Venetoclax Plus Rituximab in Relapsed/Refractory CLL

Nicole Lamanna, MD:The MURANO data was the study that looked at—and, again, this was updated; this isn’t the first time it’s being presented at ASH [American Society of Hematology], but at least now we have about a 3-year follow up; it was last a 2-year follow up. For relapsed/refractory patients with CLL [chronic lymphocytic leukemia], it looked at venetoclax/rituximab versus bendamustine and rituximab. This was another highlight that some of these novel agents are replacing chemoimmunotherapy. And the data were significantly improved for the venetoclax/rituximab combination, for both PFS [progression-free survival] and overall survival.

What was interesting about this data is that some of the earlier venetoclax trials looked at minimal residual disease [MRD]. So what does this mean for patients in practicality? Now, this isn’t really mainstream or standard yet, but this is coming. And what minimal residual disease is, is that in folks who are treated, whatever therapies they’re getting with CLL, we do not detect any evidence of disease. So CT [computed tomography] scans are normal, bone marrows are clean, which means that at least in the olden days that’s what we would do. We would actually perform their bone marrow and making sure their flow cytometry was negative as well. So not only was the bone marrow clean, but even by minimal residual disease or a more sensitive method of detection, such as flow cytometry, was negative as well. And those were considered true MRD-negative patients.

Now, technology, fast-forward to today, has obviously improved and there are more sensitive methods of detection for minimal residual disease. And this is a whole other conversation that’s going to go on because what level of detection we should do is going to be in flux as well. But years ago with chemoimmunotherapy we would get patients into a complete remission but they would still have minimally detectable disease. In other words, we still know they had some floating circulating cells around. What did that translate? So, when patients got either bendamustine, or rituximab, or FCR [fludarabine/cyclophosphamide/rituximab] therapy, they received 6 cycles of those therapies. They were monitored again until such time that they really needed to be treated again. They had bulky disease or they had cytopenias. And then they would be treated again.

When we looked at MRD in the era of chemoimmunotherapy, there were great responses, but the MRD data were less. So if 50% of patients, let’s say, received a complete response to FCR, somewhere around 25% to only 30% were truly MRD negative. Now, when we looked at that data, what was significant though is those individuals who were truly MRD-negative, their response duration was much longer. So they did better. When you broke out the folks that had a little bit of disease versus the folks that had none, even if they were both complete remissions, they tended to last longer. And so we’ve always been pursuing this notion of MRD, hoping that if we can get patients with no detectable disease intuitively, that perhaps these individuals would be ultimately cured from their disease.

Now fast-forward. So we couldn’t really meaningfully act on that. We just knew that they were better individuals, and they did better with that therapy. But in the era of chemoimmunotherapy, that was as far as we took it. Now in the era of these novel therapies, such as venetoclax, there were some inklings that on some of the early phase I studies with venetoclax that we were able to get, even early on, patients truly in MRD-negativity. So there was no evidence of their disease. And so when that initial inkling came on the beginning studies with venetoclax, this was something that we considered. Could we exploit this to the advantage of combination therapies or even looking, fast-forward, at how we can end in a time-limited duration, are there ways to tweak these therapies so patients wouldn’t be indefinitely on oral therapies?

As most individuals right now are doing, for anybody who gets started on ibrutinib, you take it indefinitely unless you’re intolerant, or you have an adverse effect, or you’re progressing. So that was very different than the strategy of chemoimmunotherapy where you got a course of therapy and you were done. These therapies are being given continuously like chronic therapies as they would be for high blood pressure or diabetes. So now when we got in evidence that these therapies possibly can render very deep remissions, can we exploit that further?

So in addition to the MURANO study showing that individuals who received venetoclax and rituximab did better than bendamustine and rituximab, we also were able to look at MRD with the combination. And again, I remind you that this study was in the relapsed/refractory population. We saw significant levels of MRD negative, even in a relapsed patient population with the combination. And I think this is significant. We were able to break that data down, looking at completely undetectable MRD, low levels of MRD, and high levels of MRD. And even amongst them, you can see that the progression-free survival was pretty good. But there was no doubt that the patients who had a higher level of minimal residual disease, some of them eventually progressed slowly. And so we can then possibly use this data to fine-tune what we’re doing to patients in real time. Can we tweak things going forward? Will this enhance our next generation of clinical trials as we start looking at combinations? And then, can we stop therapies, right?

Some of these studies are looking at venetoclax that will end at 12 months or venetoclax in combination with something else at maybe 24 months. And so can any of this information going forward help us break that down and say what is the ideal timing and ending of a combination strategy, or can it be based on the biology of that patient’s disease? For patients who have high-risk features, who have 17p or p53, or who are unmutatedIGVH, should those guys be kept longer because they’re the ones who have the high MRD? Perhaps we should be treating them a little longer than the majority of the group who have low or undetectable disease. Maybe they could just quit at 12 to 18 months.

I think all these presentations at ASH this year are very significant in showing that there’s a pathway forward. We might be able to look at MRD and finally use this information, which we tried to do in the chemoimmunotherapy era. But now we can use this to look at whether we can adjust these therapies, have time-limited duration, hopefully spare patients extra toxicity than being on continuous therapy, and save costs. Because many of these medications are extremely expensive, and if you have to stay on them for the rest of the life, what does that mean financially? I definitely think that this meeting is very significant with presenting some of this initial data that will need longer-term follow up, of course.

So let’s talk about reintroducing therapy. If we look at time-limited duration of therapy with some of the venetoclax combinations, what can we do? The MURANO study is an example of this. Individuals stopped the venetoclax actually at the 24-month mark, so at 2 years. But we amended the protocol … so they’re monitored, of course, for progression. And, if they do progress, they have the option of reintroducing therapy with venetoclax. And this is also going to be very important. If we’re going to limit any of these combination therapies and say somebody is going to be on it for X amount of time, if they should progress—and that’s going to be important—when they do progress, are they going to sensitive again to the same agent, or have we changed the kinetics of their disease?

And so, again, there was some initial data from some of the earlier venetoclax studies that when patients progressed and they were allowed to go back on venetoclax, they went back into remission. I’m not going to believe this is all patients. I mean, the data are very immature, but that’s a very important finding. So, if folks can go back on the same agent that they might have had years before and still be sensitive to the agent, that allows us to then do something like time-limited duration of therapy and spare extra time and have people off drug. We’ll obviously need to see if this is going to be with all combinations, because there are many combination strategies being looked at with venetoclax. Or will that be all the different combinations? And, obviously, what is that response duration in between? Is it short? Can we break that down again by their levels of the minimal residual disease or by the patient’s cohorts?

If they have adverse features, those guys are going to relapse sooner. Do we keep them on sooner from the get-go and then see what happens? So I think there’s a lot of unanswered questions, but I think it’s promising that a study like MURANO is allowing patients to do that because then we’ll get more information about these individuals and whether they’re sensitive again when rechallenging them with venetoclax.

Transcript edited for clarity.