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Confusing CLL Terms Defined

Confusing CLL Terms Defined from Patient Empowerment Network on Vimeo.

What is FISH testing? What is IGHV? Physician assistant Danielle Roberts explains the meaning of these often confusing terms and their role in disease monitoring and CLL treatment decisions.

Danielle Roberts is a physician assistant with the Bone Marrow Stem Cell Transplant (BMT) team at Winship Cancer Institute at Emory University. Learn more here.

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Practical Advice for Coping with a CLL Diagnosis: What’s Next?

Practical Advice for Coping with a CLL Diagnosis: What’s Next?

Could CLL Be Inherited?

Could CLL Be Inherited?

What Should You Know About CLL Genetic Testing?

 

Transcript:

Danielle Roberts:    

So, a FISH test is a test from your either blood in your bloodstream or from your bone marrow biopsy. And it stands for florescence in situ hybridization. And this is a highly specific test that looks at the chromosomal changes with CLL. This can be done in the peripheral blood or in the bone marrow.

And it’s important to remember that when we consider genetic testing and CLL, we aren’t talking about inherited genes, but the abnormalities that occur within the CLL itself.

So, an IGHV test is a mutational test that stands for the immunoglobulin heavy-chain variable gene locus. This can also be done in the peripheral blood and the bone marrow biopsy. This test can help us determine treatment options as well as help with determining what high-risk features there are for your particular disease.

So, 17p deletion is the deletion of the long arm of chromosome 17. This can be seen at initial diagnosis or it can be acquired later on in disease progression. So, for all patients this is one of the more important tests that if you’re going to ask your doctor if you’ve had, you should ask at a diagnosis. If you’ve relapsed later on, you should ask again if that mutational status is being observed or checked in your follow-up testing.

17p deletion is something that can be acquired along the course of your disease progression. It is not always seen at initial diagnosis but can be acquired if you are relapsed or refractory. Therefore I recommend that every time you’re having peripheral blood for flow or if you’re having bone marrow biopsies, especially if it’s for treatment planning purposes, you should advocate to your physician team to make sure that this test is being performed as it will drive – or as it can drive treatment decision-making.

 

 

 

 

 

Practical Advice for Coping with a CLL Diagnosis: What’s Next?

Practical Advice for Coping with a CLL Diagnosis: What’s Next? from Patient Empowerment Network on Vimeo.

After receiving a diagnosis of chronic lymphocytic leukemia (CLL), patients can have a variety of concerns. Physician assistant Danielle Roberts shares her top three pieces of practical advice for patients to move forward. 

Danielle Roberts is a physician assistant with the Bone Marrow Stem Cell Transplant (BMT) team at Winship Cancer Institute at Emory University. Learn more here.

See More From The Pro-Active CLL Patient Toolkit


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Confusing CLL Terms Defined

Confusing CLL Terms Defined

What Is YOUR Role in CLL Treatment Decisions?
What Is YOUR Role in CLL Treatment Decisions? 
Targeted CLL Therapy: What Are the Side Effects?
Targeted CLL Therapy: What Are the Side Effects?

Transcript:

Danielle Roberts:       

My recommendations if I could have three things that I would recommend all patients with CLL do, 1.) It would be to have your financial information kind of in line or know how to find that. Unfortunately, a lot of the medications that we use to treat disease are incredibly expensive. However, there are really good patient assistance programs out there. In order to be able to apply for patient assistance programs you do have to submit your financial information to them. So, I would really suggest that you have access or be able to know where to find that.

I would also really recommend you talk to your family members in so that they understand what’s – where you are with your treatment and what’s going on. As a physician’s assistant, one of the questions I generally get is when they bring in a family member or somebody who has not been along in their journey for their treatment, if they’re asking lots of questions, that was and kind of diagnosis. So, I encourage people to talk about that at the beginning, so everybody understands where they are and what the plan for the future is going to be.

And then the last thing that I always recommend to everybody is to understand that not one treatment is right for everybody. Understand that things are going to change and we’re all going to grow and we’re going to learn with the process. But if you don’t tell your healthcare team what’s going on, we can’t help you. And we say that there is no such thing as a bad question to us. You’re never bothering us. That’s what we’re here for. Rather you tell us, even if it may be something you feel is minor, ahead of time so that we can address it and work towards a solution, if there needs to be one.

