A 2-year duration of combination immunotherapy with venetoclax and rituximab improved survival compared with standard-of-care chemoimmunotherapy combination with bendamustine plus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to follow-up data from the MURANO clinical trial presented at ASH 2018. Early results were first presented at ASH 2017.
Fixed-duration venetoclax plus rituximab achieved minimal residual disease (MRD)-negative status in 78% of patients. At a median follow-up of 3.3 years, the 6-month estimated progression-free survival (PFS) was 92% among 130 patients who completed 2 years of venetoclax therapy and remained off therapy for a median of 9.9 months. At 12 months, the estimated PFS was 87%. The estimated 3-year overall survival was 87.9% with venetoclax plus rituximab versus 79.5% with bendamustine plus rituximab.
“Venetoclax-rituximab is a chemotherapy-free option with a fixed treatment duration that can potentially provide prolonged progression-free survival, along with minimal residual disease negativity, in patients with relapsed or refractory CLL,” said lead investigator John F. Seymour, MBBS, PhD, FRACP, Director, Department of Haematology, Peter MacCallum Cancer Centre & the Royal Melbourne Hospital, Australia.
“This analysis shows that a high proportion of patients treated with venetoclax/rituximab maintained minimal residual disease negativity and progression-free survival after completing the fixed treatment duration,” Dr Seymour said. “The survival benefits are clinically meaningful, and minimal residual disease 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.”
MURANO: Additional 12-Month Results
The first results from the MURANO study were presented at ASH 2017. The results presented at ASH 2018 provided evidence from an additional 12 months of follow-up. MURANO was conducted at 109 sites across 20 countries and enrolled 389 patients with relapsed or refractory CLL who were randomized in a 1:1 ratio to (1) fixed-duration venetoclax and rituximab for 6 cycles, followed by venetoclax alone once daily for a total of 2 years or to (2) 6 cycles of bendamustine plus rituximab. The current standard practice for relapsed or refractory CLL is venetoclax therapy alone until the disease progresses.
At baseline, the median age of the MURANO participants was 65 years, and the median number of previous therapies was 1. For the first results presented at ASH 2017, at a median follow-up of 23.8 months, the median PFS was not reached in the venetoclax plus rituximab arm versus PFS of 17 months with bendamustine and rituximab (P <.0001). With another 1 year of follow-up, of 130 patients who reached cessation of venetoclax therapy without progressive disease, the estimated 3-year PFS was 71% for those in the venetoclax plus rituximab arm versus 15% in the bendamustine plus rituximab arm.
“The magnitude of effect was comparable in all biologic subtypes, regardless of TP53 [mutation] or 17p deletion,” Dr Seymour said.
No new safety events emerged during the trial for any of the agents. During the single-agent venetoclax treatment phase, 10% of patients had an adverse event that led to drug withdrawal, 4% needed dose reductions, and 26% of patients required dose interruptions. Fatal events were reported in 4% of patients.
Grade 3 or 4 adverse events were reported in 35% of patients in the venetoclax plus rituximab arm during the single-agent venetoclax period. Grade 3 or 4 infections were reported in 7% of patients during the single-agent phase. The number of cases of Richter’s transformation was similar in each arm: 7 with the immunotherapy combination and 6 with chemoimmunotherapy.
MRD negativity was reported in 78% of patients who completed the 2-year course of venetoclax treatment without disease progression. Among 83 patients with MRD-negative status, only 2 patients had disease progression. “MRD-negativity correlated with disease progression,” Dr Seymour told attendees. “MRD is the strongest predictor for progression events. Other risk factors did not predict disease recurrence.”