Published on April 24, 2020
- The next wave of clinical trials is looking at time-limited therapy, with a goal of getting the patient into remission and then stopping treatment.
- BTK inhibitors cut off cell signaling, causing cancer cells to die. When combined with monoclonal antibodies, they’re even more effective.
- Other areas of research include new BTK inhibitors to address drug resistance and improving CAR T-cell therapy.
How have chronic lymphocytic leukemia (CLL) treatments evolved over time? Is there a new world of treatment options? Dr. Ian Flinn, a CLL expert from Tennessee Oncology, and Nurse Practitioner Camille Ballance, answer those questions as they share the latest news and updates with Patient Power Co-Founders Andrew and Esther Schorr.
Watch as they discuss the shift from traditional treatment approaches like FCR chemotherapy to targeted therapies and time-limited therapies. They also share what new topics researchers are working on now to advance CLL therapies for the future.
This program is sponsored by AbbVie, Inc., Genentech, Inc. and Adaptive Biotechnologies. These organizations have no editorial control. It is produced by Patient Power in partnership with Tennessee Oncology, Bag It, and CLL Society. Patient Power is solely responsible for program content.
Transcript | A New World of CLL Therapies
Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, contributors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. That’s how you’ll get care that’s most appropriate for you.
Hi there, this is Esther Schorr. Recently, Andrew and I co-hosted a virtual town meeting and learned from leading CLL experts about treatments, clinical trials and lots more. Let's listen in as we navigate through a CLL diagnosis.
So when somebody's newly diagnosed, do you tell them, "Well, we've got pills now you can take at home, sometimes used alone or in combination, sometimes it might go along with some infusion you might have for a while, and we have other pills, for example, in trials." So, Camille, you have a whole range of things now to talk to people about, right?
Yes, if we're seeing a new patient—I mean, we put patients on targeted agents. I have not seen Dr. Flinn order FCR since I've been working with him. And also, we have so many clinical trials that are really, really great, and really, really effective, and I feel really lucky to work at a place that we can offer that to our patients. So yeah, I usually talk about ibrutinib (Imbruvica), one of the BTK inhibitors, or venclexta (Venetoclax) and obintuzumab (Gazyva) and then maybe a clinical trial, but I leave that to Dr. Flinn, because he has more of an idea of what he's going to want to put them on, and what may be coming down the road.
Dr. Flinn, let's understand these treatments now, then. So first of all, you mentioned FCR, fludarabine (Fludara), cyclophosphamide (Cytoxan), two chemos, and rituximab (Rituxan) were added, a more targeted monoclonal antibody. And I had that, I was in the Phase II trial, so an earlier trial back in 2000, so a long, long time ago. And it worked for 17 years, but it was this chemoimmunotherapy approach, and Camille was just saying well, you don't really do that now. So, what's the shift that's gone on, Ian?
Well, I mean, you were on the forefront of treatment at the time, but it's really evolved. We now have numerous clinical trials showing pretty much any chemotherapy, chemoimmunotherapy option you could want, whether it's FCR, bendamustine (Treanda), rituximab (Rituxan), even obinutuzumab and chlorambucil (Leukeran). Immunotherapy-based regimens, there are very large randomized trials that show the targeted therapies are better than that. So ibrutinib, either alone or in combination with a CD20 antibody, or venetoclax in combination with obinutuzumab, they're superior to these other regimens.
There's one small group for which there's some academic debate, and that's for people who have the very, very best CLL in terms of their risk factors for progression, and based on very long follow-up data with FCR like you received, there's a group of people that tend not to relapse from that. So there’s a small group that might benefit from that, but when I had that conversation with people, I'd say, "Would you consider..." And I don't see these people very often, because usually the people I see are high risk. But when I see these patients and I say, "Would you like to receive chemotherapy, or would you like to receive one of these targeted therapies?" The conversation, frankly, is quite short. They make it quite short, and they don't want to do that, and I think that's reasonable.
And we do know that there are long-term side effects of chemotherapy, such as mild dysplasia and other second cancers, so I support that. So now it's all about these targeted therapies, and that's even evolving, right? So we were in an era where you would take one of these targeted therapies indefinitely, such as ibrutinib or acalabrutinib, and now the biggest thing is about—no one likes to take a pill for forever, and so now the next wave of trials that's going on is looking at using what's called time-limited therapy. Getting someone into a very deep remission, MRD-negative remission, using generally venetoclax in combination with either obinutuzumab or ibrutinib or acalabrutinib (Calquence), one of the BTK inhibitors, or all three drugs, and then seeing for a year and then trying to get them off. And so that's where the trend is right now.
You mentioned BTK inhibitors, and there are these other kind of inhibitors. So, Camille, I don't know if you want to comment, what are they inhibiting? What does this mean? What are they inhibiting?
