Published on November 21, 2018
What is the relationship between genes, prognosis and treatment decisions? How does a chronic lymphocytic leukemia (CLL) patient’s genetic profile impact disease course? During this Genetics 101 replay, esteemed CLL experts Dr. William Wierda, from The University of Texas MD Anderson Cancer Center, and Dr. Jennifer Brown, from Dana-Farber Cancer Institute help viewers understand the clues genetic testing reveals about disease behavior and how this knowledge can lead patients to more suitable treatment options. The panel breaks down the patient subsets of CLL by mutational status, explains how genetic test results help distinguish high- and low-risk disease, and discusses what tests are used to identify specific mutations seen in CLL. Patient advocate Michele Nadeem-Baker also shares how her understanding of genetic testing influences her journey with cancer.
Provided by CLL Global Research Foundation, which received support from AbbVie Inc., Gilead Sciences and TG Therapeutics. These organizations have no editorial control. Patient Power is solely resposible for program content.
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Transcript | Replay: Genetics 101: Everything You Need to Know About Genetic Testing and CLL
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.
Hello from Southern California, near San Diego. I’m Andrew Schorr from Patient Power. Welcome to this CLL Global Research Foundation Program, Genetics 101, Everything You Need to Know About Genetic Testing and CLL, it’s produced by our organization, Patient Power.
This program is provided by the CLL Global Research Foundation with funding from AbbVie, Inc., Gilead Sciences and TG Therapeutics. We thank them for their support—a reminder, of course, that they have no editorial control. That all comes from us wo are participating in the program. Now if you have a question, send it to [email protected], again that’s [email protected]—again, remember nothing too specific, so we can all learn from it. And as you listen to today’s program, remember to discuss it with your own doctor, so you get what’s right for you.
All right. Let’s meet our expert panel. So, let’s first go to Houston, Texas, and the MD Anderson Cancer Center, where we’re joined by Dr. William Wierda. Bill, thank you so much for being with us. I know you’re the Director—Medical Director in the Department of Leukemia in the Division of Cancer Medicine at MD Anderson. Thanks for being with us, once again.
Thanks for having me, Andrew.
Pleasure. Okay. And now, let’s skip over to Boston, to another really top cancer center, and that is the Dana-Farber Cancer Institute, where we’re joined by renowned CLL specialist, like Dr. Wierda, and that’s Dr. Jennifer Brown, who is the Director of the CLL center there. Thank you so much for being with us, Dr. Brown.
All right. And we always have a patient with us, not just me, but someone else who is living with CLL. And so, we have one of your patients with us, Dr. Brown, also from Boston, that is Michele Nadeem-Baker, living with CLL, and treated started in 2015. Michele, thanks for being with us. Oh, Michele, you’re muted.
Thank you for having me.
Michele, so let’s just hear a little bit of your story, just so we know. You, of course, were diagnosed not at Dana-Farber but chose to go to Dana Farber to see a renowned specialist, Dr. Brown. And then, it came up in discussion about being in a clinical trial, so you actually entered a clinical trial, right?
I did. I’m in a Phase II clinical trial, which is what a lot of people know about, who are watching today, FCR and ibrutinib (Imbruvica). I have been on the trial for three years this month—I can’t believe it’s been that long. And it started out with FCR and ibrutinib for the first six months, and ibrutinib ever since. And a clinical trial, I was really seeking that so that I could get advanced treatment today. And since it was Phase II, I knew that most of the risks were mitigated. But—there was a chance.
And some other clinical trials at Dana-Farber, some specifically for Jennifer Brown, some for Dana-Farber as an institution, and they’re following our family history and geneticists, and all of that.
That’s correct. That’s correct. And Dr. Brown can speak much more eloquently on that than I.
So, Dr. Brown, let’s just find out. When somebody comes to Dana-Farber today, what testing do you do to get a clear picture of their situation? And also, be able to follow people as we learn more about CLL.
Right. So, we do have quite an extensive evaluation, right, at initial presentation or diagnosis, and that’s why many people do come to see us, to get that diagnosis. So, arguably, it’s informative, but it doesn’t alter what we do at that point. And so, the first thing, of course, is to make sure that we know for sure what the diagnosis is. And so, we need to make sure we have the flow cytometry test, it’s called. Which, we usually do just on blood to evaluate the cells that are in the blood, the lymphocyte cells, to make sure that they have the right characteristics to be CLL. And so…
…flow cytometry, that’s different from the FISH test, right?
