Newly Diagnosed With CLL: What Do You Need to Know? - 2 | Transcript | Chronic Lymphocytic Leukemia | Patient Power

Newly Diagnosed With CLL: What Do You Need to Know?

Dr. Thompson:

Well, I guess the first time you meet a patient or when a patient is first diagnosed you've got kind of a snapshot in time, and you don't necessarily have longitudinal data about what's been happening for the last five years or so.  So when you first see that person you don't really know what the pace of change of the disease is going to be. 

Some patients will come to see you and their white count will be just above the normal range, and they'll have absolutely no symptoms, and it will have been picked up on a routine physical assessment.  And in that case it's likely that you could observe that patient for many years though they won't develop symptoms, they won't develop low blood counts, and their white count may remain stable. 

And then there's the complete opposite end of the spectrum.  For example, I met a patient once who had a white cell count of over a million, and he had a spleen that was almost into his pelvis, and he had very advanced CLL.  And in that case—he was anemic and a low platelet count.  In that patient I didn't need to observe for any period of time to know that watch and wait is not going to be appropriate.  But then there's everything in between. 

But for a patient who is newly diagnosed and maybe isn't going to need treatment straight away, you don't necessarily have to do a lot of tests to look at the genomics of CLL, because I guess there are two ways that you can work out what is going to happen to this patient's CLL over time.  The first is you can watch it over time, but that's not going to allow you to give any information to the person right now. 

The second is you can have a look at what are the genetics of this CLL, because that can give you a good idea about what might happen in the future.  It's not perfect, but it gives you a much better idea about what will happen to an individual patient, because there's a huge spectrum of changes that you can have in CLL where the cells look the same but genetically they're completely different, and they behave differently, and they respond to different treatments differently. 

But we can get a lot of that at diagnosis just with some simple blood tests, and it allows us to give a patient a lot more information.  So when they come to see me it's usually because they want the most information, and so we often do all of these tests at diagnosis, and that allows me, I guess, to counsel people as best—to the best of my knowledge, this is what is likely to happen in the future. 

Those tests, we look at the chromosomes of the CLL.  So everyone has 46 chromosomes.  You get 23 from your mother, 23 from your father.  And in the CLL cells you can have missing pieces of chromosomes or a whole extra chromosome, and the knowledge of that can help you determine is this going to be an aggressive CLL or a stable CLL. 

We also try and divide CLL into two groups.  One is called unmutated CLL, and the other is mutated CLL. 

And that mutated or unmutated refers to what we call the immunoglobulin heavy chain gene.  "Immunoglobulin" is another term for antibodies, and antibodies is something that your normal immune system uses.  In the normal immune response, your B cells try and make the best possible antibody to fight an infection, and by doing so they actually mutate their immunoglobulin gene. 

So a CLL cell can arise from a B cell that's previously fought infections and has a mutated immunoglobulin gene, or it can come from a B cell that's kind of newly born or naive, has never fought an infection before, and that's what we call an unmutated immunoglobulin gene, CLL. 

Now, counter-intuitively it's usually better to have a mutated CLL.  People think, oh, mutated, that must be bad.  In this situation, an unmutated CLL has the potential to grow much quicker than a mutated CLL. 

And also they have a slightly different response to treatment, which we might talk about later. 

And the last thing we can do is there's a huge array of knowledge that's come about from gene sequencing tests that have been done over the last seven or eight years, and we now know a number of gene mutations that can happen in the CLL cells that can drive their behavior.  And we have a standardized test where we look for 29 of these mutations at MD Anderson, I mean, most of our newly diagnosed patients and anyone who is about to have treatment, and that can kind of give us additional information about how the disease is likely to behave. 

So we can get, I guess, in a snapshot of time a lot of information about the CLL cells and how they're likely—how that patient's disease is likely to behave over time. 

It can vary from patient to patient even with similar genetics.  Because maybe those don't give us every bit of information, but they can be very useful. 

Andrew Schorr:

Carol, wouldn't you agree, though, for me, for you, I want to know.  I want to know because it's not do I have CLL but what version of CLL do I have mutated, unmutated.  This chromosome missing a piece, that chromosome missing a piece, I want to know, don't you?

