Strategies for Dealing With CLL Treatment Resistance

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Topics include: Treatments and Understanding

Inhibitors and targeted therapies have changed the landscape of CLL treatment, so what can patients expect from modern medicine? Dr. Jeff Sharman, from the US Oncology Network, joins our panel to explain the difference in design between newer therapies and chemotherapy. He also shares what newer medicines, like ibrutinib (Imbruvica) or idelalisib (Zydelig), are capable of and a patient’s potential for developing drug resistance while using them.

Provided by CLL Global Research Foundation, which received support from AbbVie Inc., Gilead Sciences, TG Therapeutics, Pharmacyclics LLC and Janssen Biotech, Inc., and Genentech. Produced by Patient Power in collaboration with The US Oncology Network, Compass Oncology, and Willamette Valley Cancer Institute and Research Center.

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Transcript

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. 

Andrew Schorr:

So, Dr. Sharman, I just want to understand now: we’ve had these medicines now, ibrutinib (Imbruvica) you were mentioning about four, five years. So one of the things that comes up in cancer is resistance. So I understand that the cancer cells are wily, and you kill a bunch of them but there’s some that kinda…went to the gym, and they withstand the treatment, and then they start proliferating. Where are we now with some of these medicines, on whether the cancer’s sort of breaking through. 

Dr. Sharman:       

Right. So the way I’ve kind of thought about treatment in the past is survival of the fittest. And as you point, some of them go to the gym, and so forth. What’s tricky about this conversation is the paradigm between the targeted therapies and chemotherapies are different. So with the traditional chemotherapy, it was a fixed-duration treatment and you sort of eradicated 99.99 percent of the disease, and that 0.01 percent that came back was this, sort of, super-clone, if you will. That was sort of the paradigm of resistance selection. 

With the new drugs, both ibrutinib and idelalisib (Zydelig) and the current label for venetoclax (Venclexta), these are drugs to be taken indefinitely. And so it’s not that we see this sudden eradication of all the cells with at least ibrutinib and idelalisib. And, in fact, we participated in one of the front-line studies of ibrutinib back in 2009, and I have a patient who still—I can see her CLL in her blood, despite the fact that she’s been on ibrutinib now for eight years.

What we’re learning though, is, as Michael alluded to earlier, there are some very specific mutations that confer resistance to ibrutinib. So, the way ibrutinib works is—I kind of think of BTK as like a Pac-Man if you will, it’s sort of a cell, it’s got a mouth—and the BTK inhibitor, ibrutinib, fits right in that pocket. And it actually attached to the protein right at the bottom of the pocket—there’s like a little super glue, and they just weld together.

Patients who have been on ibrutinib for a long period of time can swap out that landing spot, if you will, that super glue, and get a mutation in that protein—it’s Sistine-41 sirine—can change. And when that happens, ibrutinib and the other what we call covalent inhibitors, can no longer bind to that area, and so they don’t yield the same inhibition that they would otherwise. 

There are drugs now looking at inhibiting BTK by binding at an alternative location, so that that mutation might not be a problem. Or you could consider swapping to a different medication. There are other mutations in this protein called PI3 that can confer resistance as well—PLCgamma, excuse me—and so you can actually see these emerging, even in patients who appear to have stable disease, you can find these at times.

That test is not readily commercially available, and it’s not always sure who—whether or not insurance covers it, and so forth, so I think it’s not exactly a prime-time test. The most is known about ibrutinib. We don’t yet know about markers of resistance to idelalisib and venetoclax.

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. 

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Page last updated on December 21, 2017