That’s right. Exactly. That’s different from the FISH test. And arguably, the FISH test is the other most important test to have early. And the FISH test looks at specific chromosome abnormalities that are characteristic of CLL. And it doesn’t look at the entire spectrum of chromosomes, but it’s specific ones that we know are important. And so, those include 13q deletion, which is the most common in CLL, and a little over half of patients with CLL.
And generally, on the more favorable side, from a prognostics standpoint. We look at trisomy 12, which is an extra copy of chromosome 12. We look at loss of the long arm of chromosome 11, which is 11q deletion. And we looked at loss of the short arm of chromosome 17, 17p deletion, which affects the TP 53 gene, which people know, that is the only one of these that really affects our treatment decisions once a person needs treatment. Because, that has historically been associated with not as good responses to chemo-immunotherapy, for example. So, we moved to novel agents immediately.
As part of the FISH test, we also usually include a test for—a translocation between chromosomes 11 and 14, which is important to make sure that there is not overlap with another kind of lymphoma called mantle cell lymphoma. And that test also gives us information on whether there are any abnormalities of chromosome 14, which is also a recurrent abnormality in about 7 percent of CLLs in our patient cohort.
I just want to go over to make sure I understand. So, when we say cytogenetics, is that what you’re getting out of all of this? Is this from the blood, or do you need a bone marrow biopsy to do that?
So, generally we do this from the blood. It can be done on blood or bone marrow. But we don’t do a bone marrow biopsy just to do these tests. We can do them perfectly fine on blood. So, FISH is, I would say, a subtype of a cytogenetic analysis. The other component of a cytogenetic analysis that we do is to look at the entire chromosome complement in the cell. And this is something that historically didn’t work that well in CLL because, we actually have to get the cells to divide, and it’s hard to get them to divide.
And so, a lot of times, we’d get false negative results because we wouldn't get cells dividing. But now, there’s a special stimulation technique that’s been developed to get the cells to divide better, and we can look at the entire chromosome complement, and find out if there are abnormalities in the chromosomes that are in other places that we don’t evaluate by the FISH test. And since we’ve had this additional way of looking at the chromosomes, we’ve been learning more in the last few years that the number of chromosome abnormalities is also an important prognostic feature of the CLL probably in the setting of treatment in particular.
One more thing I’m going to ask you about, and then, I want to go to Dr. Wierda, as well. So, molecular testing. So, what’s that, and where does that come in, in CLL?
Right. So, molecular testing is looking for particular gene mutations, often by something called next-generation sequencing, which has become the way that we do many of these tests. And many of our cancer centers have panels of genes that we look at that we know are mutated in a particular type of cancer. And so, with CLL, there are certain genes that are mutated at relatively high frequencies. Although, there’s no gene that’s mutated in most CLLs. So, the most important gene to look at is the TP53, because again, if there’s a mutation in that, just like if there’s a deletion of 17, chromosome 17, that does affect, eventually, our treatment decisions.
Other mutations that are seen in CLL include NOTCH1, and SF3B1, and ATM are probably the most common. They don’t generally affect our treatment decisions, but they may have some prognostic impact. We’re still really learning their full significance.
All right. That’s what I want to ask Dr. Wierda. So, Bill, you get a report back of your patient, and it’s got whether it says NOTCH, or P53, or 17p. And there’s someone like me or Michelle, sitting in front of you, and say, “Okay, so what’s the significance?” Some of it could be real significant, and maybe you could tell us about that, and some of it, we don’t know yet, or may be not significant. So, take us through that.
Right. So, in terms of an assessment, we will routinely do here, at Anderson, a 29-gene panel. Centers are implementing now, and coming online with panels of genes that they’re sequencing. And not everybody does the same panel. So, I think probably Jennifer’s panel is different than the panel that we developed. We have been using ours for a couple of years now, and we have 29 genes that we are sequencing routinely. It’s what’s referred to as targeted sequencing, so not all the genes—not the whole entire gene for each of those 29 genes is sequenced, but portions of them that are potentially important are sequenced.
And so, we get the results in terms of the mutations that patients have in this 29-gene panel. And as Jennifer said, the most important one is TP53 because, that has implications in prognosis, and also, implications in terms of choice of therapy. And that’s the one that we could have the most full discussion about in terms of those components.
