Although chronic lymphocytic leukaemia (CLL) is one of the most common forms of leukaemia in Australia, it remains incurable.¹ While some patients enjoy good and durable responses to first-line therapy, in other patients their disease relapses quickly and can acquire adverse biologic features that render it refractory to treatment with DNA-damaging chemotherapy agents.¹ The BCL2 inhibitor venetoclax has been shown to provide a good quality of response in pre-treated patients, including those with adverse biologic features such as chromosome 17p deletion.¹ The combination of CD20 antibody rituximab with venetoclax has emerged as a promising combination for the relapsed/refractory setting due to in vitro evidence of its activity in CLL cell lines with established resistant to venetoclax therapy.² Recently, the long-term update from the MURANO trial, 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 was presented at the 2018 American Society of Hematology conference in San Diego. To understand the implications of the study, the limbic spoke with Professor John Seymour, MURANO lead investigator, Director of the Department of Haematology at the Peter MacCallum Cancer Centre & Royal Melbourne Hospital about the trial and how he sees it changing the way CLL is treated around the globe.:

Chemotherapy-free combination has demonstrated dramatic benefits in relapsed/refractory CLL

“The results of these analyses showed that a high proportion of patients with relapsed or refractory chronic lymphocytic leukaemia who were treated with venetoclax in combination with rituximab maintained minimal residual disease negativity and progression-free survival well after completing the 2-year venetoclax fixed treatment duration,” notes Prof. Seymour.^1,3,4

As Prof. Seymour highlighted, the results of the MURANO study presented at ASH were an update to the results already published from MURANO study.^1,3,4 In MURANO, patients were randomised to receive six cycles of venetoclax-rituximab followed by an additional 18 months of venetoclax monotherapy for a total duration of 2 years.^1,3,4 In the previously published analysis which followed 389 patients with relapsed/refractory CLL for a median of 23.8 months, the 2-year rates of progression-free survival (PFS) were 84.9% for venetoclax-rituximab-treated patients and 36.4% for bendamustine-rituximab-treated patients (p<0.001).¹ The benefit was maintained across all subgroups, including those with a 17p deletion (81.5% vs 27.8% respectively).¹ In the latest results presented at ASH which reports on the long-term outcome over a median follow-up of 36 months where all patients were off treatment, continued substantial benefit was observed with venetoclax-rituximab with respect to PFS and overall survival (OS) with no new safety signals.^1,3

Time-limited therapy may be a feasible option, even in the relapsed setting

“What this continues to demonstrate is the clinically-meaningful benefit of venetoclax-rituximab as a fixed duration, chemotherapy-free regimen that patients can tolerate and the majority can complete,” notes Prof. Seymour.³ “In the updated analysis we saw the 6- and 12-month PFS estimates after cessation of the venetoclax up around 92% and 87% respectively. When it came to OS, there was a clear benefit over bendamustine-rituximab with the 3-year rates from treatment commencement at 87.9% vs 79.5% respectively.”³

Thinking beyond MRD negativity, we can look to achieve undetectable MRD after relapse or treatment resistance

“We also presented the peripheral blood MRD kinetics data at ASH this year.⁴ The long-term data backs up what we saw in the original read-out from MURANO – the same pattern of undetectable MRD (uMRD) at the end of combination therapy.⁴ At the end of combination therapy [month 9], 62% of patients achieved uMRD with venetoclax-rituximab and by two years 48% of patients remained uMRD.⁴ For those on bendamustine-rituximab, only 13% at month 9, and only 2% at two years achieved the same.⁴ We saw consistent results in the high-risk subgroups, which was concordant with the PFS benefit we observed with longer follow-up,” added Prof. Seymour.⁴

The results of the MURANO long-term follow-up continue to demonstrate the value in assessing MRD status, even for novel targeted agents like venetoclax.⁴ There is now long-term evidence of distinct outcomes for patients based on MRD status for fixed-duration, chemotherapy-free regimens and the data corroborates the uMRD in addition to the intermediate-MRD positivity rate as predictors of disease progression.⁴

Additional evidence puts the benefit of venetoclax-rituximab fixed-duration therapy over 4 years from the follow-up of a Phase 1b study

Adding to the body of evidence from MURANO, follow-up data from Professor Seymour’s Phase 1b study of fixed-duration venetoclax-rituximab in relapse/refractory patients was also presented at ASH 2018.^5,6 Over a median follow-up of >4 years in 49 patients the overall response rate for venetoclax-rituximab was 86%, complete response rate 51% and MRD negativity rate 61%.⁶ The 4-year estimates for OS was 89%, PFS 61% and duration of response 88% for MRD negative patients (64% overall).⁶

“Again, what this study continues to demonstrate is the deep and durable responses we are seeing in the relapsed/refractory setting and that those patients with a deep response have been able to discontinue treatment and maintain prolonged, treatment-free remission, in some cases for more than three years.⁶ It is such exciting results that give us tangible markers of treatment success in patients and the confidence that meaningful periods of remission are still achievable in these difficult-to-treat patients,” concludes Prof. Seymour.

This article was sponsored by AbbVie, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of AbbVie.

References:

1. Seymour JF, et al. N Engl J Med 2018;378(12):1107-1120.
2. Thijssen R et al. Haematologica 2015;100(8):e302-e306.
3. Seymour JF, et al. MURANO trial establishes feasibility of time-limited venetoclax-rituximab (VenR) comblination therapy in relapsed/refractory (R/R) chronic lymphocytic leukaemia. ASH Annual Meeting 2018. O184.
4. Kater AP, et al. First prospective data on impact of minimal residual disease on long-term clinical outcomes after venetoclax plus rituximab versus bendamustine plus rituximab: Phase III MURANO study. ASH Annual Meeting. O695.
5. Seymour JF, et al. Lancet Oncol 2017;18(2):230-240.
6. Brander DM, et al. Durability of responses on continuous therapy and following drug cessation in deep responders with venetoclax and rituximab. ASH 2018. O183.