What Should CLL Patients Know About Their Blood Work?

Ask the CLL Expert

Ask the Expert: What Should CLL Patients Know About Their Blood Work? from Patient Empowerment Network on Vimeo.

CLL experts Dr. Susan Leclair and Dr. Justin Taylor discuss how to understand testing with CLL, how CLL patients can advocate for the correct testing, making the most of doctors’ appointments, and more.

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Transcript:

Andrew Schorr:

And hello from Southern California. I’m Andrew Schorr. Welcome to this Patient Empowerment Network program produced by Patient Power. We’re so delighted you are here. I’ve been living with CLL since 1996. And so, testing was not as sophisticated then, and it’s come a long way and there are a lot more choices now. So, in this program, we will be discussing how do you know when you need treatment? What tests are important when you’re in a sort of watch-and-wait period? If you start treatment, how do you know if it’s working? How it’s monitored? If you’re in remission? How do you know how deep that remission is? Should you need treatment again, are there other tests that need to be repeated, or new tests to be done? Lots to talk about. I want to thank the Patient Empowerment Network for putting this all together, and for their financial supporters who have no editorial control, that is AbbVie and Pharmacyclics. So, thanks to them for supporting patient education. Okay. If you have a question, send it to cll@patientpower.info. Many people have, so we got tons of questions, and we’ll get through as many as we can in this Ask the Expert program, helping all of us with CLL understand our blood work and what’s needed and when. And we have some great guests with us. First of all, I wanna go to my dear friend who I’ve know most of these 20-plus years as I’ve been living with CLL, Dr. Susan Leclair, laboratory science guru. She joins us from Dartmouth, Massachusetts. Hi, Susan.

Dr. Leclair:

Hi.

Andrew Schorr:

Welcome back to our program.

Dr. Leclair:

And I think we were both very young when we first met.

Andrew Schorr:

Well, you didn’t have grey hair. But I cannot say that I had a full head of hair, but here we go. And I didn’t lose it because of chemo. It was gone, hereditary. Okay. And now let’s scoot down to New York City to one of our top cancer centers in the world, Memorial SloanKettering, where we’re going straight to the lab. And that is Dr. Justin Taylor, laboratory researcher, and also CLL clinician. Justin Taylor, thanks for being with us.

Dr. Taylor:

Hi, Andrew. Thanks for having me. Happy to be here.

Andrew Schorr:

We’ve been wanting to get you with us for a while. And he, folks, is where action happens. They start with mice, and then they start working on what does it mean to all of us with our blood? And, of course, human clinical trials, and Memorial Sloan-Kettering has helped lead the way. Okay. Susan, are you ready to go?

Dr. Leclair:

Sure.

Andrew Schorr:

Okay. So, people worry, what about their tests? And one thing I wanna get off our plate right away, and I’ll just say it for me. So, I get immunoglobulin infusions once a month to boost my immunoglobulins. And you can help us understand what that is. And I get a blood test at the same time. And I worry if the platelets go up a little, or the platelets go down a little, or and then there’re all these MCVs and blah, blah, blah. I don’t understand what they mean. And I worry sometimes if there’s a little blip. But we really worry about—we’re not even worried. We watch the trend, right?

Dr. Leclair:

Right. I would not panic unless you see two consecutive numbers going in the same direction. Now there are a lot of caveats to that, but we don’t have five days on the program. So, basically, statistics don’t work, unless you’ve got at least three values. So, if you started at a value of 1.0, and the next time you got it, it was 1.5, and the next time you got that same test it was, I don’t know, 0.62, they’re not in the same direction. There’s no big change. You’re kinda okay.

You begin to worry only if it goes from a 1.0 to a 2.5 to a 5.0. Now you’re beginning to get a sense that things might be moving in a specific direction. So, you wanna wait. I know it’s not watch-and-wait; I know it’s watch-and-worry. But you have to wait for at least the third one of the values. It’s part of the reason that your physician will use that horrible word, “Fine,” when they look at things, and they say, “Oh, no, this looks fine.” It’s because they’re not seeing that trend going in one direction or another.

Now some tests, you want the trends to be higher; some you want lower. But think about you need three values going in the same direction in a row before something can be considered worthy of, well, worry, or at least worthy of a question.

Andrew Schorr:

Okay. Thank you for that. Justin, I wanna ask you about something we talk about a lot now in CLL, and as you get to the different chromosomal deletions, I guess you call it. So, we’ve known for a long time that one that led to more aggressive CLL was the 17p deletion.

Dr. Taylor:

Yes.

Andrew Schorr:

And now we have medicines that kind of work on 17p, which is cool. So, we got a question from Robert Schneider who said on the CLL patient with 17p, been treated in his case with Venclexta or venetoclax for two years, and had reached MRD, minimal residual disease negative in my bone marrow and blood, what are the pros and cons of stopping treatment if I’ve had this 17p? So, where are we now measuring 17p? And help us understand this MRD level.

Dr. Taylor:

Okay. Yeah. Lots of great points there. I’m glad you brought up the 17p. That is historically a more bad prognostic marker, although as you’ve brought up, we now have drugs that can work for patients with 17p deletions. So, we’re very excited in the clinic to have Ibrutinib and Venclexta, or venetoclax—I’ll use the generic names—as options for our patients with 17p deletions, or other abnormalities that include genes on 17p such as the p53 gene.

And so, those are effective. And we’ve seen some patients that have been lucky, as David, to get into a minimally residual disease, or measurably residual disease negative state from these treatments. But I’d say it’s still the level of our knowledge, at this time, does not allow us to know whether it’s completely safe to stop. And that’s something that’s currently being tested in clinical trials, both in the US, as well as abroad.

And so, we have a trial here at Memorial Sloan-Kettering testing patients who have been on Venclexta and get into this MRD-negative state. If they’re able to stop the drug and it’s basically randomizing—or not randomizing people, they’ll be allowed to decide whether they wanna stop or not.

And then following them to compare the patients that stop versus the patients that didn’t stop to see what the difference in terms of relapse rates are, overall survival, whether it is gonna change the outcome of the disease whether you stop or continue on the drug. So, that’s a great question, and it’s currently one that we’re trying to answer as fast as possible.

Andrew Schorr:

Okay. And, Susan, just so we understand this MRD, these are super-sophisticated tests, right, now looking for cancer cells at like I almost think, maybe not the nano level, but, right? And we haven’t had these for a long time.

Dr. Leclair:

Oh, no, they’re relatively new. For those of us who do have different colored hair than what they started out with, once upon a time, it was one CLL, and we had no treatment for it. And now we have multiple versions of CLLs. And we have, oh, maybe, I don’t know, 10 possible different fairly well-known, fairly well-described genetic anomalies. You’ve got different drugs that go along with it.

So, in each one of those, complexity adds confusion at the same time. So, some of our tests are—oh, no, I take that back. All of our tests have limits. I test for something, and my limit is one in a billion. Well, supposing you have one in two billion? I’m going to come up with a negative, not because there’s nothing in there, but that it is there at such a low number, I can’t pick it up.

So, there are times when you have these results, and minimum residual disease is a great phrase for it. All I can tell you is to the limit of my testing, to the limit of every scientific test we have out there, I can’t find a malignant cell of your CLL in there. Does that mean that it’s absolutely not present?

Andrew Schorr:

Right. But we can measure it better than ever before. And it gives us some confidence. And I think patients want to know. But so, that goes to Justin. Justin, you’re at one of the largest cancer centers. There you are in the lab, and you do all sorts of sophisticated testing. But many of our viewers are around the world and they’re not necessarily being treated at a big academic medical center.

So, the question is, what tests are necessary? So, maybe you could help us understand. If you are out there in the hinterland, and you needed to help yourself as the physician, and the patient just kind of understand what’s going on, what’s the basics? So, first, let’s start at diagnosis. What’s the basics to know what’s going on? Do you have to have a bone marrow biopsy? Do you do CBCs? Do you have to do what we call FISH testing mutational status? What’s like the basic?

Dr. Taylor:

Yeah. Thanks. And we definitely can do, as Susan was saying, many, many tests with different sensitivities and specificities, but kind of the gold standard of proving whether adding these tests makes the difference is to do a clinical trial or a prospective trial, I guess, where you measure these things before patients get treatment, and then see which of them makes a difference in the outcome.

And when you add them all into a kind of analysis that includes all of these tests, which ones are important of themselves because some tests are markers, basically, of something else that you can measure. So, that being said, there have been many studies like this to try to see whether we can add in any of these new tests that have been developed in the decade to the kind of gold standard. And many times all of the new tests that we add aren’t able to distinguish that much more than what the basic tests show, so I…

Andrew Schorr:

…okay. So, literally, let’s just tick off some. Bone marrow biopsy; critical to do?

Dr. Taylor:

That’s very controversial. We still do that. I don’t think that it’s critical in making the diagnosis. That could be made from the peripheral blood flow cytometry, which tells you the markers on the surface of the cell, that they’re different than normal B cells. We still do the bone marrow biopsy to get a sense of the stage of the disease, how much CLL there is. But it’s not absolutely required for the diagnosis.

Andrew Schorr:

Oh, okay. And what about so-called FISH testing; is that important?

Dr. Taylor:

I think it’s important, based on what we talked about with the 17p deletion. It can detect that. That’s a big change on the DNA, on the chromosomes, that can be detected by FISH. And, yeah, many of the tests I was referring to before are looking at specific genes. I don’t think that those are necessary. They definitely can give some insight to the treating physician, but.

Andrew Schorr:

Okay. And then the last one is that I always get this backwards—is it IgVH, IvGH—but the mutational status, why is that important?

Dr. Taylor:

Yes, the IgHV mutational status, if I got it right, is important because there’s—basically falls into two camps. You can have unmutated and you can have mutated, and you would think that the mutated would the worse, but it’s actually the unmutated that has the worse outcomes.

And that’s important, because it’s been shown that this unmutated set of IgHV-unmutated CLL may not be the type of patient that you want to give chemotherapy to. They may not respond as well to chemotherapy. That may be something you want to go straight to one of the new agents.

And for the mutated patients, which have a little bit better prognosis, new agents are definitely on the table for them also, but there’s a subset of those patients who, with chemotherapy, a study done at MD Anderson that followed these patients 20 or more years after chemotherapy, a subset of those with IgHV-mutated CLL did not require further treatment. Essentially, we didn’t say that they were cured, but they were as if they were cured. They only got one treatment with chemotherapy and never required anything again.

