Published on July 2, 2020
Transcript | What New CLL Treatments Can We Be Excited About?
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Hello, and welcome to Patient Power. I'm Andrew Schorr, living with chronic lymphocytic leukemia for 24 years. So believe me, I want to know what the latest is. Joining us now from MD Anderson Cancer Center in Houston, Texas is Dr. Nitin Jain, who's a CLL specialist, and also on top of the research that's going on around the world. Recently there was the meeting, virtually from Europe, the European Hematology Association or EHA meeting. And Dr. Jain led one of the major oral sessions there virtually, of course now, during the pandemic. So, first of all, Dr. Jain, thank you for joining us again on Patient Power.
Thank you, Andrew. Looking forward to the discussion.
Okay. So, for patients, we want to understand, really, which way is research headed and what could it mean for us? Let's start with this. There's a class of medicines now called BTK Inhibitors, Bruton Tyrosine Kinase inhibitors, ibrutinib (Imbruvica), acalabrutinib (Calquence). There's one in trials, maybe others, zanubrutinib (Brukinsa), perhaps others. And so, there was some data about that. Tell us about that, let's start there.
Sure. As many of our CLL patients would know, there are several BTK inhibitors now in clinical trials and actually FDA approved. The first one in the market was ibrutinib and then more recently acalabrutinib was approved by the FDA. We also have another drug called zanubrutinib, which is not yet approved for CLL, but is approved for other disease conditions. At this EHA meeting, one of the abstracts that we presented was acalabrutinib monotherapy. Acalabrutinib was given just by itself as part of a phase I, phase II study, to patients with CLL who did not have any prior therapy. Acalabrutinib was their first therapy.
This trial is of importance because this is the longest follow up of these patients to see how durable these remissions are. As we know for patients who take ibrutinib or acalabrutinib for that matter, these drugs are supposed to be taken forever. There's always a concern about long term safety of these drugs or what will happen to their blood counts? What will happen with the other side effects? What Dr. John Byrd reported in this abstract session was that when they followed these patients long term, approximately four and a half years of average for these patients. What they saw is that majority of the patients were responding. In fact, upwards of 90% patients were in remission at the time of last follow up. Most of the side effects occurred early on, and it looks like thereafter it was a very well tolerated drug.
It did have some of the side effects, which we see with ibrutinib as well, such as atrial fibrillation. It also has an unusual or peculiar side effect of headache. There are some other side effects like diarrhea and things like that. But overall, the drug appeared well-tolerated and actually very few patients actually came off study because of the toxicities of the drug. I think this is an important drug for our CLL patients. The drug, as I mentioned, is already approved for patients with CLL. It is available to you outside of a clinical trial as well. There are ongoing trials right now, comparing head to head ibrutinib versus acalabrutinib, because those are the two kind of approved drugs right now. There is trials happening head to head comparing the two.
I think once we have those results, then we can maybe clearly see maybe which of these drugs is a better drug or safer drug so, those are happening. But again, I think it was reassuring to see that long term patients are doing well on these drugs.
Many people are on BTK inhibitors. I want to ask you about another class of medicines. I think this would be BCL-2, you have venetoclax (Venclexta). And so venetoclax has been approved with a monoclonal antibody either I think rituximab (Rituxan) also with obinituzimab (Gazyva), so you get an infusion for a while and then you continue, or you take the pills for a while, hopefully where you can stop after two years. But I understand there was data presented on using venetoclax by itself. So how does that look?
Yeah, so that was a very interesting trial presented, which is called a VenUS I trial. That's just the name of the trial. But what the investigators did was the patients with CLL who had prior therapy for their CLL. So let's suppose they had chemotherapy with bendamustine (Bendeka) or FCR or chlorambucil (Leukeran) or some other therapy for their CLL, and then their disease progressed. So the investigators gave them venetoclax just by itself. They did not give them with an antibody. For example, normally at least in the United States these days, you would combine it with rituximab (Rituxan) in the relapse refractory setting. But the investigators in this trial just gave venetolax by itself and what they found was at the two-year mark, approximately 80% of the patients are still in remission, what is called progression free. So, that looks pretty good. One of the other markers we try to follow in the clinical trial setting specifically is what is called MRD, meaning that whether the patients had disease by a very sensitive assay, generally, it's a detection of one cancer cell in 10,000 normal cells.
So if you don't see a cancer cell at that level, then you say it is MRD negative remission. And the investigators did that. And approximately 35 to 40% of the patients were MRD negative or undetectable MRD we call in the medical terminology. Now, I guess I think this is an important abstract, important work, which we need to see how patients do a bit long term after they start when they will stop the therapy at two year. And then we'll have to eventually compare these data to what we know about the data we have, where venetoclax is combined with the antibody.