How Could Emerging CLL Treatments Impact Your Care?

How Could Emerging CLL Treatments Impact Your Care? from Patient Empowerment Network on Vimeo.

In the changing world of chronic lymphocytic leukemia (CLL) research, how can emerging treatments impact care for patients? Dr. Jennifer Woyach shares information about targeted therapies, immunotherapy and clinical trials, and explains why she is hopeful about the future of CLL care.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

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Transcript:

Katherine:                  

That’s a good point. Are there emerging treatments patients should know about?

Dr. Woyach:               

Yeah. There are a lot of really exciting things going on in CLL right now. And CLL is a disease that has been completely transformed in the last five to 10 years and is poised to do so again. So, I mentioned these therapies that we use for frontline treatment, and there are clinical trials now combining them together. So, these agents work so well on their own. Are they going to be even better if we add them together?

There are also newer target therapies, different targets that we are finding increasingly important in CLL, as well as a modality called CAR-T cells, which most people have heard of where we take patients’ own T cells, modify them in the lab and then, give them back with a goal of getting those cells engineered to kill CLL cells.

These are all things that are not ready for prime time in CLL yet but are available in clinical trials. And I think one other thing I’d really like to put a plug in for is clinical trials in CLL, because right now we’re at a point where our therapies are really very good. But if people just do those treatments, we are never going to figure out which one is the best or figure out, for specific types of patients, which treatment is the best. And so, I advocate that any of my patients that are eligible for clinical trials should consider them, because that’s how we make progress in the disease from an altruistic sense.

That’s how we make things better for everybody. That’s one way a patient can think about it. But more personally than that, being in a clinical trial gives somebody the opportunity to get a treatment that they otherwise wouldn’t get that might be better than our standard of care therapies.

Katherine:                  

Dr. Woyach, as a researcher in the field, why are you hopeful?

Dr. Woyach:               

I am so hopeful in CLL because there is so much that we’re learning every day about the biology of the disease, about specific mutations and other genetic factors that are important and really can be targeted by new drugs. Paralleling our understanding of the disease, there also are many more techniques to make these targeted therapies that kill cancer cells selectively while sparing normal cells and making our drugs even more tolerable.

And I think both the targeted therapies like this and the potential of combining them, figuring out sequences that are best but then, also these newer modalities where we, actually, get the immune system involved like the CAR-T cells. They’re making CAR NK cells now. And just lots of other strategies that could be used together with targeted therapies to, hopefully, cure the disease.

Targeted CLL Therapy: What Are the Side Effects?

Targeted CLL Therapy: What Are the Side Effects? from Patient Empowerment Network on Vimeo.

What are common side effects of chronic lymphocytic leukemia (CLL) targeted therapies? Dr. Jennifer Woyach discusses side effects of specific targeted therapies and the importance of reporting any issues to your doctor for optimal quality of life.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

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What Should You Know About CLL Genetic Testing?

What Tests Should CLL Patients Insist They Receive?

Could CLL Be Inherited?

 

Transcript:

Katherine:                  

If there are side effects, what would some of the side effects be for these targeted therapies?

Dr. Woyach:               

So, it depends on the drug. So, BTK inhibitors, specifically, ibrutinib can cause some joint and muscle pain, some rashes, diarrhea, heartburn. Those are things that tend to, if they’re going to happen, usually happen earlier on in treatment and tend to get better over time. It can also cause high blood pressure. It can cause an abnormal heart rhythm called atrial fibrillation.

So, those are things we watch out for with ibrutinib. Acalabrutinib really has all of the same side effects but for many of them, they don’t occur as often. And then, the tradeoff there is ibrutinib is given once a day and acalabrutinib is given twice a day. With venetoclax plus obinutuzumab with that regimen, you get a lot more hematologic toxicity. So, you see more lowering of the good white blood cell count, which is, obviously, a risk for infections. That regimen comes with a risk of something called tumor lysis syndrome, which is where the cells can break down too quickly and cause damage to the kidneys, damage to the heart.

