5-year data show sustained benefit of venetoclax-rituximab for relapsed/refractory CLL
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Five-year data from the MURANO study showed a continued PFS benefit with venetoclax-rituximab vs. bendamustine-rituximab among patients with relapsed or refractory chronic lymphocytic leukemia.
Results of the global, phase 3, open-label, randomized study, presented at the virtual ASH Annual Meeting and Exposition, also showed undetectable minimal residual disease (MRD) at the end of treatment with venetoclax (Venclexta; AbbVie, Genentech) plus rituximab (Rituxan; Genentech, Biogen) was associated with improved PFS and OS.
Researchers of the MURANO study compared fixed-duration treatment with 400 mg daily venetoclax for 2 years plus standard-dose rituximab for 6 months vs. 70 mg/m2 bendamustine plus rituximab among 389 patients with relapsed or refractory CLL.
Previously reported data after 48-month follow-up showed achieving deep responses with undetectable MRD was associated with improved PFS.
At ASH, Arnon P. Kater, MD, PhD, leader of tumor immunology and professor of translational hematology at Cancer Centre of Amsterdam, reported long-term data, after median follow-up of 59.2 months (range, 0-71.5), as well as outcomes of patients who stopped therapy due to their MRD status and patients who received retreatment with venetoclax plus rituximab in a substudy that was introduced in 2018 for patients who developed progressive disease in either treatment group.
Researchers noted the survival benefit was sustained at this longer follow-up, with median PFS of 53.6 months for the venetoclax-rituximab group and 17 months for the bendamustine-rituximab group (HR = 0.19; 95% CI, 0.15-0.26).
Among 130 patients who completed the full 2 years of venetoclax-rituximab treatment, 51.1% (95% CI, 40.2-61.9) achieved PFS at 36 months after the end of treatment.
At 5 years, 82.1% of patients assigned venetoclax-rituximab achieved OS compared with 62.2% of patients assigned bendamustine-rituximab (HR = 0.4; 95% CI, 0.26-0.62). Median OS had not been reached for either group.
Researchers then evaluated outcomes among patients treated with venetoclax-rituximab who had undetectable MRD (n = 83) at the end of treatment compared with those with MRD (n = 35) and found higher 3-year OS estimates among those in the former group (95.3% vs. 85%). Three-year PFS was significantly improved among patients with undetectable MRD (61.3%) compared with those with low MRD (40.7%; P = .0246) and high MRD (not estimable, P < .0001).
The 83 patients with undetectable MRD underwent serial peripheral blood testing every 3 months for the first year, followed by every 6 months. The median time from end of treatment to MRD conversion was 19.4 months (95% CI, 8.7-28.3). Among 47 patients who converted to MRD positivity from end of treatment, median time from MRD conversation to clinical disease progression was an additional 25.2 months (95% CI, 19.4-30.4).
Approximately 39% of patients maintained undetectable MRD at follow-up.
“There is an indication that the time from end of treatment to MRD conversion Kaplan-Meier curve ... is developing a plateau, which might suggest the longer undetectable MRD is maintained, the likelihood of conversion to MRD positivity is diminished,” Kater said during his presentation. “Conversely, the time from MRD positivity conversion to progressive disease Kaplan-Meier curve appears to be linear, suggesting MRD-positive conversion eventually leads to progressive disease.”
Factors associated with increased risk for progressive disease among patients with undetectable MRD at the end of treatment included deletion 17p, genomic complexity and unmutated immunoglobulin heavy chain (IGHV) gene. Conversion with subsequent progressive disease occurred among more patients with abnormal vs. normal deletion 17p (100% vs. 22%), with vs. without genomic complexity (44% vs. 20%) and with unmutated vs. mutated IGHV (37% vs. 4%).
Researchers also found that these factors were associated with faster median MRD doubling times at the end of treatment in the venetoclax-rituximab group (abnormal vs. normal deletion 17p, 44.9 days vs. 85.6 days; genomic vs. no genomic complexity, 61.6 days vs. 96.4 days; unmutated vs. mutated IGHV, 60.2 days vs. 120.3 days).
Kater also presented data on 34 patients who enrolled in the substudy, 25 of whom were retreated with venetoclax-rituximab and nine of whom crossed over to that treatment group. Median follow-up was 12.1 months.
Median PFS1 for 16 patients with a valid MRD assessment was 45.7 months (range, 36-58) and median treatment-free interval to progressive disease was 23.6 months (range, 10-32).
Kater noted that these patients had a high prevalence of unfavorable baseline genetics. “Deep and durable initial response alongside favorable baseline characteristics predict sensitivity to retreatment,” he said.
At the end of this second course of treatment, five patients had undetectable MRD.
“Overall, sustained undetectable MRD, PFS and OS benefits provide further support for the use of fixed-duration venetoclax-rituximab in patients with relapsed/refractory CLL,” Kater said.
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Kater AP, et al. Abstract 125. Presented at: ASH Annual Meeting and Exposition (virtual meeting); Dec. 5-8, 2020.
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