Andrew Schorr:

Right. Well, okay. Let me raise my hand. I was in the Phase II trial for chemo, fludarabine (Fludara), cyclophosphamide (Cytoxan) and then rituximab (Rituxan) added in 2000, and I had no other treatment after six months of therapy for 17 years.

Now, I had an MRD test along the way, and dear Dr. Wierda at MD Anderson said, “You know,” with the testing they had then and this is several years ago, “You’re not MRD-negative. You’re probably gonna need treatment again. I feel confident you will.” And so, I knew there’d be another shoe drop. But with the chemo, I did get a long remission. Susan, one of the questions we’ve had is, and you’ve heard this before, people get different lab values from different labs.

Dr. Leclair:

Yes.

Andrew Schorr:

Maybe they had it here. So, you’re like in the international organizations. Shouldn’t there be like one standard; if my hematocrit is this, that’s where it is for everybody? I mean, why does it vary?

Dr. Leclair:

Because you do. One of things that is critical here is that you, the patient, have different levels of hydration from the morning when you get up. This makes absolute sense when you think about it. When you roll out of bed in the morning, you’re not really as well hydrated as you might be at 4:00 in the afternoon, or that you’re not as well hydrated after you’ve run for two hours than you were before it.

Since most of the initial blood work that you use, both in diagnosis and in monitoring, is based on volume, if you got diagnosed with a CBC that was drawn at 3:00 in the afternoon, for the name of consistency, could you keep having your blood drawn at 3:00 in the afternoon? Because that will provide us probably a more constant basis of you are hydrated at this level all of the time.

Andrew Schorr:

Right. But you know what—yeah, but I’m not asking just that question. If I go to the same lab and test at the same time and drink water before, but so, we get lab test results, and in the case in San Diego, it has H’s and L’s, highs, lows, out of the normal range, and I got a bunch of them, okay? But what I wanna know is, is that standard of what’s within the normal range the same at every lab? Or if it isn’t, how come?

Dr. Leclair:

Well, in the case of hemoglobin, for example, if you live in Telluride or Vail or Aspen, you’re at a higher level. There’s a lower amount of oxygen in the atmosphere, so you need more hemoglobin to grab the oxygen from your inspired breath and bring it to the tissues. So, pretty much everybody who lives above Mile High Stadium, so to speak, it’s not that anymore, but everyone will remember it, is probably gonna have a higher hemoglobin than somebody who’s at a lower one.

If I’m in the lab and I’m developing a set of reference ranges for the physicians in that area, then if you come bouncing into Vail and have a CBC, you’re still at your California seaside hemoglobin level. To somebody who’s expecting people to have a higher one, you will look as if you have a lower hemoglobin.

Andrew Schorr:

Right. And I’m going to Colorado in a week or so, so, yeah. Okay. I get it. That was a question we had from several people. Now, Justin, I got a question from you. A lot of the people here, a percentage, have been diagnosed with SLL, not CLL, but we understand they’re basically treated the same. So, help us understand the difference. But what they want to know is should their testing be different?

Dr. Taylor:

Yeah, that’s a great question. We do think of them as the same disease. It’s just the manifestation. In CLL, the abnormal B cells are mostly circulating in the blood, leading to abnormal blood tests with high lymphocyte count.

Whereas in SLL, or small lymphocytic lymphoma, a name that was given because primarily, the abnormal lymphocytes are in the lymph nodes and they don’t circulate in the blood, so patients with SLL would be detected because they have abnormal lymph node swelling.

They might go to a physician who primarily treats lymphoma, which is another related disorder that presents with abnormally enlarged lymph nodes. And so, they oftentimes are monitored different, treated differently, because the cells are not circulating in the blood, so they can’t be detected as easily through a blood test.

So, in my practice, I use the physical exam and monitor wherever the lymph nodes are through examining them, just physical examination. And you can also do a CAT scan, or a CT scan it might be called as well, to measure throughout the body the places you can’t examine within the thorax and abdomen if there are lymph nodes there also.

Andrew Schorr:

Okay. So, the cells are not floating around, so it’s a little different as far as monitoring goes. Okay. So, let’s get to monitoring. Justin, I’ll ask you this, too. So, people wonder, okay, if I’m in remission, how often do I need to be monitored? So, you’re doing the physical exam. My doctor, Dr. Kipps, feels for lymph nodes. He digs under my armpits. He does a lot of stuff.

And that part’s not fun. But and I get these regular blood tests monthly, which are just zapped to them when I get my immunoglobulin, so they’re keeping a watch on me. And I should mention that I have another condition, too, myelofibrosis. So, I got two doctors watching me pretty carefully. But, basically, I don’t see them very often. So, related to testing, is that really an individual thing with your physician as far as just like CBCs, Justin?

Dr. Taylor:

Yeah. To me it’s dependent on each patient, and, as Susan mentioned, the trend of the blood counts, and what treatment you got, how long ago that was. In a general set of rules, the sooner it is after treatment, you might be monitoring it more closely. And then as time progresses, everything’s been looking okay, the time can be spread out, again, based on the individual patient. If there’s continuing, ongoing reason to watch some specific lab test then, as you mentioned, it might be done every so often.

I would say unless there’s something particularly that you’re keeping an eye on, such as you immunoglobulins, you probably don’t need it once a month; every three months is generally acceptable, if everything looks normal, there’s nothing. But in your case, you’re getting these IVIg infusions, and so, they’re testing the levels to make sure you need them every month. And so, it comes down to each individual patient.

Andrew Schorr:

Susan, so, we mentioned this a couple of times, IVIg. And some of our patients who are on this program get it, too. So, what is immunoglobulin, or what are Igs? What is this stuff?

Dr. Leclair:

Immunoglobulins are essentially proteins. They can be transport proteins. You eat a steak, your body absorbs the iron, and it needs to get put on a transporter, so that it can be moved around. So, there’s transport proteins. There are modifying proteins that control how fast or how slow something’s gonna happen.

But the ones you are interested are the immunoglobulins that are antibodies. Now we all know about antibodies because there’s certainly been enough argument across this country in the last few years about antibodies in terms of getting immunizations for children against measles and mumps and other childhood disorders, whether or not it’s Zika, and all the rest.

You have in you, over time, built up a body of antibodies, a collection, an encyclopedia of antibodies that remember that you had that disease 22 years ago. And while you’re not actually making a whole lot of those antibodies, you’re making enough of those antibodies to make sure you’re never gonna get it again.

What happens with CLL folks is that they don’t make either functional antibodies, or they don’t make enough, which means that you at your age might have had an immunization for mumps a long time ago. My guess is you don’t want to have mumps right now. So, we should give you some pre-informed, pre-manufactured antibodies against mumps that will help whatever cells that are in your body that are trying to make mumps antibody to give you enough mumps antibodies so that you never get mumps again.

So, this a procedure that is giving you this infusion of antibodies, is to keep your system at a place where it won’t get sick when you’re in a subway and someone sneezes, when you’re in a restaurant and someone coughs at you, when you find yourself somewhere with a friend who says, “Gee, I hope you don’t mind, but I’m still getting over X.” So, it’s protective for you.

Andrew Schorr:

Okay. And Dr. Kipps here in San Diego says, “Andrew, if you want to travel,” and that’s true, and I like to travel, and we’ve seen many of our CLL friends when we do, he said, “You gotta have the IVIg infusions.”

Andrew Schorr:

Justin, just so we understand, what about—she mentioned immunizations. First of all, where does immunoglobulin come from? My understanding is it’s made from somebody else’s blood. I’m getting like a blood product, hopefully, squeaky clean in that, and I’m getting some immune benefit from that. Is that the idea?

Dr. Taylor:

Yeah, that’s correct. So, the antibodies come from B cells, and that’s why CLL is a disease of the B cells. And so, that’s why they’re, as Susan mentioned, they’re not forming the proper antibodies. So, we can get these healthy antibodies from donors, and it’s usually a pool of those antibodies to get enough to give you that boost.

And I just wanted to mention that not every patient with CLL needs these. You can measure the immunoglobulin levels in the body, and if they’re normal, you may not need the extra boost, especially if you’re early CLL and watching and waiting. And, again, and if patients are getting recurrent infections, that’s another reason that they might need transfusion.

Andrew Schorr:

Right. Yeah, and I’ll mention, to be clear in my case. So, I went 17-year remission, folks. I did get some sinus infections. Usually, if I got a cold, I got sinus infections, took antibiotics, quicker than people who don’t have CLL, of course, and it knocked it out, okay.

What we noticed is, after I had retreatment for CLL with a monoclonal antibody, obinutuzumab or Gazyva, with steroids in my case, about almost two years ago I was getting more often infections. The CLL was controlled, but, like Susan just said, my immune system was inept and it needed some help. And so, Dr. Kipps decided I needed IVIg. But that’s a personal thing with you and your doctor. You may be monitoring how frequently, just what Justin just said, how often you’re getting infections, because it’s certainly not for everybody.

Okay. So, let’s talk. I wanna understand something, Justin. CLL can change over time. So, we mentioned the 17p deletion, or people hear this other alphabet soup, 13q, and all these different things, or trisomy, and all these things. So, the way you start out, is that the way you may be years down the road? And if not, how come?

Dr. Taylor:

Yeah. For some reason, CLL can change. A term you might read about is it’s called clonal evolution. It sounds like “Star Wars” with the clones, but you can basically have the CLL that you started with, it can acquire other mutations, or other abnormalities that you’ve listed there over time, so, even untreated CLL, does change over time. We don’t really understand fully why that is. We know, in general, cancers do that, so CLL seems to be at the faster rate of that ability to change the genetics.

And so, I think the CLL you end up with might not be the same as you started with. And so, this comes to another question that was asked of when to do this testing for 17p IgHV. You often hear the argument that you don’t need those until you’re gonna start treatment because if you get them at diagnosis, and then you’re gonna not start treatment right away, they may change over time, and you wanna reevaluate those at the time of treatment.

So, that is why some patients might not have all the testing done at the time of diagnosis. Not every doctor feels that way, so some patients do get all the tests run at diagnosis, and then again when it’s time for treatment based on the progression of the disease and symptoms. Then often we repeat those just because there’s the possibility that within that time frame, whether it’s a year or several years, that these markers can change.

Andrew Schorr:

Susan, you and I have been around this a long time, and you remember one of the really wonderful patient advocates years ago, Granny Barb Lackritz. Barbara Lackritz. We called her Granny Barb. And one of the words she told us Esther and me, years ago when I was diagnosed, was, “Chill out.”

