Long-Term Data Reinforce Feasibility of Time-Limited Venetoclax-Rituximab for R/R CLL

Long-term data from the MURANO study indicated that patients with relapsed or refractory chronic lymphocytic leukemia (CLL) continued to see substantial benefit when treated with venetoclax/rituximab (VenR) compared with bendamustine-rituximab (BR). Data from a pre-planned analysis from this trial were published earlier this year in the New England Journal of Medicine, and these long-term data were presented by John F. Seymour, MBBS, PhD, of Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Australia, at the 60th ASH Annual Meeting and Exposition.

In the phase 3 MURANO trial, 389 patients with CLL were randomly assigned to VenR (n=194) or BR (n=195). Disease status was assessed by CT scan at screening, Cycle (C) 4 and 2 to 3 months after the end of combination therapy. Disease response was determined by clinical assessment every 3 months until 3 years of follow-up had been completed, then every 6 months thereafter.

“At the primary analysis, when most patients were still on study treatment (median follow-up of 23.8 months), there was a significant PFS benefit with VenR compared with standard BR (P<0.001),” Seymour said. Estimated overall survival (OS) at 3 years was about 10% higher in the VenR arm compared with the BR arm. The primary analysis had been pre-planned at 140 PFS events, he noted.

The updated analysis includes an additional year of follow-up, after which there were no major changes.

With a median time off VenR after 2 years of treatment of 9.9 (1.4–22.5) months, PFS with VenR remained superior to BR (HR=0.16; 95% CI, 0.12-0.23]; P<0.0001). The median PFS for VenR was not reached compared with 17.0 months for BR.

The 3-year PFS estimate was 71.4% for patients assigned VenR compared with 15.2% for patients assigned BR. For patients who completed 2 years of VenR (n=130), 6 and 12 month PFS estimates were 92% and 87%, respectively.

The treatment effect with VenR was consistent across all subgroup analyses, he said.

“A clinically meaningful improvement in OS with VenR compared to BR was maintained after 3 years,” he said, but added the follow-up was relatively short.

There were 16 patients (of 130) who developed progressive disease after completion of VenR; of these, 14 patients were minimal residual disease-positive at >1% in peripheral blood at after 2 years (when VenR single agent was scheduled to cease). Ten of  the 16 patients had del(17p)/TP53 mutation at baseline.

Subsequent CLL-directed treatment was given after progressive disease in 91 patients in the BR arm. Of those, 71 patients (78%) from the BR arm received novel targeted agents, including 45 who had ibrutinib and seven who had VenR. Of the 194 patients in the VenR arm, 27 (14%) received subsequent therapy: 13 patients (44%) had novel targeted agents as next treatment, including eight patients who had ibrutinib and three who were re-treated with VenR.

“There were no new safety signals; most patients were able to complete treatment,” Seymour said. “The rate of CLL progression in the first 12 months after VenR completion was modest (13%), supporting the feasibility and safety of a time-limited VenR duration. The high rate of undetectable MRD was observed with VenR, and MRD status at cessation is a strong predictor of durable PFS off-drug.”

Based on these additional findings, Seymour said VenR use in the majority of patients with CLL is supported.