It can also cause some GI disturbance like some diarrhea, nausea, abdominal pain, things like that. I see there are a lot of side effects. And, of course, when I’m talking to a patient about treatment, we go over them in more detail than that. But I think the important thing is with all of these therapies, we do have ways to manage these side effects.

One thing I think is important for patients to remember is your doctor doesn’t know you’re having side effects unless you tell them. So, we know that people have these side effects. But if you don’t tell us that you’re having diarrhea or heartburn or things like that, we can’t help with it. And we have a lot of medicines that can help these things.

 

 

 

 

What Is YOUR Role in CLL Treatment Decisions?

What Is YOUR Role in CLL Treatment Decisions? from Patient Empowerment Network on Vimeo.

What is the chronic lymphocytic leukemia (CLL) patient’s role in making treatment decisions? Dr. Jennifer Woyach explains frontline CLL therapies and how patients help guide the treatment decision that’s best for them.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

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What Should You Know About CLL Genetic Testing?

What Tests Should CLL Patients Insist They Receive?

 What Does It Mean to Have High-Risk CLL?

 

Transcript:

Katherine:                  

Dr. Woyach, what do you feel is the patient’s role in this conversation about treatment approaches?

Dr. Woyach:               

I think that, obviously, the patient is the most important part of the talk of treatment indications. Like I mentioned, sometimes we have the discussion of chemotherapy versus a targeted therapy. More often, the discussion is we have three approved frontline CLL therapies right now. We have two BTK inhibitors or Bruton’s tyrosine kinase inhibitors, ibrutinib, acalabrutinib.

And then, we have a BCL-2, venetoclax, that’s given in combination with an antibody called obinutuzumab. These are very different treatments in terms of side effect profiles, how they’re administered, how often they’re administered, just as an example. The BTK inhibitors are pills. And they’re meant to be given indefinitely. So, you start them with plans that you’re not going to stop them, unless the patient doesn’t tolerate them or they stop working. And so, with that type of regimen, you have the kind of burden of being on treatment for a long period of time.

But on the flipside, it’s very easy to start treatment. So, if you decide you want a BTK inhibitor, I write a prescription for it, it comes to your house, you start it. I usually see patients monthly for the first six months and then, we go to every three months. It’s very easy to start treatment.

The other type of treatment, the venetoclax plus with the obinutuzumab regimen, that’s the BCL-2 inhibitor with an antibody, it’s a finite therapy. So, people are treated for a year and then, they go off treatment. The flipside of that is they’re a lot more time intensive in the beginning. So, you have the IV therapy with the obinutuzumab. Venetoclax you, actually, have to ramp up the dose so patients have to come in weekly for the first five weeks, and they have to come in monthly for their infusions. So, it’s much more time intensive up front but then, you get to stop treatment. And so, those are considerations that I can’t answer for somebody.

I don’t know which one people would prefer and people prefer different things. So, we spend a lot of time talking about all of the different scenarios and what’s going to make the therapy work best for the patient.

 

 

 

 

Could CLL Be Inherited?

Could CLL Be Inherited? from Patient Empowerment Network on Vimeo.

Can chronic lymphocytic leukemia (CLL) be inherited directly from parents? Dr. Jennifer Woyach discusses the likelihood of passing down CLL to children and the difference between genetic mutations and acquired mutations in CLL.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

See More From INSIST! CLL


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What Is YOUR Role in CLL Treatment Decisions?

Targeted CLL Therapy: What Are the Side Effects?

How Could Emerging CLL Treatments Impact Your Care?

 

Transcript:

Katherine:                  

We have another question from a patient who wants to know if their children will inherit CLL. Is there any link between inherited mutations and CLL?

Dr. Woyach:               

That’s a very, very common and really important question. I would say of the hematologic cancers, CLL is one with higher linkage in families, which means that people with CLL are more likely to have another family member with CLL though it’s still not very common.

And it’s very different from breast cancer or the solid tumors where we know that these specific mutations indicate families that are going to have risk of disease. There has actually been a lot of study over the years of families that tend to have multiple people with CLL. Unfortunately, there really have not been genes identified that are the reason for those family linkages. I think there has been only one family that I know of where they’ve actually found a gene that was likely the cause of multiple family members’ illnesses. So, yeah, there is no indication to test family members.