Carol Preston:

Well, not only do I want to know, there's a lot to unpack from what Dr. Thompson said, and he's familiar with both of us, and he and I have met several times.  Let me start with my headline that you asked for about seeking a second opinion.  Starting toward the end of what Dr. Thompson said about mutated versus unmutated and understanding that. 

Here's the difference.  We love our local oncologists, and we hope that—and I say this to anybody out there who has CLL or any other cancer with which they're dealing, we definitely would like synergy, we like the coordination between our local oncologist or hematologist and a specialist.  But a couple of things happened to me, and probably heard by some of your audience on Patient Power, but I'm going to say it again. 

The first was that the local oncologist wanted to treat immediately, and from my perspective, what did I know.  I had cancer.  He said he offered, you know, had a treatment.  Let's get to it.  He was recommended, and so that's what we did a couple of weeks after initial diagnosis.  The terms out that the regimen that he recommended, and I won't go into all of the history, was an older regimen. 

He was concerned—Dr. Thompson mentioned the different stages—I did have stage IV, which meant enlarged spleen and lower platelets, I think anything, according to Dr. Leclair, anything that could go awry was going awry, so it probably was necessary to treat, but it was with an older regimen which lasted a very, very short time.  Because his concern was the enlarged spleen.

When I went for my second opinion at MD Anderson admittedly four cycles in, it was with Dr. Thompson's mentor, Dr. Michael Keating, it was suggested to me that perhaps that wasn't the best regimen to be on, although it knocked back the CLL pretty quickly.  And so he said we don't change it if it's working.  So that's fine. 

We mentioned at the beginning that I relapsed three-and-a-half or nearly four years later, and when the genetic testing came back I got that very frightening diagnosis, 17p unmutated, poor prognosis.  Poor prognosis.  And then I really did think it's curtains, and I best get my affairs in order.  Wisely, this time, since I was already a patient of Dr. Keating, I ran as fast as I could to MD Anderson.  I sent him the slides, and he said, there's unmutated and there's unmutated.  And he said, let me tell you that you have very few unmutated cells. 

You're not going to get this from your local oncologist, which brings me full cycle about getting that second opinion.  As Susan said, take a breath, exhale.  You have time. 

And I don't know what would have been had I just stuck with that original genetic report and gone—I don't know what the local hematologist, who's a very fine doctor and I do see him several times a year for blood workup, but I don't know what would have been, what would have been suggested had not Michael Keating talked me off the ledge before Christmas.  He said, enjoy the holidays, and he said, come see me in January, and he said you fall within the normal range of treatment, in this case, Andrew, with what you were originally treated with, the FCR.  You know, the fludarabine (Fludara), cyclophosphamide (Cytoxan) plus rituximab (Rituxan), and so I actually was able to do as Susan suggested, I was able to exhale. 

But that's why—you know, I'm going to sound like a broken record—with so many superb CLL experts now around the country, and, Andrew, when you were diagnosed and even when I was diagnosed originally that wasn't the case.  By the time I was diagnosed, there were maybe six prominent names, and today we have so many more.  So there should be some major medical center where somebody can go, if you go for nothing else but that consult.  Get that second opinion.  These specialists are more than happy to work with your community oncologists. 

In fact—and I think so I don't speak out of turn to say that you don't necessarily want every CLL patient from around the country knocking on your door.  I don't think you can accommodate all of them at MD Anderson. 

Dr. Thompson:

I'd have some trouble at home. 

Andrew Schorr:

You'd never, ever get home.  Susan, so we—thank you for those comments, Carol. 

So, Susan, we were talking sort of about prognostic factors because now we're talking about unmutated, mutated, and Dr. Phil Thompson talked about parts of chromosomes missing, so those are all things we can test for now, as he said, right?  So that's where we start talking about what version of CLL you may have, and that's going to start to inform treatment either now or down the road, right? 

Dr. Leclair:

Absolutely.  And a word of—again, taking that deep breath.  Nobody learns all of this stuff in a day.  You learn it in months and maybe years because you will learn things as you need to know them.  It's—in a sense it is very much like the student who comes to you and says, do I have to know this?  Is it going to be on the exam?  No, I just told it to you to fill up time, but that's in class.

In real life the answer is no, you don't need to know all this stuff.  You need to know what you need to know that makes you feel comfortable in your current surroundings.  So if you need to know whether you're unmutated or mutated and that gives you a sense of the world as you now see it, then maybe at this point some of those other complete genome sequencing or some of the expensive now esoteric possibly not in the future tests will come, and you will understand those when they are needed to be understood.  So don't panic about the language. 