So, have this array of tests now. And there will be some of our viewers who say, “Okay, I want this test, and I want this test, and I want this test, and I want this test.” And, “Oh, my God, this has moved a little.” And, “Do I need to be retested?” What you tell people to kind of take a deep breath, even though you have this array of testing now?

Dr. Leclair:

I tell them to take a deep breath and to slow down. This is not a disease that is going to “harm you.” That may be in quotations. This is not a disease that will harm you today or tomorrow or even in a year. This is a disease that will allow you to think it through. Well, not necessarily slowly, but deliberately. What you wanna do on these tests is not say, “I want every single one of them.” Because then you’ll get a lot of information you can’t interpret. What you want is, “Let’s do one test at a time.” The results of that test will lead you to the next test.

For example, the CBC gives you a very high white count, and it looks like it’s all lymphocytes. Okay, what do you do next? Well, the next logical question is: Who are these lymphocytes? What are they doing? So, that’s when you do the flow cytometry, and you find the answer of who are they at a gross level, at a fairly simple level. Oh, they’re B cells, or maybe they’re T cells. And in that answer then provides you with the next thing you want to do.

So, instead of ordering them all like eating and taking every single bite out of a huge buffet, you might wanna just wait and follow the detective story as it goes along. And what that will allow you to do is, well, these were my answers in September. Well, these are my answers plus a new one in November. Oh, well, these are my answers in September and November, and now in February. And so, you begin to develop a story. You begin to know your cells. Your physician begins to know your cells.

You can say things like, “Oh, well, in January, I had a cold.” All right. Let’s about then how that cold might have affected the results in January. You already know what the results were in September and November. Let’s look at this in context. You have the time. Use it.

Andrew Schorr:

Right. Now, Justin, we’re talking so much about testing, but you referred to physical exam. So, I think we have to be fair and say you guys look at the complete picture. Like, for instance, is my spleen enlarged? Do I have night sweats?

Do I have new lymph nodes? How big are they? Where are they? Right? Am I getting a lot of infections? Right? So, you gotta look at the whole picture, right? It’s not just the numbers. Correct?

Dr. Leclair:

Absolutely.

Dr. Taylor:

That’s right. Absolutely. Yeah, it’s personalized medicine before that term came to mean doing genomics. It’s every person is different; every situation is different. As Susan mentioned, situational things can happen with infections that change the numbers, and it’s important that – We’re not gonna be able to guess that, so discussing with the patient, hearing the history, taking the time to do the exam, and then, again, putting that into the context and the historical context with that patient.

So, that’s why the patient-doctor relationship is very important. Of course, it’s always recommended, if you want a second opinion, to hear from another doctor or someone that specifically does CLL. But just having your physician that’s known you for a long time is very valuable, as well.

Andrew Schorr:

Let me put in a plug for second opinions for a second. So, Justin’s at one of our premier cancer centers, Memorial Sloan-Kettering. There’re a few of them in New York, where he is. There may be one this way down the interstate from you in New York, or in London, wherever you may be.

And I would say, with a long-term illness, it gave me confidence to check in with an academic medical center. And I actually had teamwork, when I was in a clinical trial, between a local cancer center and a university cancer center.

And I got those doctors talking. That gave me confidence. And when I needed treatment, actually, and ultimately in a trial, they worked together.

So, one of the questions came in and said, “Well, when should I check in with a CLL subspecialist like Dr. Taylor is, even in the lab?” Well, along the way. But as Susan said, “The house is not burning down today.” Okay?

Now, Justin, you’re in the lab there. I have a question for you. So, I have three kids. And one of them, and some people know, are Ruthie, are the producer of this program. And so, we wonder, when you talk about genomics, is there some test we should do to see if my children are at risk for CLL? And should we do that routinely, like you might do in some other more hereditary conditions, when we really don’t know, is there a real hereditary connection in CLL?

Dr. Taylor:

Yeah. We talk about the genetic tests, or the genomic mutations, and that always invokes something hereditary in the genes. But when we actually do these tests here at Sloan-Kettering and other places, we will take the CLL cells, take the DNA from those, and we also get a sample of normal tissue. So, often it’s a swab of the side of the cheek, a swish of saliva, sometimes fingernail DNA, something that we can get that we don’t think has any CLL in it.

And then we sequence them both, and we’re comparing the CLL cells to the normal cells to try to detect the mutations that occurred in the CLL that make them different than the normal cells. So, all of these mutations that we’re talking about are something that happened in the CLL cells sometime during your life. And we’re finding out now that these could have been there, these mutations could have been there for years before they finally manifest this CLL. But they’re not something you were born with. They’re not in the cells of your body or the cells that are passed down to your children. There are very rare cases of heredity CLL, but my understanding is they’re exceedingly rare. I haven’t come across them, but they’re reported in the literature. So, if there’s a very, very strong family history of cancer between generations, a bunch of siblings have a cancer, then that might be a time to consider hereditary genetic testing. Otherwise, CLL is typically thought to arise in these cells along your lifespan. You’re not born with them. They’re mutations that are occurring as you age.

Andrew Schorr:

Okay. So, I’m not recommending my kids get some tests. And also, I’d say, and Susan knows this so well, and Justin, as you’ve gone through your training and graduated to be in the lab and seeing patients, everything’s changed. Everything has changed during my time. And so, if God forbid, one of my family members developed CLL years down the road, it’s gonna be different from what it is now. It’s gonna be different.

So, Susan, just so we understand, go back to something that we talked about, about clonal evolution, okay? And the CLL kinda changing, taking the winding road. Is it the idea that the cancer cell is kind of trying to figure out a way around the medicines, and just proliferate? It’s like sneaky?

Dr. Leclair:

Oh, they’re definitely sneaky. That’s absolutely correct. There are a number of situations that are involved in here.

We don’t really know which one goes with which disease, or if maybe more than one does. But, yes, I suppose, philosophically, you can think of these cells as wanting to live. And they’re gonna do whatever is necessary for them to live. So, you hit them with a medication that is rituximab, probably one of the better known ones. Rituximab hits a particular compound on the cell. And the loss of it, a lot of times, will cause the cell to be damaged and die.

Well, on the cell, and I’m a little on the smart side, I’m just not gonna make that marker on your cell. Or I’m going to put a hinge on it so that it breaks off, so that there’s minimal damage to me. And so, those kinds of things can and do happen to those cells. There is also the issue that, whether we like it or not, every day we go out and interact with something that’s gonna challenge ourselves or our genes in some way.

Three weeks ago, I went to the dermatologist with my husband, because he’s the one who has problems. We walked into this guy’s office and he said, “I’m taking you first. You have skin cancer.” “Excuse me?” That was a surprise to me. Well, how did that happen? It couldn’t have been because I’ve spent a lot of time outside without a hat on or anything like that, but I am not 22 years old. This took a long time for this to happen to me.

So, that’s a sense of a clonal evolution that occurs with repeated incidents of stress. And we all have that, every single day. Sometimes the only thing that happens is nothing. Sometimes you have to get your nose skinned to get stuff off.

And that’s what happens with these cells, as well. They will adapt because they want to live. We don’t, but they do. It is a matter—a contest to see who wins.

Andrew Schorr:

So, Justin, there you are in the lab. And as we come to the end of our program, I guess we wanna make clear, we talked about the whole picture, not just lab tests. But you’re looking at what could be tomorrow, okay. So, it sounds like there’s a pretty good pipeline of treatments of CLL should you have this clonal evolution, whether it’s 17p or something else, where you are gonna have something, please God, to bop it on its head again. How do you feel about it?

Dr. Taylor:

Yeah, we have good treatments now. We mentioned a few of them. I’ll just list some again. Ibrutinib (Imbruvica), venetoclax, idelalisib (Zydelig), obinutuzumab was mentioned, rituximab was mentioned, chemotherapy was mentioned. And so, we have a lot of tools and armamentarium in our pocket. But despite that, none of these are home runs, as it was put recently. So, we’re still trying to come up with other things and figuring out how to sequence them.

So, if you start off on Ibrutinib and then you can go to venetoclax, is that better? Or should we put the two together up front? And that was recently tested. We’re comparing these things and trying to figure out what’s the best way to give them in combination or sequentially to try to prevent this clonal evolution. And in the meantime, we’re coming up with more things to use in the future should these combinations not work.

Andrew Schorr:

Right. And you are. And I just wanna echo something that really the father of CLL study and treatment, Dr. Kanti Rai, talked to us about years ago, as we saw more of these tools you have come together, and you continue as, he said, to try to figure out how to arrange them.

It’s like arranging furniture in the room. There’s more furniture than ever before and you, Dr. Taylor, and your peers start to figure out how to arrange it, and people in laboratory science, Susan’s students, try to give you data to go along with the physical exam to get the whole picture of where that individual patient is. Did I get it right, Justin?

Dr. Taylor:

Perfect.

Andrew Schorr:

Okay. Susan, thank you so much for your devotion. What I get from you, always, is like what Granny Barb says, “Chill out.” You said, “Take a deep breath.” We’re on a long-term journey with CLL. And thank God we have a greater array of treatments. Are you hopeful for all of us, Susan?

Dr. Leclair:

Oh, I’m very hopeful. I think there will be a time when we will see the last person with CLL, just like we will see the last person with a lot of other ones. Look at yourself, Andrew, it’s the perfect example. Seventeen years ago you said, “Oh, God, what am I gonna do? I have to have therapy.” And you had the only therapy we had, and you got 17 years. And now when this happened, you said, “What am I gonna do?” And I said, “Have another 17 years.”

Andrew Schorr:

Right. Right, right. She did. And Esther and I just got back from Sweden, and we had a great time.

Dr. Leclair:

Oh, I’m sure.

Andrew Schorr:

I am so grateful to the medical community, the pharmaceutical community, the healthcare providers. I wanna thank the Patient Empowerment Network for putting this all together. I wanna thank AbbVie and Pharmacyclics for funding it. They had no control. Justin said what he was gonna say. I said what I was gonna say. Susan said what she was gonna say. Justin Taylor, thank you for being with us from New York in your lab. Go get ‘em, Justin.

Dr. Taylor:

Thank you.

Andrew Schorr:

Cure CLL, okay? Susan, thank you so much. You’re retired, but not really. You’re never retired for us, okay.

Dr. Leclair:

You told me I couldn’t.

Andrew Schorr:

No, you’re not allowed to retire. Okay. In Southern California, for Patient Power, but for the Patient Empowerment Network, I’m Andrew Schorr. Remember, knowledge can be the best medicine of all.


