On the first day of the 2018 American Society of Hematology (ASH) Annual Meeting, an additional year of follow-up data from the practice-changing MURANO study were presented to the audience by Professor John F. Seymour. In the trial’s setting of relapsed/refractory (R/R) chronic lymphocytic leukaemia (CLL), the non-chemo-containing regimen venetoclax (Venclexta®, AbbVie/Roche) plus rituximab was associated with maintained superior progression-free survival (PFS) and overall survival (OS) over standard-of-care chemoimmunotherapy with bendamustine plus rituximab. At the same time, a durable post-treatment disease control is also attainable with the fixed-duration chemo-free regimen.

ASH 2017 Results

First presented at the late-breaking abstracts session at 2017 ASH Annual Meeting, MURANO (NCT02005471) is an international, Phase III, open-label, randomised trial that compared (1:1) the combination of fixed-duration oral venetoclax in patients with R/R CLL for 2 years with 6 cycles of rituximab (N=194) to 6 cycles of bendamustine + rituximab (N=195). The primary analysis showed an 83% risk reduction for disease progression or death with venetoclax + rituximab (hazard ratio [HR]=0.17; 95% confidence interval [CI], 0.11-0.25; P<0.001), as published in the New England Journal of Medicine.

“Overall, these data establish the feasibility and support the use of fixed-duration venetoclax-rituximab combination therapy for the majority of patients with relapsed/refractory CLL”
~Professor John F Seymour of the Peter MacCallum Cancer Centre, Melbourne, Australia

ASH 2018: Follow-Up of 36 Months

In the published primary analysis, most patients were still on study treatment at the median follow-up of 23.8 months. This longer-term analysis covered a median follow-up of 36.0 months with all ongoing patients in the venetoclax + rituximab arm having completed the 2-year venetoclax treatment.

The median PFS did not differ from the initial primary analysis (not reached [NR] versus 17.0 months) and a stratified HR of 0.16 (95% CI, 0.12-0.23) favouring patients on venetoclax plus rituximab. The 3-year PFS rate was 71.4% in those had taken venetoclax versus 15.2% in those treated with bendamustine with rituximab. The median OS was still NR in both groups, but the median OS, as demonstrated in the primary analysis, was significantly prolonged in patients treated with venetoclax plus rituximab (HR=0.50; 95% CI, 0.30-0.85). The 3-year OS-rate was 87.9% with the chemotherapy-free approach compared to 79.5% with chemoimmunotherapy.

Off-Drug Progression-Free Survival

Among the 130 patients who completed two years venetoclax treatment without developing disease progression, the majority (N=83; 63.8%) had undetectable minimal residual disease (MRD), defined as <1 CLL cell per 10,000 leucocytes, at the time of venetoclax cessation. During the off-treatment follow-up (median: 9.9 months), 97.6% of these patients remained progression-free. Among patients who completed the two years of oral treatment and who had low MRD-positive (<1 CLL cell per 100 leucocytes, but ≥1 per 10,000 leucocytes) disease (N=23; 17.7%), 87.0% remained progression-free during off-treatment follow-up. Overall, the 1-year PFS-rate after venetoclax cessation was 87.4% (95% CI, 81.1%-93.8%).

Safety

The investigators reported the safety of the combination venetoclax plus rituximab was consistent with the documented safety profiles of the individual medicines alone. In MURANO-patients receiving venetoclax as single-agent (N=171), 10% of patients stopped the treatment due to an adverse event (AE), 26% had dose interruptions for AEs, and 4% of patients had a dose reduction because of AEs. Fatal AEs occurred in 4% of patients (other cancers [N=4], cardiac [N=2], pneumonia [N=1]). Grade 3/4 AEs were reported in 35% of patients. Common Grade 3/4 AEs included neutropenia (12%), anaemia (3%) and thrombocytopenia (2%). Grade 3/4 infections occurred in 7% of patients during the single-agent phase.

References

Seymour JF, Kipps TJ, Eichhorst B, et al. 60^thASH Annual Meeting and Exposition; 2018 Dec 1-4; San Diego, CA (United States). Oral presentation 184.

Seymour JF, Kipps TJ, Eichhorst B, et al. 59^thASH Annual Meeting and Exposition; 2017 Dec 9-12; Atlanta, GA (United States). Oral presentation LBA-2.

Seymour JF, Kipps TJ, Eichhorst B, et al. N Engl J Med. 2018;378:1107-1120.