“What the 4-year data from the MURANO [trial] gives clinicians treating chronic lymphocytic leukaemia (CLL) is confidence that in a majority of patients durable disease control is possible after treatment cessation,”¹ notes Professor John Seymour, MURANO lead investigator, Director of the Department of Haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital. The limbic caught up with Prof. Seymour following the first look at the 4-year data presented at the XVII/ International Workshop on CLL (iwCLL) in Edinburgh this September and the American Society of Hematology 2019 conference in Florida to discuss its impact for treatment of CLL in the future.

Where we left off at the 3-year time point

“As we’ve discussed before, [see previous coverage here] the MURANO trial was a phase 3, randomised, open-label trial of a fixed duration of venetoclax in combination with rituximab compared to 6 cycles of bendamustine with rituximab in relapsed/refractory CLL. The initial results showed the rate of progression-free survival (PFS) at end of treatment was higher with venetoclax-rituximab-treated patients, [84.9% for venetoclax-rituximab (VenR)-treated patients vs 36.4% for bendamustine-rituximab (BR)-treated patients; p<0.001];² a benefit that was maintained across all sub-groups [for those with a 17p deletion; 81.5% vs 27.8% respectively],”² he recalled. “So why look at time-limited therapy? Well it’s important not only from a patient’s perspective – the less treatment the better, but conceptually we’re also trying to minimise the risk of developing treatment-resistant mutations through drug exposure.”

Prof. Seymour further explained, “at 3 years, all patients were off treatment and the  results demonstrated a continued substantial benefit with venetoclax-rituximab-treated patients, compared to those treated with bendamustine, with respect to PFS and overall survival (OS).^2,3 However, despite these promising results, at the 3-year time point durability of this regime remained unclear.” ³

4-year data confirms PFS and OS can be durable

Prof. Seymour explained the latest data from the MURANO trial focuses everyone’s attention on what’s happening in the VenR arm to understand what’ happens when you cease treatment.“The latest analysis which continues to follow the 194 patients initially randomised to VenR and 195 to BR demonstrated the PFS at 4 years continued to show a similar benefit to previously published data, which gives us greater clarity on outcomes and expectations for patients treated in a time-limited manner with VenR therapy.^1-3 It was reassuring to see the OS benefit is also maintained, with a widening of the gap between the treatment groups – suggesting to me there is value of using it early in therapy for patients who have relapsed. There’s no reason to wait – use it first after chemo-immunotherapy.”¹

As Prof. Seymour noted, the 4-year data reports on data for patients who have been on therapy for two years and off therapy for two years. The PFS estimates for the intent-to-treat population VenR arm as 57.3% (95% CI, 49.4 to 65.3), compared to 4.6% (95% CI, 0.1 to 9.2) for BR.¹ The OS rates were 85.3% and 66.5%, respectively despite 79% of bendamustine-rituximab-treated patients receiving a novel targeted anti-CLL agent after disease progression.¹

“Another important thing to note,” explained Prof. Seymour, “was no new safety signals were reported since the last update.”¹

VenR therapy demonstrated durability in patients with undetectable minimal residual disease (uMRD)

In the MURANO trial minimal residual disease (MRD) status was assessed via peripheral blood samples every 3–6 months for the follow up period.

Whilst the PFS is highly favourable, there is still some variability and the strongest predictor of a positive outcome is the MRD status at the time of treatment cessation. When patients (n=83) showed undetectable MRD (uMRD) in peripheral blood, their  PFS at 18 months was around 90% [after the landmark visit]. For patients with low-level MRD (<1%) PFS at 18 months dropped to 64%, and for those with high MRD it dropped further to only 8% of patients,”¹ Prof. Seymour said.

At the end of treatment patients with uMRD had a longer PFS vs those with low-MRD (HR 0.25; 95% CI 0.1, 0.64) and longer PFS vs those with high-MRD (HR 0.03; 95% CI 0.01, 0.09).¹ “These data indicate MRD status via peripheral blood analysis is a good predictor of PFS in patients treated with VenR therapy,” explained Prof. Seymour. “For those 14 patients [with high MRD positivity at the end of treatment] who eventually relapsed, when we look back at their MRD level and we see it had been on the rise in the preceding months prior to treatment cessation. So there’s more to unpack there in terms of what to do in those cases.”

Unanswered questions still remain

Prof. Seymour explained his continued interest in following the MURANO cohort to understand more about the place of time-limited therapy. “This is a story that’s by no means over – yet. We’ll continue to follow these patients and explore what our options are when the disease fights back.”

This article was commissioned and sponsored by AbbVie Pty Ltd, Mascot NSW, which has no control over editorial content. The content is entirely independent and based on published studies and the speakers’ opinions and the views expressed are not necessarily those of AbbVie. Treatment decisions based on this information are the full responsibility of the prescribing healthcare professional.

Before prescribing Venclexta (venetoclax), please review the full Product Information which is available on request from AbbVie or by clicking here.

References:

1. Seymour JF, et al. Time-limited venetoclax-rituximab in relapsed/refractory chronic lymphocytic leukaemia: first presentation of 4-year data from the MURANO study. XVII/ International Workshop on CLL (iwCLL) 2019. Poster #2266.
2. Seymour JF, et al. N Engl J Med 2018;378(12):1107–1120.
3. Kater AP, et al. J Clin Oncol 2018;37:1-9.

Date of preparation: Dec 2019 AU-VENC-190104