Please remember the opinions expressed on Patient Empowerment Network are not necessarily the views of our sponsors, contributors, partners or PEN. 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.

Ask the CLL Expert – Dr. Richard Furman

Ask the CLL Expert – Dr. Richard Furman

CLL specialist Dr. Richard Furman, Director of the CLL Research Center at Weill Cornell Medicine, answered patients burning questions live in this installment of Ask The Expert.


Transcript

 

Andrew Schorr:

And hello.  Greetings.  I’m Andrew Schorr in southern California, San Diego area, and I’ve been living with CLL for 22 years, so I’m vitally interested in today’s Ask the Expert session, this Patient Empowerment Network program.  We want to thank PEN, as we call it, and also the financial supporters of this program, AbbVie Incorporated and Pharmacyclics, although reminding you that they have no editorial control.  You’ll be hearing from our leading expert in CLL in just a minute.

Over the next 30 minutes or so we’ll get to as many questions as we can.  Remember not to make it too personal.  Let it help everybody in the community.  And also discuss what you learn with your own CLL provider so you get the treatment that’s right for you.  Okay.

Let’s meet our expert joining us from New York City and Weill Cornell medicine, and that’s Dr. Richard Furman, who is the director of the CLL research center in New York City at Weill Cornell.  Dr. Furman, welcome back.  Thanks for being with us.

 

Dr. Furman:

Thank you.  It’s my pleasure.  Thank you for having me.

 

Andrew Schorr:

Okay.  We have lots of questions.  One of them that somebody wants to know about is, first of all, if they’ve been‑‑maybe this is an easy one.  If they’ve been diagnosed with SLL, small lymphocytic lymphoma, is that the same as CLL and what we’re talking about with CLL applies to them?

 

Dr. Furman:

So that’s a very important question, and this is one that I actually think is very indicative of how little we used to know.  So in 1993 we actually had a diagnosis of CLL, chronic lymphocytic leukemia, and a diagnosis of small lymphocytic lymphoma.  And we had patients that were diagnosed with SLL if they had a lymph node sent to the pathologist, or they were diagnosed with CLL if they had a bone marrow biopsy sent to the pathologist.

Clearly, we knew that patients could only have one diagnosis and not two, so in 1994 with the new lymphoma classification system the term was actually changed to be CLL/SLL.  So they really are exactly the same entity.  We don’t actually refer to differences anymore, and the whole, the whole individual‑‑the whole disease should be called CLL/SLL.

Now, an important thing is sometimes people require having a lymphocytosis to meet the definition of CLL, but the truth is both conditions are exactly the same.  Both should be treated exactly the same, and there should be no difference based upon having a lymphocytosis.

 

Andrew Schorr:

Okay.

 

Dr. Furman:

Why this is most important, let me just add, is that there are sometimes people will be diagnosed with stage IV SLL and it’s very important to recognize that these stage IV SLL patients unless they have thrombocytopenia below 100,000 like the Rai stage would indicate really are not stage IV.  So the lymphoma staging system would automatically make them stage IV, and that’s certainly not correct.

 

Andrew Schorr:

Okay.  Good point.  All right.  Here’s a question we got in from Julia and Betty and Shelly and Mark.  They all asked a similar question.  They’ve been on Imbruvica for five years now with success.

Is it working for most people, and what are some reasons why it doesn’t work for everyone?  And then what treatment options do you recommend if they relapse on Imbruvica?

 

Dr. Furman:

So right now I think the most important, there are a lot of prognostic markers available for CLL.  At last count we’re probably up to 115.  What’s most important is in 2018 what are those prognostic markers that really are relevant to the patient, and really as long as you stay as CLL you’re going to be able to have your disease very nicely controlled with our current agents and our novel agents.

So there are certain things that do indicate patients are likely to progress on ibrutinib, not likely progress must but who may progress, and people who might need something more, and that’s where a lot of our current clinical are research is focused.  So patients who have a risk of developing a Richter’s transformation or patients who have a likelihood of developing a BTK mutation that might generate resistance to ibrutinib are the two groups of people that we worry about most.

17p deletion is probably the most important predictor for predicting those patient outcomes.  There are other things that are predictive as well like having a NOTCH mutation.  Those are all readily obtainable prognostic markers that allow us to determine who’s at risk and who’s not at risk for progressing on ibrutinib.  If you don’t have 17p deletion or NOTCH1 mutation you have almost a 99 percent chance of being free from progression at five years on ibrutinib.  And it looks like most of the people who are going to progress will progress within five years.  So I think making it to that five‑year mark is really very‑‑is the most important thing.

 

Andrew Schorr:

Okay.  So if you do progress, what then?

 

Dr. Furman:

So fortunately we have a lot of great agents.

Venetoclax works very effectively in patients who progress on ibrutinib, generates some very, very deep responses and very long‑lasting responses.  So that’s certainly one option.  Another option is to be treated with a PI3‑kinase inhibitor.  So we have idelalisib and duvelisib now approved.  We will shortly have umbralisib approved as well as a novel agent.  We also have a whole array of other agents coming down the pipeline looking specifically at means for progression on venetoclax.  So we have an MCL1 inhibitor which targets the protein that’s likely responsible for resistance to venetoclax.  So all these things are actually currently in clinical trials and certainly will hold a great deal of promise.

 

Andrew Schorr:

Okay.  Here’s a question we got in from Jeff.  He says, for young and fit patients with relapsed disease what are the best combos now and coming.  And I suspect maybe Jeff had received FCR, so if he relapses after FCR, what about that?

 

Dr. Furman:

So my belief is that these novel agents should always be used up front, or if you’ve gotten chemotherapy up front they should be used immediately at relapse.  A lot of patients and physicians have the idea that there’s a benefit to holding back until you really need something, but I believe putting our best foot forward first is always the best approach.  So I always recommend going forward first with BTK inhibitor therapy, followed by venetoclax or venetoclax followed by BTK inhibitor therapy.  And I think so in a patient who has relapsed after FCR it will be ibrutinib or acalabrutinib.  In a patient who has relapsed after acalabrutinib and ibrutinib would then move on to venetoclax.

Now, what I’m really very excited about is the possibility of the combination of either BTK inhibitor therapy plus venetoclax or PI3 kinase inhibitor therapy with venetoclax.

You know, both of these combinations really take advantage of the synergy that happens when you take a BCR antagonist like ibrutinib, acalabrutinib or idelalisib and duvelisib and combine it with a Bcl‑2 inhibitor.  And it really sort of enables us to get very, very deep remissions with actually as short as just 12 months of treatment.  And so those are what we’re currently testing in patients right now and what I hope will be the frontline treatment for patients in the not‑too‑distant future.

 

Andrew Schorr:

Now, one of the things people wonder about is if you take these big guns and put them together could you, like you’ve been able to do with FCR, stop treatment or take a break from treatment at some time.

 

Dr. Furman:

So I’m a big believer in that if something’s working and you’re tolerating it well that we shouldn’t mess with it, but we are currently studying two different processes with relationship to the ibrutinib plus venetoclax combination.  So we’re taking patients who become MRD negative on the combination after 12 months and randomizing them to either just get ibrutinib or to get placebo.  And so that’s going to give us information as to whether or not it’s safe to stop patients on the combination and treat them with nothing long term.  We’ll see, one, how many patients relapse, and hopefully none, and, two, if they do relapse whether or not we can then restart ibrutinib and control their disease.  So this will provide us that important question as to whether or not we’re giving up something by discontinuing the therapy.

We’ll have as our comparative those patients who got ibrutinib plus venetoclax for 12 months and then just remained on the ibrutinib.

And so that will sort of be the patients who will continue on with their therapy, and then the other half will be patients who have discontinued all their therapy.

My belief for going to venetoclax is that you’re going to get almost all of the bang for your buck out of the first 12 to 24 months, so continuing it is unlikely to yield an additional benefit, so I think stopping it is safe.  But, once again, these are the studies that will provide us with those data.

 

Andrew Schorr:

Okay.  Now Maureen sent in a question where they responded to venetoclax and rituximab and they wondered what about testing for minimal residual disease?  They don’t have any lymph nodes or anything, but is that then appropriate to do a MRD test to see how deep the remission is?

 

Dr. Furman:

So the real important question should be whether or not that’s going to impact upon clinical management.

So MRD testing is easy, it’s noninvasive, it’s a peripheral blood test or a bone marrow biopsy, which I guess is only relatively noninvasive, and the information though is really not going to be of use.  So if you’re taking a patient who’s on ibrutinib and you’re going to continue the ibrutinib knowing the MRD status won’t change anything.  Likewise, if you have a patient who’s on venetoclax, who’s going to get a year of venetoclax on trial and then stop, knowing the MRD status won’t change anything as well.  So currently there’s no real reason for doing MRD assessments in patients except for just the ability to know.

Now, one day there’s some modeling that suggests that the time it takes you to reach MRD negativity is half the time you need to be on a substance, an agent, before you can actually claim to have a deep enough remission that you won’t relapse.  So we may one day say if you’ve been on ibrutinib for five years and became MRD negative, then 10 years of ibrutinib is enough and you can stop.  But that’s currently just theoretical and based on mathematical models.

 

Andrew Schorr:

Theresa wrote in, she said, my husband is being treated with acalabrutinib for five months.  He’s doing well, but should he have some sort of testing to know whether he will develop some sort of resistance in the future?

 

Dr. Furman:

So that’s a very important question, and the answer really is, you know, testing for it now isn’t going to be able to change anything.  Right now we would still continue the acalabrutinib until we see signs of clinical progression.  There’s some early data emerging from Ohio State where they’re doing PCR testing on all the peripheral blood of patients, on the peripheral blood of all patients to see whether or not they can detect any of these mutations that lead to resistance.  The problem is you’re still going to continue the treatment until you see the clinical relapse.

And, two, is you really‑‑you know, in essence when you look at the data that suggests that 92 percent of patients who get ibrutinib as a first‑line therapy will remain in remission at five years you’re talking about treating‑‑or testing a lot of people for very, very few people that will likely benefit.

 

Andrew Schorr:

Okay.  So if you have a question now, send it in, cll@patientpower.info, and we’ll do our best to pose it to Dr. Furman.  Okay.

So Beth with wrote in and wanted to know is there work going on on a CLL vaccine?

 

Dr. Furman:

So we’ve been playing with CLL vaccines for at least the past 25 years, and a lot of these vaccines were originally designed to be what we call antiidiotype, meaning they were directed against the antibody made by the cell itself.  Unfortunately, a lot of those vaccines have not proven effective, and we’ve gone through a lot of different iterations.  We’re still trying, and hopefully one day we will have better success.

