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Understanding BTK Inhibitor Treatment Resistance in CLL

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Published on July 7, 2021

Expert Explains Resistance to BTK Inhibitor Treatment in CLL

In this segment, Christopher D'Angelo, MD, Hematologist/Oncologist at the University of Nebraska, answers questions about BTK inhibitor treatment resistance in CLL. What is treatment resistance? How and why does it occur? What are the available treatment options if a patient develops resistance? Keep watching to hear the answers to these questions and more.

Support for this series has been provided by Janssen Oncology and Pharmacyclics LLC. Patient Power maintains complete editorial control and is solely responsible for program content.

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Transcript | Understanding BTK Inhibitor Treatment Resistance in CLL

Dr. D’Angelo: Hi. My name's Chris D’Angelo, and I'm an assistant professor in hematology/oncology here at the University of Nebraska Medical Center.

What Is Treatment Resistance, and Can it Be Predicted?

Dr. D’Angelo: In general, use of BTK inhibitors like ibrutinib (Imbruvica) or acalabrutinib (Calquence) or any of the other options currently available, are ultimately fraught with risk of disease progression. And in general, since we think about CLL as a generally incurable malignancy, treatment resistance is probably at some point an inevitable outcome. That being said, while it's difficult currently to predict which patients are highly at risk of developing treatment resistance, the main mechanism that seems to happen is a mutation at the binding site of these drugs, where they're no longer able to adequately bind and cover, and actually do their jobs. That's not the only mechanism of resistance. There are certainly other ones. And this is an active area of research. But the encouraging thing is that there are strategies available with dealing with them.

If a CLL Patient Develops Resistance to a BTK Inhibitor, What Is the Next Treatment Option?

Dr. D’Angelo: The important part about managing a disease like CLL is that the treatment is very much a marathon and not a sprint. And the good news about this disease and, in something that's really revolutionized in the last decade or so, is that there are more and more treatment options available. One of the first things that one could consider, if they're experiencing either bad side effects on treatment, or if the treatment stops working as the CLL grows or begins to outsmart the treatment, is to consider an alternative agent. There are multiple different mechanisms that can be targeted, that can control CLL, and a variety of options that are very well tolerated overall and have a really good quality of life while they're on them. Even more so, some of the emerging therapies in the pipeline are still BTK inhibitors that are actually designed and work a little bit differently than the first-generation ones that are currently available, and can overcome some of the natural resistance or mutations that sometimes come up on patients that are treated with BTK inhibitors.

There are lots of different therapeutic strategies that are being targeted for CLL. Some strategies include combining different therapies, so if the cancer learns how to outsmart one treatment approach, it's very hard for it to outsmart another treatment approach if they're both given at the same time as a way of being extra effective.

Combination strategies using drugs that target multiple different pathways are emerging as very important possible future therapies for patients with CLL. Alternatively, there's active research in understanding the mechanisms of resistance that some of these drugs develop, or become at risk for, while patients are receiving them. In fact, we’ve actually opened a study here at the University of Nebraska that's looking at a new BTK inhibitor that can work and is as effective in patients with certain mutations that acquire after BTK inhibitor therapy. In general, the early studies on this also demonstrate its safety and how it leads to a really good quality of life for patients on it, so we're very excited about the opportunity for our CLL patients on this potential trial.

What Is Your Advice for CLL Patients Experiencing Treatment Resistance?

The most important thing here for anybody that is currently on a therapy or on a BTK inhibitor and the disease is starting to grow, and your doctor is recommending stopping treatment, is that there is still lots of room for hope available in this disease. There are emerging medicines and therapeutic approaches that are occurring on a regular basis. The University of Nebraska here are very much on the cutting edge of trying to be able to offer these therapies and learn more about them to better treat and care for our patients with CLL. Some of them are going to be new drugs. Some of them are going to be new therapies that use the immune system. You've heard about CAR T-cells, for example, in other types of lymphoma, and it's certainly an emerging therapy under investigation in CLL as well. The best part about this is if plan A doesn't work, there's a plan B, a plan C, and a plan D, and even more so for this disease. So, lots of options still remain available.

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