I tell people do not worry that you’re going to pass this to your children or your grandchildren. CLL is not something that we should be using as like a marker of whether you should have kids or should have anything like that.

So, maybe a little more likely in family members but not enough to really be worried about that.

Katherine:                  

What are the differences or difference between inherited and acquired genetic mutations?

Dr. Woyach:              

So, inherited mutations are those that you get from your parents. And there are lots of inherited mutations that, actually, can predispose to cancer. Specifically, I mentioned the TP53 mutation and CLL cells. Well, there are also people who inherit a TP53  mutation have risk factors for multiple cancers. And CLL, specifically, every mutation that we talk about is an acquired mutation. So, that’s also known as a somatic mutation. So, they’re mutations in the cancer cells. But if you did DNA sequencing of the normal cells, they would not be there.

What Does It Mean to Have High-Risk CLL?

What Does It Mean to Have High-Risk CLL? from Patient Empowerment Network on Vimeo.

What does high-risk chronic lymphocytic leukemia (CLL) mean exactly? Dr. Jennifer Woyach explains the meaning of high-risk CLL, factors in determining disease progression, and the impact on treatment decisions.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

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Transcript:

Katherine:                  

We have a patient question. I have 17p deletion. Should I be worried?

Dr. Woyach:               

So, 17p deletion is usually associated with more aggressive disease biology almost always associated with that unmutated IGHV. The reason I bring that up is there are a very small subset of patients who have 17p deletion and mutated IGHV who, actually, have pretty indolent or slow growing disease.

People who don’t, which is the majority of them with 17p deletion, do have a shortened time to treatment and shortened survival with most of our current therapies. There have been a lot of advances though in the treatment of 17p deleted CLL. And may of our newer therapies can very much prolong the remission time in the lives of patients with 17p deletion.

Katherine:                  

Dr. Woyach, how do these chromosomal changes affect disease progression and prognosis?

Dr. Woyach:               

So, the markers that are associated with more aggressive disease biology usually are going to be associated with people that need treatment within the first few years after diagnosis, especially those people who have 17p deletion, 11q deletion, unmutated IGHV.

Katherine:                  

What exactly are prognostic factors? Would you define that?

Dr. Woyach:               

Sure. Prognostic factors, and I mentioned three of them, the IGHV, FISH, and the TP53 mutation, are ones that have been studied extensively and shown that the presence of this marker or some change in this marker is associated with a change in the biology of the disease or in the response to therapy.

Katherine:                  

How does the identification of these changes or mutations affect treatment options?

Dr. Woyach:               

Well, right now, we’re lucky in CLL because we have a lot of treatment options. I would say the most important changes when we’re talking about somebody with CLL that is about to start their first treatment is the decision of whether chemotherapy is ever appropriate. So, almost everybody with CLL now is treated exclusively with targeted therapies.                              

So, nonchemotherapeutic options. There are some people who are young, and in CLL terms that means under the age of 65, who have mutated IGHV and who otherwise have good genetic list disease. So, normal chromosomes of the 13q deletion, no TP53 mutation. That small subset of patients, actually, has the potential to be cured with a specific type of chemotherapy. It’s called FCR or fludarabine, cyclophosphamide, rituximab. So, for those young, healthy patients, it’s really important to know those risk factors to know if they are in that group that has that potential for cure.

The converse to that is if patients don’t fall in that group, they probably shouldn’t receive chemotherapy as their first treatment, because it’s not as effective as our other therapies.

Katherine:                  

Yeah. It makes sense.

Dr. Woyach:               

And then, even in the future with first and other treatments with novel therapies, we know that patients with 17p deletion and TP53 mutation tend to have a shorter response time. And so, what I use that for in my practice is I know that those are people that I really have to be sure that we’re following them closely, taking any signs of progression seriously, and always have a back-up plan for what we’re going to do if this treatment doesn’t work.

What Tests Should CLL Patients Insist They Receive?

What Tests Should CLL Patients Insist They Receive? from Patient Empowerment Network on Vimeo.