Right now a lot of our current research is focused on not so much the target that the vaccine should be against but ways to make the vaccine more effective.  Things like using PD‑1 inhibitors, which can actually make the tumors more apparent to the immune system.  Or using things that can actually enhance the presentation of the actual vaccine to the immune system, and that includes everything from idelalisib and ibrutinib to other different molecules that may actually make it more readily apparent.

Now, we do also have some new targets like ROR1, which may prove to be very exciting and interesting, but this is still all very far away from anything that will be approvable.

 

Andrew Schorr:

Okay.  Now, here’s a question we got in from Cerisa, said, my understanding is that most drugs aim at destroying the CD20 protein like rituximab or obinutuzumab, etc.

Well, what about, CD9, CD15, CD23?  Are they not as bad as CD20 in CLL?

 

Dr. Furman:

So the thing that’s really important to keep in mind is only our monoclonal antibodies attack one protein in particular, and so we have obinutuzumab, rituximab, and ofatumumab all of which address or target CD20.  CD20 was the first protein targeted for two reasons.  One is it’s ubiquitously expressed on all B‑cell lymphomas, and so it’s a way to identify a target that we can actually generate one treatment for that will work in a large number of people.

The second is it’s a protein that doesn’t seem to actually get endocytosed or down modulated so that it remains positive in the cases most of the time.  One of the problems with some of the other proteins you mentioned is that they’re not expressed on the CLL cell.

So CD3, CD15, those are not present on CLL cells, but they’re also present on a lot of other cells as well.  The key about CD19 and 20 is that they’re only on B‑cells, and we really can actually do okay without our B‑cells.  And so that way the down side to knocking an out all our B‑cells is actually relatively minor.  And the CAR‑T cells, which are T‑cells taken out and reprogrammed, they’re reprogrammed to be directed against CD19 and 20, so in a way they work like the monoclonal antibodies.

 

Andrew Schorr:

Okay.  Lynn wrote in and asked about transplant in CLL, and I’ve met people who have had transplant, so where does transplant fit in now, and does CAR‑T cell experimental therapy maybe supersede that?

 

Dr. Furman:

One well, one of the things that’s important to keep in mind is that CAR‑T cells are still very novel, and the long‑term efficacy is not yet there, so we still need to do a lot of work to help that.

My belief is allogeneic transplants are very effective but they’re also very toxic and dangerous, and I do believe that they should be avoided if at all possible.  So I am very, very selective in who I refer for allogeneic transplant.

With our novel agents like ibrutinib, idelalisib, duvelisib, umbralisib, acalabrutinib, vecabrutinib, zenabrutinib, the list is just rapidly growing, I almost believe that the patient who really needs an allogeneic transplant will only be those patients who have developed or are at high risk of developing Richter’s transformations.  So I really do believe there’s a very limited role for allogeneic transplant at this point in time.

 

Andrew Schorr:

Okay.  And CAR‑T, you’re watching it.

 

Dr. Furman:

I am.

 

Andrew Schorr:

Okay.  Here’s a question that came in from Mike, and this is the bottom line for a lot of people when they’re diagnosed, and he says, what is the current state of treating CLL for those of us watch‑‑he says wait and see patients or watch and wait.  In other words, is it curable?

 

Dr. Furman:

So right now CLL is not curable.  The way that I would love everyone to start approaching CLL is very analogous to high blood pressure.  So we don’t cure high blood pressure, but if you take a pill a day it’s not going to have an impact on your longevity.  And I believe we’re there for about 75 to 80 percent of CLL patients, where they will be able to get a BTK inhibitor or a Bcl‑2 inhibitor or a combination and they will be able to not have to worry about their CLL for the rest of their lives.

There’s still the 20 percent who are going to develop either a Richter’s transformation or a progression on ibrutinib, and those are people we’ve got to figure out what to do differently for.  But all the others, even though it’s not curable, we can definitely I think keep it from having an impact on longevity.

People on watch and wait who are high risk of progressing and developing a Richter’s or progressing onto developing resistance to ibrutinib, we do have a couple of trials that are very interesting right now where we’re treating people at diagnosis with BTK inhibitors with the hope, because they’re so well tolerated and because they’re so effective, we might be able to have an impact and prevent those patients from developing resistance or developing a Richter’s transformation.

 

Andrew Schorr:

Wait a minute.  So are we looking at what has been the traditional watch and wait period differently now and some people will be treated much earlier?

 

Dr. Furman:

Well, we’re just starting to look at that right now in clinical trials.  So this is very early.  It’s for a very select group of people.

We know from the data‑‑so we have seven‑year data coming out at ASH this year where we’re going to have a group of people who were watched and waited and only when they had evidence of disease progression and needed treatment and got ibrutinib, 92 percent of them were still doing well and free from progression at seven years.  So for those 92 percent of patients we couldn’t do any better.  So it’s really just a very small group of patients who need something extra.

So, yes, we’ve proven I think in a large number of patients that BTK inhibitor therapy might be all that’s necessary, but in everyone else, in those 8 percent we do have studies going on to try to answer how to treat them differently.

 

Andrew Schorr:

Okay.  So we got a question early on about somebody who was asking about should he be taking a statin along with his oral therapy for CLL.  So people have other conditions.  So what about that?

 

Dr. Furman:

So if you have hyperlipidemia you should definitely be on a statin, otherwise, no, you don’t need a statin.  I think it’s important to keep in mind that there was a lot of data generated at one point about statins perhaps changing the CD20 expression on the surface of the CLL cells or making rituximab or other anti‑CD20 antibody therapy more efficacious.  I’m not aware of any data that suggests there’s an impact to statins on non‑anti‑CD20 therapy efficacy, and I think the impact on anti‑CD20 antibody efficacy is actually really quite small and unlikely to generate a significant difference.  So I really don’t believe there’s a need to do anything outside of just treating your lipids.

 

Andrew Schorr:

I promised our audience weeks ago that I’d ask you about this.  So should we have flu shots?  Should we have the shingles vaccine?

 

Dr. Furman:

So, absolutely.  Everyone should definitely get a flu shot each year.  And it’s important to get the flu shot each year because the immunity doesn’t persist.  So I actually recommend people get vaccinated either October or early November.  All right?  So any earlier than that I worry that you’re going to have your immunity peak before the height of the season, and later than that you may not actually have sufficient time to respond.

Regarding the shingles vaccine, so there’s a new shingles vaccine called Shingrix which is a recombinant vaccine, so it’s not a live vaccine, and that’s how it’s different than the previous shingles vaccine.  The previous shingles vaccine was an attenuated or live virus vaccine, and CLL patients really shouldn’t have taken it because it really theoretically could have caused shingles.

Now, the old shingles vaccine was also not very effective, so even though the risk was low with low efficacy there’s really no risk/benefit assessment that puts it in favor of doing.

But the new shingles vaccine actually has been tested in patients post autologous bone marrow transplants, so it’s very effective in patients who are very immunosuppressed, and because it’s not a live vaccine it is safe.  So I do recommend it for everyone.

 

Andrew Schorr:

Okay.  Dr. Furman, so you mentioned it earlier and we’ve heard about a lot of programs, the 17p deletion and I almost think of it as the dreaded 17p deletion, but is that necessarily true?  Pam wrote in, she said, I have the 17p deletion.  What are my options?  So first of all, are all 17ps alike, and then what are the options?

 

Dr. Furman:

So the thing that’s most important to keep in mind when we talk about prognostic markers is they’re really just surrogates for clinical behavior.  And so the answer always is going to be if you have historical data that’s always going to trump the prognostic marker.

So someone who is 17p deleted and their disease has remained stable for the last five years, their disease is stable, and the 17p deletion is not going to be what drives the prognosis.  I think that’s very important because when you look at a curve you’re going to see some people doing well and coming off the curve late and some people doing poorly coming off the curve early.  You know, where they are on the curve we have no idea how to predict.  All we know is that they’re on a particular curve.  So prognostic markers tell us about the population, never about the individual.

Now, with that being said, we do know 17p deletion a lot of it, the percentage of the deletion if you’re above 20 or below 20 does have an impact on how you do overall.  So 20 percent and below, they‑‑patients seem to have a better prognostic outcome than the patients who have 20 percent and above.

With that being said, I do have patients who have 17p deletion in 70 percent of their cells and they’re just hanging out doing quite nicely.  So clinical behavior does trump everything else.

 

Andrew Schorr:

Okay.  So, obviously, most CLL patients are older.  I’m 68 now, but I was diagnosed at 45, which is pretty young, but here’s Matthew who writes in he was diagnosed at age 31 and he wonders, he knows a lot of the statistics but he knows it’s mostly older people.  He’s trying to figure out, well, what’s his life going to be like.  So what do you say to younger patients with CLL today?

 

Dr. Furman:

So, remember, we’ve only had these novel agents since 2010, and so what I really do believe is that we really don’t know how good things are going to be yet.  I think things are going to be a lot better than we ever envisioned, so I am quite optimistic about the future.

We don’t know whether or not a 31‑year‑old could enjoy a normal long life expectancy but if they don’t have evidence of or suggestions that they’re going to have particularly aggressive disease and develop resistance to a BTK or a Richter’s transformation, they could theoretically have 40 years on a BTK inhibitor.  And so that’s certainly what my hope is for the future.

You know, all the survival curves that people talk about and all the survival curves that people show really don’t take into account any of the novel agents, and that’s always very important to keep in mind.  So we do some have data.  As I mentioned, the seven‑year data is coming out from‑‑will be out at ASH, and the seven‑year ibrutinib data really suggests almost a nearly flat curve for patients with CLL who get ibrutinib as a front‑line treatment.

 

Andrew Schorr:

So you mentioned over the years the Rai staging system, and Dr. Rai, the grand old man of CLL.

So how does that apply now?  You know, somebody’s diagnosed with CLL, they come across this Rai staging system, but is that meaningful for them today, or are there new ways of looking at it?

 

Dr. Furman:

So the Rai stage really still drives when we’re going to treat patients.  So patients are still treated based on meeting, you know, the classic indications for initiation of therapy.  So Rai stage 3 and 4, namely hemoglobin less than 11 or a platelet count less than 100,000, really are the two primary reasons why people initiate therapy.  We know that if you watch and wait someone until they meet classic criteria and they have disease that doesn’t harbor one of these high‑risk changes we know that they’re going to do extremely well.  So that’s good news.  Whether or not patients who have these other markers should be treated before they have aggressive disease is on open question.

