Venetoclax, or what used to be called ABT-199, is a targeted small molecule that specifically inhibits one of the anti-apoptotic proteins, BCL2. So it restores the sensitivity of these cells to the normal cell death processes.
What did you do with this particular study?
In this particular study, the so-called MURANO study, was in patients with CLL, chronic lymphocytic leukaemia, with at least one prior therapy, so relapsed refractory disease. Patients were randomised between standard treatment with bendamustine and rituximab for six cycles compared to the novel combination of venetoclax given orally for a total of two years together with six doses of monthly rituximab.
How many patients were you looking at?
389 patients, equally split between the two treatment arms, a median age of about 65. 60% of the patients had one prior therapy but overall 80% of the patients had been previously treated with FCR.
What did you find?
The primary endpoint of the study was investigator assessed progression free survival. At the interim analysis that was event triggered there was a very strong difference between the two arms with superiority for the venetoclax and rituximab. The hazard ratio was actually 0.17, so an 83% reduction in the risk of death or progression in the investigational arm. So at two years from enrolment the likelihood of being progression free was 82% compared to 36% with the standard treatment, so a very strong improvement and secondary endpoints were consistent with that. Two notable secondary endpoints were the rate of attainment of negative MRD status, so very deep remissions based on peripheral blood assessment. At the end of the combination period of treatment that was 62% compared to under 30% in the bendamustine arm. Also, overall survival, even with this short follow-up, was improved so that at two years that was 92% compared to 86% in the bendamustine arm.
What about the safety profile?
Yes, the safety profile, firstly the bendamustine was able to be delivered effectively without any unexpected safety events; this is the known standard treatment arm. In venetoclax plus rituximab, again there were no new safety signals. Importantly tumour lysis syndrome is a potential risk and there’s a carefully monitored weekly stepwise dose escalation with specific prophylaxis. But with those precautions even in these 20 countries and 109 sites the venetoclax rituximab was able to be delivered safely, a 3% incidence of biochemical tumour lysis but there were no clinical events. Other toxicity – the rate of neutropenia, grade 3/4 neutropenia, was relatively high at just under 60%, most of those in the combination treatment period, a low rate of 11% only during the venetoclax monotherapy period. But infections were uncommon so both the rate of pneumonia as the most frequent significant infection was actually lower with venetoclax at 5% than compared to bendamustine and the rate of febrile neutropenia with venetoclax was under 5%. So a relatively high rate of neutropenia but infrequent infections. The other common toxicities were low grade in terms of nausea, mild diarrhoea, but very manageable.
How can the neutropenia be managed?
In many patients the neutropenia is a laboratory phenomenon and is asymptomatic. Patients generally respond to brief or intermittent growth factor use but there were about a quarter of patients where there was some temporary dose interruption or dose reduction because of the neutropenia.
What are your conclusions?
The strongest conclusion here was that venetoclax and rituximab provide superior progression free survival and overall survival compared to bendamustine rituximab and even when that’s given on a time-limited schedule of two years of treatment. So venetoclax rituximab should be considered as one of the standard treatment options in the relapsed refractory setting and the time limited therapy with no chemotherapy exposure would have appeal for a number of patient groups.
