Venetoclax + Rituximab in Relapsed CLL

Transcript:William G. Wierda, MD, PhD: Let’s move on to salvage treatment or treatment for relapsed patients with chronic lymphocytic leukemia [CLL]. The MURANO study was reported last year as a late breaker. This was a randomized trial for relapsed patients with CLL. Patients were randomized to bendamustine/ rituximab, or venetoclax plus rituximab, both as a fixed duration of treatment. That showed an improvement in progression-free survival and there was an improvement in overall survival favoring patients who received venetoclax/rituximab.

The venetoclax treatment in that trial was for 2 years, 6 months or 6 cycles of rituximab initially, and then a total of 2 years of venetoclax. And most of the patients were still on treatment when we saw the results last year of that trial. The trial was updated this year 2018 and there were a couple of abstracts that reviewed different aspects of the data from that clinical trial. But I wonder, Susan, if you could comment on what the updated clinical data were from MURANO and why that was important for us.

Susan M. O’Brien, MD: You’re right. Last year 2017 at the presentation, which was around the same time that the paper was published, they had about 50 to 60 patients that had completed therapy, but the median follow-up of those patients was 3 months. So they couldn’t say anything. So this presentation was very important because what it showed us is what happens when you stop therapy. And it is very clear that there’s a change in the progression-free survival curve where it does start to go down. I wouldn’t say it plummets, but it does start to go down at the time that people are discontinuing. However, only a minority of the patients had progressed with another year of follow-up. So that was quite encouraging.

It will be important to get these follow-ups every year to see how durable these remissions are. Because it’s great to talk about time-limited therapy at 2 years, but, and I don’t think this will happen, if everybody had relapsed by 4 years, that sort of defeats the purpose of your time-limited therapy. So, again, we did see some drops on the progression-free survival curve. Not unexpected, but I wouldn’t say that it was plummeting, and most of the patients were still in remission.

Matthew S. Davids, MD, MMSc: If I could just add, I think that one of the potential advantages of the MURANO approach is the simplicity of having a 2-year time-limited regimen for all. And we would love to have that if that could be proven to be valuable. But I think what we’re learning here is that the MRD [minimal residual disease] status at the end of the 2-year period actually may make a big difference. And so those patients who are MRD detectable at the end of the 2 years, actually most of them have progressed relatively quickly after stopping. And so I think this speaks to the point that we may need to incorporate MRD testing to know when to stop these time-limited treatments.

The other thing that was interesting in the presentation is that they were testing MRD serially, even when the patients were on treatment. And it was noted that several of these patients who are MRD detectible at the end of treatment had earlier time points where they were actually rising their MRD, suggesting that perhaps continuing that therapy of venetoclax for longer may not be the optimal approach, and that rather either something should be added or maybe even the patients should switch to a completely different therapy.

William G. Wierda, MD, PhD: Perhaps the other comment that I would add is in terms of the patients at risk for progression after discontinuation of the venetoclax. It appears that perhaps 17p deletion was a factor that was associated with increased risk for progression. I’m interested in MRD. Alexey, we can talk a little bit about MRD and where it’s coming into management, or not coming into management, but where is it important? Where are we seeing data generated? What agents are important for MRD?

Alexey V. Danilov, MD, PhD: Of course MRD has been implicated in treatment prognosis since the chemoimmunotherapy age. The CLL8 study demonstrated that patients who achieve undetectable MRD have better survival, and with novel therapies it wasn’t so clear until this ASH [American Society of Hematology annual meeting]. We have known before that patients who are on a BTK [Bruton tyrosine kinase] inhibitor such as ibrutinib do not actually achieve MRD. The MRD right there is really in single percentage points, for both previously untreated and, in particular, relapsed/refractory patients. So this is not where MRD would be of importance in single-agent treatment, I believe.

In the MURANO study, as Matt has already alluded to, there was close to a 60% rate of undetectable MRD on the venetoclax in the rituximab arm. So this is clearly an agent that can achieve deep remissions. Just by comparison, on the BR [bendamustine/rituximab] arm, the rate of MRD was only 2%, and they didn’t do much of an analysis among those patients because the numbers are so small. However, how to use it is still not entirely clear. And the reason is, as Matt has mentioned, there has been a drift from the undetectable MRD group towards the intermediate MRD, or detectable MRD, while patients are on therapy with venetoclax. That suggests to me that more venetoclax beyond the 2 years as initially planned is probably not the right answer for those patients.

I think ultimately though, I agree with Matt. How we can use MRD is to determine what is the right combination where we can know this earlier, say after 3, 4 months. And the iFCG study is a very good example of that. In that study, a combination of FC [fludarabine/cyclophosphamide], Gazyva [obinutuzumab], and ibrutinib achieved 100% bone marrow MRD at later time points. So I think combination studies are where we will see the high rate of MRD both in blood and bone marrow, and this is how we can learn what is the right combination so that we can stop therapy early.

And in terms of venetoclax, I still agree with Matt. I think that right now I would say if somebody drifts the MRD status toward detectable, I don’t need to change therapy. If you have to, you stop the drug and watch, or add another novel agent.

Transcript edited for clarity.