Now, what I really do think that’s also important to keep in mind is, you know, the watch and wait ideology really came about when we had therapies that were not very effective and also were quite toxic.  Now that we have these novel therapies that are far less toxic and highly effective, maybe the bar should move towards initiation of therapy sooner, but that’s still on open research question and not one that we know the answer to yet.

 

Andrew Schorr:

Okay.  And Bob has had the same treatment I’ve had.  He had Gazyva or obinutuzumab with high‑dose methylprednisolone, and now that was, gee, about two years ago, and now his CLL has started to show up in his spleen and his lymph nodes.  He said, well, can he be treated with the same combination again, or might he move to something else?

 

Dr. Furman:

Well, that’s going to depend on a lot of factors.  Most importantly is whether or not there was, you know, he had received the full dose in which case the likelihood is that with just a two‑year remission I would expect that retreatment would generate a shorter remission this time, and the risks associated with high‑dose methyl prednisolone plus obinutuzumab probably don’t outweigh, or aren’t going to be‑‑the risks are going to outweigh the benefits that would be gained if we’re talking about a response that’s going to last less than two years.  So it would probably be better to move on to additional agents.  And, fortunately, we have so many others that I think it would be a way to avoid resistance and also develop‑‑avoid, actually, the toxicities associated with high‑ dose methylprednisolone.

 

Andrew Schorr:

Okay.  We’ll take just a few more questions, and thank you, Dr. Furman, for sticking with us.  And I relate to this one.  So I did have the obinutuzumab and rituximab years ago, and I developed sort of a history of sinus infections for a while and even some chest congestion and I’ve seen other people write in about it.

Do we have the sinus or the respiratory issues from the CD20 antibody or is it something else?

 

Dr. Furman:

So it’s important to recognize that CLL patients, 75 percent of CLL patients will develop hypogammaglobulinemia, and that hypogammaglobulinemia is probably most of the cause of the chronic sinusitis, chronic bronchitis, sort of that‑‑those issues with having the constant drainage.  So I do believe that CLL in and of itself is certainly the first factor that impacts upon that.

The anti‑CD20 by itself will also cause a lot of those problems as well, so the two together are just a double hit.  But we do know that CLL patients, totally regardless of their prior‑‑regardless of their prior treatments will run into those issues.

Now, with that being said, what people often forget is the most common cause of a chronic sinusitis in anyone, even a CLL patient who’s gotten obinutuzumab, is still going to be a deviated septum,  or it’s going to be a blocked sinus channel, so I always recommend and I always insist on all my patients being evaluated by an ear, nose and throat doctor first just to make sure there isn’t something anatomical that could be fixed.

 

Andrew Schorr:

I went to an ENT the other day, and also I’ve been doing‑‑and I know my Dr. Kipps here is urging me, I’m doing the nasal wash and all that stuff, just trying to have sinus hygiene, if you will, working on that.

Okay.  Couple more questions.  Aukie wanted to know, and we’ve talked about this in the CLL world forever, should he be taking a green tea extract?  Is there any validity for that?  What do we know?

 

Dr. Furman:

So my belief is no.  I think it’s important that we have a lot of alternative medicines, medicines that have been studied, and until they show evidence clinically I do believe that it’s important to actually stay clear of them, and there are a couple of reasons why.

So a lot of things work in the laboratory, but that doesn’t mean they’re going to translate into working clinically.  And a lot of the medications that are sold as alternative medications or homeopathic medicines are unregulated and can make claims that aren’t substantiated, but they also don’t have their products necessarily vetted.  So we’ve had a number of examples of people who have been taking a root or have been taking some leaf that’s turned out to be laced with amphetamines.  So a leaf that claims to enhance your energy output, absolutely, if it’s laced with amphetamine will certainly be able to accomplish that.

So it’s important to keep in mind that anything that’s made naturally or that occurs naturally doesn’t actually get regulated the same way as pharmaceuticals.  There was also a change in the laws in the 1990s where anything that was natural didn’t have to be tested and approved by the FDA, so the claims that they make‑‑like Tony the Tiger can say that Frosted Flakes are great without proving that in a randomized controlled clinical trial.  Because it’s a naturally occurring substance it can make claims that aren’t necessarily substantiated.  I do worry about that.  And there are some definite cases of patients coming to harm from taking medication‑‑from taking supplements that weren’t well regulated.

 

Andrew Schorr:

So, as you know, so many of us complain about fatigue with CLL.  What can we do about that?  Is there any medication or something you feel comfortable about as a supplement that could help with that?  Certainly, we’ve been telling people exercise is a good thing and can give you more energy, but what do you tell your patients when they talk about fatigue?

 

Dr. Furman:

So this is actually a very common question, and I really do believe it’s very important to remember that having CLL doesn’t protect you from the things that befuddle the rest of us.  So the most common cause of fatigue in a CLL patient is not going to be the CLL but it’s going to be the same thing that befuddles the rest of us.  So it’s poor sleep hygiene.  It’s not sleeping long enough.  It’s all those things that really should be addressed first and foremost.  So we see a lot of sleep apnea that’s undiagnosed.  We see a lot of people who are just not sleeping long enough.

If we’ve ruled out everything else and a patient seems to have progressive disease, yes, there are definitely patients with CLL whose fatigue is related to the CLL, but I’m a big believer that fatigue related to CLL should only be present in a patient who really has active signs of CLL.  So if someone is on watch and wait and their lymphocyte count is not changing and their lymph nodes are not enlarged, their fatigue is not going to be related to their CLL.

But if someone’s lymphocyte count’s climbing and their lymph nodes are growing then certainly their fatigue might in part be related to their CLL.

 

Andrew Schorr:

Okay.  This has been like being on a game show.  I keep throwing things at you.  I want to thank you for all your time.

Folks, we’re going to let Dr. Furman go, but we will be doing other Ask the Expert sessions and doing some live broadcasts in from ASH.  ASH, you alluded to, Dr. Furman, always has more coming out, more longer range studies, combination information.  So just to wrap up with, for those of us living with CLL, and, thank god, so many of us long term, me, 22 years, are you very hopeful that you have more options for us now no matter what our CLL situation is?

 

Dr. Furman:

I really do.  I think we have some amazing options now.  We have also the data that our current crop of novel agents really can be safe and effective long term, and that’s what I really think is so important to be cheerful about.

And in those patients who do progress we have a whole crop of other agents that will prove to be hopefully effective in those situations.  But I think it’s going to be the‑‑you know, the home run though is going to be the combination of BTK and Bcl‑2 inhibitor therapy or PI3 kinase and Bcl‑2 inhibitor therapy because in those situations I really do see patients getting very, very deep remissions that I hope will be extremely long lasting.

 

Andrew Schorr:

Think about it, folks.  I mean, I got FCR, a three‑drug combination, in 2000, 18 years ago, and it worked for a long time.  So the idea of combination therapy has worked well in cancer therapy hitting those cancer cells in multiple ways.  Dr. Furman, thank you so much for being with us today.

 

Dr. Furman:

My pleasure.

 

Andrew Schorr:

Okay.  From Weill Cornell.

And I just want to mention for our audience, remember we’ve got a lot coming up.  On Wednesday, November 28, we’re going to understand the ins and outs of watch and wait for those of you who are in that situation.  From the big ASH meeting in San Diego‑‑yay, I don’t have to get on a plane to go anywhere‑‑we’ll be also doing live broadcasting so be sure to be signed up for that.

And then on December 5th we’re going to talk about the financial issues because, as Dr. Furman talks about, combining these oral therapies, these are expensive, and so what support is there for you so you get the combination should you need it and it’s affordable.  So keep an eye on that.  Go to the Patient Empowerment Network’s website, powerfulpatients.org, and take a look at what we have on Patient Power as well.  Thank you so much, Dr. Furman.  Thanks to our audience and stay tuned for what comes out of the ASH meeting.  I’m Andrew Schorr.  Remember, knowledge can be the best medicine of all.

Please remember the opinions expressed on Patient Empowerment Network (PEN) are not necessarily the views of our sponsors, contributors, partners or PEN. 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.

Ask the CLL Expert – Dr. Jeff Sharman

Ask the CLL Expert – Dr. Sharman

 

“Ask the Expert” session with CLL specialist Dr. Jeff Sharman from Willamette Valley Cancer Institute and Research Center.


Transcript:

Recorded on: September 27, 2018

Andrew Schorr:
Greetings to this live Ask the Expert program for those of us dealing with CLL. I’m Andrew Schorr from Patient Power. Welcome to this Patient Empowerment Network program with financial support from AbbVie and Pharmacyclics. Thank you so much for being with us.

We have a wonderful expert with us today who is so knowledgeable about this, and that is Dr. Jeff Sharman. Dr. Sharman is the medical oncologist, of course, one of them at the Willamette Valley Cancer Institute and Research Center in Oregon. He’s also the medical director for hematology research at the US Oncology Network with oncologists all across the country. Jeff, welcome back to our program.

Dr. Sharman:
Thank you so much. It’s nice to be here today.

Andrew Schorr:
Okay. Let’s get started. We have a lot of questions coming in, and if you, our viewer, have an additional question send it to cll@patientpower.info and we’ll cover as much as we can in the next half hour.

Here’s a question that came in based on news events that people follow related to CLL, and this is from William. He says, I heard there’s a new drug approved for CLL, duvelisib. Can you tell more about this? Where does it fit in in the CLL landscape?

Dr. Sharman:
Absolutely. Duvelisib is another PI3 inhibitor. It has considerable molecular similarity to idelalisib, which was the first in class medication approved amongst the PI3 inhibitors a few years ago. This molecule has considerable both biochemical similarity, structural similarity but also quite a bit of clinical similarity. So when you look at the patient population in which it’s approved, similar clinical trial designs led to approval, and so as a result it’s sort of in the third‑line setting that you could use it.

It is a‑‑the drug class is a sort of the whole PI3 family of which there’s a growing number. There’s idelalisib, umbralisib is in late‑stage clinical trials. Copanlisib is approved in follicular lymphoma but not CLL. And as a family they tend to be utilized less frequently than the BTK inhibitors such as ibrutinib and to some degree less frequently than venetoclax, as well, the Bcl‑2 family, and that has to do with some of the side effects, that there is, a frequency of diarrhea, LFT abnormalities and so forth. So it follows on the heels of idelalisib, and I would say has more similarities than differences.