Which chronic lymphocytic leukemia (CLL) tests are most critical in CLL care? Dr. Jennnifer Woyach details the key tests, what the tests identify, and how they help provide optimal care personalized to each patient.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

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What Should You Know About CLL Genetic Testing?

What Is CLL and How Is It Diagnosed?

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Transcript:

Katherine:                  

The goal of this program, Dr. Woyach, is to provide the confidence and tools for patients to advocate for the essential tests to get the best care personalized to them. Are there specific tests that patients should make sure they have?

Dr. Woyach:               

Yeah. In CLL, I would say there are three that are very, very important before starting treatment. The first is something called the IGHV mutational status.

What that is defined as is the changes in the variable region of the immunoglobulin heavy chain. That’s a big mouthful that doesn’t mean a lot to most people. So, I’ll give you just a little background on what that really means biologically and then, what that means clinically. So, every B lymphocyte, so a normal B lymphocyte and a CLL cell, has receptors on the surface of the cell that allow it to interact with the environment. And in a normal B lymphocyte, this is really important for the immune system. So, bacteria, virus, something is in the body and the B cell surface receptor is going to be able to recognize that that’s not supposed to be there and then, do something about it.

In CLL, the surface receptors don’t do a lot of interacting with the outside environment but they’re still present there. And in a normal B cell development, the B cells are initially formed in the bone marrow.

And at the time that they’re formed, every one of those receptors is exactly the same. So, we can do DNA sequencing on those receptors and you’ll see that every one is identical. So, during a normal development of a B cell, it undergoes this process that’s called somatic hypermutation, which is where those receptors mutate or change. And that’s important because then, they can recognize different things. And so, you end up with this whole repertoire of thousands or millions of B cells that all are a little bit different and can recognize something different.

So, CLL cells, they’re all clonally related to each other. They’re all going to have the same receptor on their surface. And about 60 percent of the time that receptor is different than the newly born B cells. And so, this is probably a little bit more simplistic than it actually is. But the way we think about that is that those B cells or those CLL cells, which we call mutated because they underwent that mutational process, we think that that means that they come from a more mature initiating cell.

And they tend to be less aggressive, more slow growing. The other 40 percent of patients, if you look at the receptor on their surface, it’s exactly the same as the new B cells in the bone marrow. And we call those IGHV unmutated because they haven’t done that mutational process. And they behave very differently. So, in mutated CLL, only about half of people will ever need therapy in their lives. An average time from diagnosis to first treatment is about 10 years. In contrast to those patients who have unmutated IGHV, basically, all of those people will need therapy at some point in their lives. And average time from diagnosis to first treatment is about three years.

So, you can see how it really breaks people up into two very different categories of disease.

So, that’s the first test and one that’s really important. That’s also one that doesn’t change during the course of the disease. So, if somebody is diagnosed with mutated CLL, it’s always mutated. So, the next marker that’s important is, actually, chromosome changes. So, we know that there are a few different recurrent chromosome abnormalities in CLL that are common and important prognostically. So, one of these is a deletion of part of chromosome 13. It’s called a 13q deletion. It indicates, again, very slow-growing CLL. Patients how have normal chromosomes also are very good disease biology.

Some people have an extra copy of chromosome 12. That’s called trisomy 12, and that’s an intermediate marker. And then, there are two markers that are associated with a little bit more aggressive CLL. One is a deletion of proto chromosome 11. That’s called an 11q deletion.

And the other one is a deletion of proto chromosome 17 called a 17p deletion. These are all abnormalities that are important to test for. And the way that we test for these is something called FISH testing. And FISH stands for fluorescence in situ hybridization. And it’s a way to use an antibody to look for specific abnormalities in the CLL cells. So, that’s important. And another thing that can be done at specialized centers is something called stimulated cytogenetics. So, I mentioned to you with FISH testing, we’re looking for specific abnormalities with antibodies. But the things that we don’t test for we’re not going to see.

So, if they have a chromosome change that we don’t have an antibody looking at, we’ll never detect it. And we know that patients with CLL who have what’s called a complex karyotype, which is three or more chromosome abnormalities, they also have more aggressive disease.