The other genes, we’re still learning about, and they are not real common. They happen usually—they happen to—they are found in, usually, the minority of individuals. And right now, and over the past couple of years, we’ve been doing sequencing for this 29-gene panel, and we’re looking at clinical metrics such as time to first therapy, such as response to therapy, duration of response to therapy. We’re looking at all of those clinical components to try to understand what the significance, what the clinical relevance and significance is for the various mutations that we’ve identified.
We’re now—we have recently submitted a couple of papers, one, that describes the frequency of these mutations in an unselected patient population who’s come to MD Anderson to be evaluated. The other paper that we’ve recently put together, and reported is what gene mutations correlate with time from diagnosis to first treatment. So, we’ve identified a gene that when mutated is correlated with shorter time to first treatment. But most of them, we’re still learning about. TP53, we have the most perspective on and the longest—most data related to this, mutations in TP53.
Dr. Brown, back to you. So, you took us through these different parts of genes, you know, 11, and 13, trisomy. So, help us understand, again, if one of us is sitting in front of you, help us understand the choices. TP53 significant, and that’s tied in with this 17p deletion, right?
So, we get it, that that’s a concern, but what about the others? Are they all the same? Are they different? As far as significance goes.
Right. Well, they’re all somewhat different. 11q deletion has historically been associated with higher risk in the setting of chemo immunotherapy, shorter time to therapy as well as relatively poor response, shorter response time. So far, we’re still evaluating the effect of 11q deletion in the setting of novel agents. But with ibrutinib in the clinical trial, so far, it appears that the patients with 11q deletion are doing as well on ibrutinib as the patients without 11q deletion in the patients who’ve had fewer prior therapies, those who are frontline, or first or second-line.
In patients who had more like four prior therapies, we do see a somewhat shorter response duration with 11q deletion. But so, it appears that the novel agents may mitigate the historically worse effect of 11q deletion. And so, with Trisomy 12 and 13q deletion, they can be quite variable. And what I usually tell patients is that with those two, I look a lot at another test, the IGHV mutational status when I think about how the disease is likely to behave.
Because, Trisomy 12 can be associated with relatively more aggressive behavior, but it can also be associated with slower moving behavior. And to some extent, that depends on whether or not, how it’s associated with the IGHV test. And similarly, with 13q deletion.
So, the IGHV test, we know, divides people with CLL roughly half and half between two groups. One group, that has much slower-moving disease toward treatment, and which has historically very good responses, potentially even curative responses with chemo immunotherapy with FCR, that’s the mutated IGHV. And the other group, the unmutated, as a shorter time to treatment, and historically, not as durable responses with chemo immunotherapy.
But again, in the setting of ibrutinib, we’re seeing that in patients who are getting ibrutinib frontline or second-line, that responses appear to be as durable with the unmutated as the mutated type.
And, Michelle, I think you found out that you were unmutated in your…
…correct, 11q deletion, and unmutated IGHV.
But you had the FCR, but then, as Dr. Brown was just saying, you’ve had the ibrutinib, which seems to be effective, even in the unmutated…
…correct, and frontline treatment for me. Frontline treatment setting, as Dr. Brown was speaking of.
A question for you, from the patient perspective, as you listen to this, and this has been discussed with you over the years, is it unnerving? I mean, look, we come to CLL, we’ve never heard of any of this. And then, you start hearing about mutated, unmutated, 11, 13 trisomy, 17p—it’s a whole other language. Have you made peace with all this stuff?
Somewhat. Somewhat. Of course, it’d be great to hear that I’m cured, someday, that would be wonderful. I’m hoping that will happen. But I have. And it’s you really have to become educated in that. I feel like I have—you know, I drank from a fire hose in the beginning, and there continues to be all sorts of new information due to the advancing research out there. So, you have to stay on top of it. That’s one thing I would tell patients.
But the more you learn, and as Dr. Brown can attest, I always want to know everything, and I ask a million questions—probably, my journalism background. But I find for me, anyway, it’s better to – and not everyone’s like this—but for me, it’s better to know. And the more I learn, the more at peace I can become, because I understand CLL better, and how what I’m on is basically keeping it in check at this point. And for everyone out there, that’s my suggestion, is that you really do learn all these things.
And yes, in the beginning, I just remember looking at this list from a test, and not understanding a thing, what all this meant, what was this series of numbers and letters I’ll put together; it was alphabet soup. And then, when I started learning more about it, I realized what it meant, but what it also meant for me. Not only for other patients, but there’s so many different variations of CLL.