Andrew Schorr:
Okay. Let’s go on. You mention about side effects. People ask about that all the time, so here’s a question from Judy. She says, I’m not able to get an answer from my husband’s oncologist regarding ibrutinib and severe body cramping. Have there been any reports showing this is a possible side effect from ibrutinib?

Dr. Sharman:
Absolutely, it is. It is‑‑well, absolutely possible, let’s say that. It actually is what I would say one of the most common side effects that I encounter as a limitation for ibrutinib. The medical term for it is arthralgias, which is sort of translates into joint pains. Sometimes you’ll also see actual cramps or spasms. I’ve had patients’ hands lock up when they’re driving sometimes, which can be a little bit concerning.

There is I think considerable question in the field. There are differences amongst thought leaders on this as to whether‑‑how to best manage it.

There’s some studies that suggest that lower dosages may‑‑after a patient has been on ibrutinib for a length of time you may be able to get away with lower dosages. Those pieces of clinical trial data are not as large and not as well validated, so I think it’s still in the hypothesis‑generating mode, but there’s some data that suggest you could do it. And if the choice was lower dose of ibrutinib or no dose of ibrutinib, I would probably go with a lower dose.

The other potential solution now is acalabrutinib, which is a second BTK inhibitor approved. It is approved by the FDA for mantle cell lymphoma. However, a lot of the clinical trials are in chronic lymphocytic leukemia, and there have been studies that looked at patients who have limited tolerance of ibrutinib, and in many cases they were able to go on acalabrutinib without a recurrence of the same side effects.

So that’s another possibility. It is in the NCCN guidelines that for those patients who have intolerance of ibrutinib consider acalabrutinib. So whether it’s dose reduction or drug substitution, those are sometimes two ways that I use to get around that scenario.

Andrew Schorr:
Okay. Now, we should be clear that acalabrutinib is not yet approved for CLL. Does it seem like that’s forthcoming? I mean, nobody can guess the FDA, but.

Dr. Sharman:
Yeah. So the clinical trial that will lead to approval, presumptive approval, was a head‑to‑head comparison against investigators’ choice of bendamustine rituximab or idelalisib rituximab, and that study is fully accrued and waiting for end points.

And I think that the feeling would be that should be a positive test and that it would eventually get CLL approval. Most of the studies have been done in CLL. It’s just the mantle cell indication came along more quickly.

Andrew Schorr:
Okay. All right. A lot of people worry about other side effects like fatigue, of course, in CLL. So here’s a question from Patty. She says, I’ve been taking 60 milligrams of Vyvanse, which is often used for ADHD, for extreme fatigue that she struggles with. And she says her blood pressure is elevated, and she’s read that that can be a side effect of Vyvanse. Are there any new or additional medications that can be used to treat fatigue without the worry of high blood pressure?

Dr. Sharman:
The way I would approach that situation, fatigue‑‑what I don’t know about this particular patient, is this fatigue that is attributable to the CLL or fatigue that’s attributable to medications?

CLL fatigue is probably one of the most bothersome sort of clinical realities, and for some patients even though they may not meet other treatment criteria such as rapid rise in white blood cell counts, systematic (?) inaudible adenopathy, marrow dysfunction. Sometimes fatigue is so debilitating that you need to do treatment for it. In the 2008 guidelines, fatigue was one of the‑‑it was like the sixth indication for when you treat CLL.

And I’ve seen some patients, you know, one immediately jumps to my mind. He’s clinician himself, very busy individual, likes to surf and so on and so forth, but his CLL left him so fatigued that he had to cut back on clinical work and so forth. And getting his CLL under control really made a huge difference for him. So in the setting of CLL I think that you may wish to consider talking to your doctor about going ahead and treating.

I find those are difficult, difficult discussions because if you don’t have the more classic indications for therapy it’s hard to know. Because fatigue can be a number of things. It can be thyroid dysfunction. It can be hormone imbalance with other hormones. It can be nutrient deficiencies and so forth.

Andrew Schorr:
It could be having three kids.

Dr. Sharman:
Absolutely.

Andrew Schorr:
Yeah, I know. Lots of things.

Here’s another question from Bob. Bob wants to know, will approaches likely change for first‑line treatment, for instance venetoclax, or Venclexta, within the next two years? You have ibrutinib first line.

Dr. Sharman:
Yeah.

Andrew Schorr:
You have FCR that’s been around. You have idelalisib I think could be used first line.

Dr. Sharman:
Actually, idelalisib is specifically contraindicated for first‑line therapy because of side effects.

Andrew Schorr:
Okay. So what about first‑line therapies, Jeff? Where are we there and what’s coming?

Dr. Sharman:
Yeah, so you’re kind of in this bind currently where your choices are chemoimmunotherapy or targeted therapy, and both of them have strengths and weaknesses. The strength of chemoimmun0therapy is that you give treatment for a fixed duration of time, and then you get treatment‑free interval that in properly selected patients should be measured in multiple years.

Andrew Schorr:
I went 17 years.

Dr. Sharman:
Yeah, absolutely. So effective therapy in appropriately selected patients. Now, when I say appropriately selected patients, that does get into some of the nuance about FISH changes and IGHV mutation, and I will tell you even amongst thought leaders in the field there’s some debate as to where you draw the line. Some patients are more suitable for ibrutinib either because of co‑morbidities or wish to avoid chemotherapy, but at least as of today ibrutinib is something you start and then stay on indefinitely.

And per the prior question, some patients have difficulties with that, whether it’s arthralgias or bruising bleeding and so forth. The medication you made mention of I think is the frontline therapy that may have the most profound impact on treatment selection in the next two years.

Andrew Schorr:
Venetoclax.

Dr. Sharman:
So the German Research Group, which is really just absolutely one of the best out there, have fully enrolled a clinical trial of obinutuzumab venetoclax versus chlorambucil and obinutuzumab, and I have to believe that that is going to result in a superior outcome for the venetoclax arm and that we will have the combination of obinutuzumab venetoclax for front‑line setting.

And what’s really appealing about that is that is one year of treatment and then treatment is suspended and stopped. And though we haven’t compared that to more traditional BR or FCR, I think it would be a highly effective regimen. We are currently conducting a study in the United States in our research network looking at the combination of obinutuzumab and venetoclax, and what I like about our study is we give‑‑for the listeners who might not be familiar with venetoclax, starting venetoclax is a little bit clunky because it works so quickly we have to be careful about a condition called tumor lysis syndrome, which is if you kill too much cancer cells too quickly that can cause some dangerous conditions, and venetoclax does do that.

And so what we’re doing is we’re giving two months of obinutuzumab and sort of getting rid of the bulk of the CLL and then starting the venetoclax hopefully under much safer conditions because, you know, in the Pacific Northwest we would say you can’t have forest fires if you don’t have any trees. So if we get rid of all the CLL or a substantial fraction of it somebody is less likely to have tumor lysis. So I think that’s the approach that is probably the next up in frontline.

The one other thing that could potentially change is acalabrutinib has conducted a three‑arm study‑‑excuse me, Acerta with acalabrutinib, where they give‑‑it’s a three‑arm study with either chlorambucil Gazyva, acalabrutinib or acalabrutinib with Gazyva. And so does the addition of a C‑20 antibody make BTK work better, remains the question outstanding.

Andrew Schorr:
All right. Let me just explain things to people. I’ve been around this for a long time and Jeff deals with these acronyms all the time. So, first of all, Gazyva is the same as obinutuzumab.

Dr. Sharman:
Thank you, yes.

Andrew Schorr:
It’s an infused CD20 that’s targeting the CD protein on the B‑cell, the bad guy, and it is sort of I don’t know if you’d describe it as a more powerful version but it followed from Rituxan or rituximab that many of us had. So the idea is you have an infused therapy for some length of time, and then you may have an acalabrutinib with it or you may have a venetoclax or Venclexta with it. Get I get it right, Jeff?

Dr. Sharman:
Yes. And if I just had one other comment. I think there are a lost questions and certainly some very compelling data about the combination of a BTK inhibitor such as ibrutinib with a Bcl‑2 inhibitor such as venetoclax.

Andrew Schorr:
Two pills.

Dr. Sharman:
Two pills, yes. And I think the preliminary data really looks extremely encouraging.

The challenge with that approach is it’s not approved in that combination and probably not going to be approved in the next two years unless the FDA does something that maybe I’m not anticipating at this point. That clinical trial that compares that to an existing standard is really only just getting off the ground now.

Andrew Schorr:
Okay. All right. Let’s buzz through some others. So John writes in, please compare purpose and benefit differences for FISH testing versus next generation sequencing. So maybe you could explain them too.

Dr. Sharman:
Absolutely. Thank you for the question. It’s one that I think is often very difficult to comprehend.

So a little bit of history here is that we’ve known for a long time with that patients with chronic lymphocytic leukemia have a pattern of common chromosome gains or losses, and we generally pay attention mostly to five separate categories.

There are some others that people sometimes look at, but ranging from sort of worst to best, worst is having a loss of chromosome 17p and P stands for petite arm, so part of the short arm of chromosome 17 is lost. 11q, Q stands for the long arm of chromosome 11. And then you have normal chromosomes or the addition of an extra chromosome 12 or the loss of a portion of chromosome 13 that kind of goes from worst to best. And that is very different than actual mutations in genes. So these are wholesale losses of large clunks of chromosomes.

And if you look at 17p the reason that 17p is bad is because there’s a particular gene there that’s very important called TP53, and you can actually have a mutation in TP53 without the presence of a chromosome loss. And so next generation sequencing looks at a host of additional genes that really until the last three to four years we didn’t know have the significance that they have. So TP53 is probably the most important, but you’re also seeing things such as SF3B1, NOTCH1, FA1. There are a variety of them that are out there. Some are better understood than others, and I think to some degree we’re still as a field even trying to figure out how best to integrate these into our clinical practice.

Andrew Schorr:
Okay. So would you recommend for the typical CLL patient that they have FISH testing, which tells you about the chromosomes, right?

Dr. Sharman:
Yeah.

Andrew Schorr:
And when do we need to do genomic testing to see with whether if any of those genes you just rattled off?

Dr. Sharman:
Yeah. So I can tell you about my own personal practice on that. I do think that the field, as I indicated before, is still trying to digest this, and a number of those specific mutations there isn’t necessarily super robust consensus as to when is the best time to draw those. So I’ll explain how I’ve thought through it, and if that resonates with you.

