfavorable baseline genetic characteristics compared with the overall study population. The substudy participants also had a lower median PFS of 45.7 months, compared with 53.6 months for all patients receiving venetoclax-rituximab.
Data from the 5-year follow-up from the MURANO trial demonstrates sustained PFS and OS benefit of treatment with venetoclax-rituximab compared with bendamustine-rituximab. In patients treated with venetoclax-rituximab, uMRD at end of treatment is associated with improved OS. Fixed-duration 2-year treatment with venetoclax-rituximab overall demonstrated durable response, and a substantial proportion of the patients completing treatment retained uMRD 36 months after treatment cessation.
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