So the most important trial in the field is what is called the MURANO study, where similar patients were given venetoclax plus an antibody and in this trial was venetoclax alone. So I think at the end of the day, we have to compare these two trials and see if we can get some input of which may be a better approach. Just on the face of it, it looks like adding an antibody does increase your chances of getting that deep remission of MRD negative remission. But eventually we have to see how these patients eventually do long term two, three years down the line. So, that's again an important abstract, which I think we all would be looking forward to in future for updates.
Okay. And in this study, you're talking about people were given venetoclax for two years and then stopped just like they're doing now where there's the addition of the antibody, right? It wasn't really taking pills.
Correct. Correct. That's what my understanding is that the patients stopped it. I'm not sure if for certain patients were allowed to continue longer than two years. I need to check on that. But I don't think the intent was to have a continuous long term therapy.
Okay. All right. So BTK inhibitors, continuing therapy, venetoclax may be not with or without an antibody in that scenario of research. All right. Now, one last thing I want to ask you about is combinations in the data from the EHA about combining drugs, just like we've had FCR or BR. Typically in cancer, sometimes you say you get a bigger bang if you combine medicines that work synergistically. So what about in CLL?
Yeah. So there were actually a couple of abstracts, which I would highlight, which combined the drugs we just kind of talked about. So one abstract combined ibrutinib with venetoclax and with obinutuzumab. So three regimens together, three drugs together. To are pills, ibrutinib and venetoclax and obinutuzumab is the IV CD20 antibody. So the investigators from Germany, what they did was they did a trial for patients who had no prior therapy. But the trial was designed specifically for patients who have this very high risk feature called deletion 17P or P53 mutation. So that's I think one of the important markers you should know about your disease, and I'm sure your doctor would be checking for it, that whether you have a deletion 17P or a P53 mutation. So the investigators just focused on those patients because we know these patients do well with new therapies, but still their outcomes are not as good as if they did not have these markers.
So they enrolled 41 patients with this high-risk marker and they give them these three drugs together for over one year. And what they reported was that, again, the majority of the patients responded with this regimen, they achieved MRD negative remission, and then they were able to stop the therapy at the specified time point, and then they were in remission free. So I think that's very kind of an important landmark in a way to see that the patients were responding. Now, I think a big question in the field is that whether you need all the three drugs together. Could you have accomplish this by just using two drugs? We and others have done work with combining ibrutinib plus venetoclax together without the antibody where also we see something of a similar result. Or could you just achieve it by combining venetoclax with obinutuzumab and you don't need the ibrutinib part of it?
So I think that's the big question in the field which is not answered by this study, but I think this study does provide another kind of a dataset that what would happen if you combine the three drugs together. And I think the important thing about this study is it's only focusing on the worst of the worst, in a way, the patients who really need really effective therapy to get the permission. So the study did show the remissions, but I think the question is whether you need all the three drugs. And I think one other study which I would like to highlight, which is also what is called now, we call it triplet study in the field of CLL.
Triplet is all three drugs together, or all the classes of drugs together was a trial, which was reported by Doctor [inaudible 00:11:13] from Memorial Sloan Kettering, where he and investigators did three drugs, zanubrutinib, which is a pill not yet approved for CLL, venetoclax, and obinutuzumab together for again, newly diagnosed patient with CLL who need treatment. And these investigators again, showed very high rates of remission, the short comparatively less neutropenia than some other studies have shown. And they also showed very high efficacy of this regimen.
So again, that's a relatively new trial. On an average patients were followed for less than one year. So I think we have to see how these three drugs together would do, because we also know there are other three drug combinations together, which are being pursued, which was not presented at the EHA meeting, but have been presented previously at ASH and other meetings. So I think at the end of the day, I think in the next one year or so, maybe in the next one to two years to say, we would know when all these combination regimens, when we'll see a further update of this data and try to figure out maybe which one is the best for an individual patient. So I think that was some of the updates from the EHA.
Okay. Thank you for doing that. I just want to see if I can pull it together. So you're on faculty there. Let's see if I get a good grade. Okay? So BTK inhibitors, there was positive data with acalabrutinib, and you're going to be measuring different BTK inhibitors as to what works, lowest side effects. These are pills you continue to take to control your CLL. Then there is whether you can take a different class of drugs, venetoclax in this case, and you can stop and do that just by itself and there's promise there.
And then there's also the combinations, particularly for the sickest patients. Do you throw more at it approaching the CLL cells with different mechanisms of action to help those people who otherwise have very aggressive CLL? Did I get it right?
Yep. Perfect summary.
Okay. Thank you so much. And of course, we'll talk more. You mentioned the ASH meeting, American Society of Hematology meeting now six months in the future. What will we know then? And we'll report that on Patient Power. Dr. Nitin Jain from MD Anderson Cancer Center in Houston, thank you so much for being with us.
Thank you, Andrew. Thank you, everyone.
I'm Andrew Schorr. Remember knowledge can be the best medicine of all.
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