So my question in the previously untreated patient is whether or not this patient is suitable for chemoimmunotherapy. Previously I said appropriately selected patients get very long duration responses. I don’t want to give chemoimmunotherapy to a patient who is not going to get a sustained benefit.

If I anticipate that I’m only going to get 18 months benefit or two years of benefit, it is not worthwhile in my mind going through the chemotherapy to get that. I would rather put those patients on a tyrosine kinase inhibitor.

So my first stratification is the IGHV mutation status, and I would say in general if somebody’s mutated, which is the more favorable form, I would tend to err more on the side of chemoimmunotherapy for those patients. For those who are unmutated, which is the bad one, I would tend more towards targeted therapy. These aren’t totally black and white.

But my next level of stratification is FISH. So if you’ve got a bad FISH finding even if you’re in that favorable category I strip you out from the chemotherapy group.

Andrew Schorr:
So like if you had a 17p deletion, those chromosome deletions?

Dr. Sharman:
Yes. So if you’re mutated, which you think is good, but you also have a 17p, then I wouldn’t give that individual chemoimmunotherapy.

So if you have good IGHV, good FISH, good functional status and I’m thinking about give you FCR, that’s my final check is let’s make sure there’s not something lingering underneath the surface here that I don’t know about. So that’s where I check it.

Now, in the relapsed/refractory setting it is more the norm that those patients are almost all going on novel agents where those mutations are sort of a little bit less salient, so I don’t necessarily check that. However, I do recheck FISH with successive lines of therapy because that certainly can evolve. And to make things even a little bit worse now for somebody who has been on BTK, we need to think about BTK mutations and whether or not that patient might be suitable for a second‑ or third‑generation BTK inhibitor that can get around that.

Andrew Schorr:
Okay. And the genomic testing, when do you do that?

Dr. Sharman:
Well, so genomic testing is looking for those smaller mutations that don’t show up on FISH.

Andrew Schorr:
Okay.

Dr. Sharman:
So that’s my final break point before I would give somebody chemoimmunotherapy. But I will tell you, there are opinion leaders out there who will argue that chemoimmunotherapy is dead and shouldn’t do it.

Andrew Schorr:
Right. There are.

Dr. Sharman:
I’m in the camp that thinks there’s still purpose and value in doing that in appropriately selected patients.

Andrew Schorr:
Okay. Let’s get to some others. So Grant said he was diagnosed with a double diagnosis of diabetes and then, as he had additional testing, voila, he also had CLL. So he’s currently able to control his diabetes, and he’s in watch and wait for CLL. Is there any advice for me going forward with these two conditions? Diabetes and CLL.

Dr. Sharman:
It‑‑so I guess my question in such a circumstance is how is that CLL behaving. If he has a molecularly favorable CLL and he’s on watch and wait and things are simmering along, it may very well be that his diabetes poses a greater threat to his overall health than the CLL.

In contrast, somebody with an unmutated 17p deleted CLL, it’s the CLL that’s going to be more dangerous. Fortunately, the treatment interactions don’t overlap all that much. Sometimes with chemoimmunotherapy we give steroids, and that can be problematic for patients with diabetes, but I would manage them by and large independently.

Andrew Schorr:
Okay. We’ve gotten several other questions. Sharon, we got yours and Jason. They were asking about first line with ibrutinib, and I think we spoke about that and other choices that may have a different side effect profile if ibrutinib has a problem. And also Sharon had written in about she’s in this watch and wait and she wonders about FCR, and I think we can hear from you that FCR and maybe BR in some cases, which is this chemoimmunotherapy approach, still has a place in your mind. So, Sharon, stay tuned.

Lucy wrote in. She says, given the 17 (?) (p53) deletion what role does that play in determining the beginning of treatment for the CLL naive patient, and you were just saying probably not FCR or BR.

Dr. Sharman:
Yeah. Boy if somebody had a 17p deletion I would strongly advise against traditional chemoimmunotherapy. I think it can actually be more harm than good in some cases.

There is a more subtle point though that I would jump onto, which is what factor does it play in first‑line therapy. It’s not so much the agent. Some people feel like because they’ve got a 17p they need to jump into treatment sooner rather than later.

I will tell you I have several patients with 17p deleted CLL that I’ve been able to watch for years and years and years without treatment. The indications for starting therapy really remain the same. If I see somebody clearly heading towards treatment with a 17p I may start them a little bit earlier, but again some of these folks can be watched and wait quite well.

Andrew Schorr:
Okay. You’re a director of research, and we’re starting to hear about CRISPR or gene editing.

Dr. Sharman:
Yeah.

Andrew Schorr:
So do you think this gene editing will play a role in CLL?

Dr. Sharman:
Hoo, boy. You know, I think that probably dovetails with the question you didn’t ask, which is about CAR‑T cells. I think CRISPR, for members of the audience who may not be familiar with it, is a highly efficient, highly directed way of making genetic manipulation within cells,

and with a lot of the gene therapy that’s been done over the years we sort of randomly insert genetic material into cells to sort of reprogram them. That’s sort of the classic way of doing gene therapy. The problem with that is there are parts inside the genome that don’t like to be broken, and so the field really was set back a number of years when there were some early cases of leukemia caused by gene therapy.

And so what CRISPR does is it does allow you to make very targeted genetic modifications so that you can precisely put in new genetic material sort of wherever you want it. And I think that in the context of CAR‑T therapy there’s now goals to make it much more off the shelf than this sort of highly manufactured thing, and that’s where I would see CRISPR having the most likely early role.

Andrew Schorr:
Okay. So CAR‑T, chimeric antigen receptor T‑cell therapy, taking a virus, I think, and combining it with stuff for your T‑cells, targeting your CLL. So Lynne just asked, she’s 71, would somebody older like that‑‑tomorrow is my 68th birthday, folks‑‑would we be candidates for CAR‑T should we need it?

Dr. Sharman:
Well, I need to articulate some of my limitations as a community practice oncologist, thus far the CAR‑T research has been sort of in the exclusive purview of academic centers, so I haven’t had the chance to do it yet. That having been said, we are working with a variety of sponsors to get such a program up and running.

However, I will say there’s a lot of enthusiasm in CLL because the original New England Journal of Medicine paper that described CAR‑T was done in both pediatric acute leukemia and adult chronic lymphocytic leukemia, and it is now approved by the FDA for the pediatric ALL, acute lymphoblastic leukemia. It is not approved for CLL. And part of that‑‑there’s a lot of reasons why it doesn’t work as well in CLL as it does in other diseases, and I think that the‑‑it’s okay that this is moving a little bit more slowly in the CLL field because I think we’re getting a lot of benefit of accumulating knowledge in how to make it work best in CLL. I think it will become an important therapy in CLL.

Keep in mind that the toxicity of chimeric T‑cell is significant, and the possibility of neurotoxicity or this syndrome that looks a little bit like sepsis that’s not sepsis but it looks like it in a lot of ways, what we call cytokine release syndrome make this a therapy where caution is advised.

And so if it’s something you’re thinking about I would say go get yourself seen in your very specific circumstances with somebody doing this in research studies and decide if it’s right for you.

Andrew Schorr:
Okay. And we’ll have‑‑in other programs we’ll talk about CAR NK research that’s going on. Lot to talk about, maybe at ASH, folks. Dr. Sharman will be at the American Society of Hematology meeting, the ASH meeting here in San Diego in a couple of months. We’ll have coverage from that as these new areas come out.

Now let’s go back to the basics before the end, Jeff, and this that is flu season coming up.

Dr. Sharman:
Yes.

Andrew Schorr:
And there’s also a shingles vaccine. And also some people related to hepatitis B.

What are you telling your patients about vaccines? My friend Jeff Folloder said somebody at MD Anderson had them maybe getting two flu shots.

Dr. Sharman:
Yeah.

Andrew Schorr:
So first of all, flu shots, and do we need more than one? And what about these other shots?

Dr. Sharman:
Yeah, so starting with flu I would encourage all my patients CLL patients to get flu shots. The response is nearly universal. Everybody always says, well, I got a flu shot and I still got sick. A flu shot does not prevent all illness. Flu prevents flu. And patients with CLL get more complications from flu because their immune system has a cancer in it. So CLL is a cancer of the immune system, so to whatever extent you can give yourself a head start to fight off flu I would encourage patients to do so.

Andrew Schorr:
More than one shot?

Dr. Sharman:
Well, so I will say that patients with CLL generally have less of a response to a flu vaccine than somebody without CLL.

So you don’t get as much protective benefit if you have CLL as somebody without it. I don’t think, at least, I’m not familiar with data that says two flu shots are better than one. It may be out there and I’m not aware of it, but I mean I could understand why you might. It at least biologically makes sense.

Andrew Schorr:
And the shingles vaccine?

Dr. Sharman:
Yeah, so very few clinic days go by where I don’t curse shingles at least once. For anybody who has had shingles you know it can hurt really badly, and there is this condition called post herpetic neuralgia, which is a sort of a lingering pain syndrome that can go on for years for patients who have had shingles and can be a life altering pain. And so, again, I think whatever head start you can give your immune system it’s worth doing.

And I guess the reason why I curse shingles so frequently is because it does seem to go part and parcel with lymphomas and CLL. Again, you have a cancer of the immune system. The immune system doesn’t work as well, and, boy, I can’t count the number of times where somebody gets shingles just as their CLL is acting up and then it delays treatment, or somebody is going through treatment with a lot of pain as a result.

Andrew Schorr:
So you’re not worried about the vaccine?

Dr. Sharman:
No. Not only am I not worried I highly encourage it. But I would point out that the old vaccine was a live virus, and there were problems giving that to patients with CLL. There is a new dead virus, Shingrix, that’s in short supply.

Andrew Schorr:
Okay. Well, we’re going to wrap up. I want to just help everybody understand what I alluded to a minute ago, the world series of blood cancer‑related discussions where a lot of data, and, Jeff, you may have data presented there, is the American Society of Hematology meeting which is near me in San Diego in December and about 30‑, 40,000 people come and discuss all this.

So stay tuned. We’ll be doing programs from there, and we’ll bring you updates. Dr. Jeff Sharman, thank you so much for being with us once again.

Dr. Sharman:
My pleasure, Andrew. Thank you for your time.

Andrew Schorr:
All right. And this is what we do. Thanks to the Patient Empowerment Network so devoted to this. We’re happy to help from Patient Power, and thanks to the supporters for this program. They had no editorial control, but they believe in education. That’s AbbVie Incorporated and also Pharmacyclics.

I’m Andrew Schorr. Remember, knowledge can be the best medicine of all.


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