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Managing CLL Treatment Side Effects & Minimal Residual Disease (MRD)

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Published on November 9, 2020

Understanding MRD & Side Effects of CLL Treatment

What are the side effects of drugs used in CLL treatment, such as BTK inhibitors? What does minimal residual disease (MRD) mean? What is tumor lysis syndrome, and why is FISH testing important? Listen in as a doctor and two CLL survivors respond to these questions on CLL treatment side effects and MRD.

Dr. Brian Hill, Director of Lymphoid Malignancies at the Cleveland Clinic Taussig Cancer Institute, is hosted by Patient Power Co-Founder and CLL survivor Andrew Schorr and CLL patient & advocate Carol Preston as they explore these questions together.

This series is sponsored by AbbVie Inc., Genentech Inc. and Adaptive Biotechnologies. This organization has no editorial control. It is produced by Patient Power, and Patient Power is solely responsible for program content.

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Transcript | Managing CLL Treatment Side Effects & Minimal Residual Disease (MRD)

What is Tumor Lysis Syndrome?

Dr. Hill: So, as we talked about venetoclax (Venclexta) is very potent for CLL in particular, and we know that if you take the full dose, which is a 400 milligram strength pill, if you take this with a very high white blood cell count and big lymph nodes, that those cells are going to pop open, and we call that lyse, very quickly, and when too many of them pop up too quickly, we actually wind up getting a release of substances into the bloodstream that can cause very serious damage to the kidneys and so forth. So, that condition called tumor lysis syndrome is easily avoidable, by instead of giving 400 milligrams, we actually give just 20, usually, on the first dose, and we monitor folks, more often than not actually for overnight in the hospital.

You could do it as an outpatient and be monitored, but then after that 20-milligram dose is given and as long as it goes fine, then you stay on it for a week. And then a week later, you go up to 50, and then so forth, 100, 200 and 400. So, it takes about five weeks to get to the full dose, and I will say, with that approach, we don't have any major problems with tumor lysis, and all the other kind of CLL specialists I've talked to are all very comfortable doing this.

What is Minimal Residual Disease (MRD)?

Carol Preston: And this initialization of MRD. Can you tell us what it is? And what it means? And maybe can I discontinue treatment even if there is a little bit of measurable CLL cell in there?

Dr. Hill: What we historically have called remission for CLL, means essentially that you have normal blood counts and no big lymph nodes, and that means we can't detect with just a standard once over of the patient. That we can't detect it, maybe when we do a CAT scan and we don't see any lymph nodes, and then I have many patients, many people wonder if you can't detect it, why am I not cured? And the answer of course, is that the cells are tiny. So, it's sort of like scooping salt out of a glass of water, just because you don't see the salt you may still be able to taste it because it's still there.

Carol Preston: The MRD test, is that from regular blood testing? Or is that a bone marrow biopsy?

Dr. Hill: Right. Yeah. So, you can do MRD testing from the blood or the bone marrow. Sometimes people have no detectable, minimal residual disease in the blood, but if you actually then look in the bone marrow, you can find it.

So, the MRD test stands for minimal residual disease, and what this test can do is detect one in 10,000 cells, or even one in 100,000 depending on the test and the technology that's used. So, if you can't detect if you have less than one in 10,000, that's way down on this curve that is being shown, that means that we can't detect it - does that mean you really have zero? Or we just don't have a test that's sensitive enough to find it? And that's, I think, what time will tell. It may be that some people got the last cell gone and they're really going to go on to be cured, but we know that if probably, we know very well actually that if you have minimal residual disease, still detectable at the end of treatment, that your remission is going to be shorter and you're going to grow again in a shorter period of time.

Is MRD Associated with Improved Survival?

Carol Preston: But having said that, one of our audience members wants to know is MRD associated with improved survival? Is it a necessary cause and effect?

Dr. Hill: Yeah. So, it is associated with a longer, what we call, a longer time to progression. So, progression is sort of a funny term that doctors use, because progress sounds like a good thing, but when a cancer progresses, that's a bad thing. So, the time to progression, if you have no minimal residual disease, could be, let's say, eight years, whereas if you do a treatment and you still have minimal residual disease at the end, the time to progression maybe three years, for instance. So, longer remissions mean longer time to progression, and those, to say it associates with how long you're going to live, it hasn't been shown to really correlate and that probably is because we have so many good treatments so we can cycle through when the progression occurs.

What is FISH testing?

Andrew Schorr: Could you just explain what FISH is, so we don't get confused?

Dr. Hill: Right. Yeah. So, I think we've talked about three different tests today. One was the IGVH, which is the immunoglobulin mutation status, which is either sort of favorable or unfavorable. Then we have MRD, which is really something that's done at the end of treatment. FISH is a test and I'll tell you what the acronym means. It's fluorescence in situ hybridization, and hybridization means you take a probe that fluoresces and you look under the microscope with the cells, and if the cells light up with particular probes, then you can determine whether or not certain chromosome segments are present or absent within the cell. The FISH test is a panel that's commonly used at most U.S. centers to detect for about four or five different chromosome abnormalities. Most important of those is 17P, which I think we did allude to, and then there's a couple others; chromosome 11Q, and then chromosome 13Q, and then chromosome 12.

Is it Possible to Switch Treatments if I Am Having Side Effects with a Drug?

Carol Preston: And if I'm on one drug, but I'm having side effects, how easy is it to switch to another drug? Or can you?

Dr. Hill: Sure. Sure, sure. Yeah. So, if you have side effects from one of them, you can sometimes get away from, let's say headaches by taking a different one, and those switches now are actually easier, because we have more options than we used to.

Carol Preston: If I've been on one of these great drugs, but I've relapsed anyway - I certainly have relapsed - what are the options? Do you just go to another one?

Dr. Hill: Yeah, so we know that you can sequence these probably. The most more common sequence is for people who are treated in the past with chemotherapy, traditionally or more recently, the first targeted agent that's I think most commonly used is a BTK blocker. You can develop resistance to those, and in those cases, venetoclax actually, we know works very well. The opposite sequence where you start with venetoclax and then wind up going on to a BTK inhibitor, we're getting data now that show that that sequence is also effective.

Andrew Schorr: Carol, I just wanted to jump in for a second. So, we talked about, and Dr. Hill explained, venetoclax, very powerful drug. Tumor lysis syndrome had been a worry, they've learned to control it and ramp you up over time. You can have fixed duration therapy and MRD testing. If you have a BTK, which many people do, those go on and it seems like you can switch between, for instance, Imbruvica or ibrutinib and acalabrutinib (Calquence), and maybe there'll be others that come. Some people do, for instance, one of the concerns I've heard with ibrutinib is some people have atrial fibrillation. So, you're monitoring different things there too. There's no free lunch.

What Are the Side Effects of BTK Inhibitors?

Dr. Hill: Right. Yeah. So, early on when ibrutinib was introduced, I probably have many patients out there who literally wouldn't be alive today without that drug. So, it was such a ray of sunshine that we were all so happy to have it, and like many things as you use it more, you find out that there can be some side effects. And so, one of the side effects that was seen early on, and with time, we came to appreciate more, is that because this is something that you're taking by mouth and is going everywhere in your body, something that it's blocking in the conduction system of the heart can seem to trigger atrial fibrillation. Now we do see that with the other BTK inhibitors, but it seems like probably less so. So, if you develop or have symptoms like lightheadedness, or palpitations of atrial fibrillation while taking ibrutinib, you have to discuss with your treating physician or oncologist if it's time to switch or if you want to just treat the atrial fibrillation.

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