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The Long-Term Use of Ibrutinib for CLL

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Published on December 28, 2020

What Do We Know About the Long-Term Use of Ibrutinib?

Many chronic lymphocytic leukemia (CLL) patients remain on ibrutinib (Imbruvica) treatment for years. Are there long-term benefits, or side effects, to remaining on ibrutinib? Dr. Jennifer Woyach, MD, of the OSU Comprehensive Cancer Center and Patient Power co-founder and CLL patient, Andrew Schorr, discuss what experts have learned from patients and what side effects may appear later on in treatment. Dr. Woyach explains which symptoms can be managed and when a patient and their medical team should discuss changing treatment.

This program is sponsored by Janssen Oncology and Pharmacyclics LLC. These organizations have no editorial control. It is produced by Patient Power. Patient Power is solely responsible for program content.

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Transcript | The Long-Term Use of Ibrutinib for CLL

Andrew Schorr: Hello and welcome to Patient Power. I'm Andrew Schorr and I'm delighted we have one of the leading CLL experts with us, Dr. Jennifer Woyach from the Ohio State University and the James Cancer Center in Columbus, Ohio. Welcome back to Patient Power.

Dr. Woyach: Andrew, thank you. I'm very glad to be here.

Andrew Schorr: At Ohio State, you've had really long-term experience with one of the main CLL drugs now, ibrutinib (Imbruvica). And we've just finished the American Society of Hematology meeting where you this year got together virtually with your peers around the world. What do we know about ibrutinib now, because so many patients are on it and they're wondering the long-term benefit, monitoring, side effect management? What do we know?

What are the Long-Term Effects of Ibrutinib Treatment for CLL?

Dr. Woyach: Well, I think every year we learn more and more about this particular drug and this class of drug and really CLL therapy, in general, of course. I think things that have changed over the past few years related to ibrutinib, good news is in the upfront setting, so for people who are getting ibrutinib as their first therapy, we still don't know how long it's going to last because people's remissions are so long. I think the longest follow-up we have is still from the RESONATE Study, where at five years, about 70% of people were progression-free. In the relapsed refractory setting, so people who have had one or multiple prior lines of treatment for CLL, we expect that the drug has a median progression-free survival time of somewhere around four years. So between 44 and 52 months, depending on the study.

We know that certainly there are many people that can tolerate the drug for years and years. Other people have side effects that either make them come off of the treatment or require additional therapy. I think that's probably where we've had the biggest change over the past couple of years, is really understanding that side effect profile, things that happen early, things that happen late and what side effects can we manage through, and what side effects should we really change treatment for. One thing that has become more obvious as time goes along is that there are cardiac complications of ibrutinib. We see those especially in people who are a little bit older. This is primarily in the form of hypertension or high blood pressure, which often happens months to years after starting the treatment. And it's really one of the only side effects that is more common the longer people are on the drug. And then atrial fibrillation, which could happen really at any point.

With some of the newer BTK inhibitors, like acalabrutinib (Calquence), we have a little bit less follow-up data, but it does seem like some of those cardiac complications are decreased with a more specific inhibitor of BTK. That's something that we're really going to continue to keep our eyes on over the next few years. I think one thing I thought was very interesting at this ASH meeting, there was some real-world data presented with many patients, mostly treated in community practices. And if you look at real-world data from a few years ago, compared with today, and these were both presented by Dr. Anthony Mato, it seems like the rate of discontinuation is actually much lower now than it was a few years ago. I think suggesting that we're becoming better and better at managing side effects.

Andrew Schorr: Okay. A couple of questions for you. So CLL as a disease tries to find its way around medicines. So the medicine that may be effective, cancer tries to outwit it, if you will. I think you'd call that resistance, where the cancer cells are resistant to the therapy that maybe many of the cancer cells died from or were managed with earlier. Where are we now with long-term data about resistance to ibrutinib or ways to overcome that?

What is the Data on CLL Patients Who Become Resistant to Ibrutinib?

Dr. Woyach: We know that with ibrutinib, also with acalabrutinib, it probably was the ibrutinib. The majority of people who relapse with CLL do so because the BTK protein or the BTK gene develops a mutation that changes how the drug can bind to the protein. So normally, ibrutinib binds irreversibly. It clamps on to BTK, which is its target and then it never lets it go. The mutation that's the most common, it's called a C481S mutation, which is a cysteine to serine amino acid change, changes that binding from irreversible to reversible. So the drug, instead of binding really tightly, just weakly binds and falls off the target a lot. This year at the ASH meeting, we showed some data in collaboration with a number of different groups and Pharmacyclics, where we looked at samples from company-sponsored studies and looked at people who had been on the drug for years and years who hadn't relapsed. We actually found that mutation in about 30% of people who had relapsed CLL.

So, ibrutinib wasn't their first therapy, a much, much lower percent, only about 5% of patients who were on their frontline therapy with ibrutinib. We're starting to understand in very large groups of patients, how common those mutations are. The next step for that project is, from the time we can detect a mutation, does everybody relapse? And if so, how long does that take? At Ohio State, with our own institutional data, we saw that there was a median of about nine months between the time we can first detect a mutation and when the drug stops working. Hopefully, we'll be able to figure that out in a much larger group of patients.

We're also starting to see, there was some laboratory data presented at ASH showing how those mutant cells affect the cells around it and create a lot of disease that is resistant to a drug. The more exciting thing though, I think, especially for patients, is that with that knowledge we can actually develop drugs that target people who have progressed on ibrutinib. With the knowledge that these mutations in BTK confer resistance, a number of companies have developed what are called reversible BTK inhibitors. We've seen some data now with the reversible BTK inhibitors. LOXO-305, there was some data presented at the ASH meeting with that drug that's looking really promising. Hopefully, in the next few years that will actually be a standardly available treatment for patients.

Andrew Schorr: So just to sum up, Dr. Woyach, where we are now is ibrutinib remains a very positive medicine for many people, in some, quite long-term. In others, you continue to monitor to see, is there a reason to have a different option and some are in research now that could pay off in that way. Did I get it right?

Dr. Woyach: That's right. Yep.

Andrew Schorr: Well, Dr. Jennifer Woyach from the Ohio State University and the James Cancer Center in Columbus, Ohio, thank you for your devotion to CLL research and CLL patients. Thanks for being with us.

Dr. Woyach: Thank you very much.

Andrew Schorr: I'm Andrew Schorr. Remember, knowledge can be the best medicine of all. 


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