So, for me, in the beginning, I honestly did not know what unmutated and mutated meant. I thought unmutated—wrongly, I thought it meant a better thing because it meant it hadn’t mutated. And then, I soon learned that that was not necessarily so.
Right. But now, we’re hearing maybe newer drugs will equalize it, too. Dr. Wierda, so is the question about—I guess you’d call it serial testing. So, we talked about the workup somebody might have to know what are you dealing with at the beginning, but when is it important to do any of these tests either for care or even for research down the road?
So, I think there’s a couple of comments that I probably should make before I comment on that. And that is, these prognostic factors are not required when somebody is initially diagnosed. For some individuals, they may even heighten their anxiety that is not necessary. Not all of them always behave like we’ve been talking about. For example, if you do FISH when somebody’s initially diagnosed, and you notice that a patient has 17p deletion, not all of the 17p—patients with 17p deletion will have disease that’s aggressive.
In fact, early on, when we were first doing FISH analysis, we noted that if in patients who are untreated, who came to our institution, about a third of them—a third of them who had a 17p deletion did not progress, and did not need treatment. And so, you can observe those patients with 17p deletion. If they don’t have an indication for treatment: they don’t have symptoms, they don’t have anemia; you monitor them, and you watch them. And you watch them closely, but a third of them won’t necessarily need treatment.
And you do a disservice, I think, by treating them too early. And you should not treat them with chemotherapy or chemo immunotherapy, as was already mentioned. So, not all 17p-deleted patients act with aggressive disease. There is some heterogeneity in terms of the clinical characteristics within the categories. And we’ve done a lot of work with prognostic factor modeling and trying to use multiple prognostic factors to get a better sense and estimate of the aggressiveness of disease. And it’s challenging, and it doesn’t give you a full picture. It gives you some idea, but it’s—you have to take it in context.
And so, as I mentioned, you don’t need to do the testing initially, you definitely need to make a diagnosis, so CLL, which is done by flow cytometry. You don’t necessarily have to have the prognostic factors checked. We do it routinely here, because I think it’s informative, and I want to know, and I know what to do with that information. And I don’t act on it unless a patient has an indication for treatment.
The immunoglobulin V gene mutation analysis doesn’t change through the course of the disease. So, that’s something that we think of as a fixed feature. So, if a patient starts out as having an unmutated V gene, they’re going to keep that unmutated V gene through the course of their disease. Similarly, if they’re unmutated—if they’re mutated or unmutated, they stay as they were initially identified. So, you don’t need to recheck mutation status. Through the course of the disease, and particularly in patients who’ve had treatment, you can acquire gene mutations other than immunoglobulin genes.
So, for example, you can acquire mutations in TP53, or in ATM, or any of the other various genes that we sequence. You can also acquire the larger chromosome abnormalities that we identify with FISH. So, for example, you can acquire the 17p deletion, or you can acquire an 11q deletion through the course of your disease. Typically, we don’t see acquisition of high-risk features in the absence of treatment. So, usually, patients will have the same prognostic profile when they’re initially evaluated here, at Anderson, as they have when they start on their first therapy.
But what we do see, is the acquisition of high-risk features, particularly after treatment, and it’s more common among patients who’ve had chemo-immunotherapy base treatment in terms of acquiring the high-risk features. So, patients should be retested for FISH, and a gene sequencing profile, particularly TP53, if their disease relapses and progresses, or if they develop resistance to a therapy like ibrutinib.
The other tests that we’re doing, particularly for patients who are developing resistance to BTK-based therapies; so ibrutinib and acalabrutinib (Calquence) is mutation analysis in BTK, and PLC gamma 2. And those two genes, we sequence, and have been associated with resistance, particularly to the BTK inhibitor-base therapy.
Very complete. I just want to mention for our audience, you’re going to have questions about your situation, ask in a not too specific way, where we can all learn from, and send them to [email protected]. Again, that’s [email protected].
So, Dr. Brown, you were discussing these genes that are identified, and it’s sort of a moving target; you’re still trying to, in some of the cases, know what’s significant. Now, we’ve seen that in lung cancer, and a number of other areas where we didn’t know a year or two years ago, and then, we say, “Wow, we do know” and there’s a medicine maybe that’s even been developed to help go after that cancer gene. So, talk about that a little bit, where we’re headed, as you identify some of these other genes. You were muted. There you go.