And, yes, it is true.  When science became acceptable again in the renaissance you got burnt at the stake if you were doing that, so you invented a language no one understood.  And then when people starting understanding that language you went to abbreviations, so now we talk about FCR, because we're not going to explain to you that that's really these three different names of tests, because we still think we're going to get burnt at the stake. 

Andrew Schorr:

Three different medicines, all kind of medicines.  It's bewildering. 

So I think, to underscore something Carol said, is where you want to end up with is a CLL healthcare team that you have confidence in and where you can have dialogue where you each have an understanding of what you're dealing with now or on your journey.  And then that will ultimately lead to a question of do you need treatment and then how do you decide what.  So let's go on to that, Phil. 

So I had this four-and-a-half year, 1996 into 2000, watch and worry, and at some point Dr. Keating said, hmm, we're observing this and that, not just the white count but the lymph nodes and the spleen and the fatigue, some sweating, people can get night sweats, other symptoms, I think it's time to treat, and I think I have something for you that I'd recommend. 

So let's go through is, am I right?  Those are the kind of triggers for treatment, some of these things?  Carol had spleen.  You said everything had gone awry.  So what does it say?  When is it time to treat?  And then help us understand the discussion about goals of treatment. 

Dr. Thompson:

So the decision about when to treat, I think of it as when the symptoms of the disease and what the disease is doing to you is worse than potential risks of treatment. 

Historically, we didn't have very good treatments, and so the kind of paradigm of watch and wait came from an era when we may not have had treatments that could dramatically affect the disease course, and so there were some big studies done that showed if you treated someone at diagnosis or soon after diagnosis, it made no difference to how long they lived compared to if you waited until they developed significant symptoms, and so that's really where that paradigm comes from, is this idea it's not going to make you live longer if I treat you earlier.  And so that's why in terms of the approach to decide when to treat someone it's really based on symptoms. 

So symptoms can be things like exhaustion and severe fatigue.  It can be drenching night sweats.  It can be lymph nodes that are growing and becoming uncomfortable. 

It can be hemoglobin dropping in the blood or the platelet count dropping in the blood to the point where that puts you at risk of, in the case of platelets at the risk of bleeding and in the case of hemoglobin of being severely fatigued.  We look for those things.  The white count is not a useful marker in terms of do we need to treat you or not because if the lymphocytes are circulating around in the blood they're usually not doing much.  It's when they're packing out the bone marrow and preventing you from making normal blood that may cause some problems—or if they're growing in the lymph nodes and the lymph nodes are getting very big, and they're causing problems. 

But some patients may have a white count of 200,000 but completely normal hemoglobin, completely normal platelet count, no lymph nodes and feel absolutely fine.  Now, that patient doesn't need to be treated.  Whereas another patient may might have a white count of 20,000 but actually have an enormous spleen that's pressing on his symptom, and he can't eat properly, and he's losing weight, so that patient needs to be treated even though their white count is much lower. 

Where the white count is useful I guess is if it's changing very rapidly over time.  So we look for how quickly it doubles.  We think of a lymphocyte count that doubles in less than 12 months as being fast, and particularly it's less than six months.  Anything more than 12 months to double is relatively, relatively slow.  So I guess those are the things that we base a decision to treat a patient on is like what are the symptoms, and do those symptoms warrant treatment that will hopefully actually make you feel better. 

People often think, oh, I'm going to go into treatment, the treatment is going to make me sick.  But usually when you've made the decision to treat actually once you get onto treatment you feel a lot better.  And sometimes the symptoms sneak up on you.  So people don't quite realize how many symptoms they have from the disease. 

I remember a relatively young woman that I treated who had a white count of 350,000, hemoglobin of 8.5, and she said she felt absolutely fine.  And so we actually watched her for some months, and eventually she decided, oh, look, I think I'll have treatment.  And after we treated her and the white count was back to normal and the hemoglobin came back to normal she said, oh, my God, I can't believe how much better I feel. 

Andrew Schorr:

Yeah, that was me.  That was me.  I didn't realize how fatigued I was.  Let me ask you about this:  So now we talked about these different prognostic factors. 

