In patients with relapsed or refractory chronic lymphocytic leukemia (CLL), fixed-duration venetoclax -(Venclexta) combined with rituximab (Rituxan) reduced the risk of disease progression or death compared with standard-of-care bendamustine/rituximab, according to longer-term follow-up of the MURANO trial, presented at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition.1
At a median follow-up of 3.3 years, 130 patients who completed rituximab treatment plus the 24-month fixed-duration venetoclax after the initial dose ramp-up period and remained off therapy for a median of 9.9 months (range = 1.4 –22.5) had an estimated progression-free survival at 6 months of 92% and at 12 months of 87%. For all enrolled patients, the 3-year estimated overall survival was 87.9% for the venetoclax/rituximab combination vs 79.5 % for bendamustine/rituximab.
John F. Seymour, MBBS, PhD
“There is a need for a chemotherapy-free option with a fixed treatment duration that can potentially provide prolonged progression-free survival, along with minimal residual disease [MRD] negativity, in patients with relapsed or refractory CLL. This analysis shows that a high proportion of patients treated with venetoclax/rituximab maintained MRD negativity and progression-free survival after completing the fixed treatment duration,” said lead investigator John F. Seymour, MBBS, PhD, Director of the Department of Hematology, Peter MacCallum Cancer Centre & Royal Melbourne Hospital, Melbourne, Australia. “The survival benefits are clinically meaningful, and MRD status at cessation of therapy is a strong predictor of durable progression-free survival off the drug. These findings establish the feasibility and support the use of fixed-duration venetoclax/rituximab for all patients with relapsed or refractory CLL.”
The MURANO trial was conducted at 109 sites across 20 countries and utilized a fixed duration of treatment, stopping venetoclax after 24 months of administration at the target 400-mg dose level. Typically, with other targeted agents, patients with relapsed or refractory CLL are treated until disease progression. The first results of the MURANO trial were presented at the 2017 ASH Annual Meeting.2 The results presented this year were based on an additional 12 months of follow-up.
A total of 389 patients with relapsed and refractory CLL were randomly assigned 1:1 to receive fixed-duration venetoclax/rituximab for 6 cycles followed by venetoclax once daily for a total of 2 years after dose ramp-up vs 6 cycles of bendamustine/rituximab. At baseline, the median patient age was 65 years. The median number of prior therapies was one. The population was strongly enriched for prior exposure to a purine analog (81% of patients). In the primary analysis of results, the median progression-free survival was not reached for venetoclax/rituximab compared with 17 months for bendamustine/rituximab (P < .0001). The median follow-up for the primary analysis was 23.8 months.
With an additional year of follow-up, the estimated 3-year progression-free survival was 71% with venetoclax/rituximab vs 15% with bendamustine/rituximab in all 389 enrolled patients. “The magnitude of treatment effect was comparable in all biologic subtypes, regardless of TP53 or 17p deletion,” Dr. Seymour said. “With this relatively short follow-up, there was an 8% survival difference at 3 years favoring venetoclax,” he added.
Safety data were consistent with the known safety profiles of the agents used in the trial. During the single-agent venetoclax treatment phase, 10% of patients experienced an adverse event leading to drug withdrawal, 4% needed dose reductions, and 26% required dose interruptions. Fatal events were reported in 4%.
Grades 3 and 4 adverse events were reported in 35% of the venetoclax arm during the single-agent period. The most common adverse events were neutropenia (12%), anemia (3%), and thrombocytopenia (2%). Grade 3 or 4 infections were reported in less than 2% of patients during the single-agent phase, which Dr. Seymour considered to be low. The number of cases of Richter’s transformation was similar in each arm: seven with venetoclax and six with bendamustine.
“MRD negativity correlated with disease progression,” Dr. -Seymour told listeners. “MRD is the strongest predictor for progression events. Other risk factors did not predict disease recurrence.”
MRD negativity in the peripheral blood was observed in 64% of patients who completed the 2-year treatment course of venetoclax without disease progression. Among these 83 patients with MRD-negative status at the end of venetoclax treatment, only 2 cases of disease progression were observed. Among 23 patients with low-MRD status, 3 experienced disease progression, whereas among 14 patients with high-MRD status, 11 experienced disease progression. All 11 of these patients had manifest rising MRD levels over preceding months while still receiving venetoclax.
Joanna Rhodes, MD, a fellow in hematology/oncology at the Abramson Cancer Center, University of Pennsylvania, Philadelphia, noted that these data may change the current practice of venetoclax treatment until disease progression.
Joanna Rhodes, MD
“Updated data from the MURANO trial have demonstrated that time-limited treatment with venetoclax/rituximab have both progression-free and overall survival benefits as compared with bendamustine/rituximab across subgroups, including high-risk patients. At a median of 9.9 months since completing venetoclax therapy, there were few relapses in the venetoclax/rituximab group, and minimal residual disease positivity at the time of completion of venetoclax [24 months] predicts for relapse. These findings further support the use of venetoclax for patients with relapsed or refractory chronic lymphocytic leukemia and demonstrate that time-limited treatment is effective. Currently, we treat patients until disease progression with venetoclax, and these data support changing this practice,” Dr. Rhodes commented in an e-mail. ■
DISCLOSURE: The MURANO trial was supported by Genentech and AbbVie. Dr. -Seymour is a consultant for Celgene, Genentech, F. Hoffmann-La Roche, and AbbVie; has received honoraria from Janssen, F. Hoffmann-La Roche, and AbbVie; is a board member and advisor for Genentech and F. Hoffmann La-Roche; and has received research funding from Janssen, Genentech, and AbbVie. Dr. Rhodes reported no conflicts of interest.
1. Seymour JF, Kipps TJ, Eichhorst B, et al: MURANO trial establishes feasibility of time-limited venetoclax-rituximab combination therapy in relapsed/refractory chronic lymphocytic leukemia. 2018 ASH Annual Meeting & Exposition. Abstract 184. Presented December 1, 2018.
2. Seymour JF, Kipps TJ, Eichhorst B, et al: Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia: Results from pre-planned interim analysis of the randomized phase 3 MURANO study. 2017 ASH Annual Meeting & Exposition. Abstract LBA-2.