So, like I said, at specialized centers, we can do what’s called a stimulated karyotype, which is where we look at all of the chromosomes. So, that’s FISH testing and karyotype. And then, the last thing is, actually, doing DNA sequencing for a specific mutation called a TP53 mutation. And TP53 is an important tumor suppressor protein. And it is mutated quite commonly in CLL. About 8 to 10 percent of patients at the time of first treatment and, actually, up to about 40 percent of people later on in the course of the disease. Most of the time, we see TP53 mutations occur at the same time as 17p deletions. About 80 percent of the time, those occur together but they can occur on their own.

So, that’s the third test that’s often helpful, especially prior to starting treatment.

Katherine:                  

Do patients need to be retested over time?

Dr. Woyach:               

Yeah. So, for the TP53 mutation and for FISH, it’s important to test for those before each line of therapy. Because those are so important in indicating disease biology and, specifically, with the 17p deletion and TP53 mutation, those indicate patients that are likely to not have as good of a response to treatment. It’s always important to check for those prior to therapy.

What Should You Know About CLL Genetic Testing?

What Should You Know About CLL Genetic Testing? from Patient Empowerment Network on Vimeo.

In chronic lymphocytic leukemia (CLL) diagnosis and disease management, genetic testing plays a key role. Dr. Jennifer Woyach explains what is examined in CLL genetic testing, the timing and administration of testing, and testing advances.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

See More From INSIST! CLL


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Could CLL Be Inherited?

What Tests Should CLL Patients Insist They Receive?

What Does It Mean to Have High-Risk CLL?

 

Transcript:

Katherine:                  

Before we get deeper into our conversation about genetics, there are a few terms that patients are often confused by. As a primer, I thought we could start by defining some of these terms. First, what is genetic or molecular testing?

Dr. Woyach:               

So, all cancer cells will have a collection of mutations or abnormalities in the DNA that either make the cell a cancer cell or make it behave in a certain way. And so, these mutations are referred to as the genetic abnormalities of the CLL cells. So, when we talk about genetic testing in CLL, we use it to mean a number of things. We can use it to look specifically for types of mutations so types of genetic abnormalities.

 We also sometimes use that as a kind of catch-all term like genetic or molecular testing also to refer to looking at changes in the chromosomes inside of a CLL cell. That’s also called cytogenetic testing. And then, we also use a number of tests in CLL where we look at specific, not necessarily abnormalities, but just changes in the cell that can indicate a certain type of behavior.

Katherine:                

How is this different from genomic testing?

Dr. Woyach:               

So, genetic and genomic testing, I think, are usually used interchangeably. But sometimes, we use them in different contexts but they really mean the same thing in this case.

Katherine:                  

Okay. And what is a chromosome change?

Dr. Woyach:              

So, as you might remember from biology class maybe a long time ago, as it was for me, inside a cell, so a normal cell or a cancer cell, you have the nucleus, which holds the DNA.

And the DNA is organized into chromosomes. And so, when a cell goes through division, it takes those chromosomes, copies them and then, breaks them apart into two different cells. So, changes can happen in the level of the DNA itself. So, a mutation where one base is changed to something different. So, that would be just like a single nucleotide change. And that’s something you’re not going to see as a change to a chromosome. Another thing that can happen in CLL and in other cancers, too, is that during that process of cell division, an entire chromosome could be duplicated. It could be absent.

More commonly, parts of chromosomes can change. This is all because cancer cells just do a very poor job of editing their division.

An in normal cells, there are multiple steps along the way from the process of copying the genes to copying the chromosomes to doing the division. And every step along the way, if something happens incorrectly, which happens a lot, the cell usually just dies. But a cancer cell is not going to do that because it has so many signals that keep telling it to stay alive that it can tolerate a lot of different abnormalities. And so, you end up with cells that are just very different from what you would see normally.

Katherine:                  

All right. Well, that’s a great way for us to start. Let’s go into the discussion of the relationship between testing and CLL. How is testing administered?

Dr. Woyach:               

So, almost all testing, in terms of molecular genomic testing in CLL, can be done on a blood sample. So, that’s one important thing.