Dr. Thompson:


Andrew Schorr:

Mutated, unmutated.  Carol found out she had the 17p deletion.  Some other people have other deletions, you know, when you do these tests, workups that Susan's—all her lab students all over the country now do. 

So, okay.  So how do you know what—and this get to the goals of treatment.  Like, for instance, the FCR acronym, fludarabine, cyclophosphamide and rituximab that I had years ago, some people have and Carol had.  So that was six months of infused therapy.  Now you have oral therapies.  Now you have oral therapies combined with infused therapies.  You have some traditional chemotherapy drugs, like the cyclophosphamide and all that that sort of blasts a lot of stuff, and you have other targeted therapies.  So what discussion do you have with people about what's right for you? 

Dr. Thompson:

Right.  So I think actually this is where these prognostic factors that you're talking about are really important because they're not only prognostic in the sense of—we think of a prognostic factor that tells you what is your outcome likely to be. 

But actually some of these tests will tell us you'll respond to therapy A but you won't respond to therapy B, so we're heading into a world of kind of individualized therapy based on what a patient's CLL genetics are like and also I guess based on what the patient themselves is like. 

But the two things that enable me to decide what's the best option for a patient is what are the genetics of this patient's CLL and what are the—I guess how old is a patient, how fit is a patient, what are their other medical problems because those things will enable me to determine will they tolerate the treatment well. 

So the traditional—I guess, prior to 2010 we treated most patients with two regimens. 

The younger, fitter patients would get FCR or something similar to FCR, which is a relatively intense multiagent chemotherapy or chemoimmunotherapy treatment, and that is very good at getting the CLL down, but perhaps an older patient or a patient who's got other medical problems might not be able to tolerate the FCR well. 

And then the other thing we used was chlorambucil, which is an oral chemotherapy medication which we tended to give to older patients we didn't think would be able to cope with FCR.  Now we have this whole array, as you said, of oral targeted therapies, and the advantage of these oral targeted therapies—well, there are two major advantages.  One is they tend to be easier to take for patients than FCR. 

The second is they work better than FCR in certain situations, in particular patients who have a 17p deletion or a mutation in this TP53 gene because those patients don't tend to respond well to therapy. 

So I guess it then brings us to a discussion with patients about what is the goal of care.  So in a young person, maybe someone in their 60s or younger, the ideal treatment I think you want to have is something you can take for a short time and then hopefully get a very long remission from the treatment, and in that sense we're hoping for 10 years or more and potentially even for some patients a cure of the disease. 

Whereas for a patient maybe who is 80 and has a lot of other medical problems, the main goal may be you want to control the disease, have minimal symptoms from the disease, minimal symptoms from the treatment and have a good quality of life without necessarily needing to have a 10- or 15-year remission.  So that's where the kind of patient and the genetics comes in. 

Now, in terms of the genetics, we've worked out a profile for the group of patients who are likely to have a very long?term remission from FCR.  Again, it's not perfect, it's not a crystal ball, but we've identified a group of patients where about 60 percent of them we think are potentially cured with FCR. 

So the conversation I tend to have with patients once I have all of these prognostic factors back is, this is the prognostic group you're in, this is what I would expect if I gave you FCR, and this is what I can expect from some of the newer therapies.

Now, the new therapy that's approved for untreated patients by the FDA is a drug called ibrutinib (Imbruvica), a pill that you take every day, and it blocks a protein called BTK in the CLL cells that they need to grow.  It's very effective at reducing lymph nodes, at reducing the white count, at improving other blood counts and improving symptoms, but most patients end up with a small amount of CLL left over.  And what that means is you pretty much have to take the drug indefinitely. 

And so it then gets to a conversation about, well, do you want to take a pill every day for the rest of your life.  And so some patients who have the good-risk CLL that do well with FCR may prefer to say, okay, I'm going to take six months of treatment and then I'm done for a long time rather than taking pills for the rest of their life. 

So I guess there are those two different treatment paradigms that we can offer. 

But the really important thing about the prognostic factors is that if you have, say, a 17p deletion on your CLL the average remission after FCR for a patient like that is only about a year, and generally when the disease comes back it comes back worse than what it was before.  And so for patients like that they tend to do much better with some of these new drugs like ibrutinib than they do with FCR, and that's a conversation that you can have after you...

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Page last updated on September 9, 2019