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Published on November 23, 2020
Doctors Consider New CLL Treatment Possibilities
The landscape of chronic lymphocytic leukemia (CLL) treatment is constantly changing and improving. Research is currently underway for new combination therapies, classes of BTK inhibitors, and clinical trials. With this in mind, what new CLL treatments can we expect in the near future?
Dr. Paolo Caimi, Hematologist/Oncologist at University Hospital (UH) Cleveland Medical Center, and Dr. Brian Hill, Director of the Lymphoid Malignancies Program at Cleveland Clinic Taussig Cancer Institute, joined us in a recent CLL Town Hall meeting to discuss new CLL treatments on the horizon and more.
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Transcript | Are New CLL Treatments on the Horizon?
Do CLL Drugs Work Better as Combination Therapies?
Dr. Caimi: The answer is probably yes. Those studies are actually being done right now, where we’re looking at a large scale, already we've done that in the smaller scale with less patients and shown that it's safe. But whether combining venetoclax (Venclexta) with a BTK inhibitor like ibrutinib (Imbruvica) or acalabrutinib (Calquence) with an anti-CD20 antibody, like rituximab (Rituxan) or obinutuzumab (Gazyva), and whether all those three together can work better and can achieve deeper control of the disease, will be set at MRD negative status and whether you can stop and have a longer period of time without requiring more treatment. From then, the longer horizon of treatments goes into newer and better drugs and the newer and better combinations of them in a newer strategy: cell therapy, immunotherapy.
Will There Be New BTK Inhibitors?
Dr. Hill: Cancer cells are really tricky little guys, and if they've learned that they can actually get rid of that little docking site for the drugs, then these drugs like ibrutinib and acalabrutinib which chemically make a chemical bond in that little pocket. If that landing site isn't there anymore, the drugs actually become ineffective.
And we actually know down to the molecular level, what this amino acid changes and the chemical composition of the BTK is, so resistance can develop to BTK inhibitors. Thankfully, we've known about this for a few years and there's already work going on to find... Well, if that little spot is gone, can we just do what's called a non-covalent blocker? Which is something that just kind of binds into the pocket without making a chemical bond to the protein. Can we use a non-covalent BTK inhibitor? And these actually work and they work, we think, when you have that little what we call mutation or acquired abnormality and resistant CLL.
Can You Switch BTK Inhibitors if You Become Resistant?
It's not going to work most likely because it binds to the same site. Referral centers usually have access to a test that can specifically ask the question if they have that change or not. That's the situation where you either want to move to venetoclax or there are ongoing clinical trials of these, what we call non-covalent BTK inhibitors. It's like an alphabet soup right now, one of them I think is called loxo and there are others out there that may eventually get a name that approaches normal English, but it'll take time to get there.
What Clinical Trials Are Available for CLL Patients?
Dr. Caimi: The trials that are ongoing include drugs like the one Dr. Hill mentioned, newer drugs, newer versions of the current drugs, like newer PI3 kinase inhibitors that we've mentioned are a little bit less commonly used in CLL, but there are versions that actually may be better tolerated than were before. And then come studies such as the ones for the cell therapies that are now being used in lymphoma, trying to figure out whether they work as well as in lymphoma, if they work in CLL. CLL, it's a lymphoma, but it has a few different characteristics. Then you need to validate how the treatments are working, how the diseases work here. Those studies are ongoing.
Another group of cells is called CAR NK cells, which is a different type of immune cell that can be modified and there are two types of those. Some of them are using your own cells, but I think probably what we'll see earlier maybe using donor cells that are targeted for patients. From cord blood, or from specific donors, depending on their marker. I think from part of what’s been coming from MD Anderson, already published earlier in the year. And I’ll be very interested to see if they work different or better than what we've seen so far.
How Do Combination Therapies Come About?
Dr. Hill: So, if you have a drug that's FDA approved for CLL, like let's say ibrutinib and another like venetoclax, that's FDA approved. They're not currently FDA approved to be given together. You really can’t give them together unless you know that it’s safe and effective to do that. There have been cases over the years where A is good and B is good but when you put A and B together, something unexpected happens. And so, usually when you’re starting off a new combination like this, we’re going to be doing a quick run-in to make sure the doses are appropriate to use together, and that’s called the phase one part. Then, usually, phase two means that you know the doses, you know it’s safe, and let’s go and see how well it works.
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