Yeah, has the cell not proliferated, or what does it do?
Yeah, it basically cuts off cell signaling. So cancer cells proliferate by receiving different signals from cells, and it basically cuts off those signals, is what it does. It inhibits BTK so that the signals stop basically, and then the cell dies, because it can't proliferate.
Well, I'm for that. So, Dr. Flinn, you talked about combination. So FCR was a combination, or bendamustine-rituximab was a combination. So you're talking now moving to the age of combinations of oral therapies. They're inhibiting the cancer cell in different ways, Ian, is that the idea?
Yeah, exactly. So Camille described the B-cell receptor pathway, where the lymphocytes proliferate through external signals through the B-cell receptor, which is present on the CLL cells. Well, there are other pathways that are important to this as well. So for instance, venetoclax inhibits something called Bcl-2, which is basically a break on cells going through their normal cell cycle and dying, and so by blocking that it allows the cells to go ahead and die. And so, combining a BTK inhibitor with a Bcl-2 inhibitor is one strategy, combining either of these agents with monoclonal antibody that targets receptors on the outside, or antigens on the outside of the cells is a third strategy. Using any two or any three of these drugs is very attractive, and generally in most series gets people into a better and deeper remission.
Okay, so it's a one-two punch, or a one-two-three punch we're moving to. But many people are doing well on single therapy, too. So you may start somebody on one, not in a trial but just with approval, right? And that could work, and then you assess it over time, right, Ian?
Yeah, exactly. I think that truthfully outside of the—we don't have a lot of evidence except for the venetoclax and obinutuzumab therapy that's been approved, we don't have a lot of evidence that combining these drugs is better than just giving a single agent. And there's a huge debate, honestly, about whether we're better off using these things concurrently, giving them together or sequentially, and that's really not known. I mean, I think there's some empiric value or interest in trying to get people into really deep remission and then off of these therapies.
The problem with the BTK inhibitors is that generally once you start them you're staying on these therapies forever as long as you're tolerating them.
Okay, and then just so people understand, that's ibrutinib with the trade name Imbruvica, or acalabrutinib, trade name Calquence, those are the approved BTK inhibitors. There are others that I know are in trials. So those are the BTKs, and then you have the Bcl-2 inhibitor is venetoclax, known as Venclexta, right? And then you mentioned monoclonal antibodies, I just want people to understand that. That was the R in FCR, rituximab, targeting a protein on the outside of the B cell. CD20, that Dr. Flinn referred to, and then later came a newer one called obinutuzumab, also known as Gazyva. Did I get it right, Ian?
You sure did, and just to explain a little bit more. I mean, so a lot of people think that Rituxan/rituximab, or Gazyva/obinutuzumab, these antibodies, that they're chemotherapy. They're not, they're immunotherapy. We can make antibodies that if we gave you a flu shot, right? You would develop an antibody that protects you against the flu. We can make antibodies in the laboratory that target pretty much anything we want. The most common thing is a protein, an antigen on the surface of the CLL cells called CD20, and that's a very popular target, and there are many CD20 antibodies, the two you just mentioned and others in development.
So people get into a remission, Ian, but they may come out of it. So how do you decide what to do then?
Well again, I generally watch and wait. So just because it comes back, depending if you're on chemoimmunotherapy, or depending on what you're on, just because someone's progressing doesn't necessarily mean that you need to dive directly into another therapy. But let's say you do meet the reasons for being treated again, well then it's all about what you had before, right?
If you had chemoimmunotherapy or PI3 kinase inhibitor or ibrutinib, if you've had that before, then you would generally switch classes to a different class of drugs. And so again, I think today the most common frontline therapy is a BTK inhibitor. So if someone had a BTK inhibitor as frontline therapy, then most likely you would switch to venetoclax in combination with one of the antibodies.
So I've got a question from somebody in the audience saying, "What's next? Can you as experts tell us what's on the forefront coming after that?" Because patients and care partners are always looking like, "Okay great, this worked now, but what's my next plan if something happens?"
Sure. I mean, I think one of the hottest areas of research in terms of novel agents, instead of combining these things or how you do that, is looking at why someone becomes resistant. One of the reasons that someone becomes resistant to a BTK inhibitor is mutations, and how the drug binds to the CLL cells, and it's called a C481 mutation. And so there are now a whole host of new BTK inhibitors that get around this problem, they're called non-covalently bound BTK inhibitors, and that's a mouthful, but basically you should know there's a next generation of BTK inhibitors that are being designed to overcome the issues with resistance with the first generation.
I think there are also a variety of other immunotherapies that are trying to be developed. Probably the most prominent one is CAR-T cells that are being developed, trying to make them better, safer, easier to give is where the research is right now.
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