The CLL guidelines recommend that testing for certain prognostic factors be done before the administration of therapy. So, at the very least, before somebody starts treatment, they should have these tests performed. In my practice and I think most CLL specialists find it really helpful to do these tests, not necessarily just at the time of treatment but really at the time of diagnosis or the time we first see the patient because CLL is a very heterogenous disease, which means that it behaves very differently in different people. So, there are some people that are diagnosed and will go 10 or 20 years before they need any treatment.

And many don’t need treatment at all. Whereas other people are very likely to need treatment within the first few years after diagnosis. Some of the genetic tests that we do can help counsel patients on where they’re likely to fall in that spectrum.

And so, I think that’s helpful for people to know early on in the disease course. But really, the tests can be performed at any time before treatment

Katherine:              

Have there been advances in testing?

Dr. Woyach:               

Absolutely. I think in every cancer, we’ve learned so much more about the biology of the disease, specific mutations that cause specific behaviors of cells, and really much more in CLL about the common genetic changes and what those means to response to therapy.

What Is CLL and How Is It Diagnosed?

What Is CLL and How Is It Diagnosed? from Patient Empowerment Network on Vimeo.

What exactly is chronic lymphocytic leukemia (CLL), and what factors help determine a diagnosis? Dr. Jennifer Woyach explains how CLL originates and transforms, the tests involved in diagnosis, and shares a common misconception about CLL.

Dr. Jennifer Woyach is a hematologist-oncologist specializing in chronic lymphocytic leukemia (CLL) at Ohio State’s Comprehensive Cancer Center – James Cancer Hospital & Solove Research Institute. Find out more about this expert here. 

See More From INSIST! CLL


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What Should You Know About CLL Genetic Testing?

What Tests Should CLL Patients Insist They Receive?

What Does It Mean to Have High-Risk CLL?

 

Transcript:

Katherine:                  

Well, Dr. Woyach, let’s start by understanding CLL. Would you briefly walk us through what CLL actually is?

Dr. Woyach:               

Sure. CLL is a cancer of the blood, the lymph nodes, and the bone marrow.

And it happens when a particular type of white blood cell called a B lymphocyte acquires genetic mutations and transforms into a cancer cell. And then, over time, those cancer cells continue to grow and divide. And they can cause symptoms such as enlarged lymph nodes if the cells get stuck in the lymph nodes and continue to grow there. It can cause a high white blood cell count, which usually doesn’t cause any symptoms but is one of the things that we see often in CLL. And then, it can also cause the bone marrow to not be able to produce normal cells because it can get so infiltrated or so full of CLL cells.

And this can cause things like anemia, which is lowering of the red blood cell count and thrombocytopenia, which is lowering of your platelet count.

Katherine:                  

What are the steps involved in reaching a diagnosis?

Dr. Woyach:               

CLL is an interesting disease because it’s one of the only cancers that does not require a biopsy of something for a diagnosis.

So, we can, actually, make the diagnosis of CLL based on the peripheral blood. So, just a blood draw in somebody’s doctor’s office. Usually, CLL is diagnosed in the asymptomatic stage. So, somebody goes to their primary care doctor, has blood drawn usually for another reason, and is found to have a high white blood cell count or sometimes even a fairly normal white blood cell count but a high percentage of lymphocytes. That certain type of cancerous white blood cell. So, the next step in the diagnosis then is something called peripheral blood flow cytometry, which is a specialized test where we look at the markers or antigens on the surface of white blood cells.

So, there is kind of a code of these markers on the surface of all of your blood cells that can tell what type of cells they are. So, for CLL in particular, we’ll see that the cells express some of the normal markers we would see on a normal B lymphocyte.

Things like CD19, CD20, CD23. But they also express a marker called CD5, which is found on normal T lymphocytes but shouldn’t be found on B lymphocytes.

And so, this collection of surface markers can make the diagnosis of CLL. Sometimes, we do need to do extra studies like a bone marrow biopsy or a lymph node biopsy. But often times, those are not necessary at the time of diagnosis.

Katherine:                  

When you meet with patients, Dr. Woyach, what are some common misconceptions that you hear about?

Dr. Woyach:               

I think the biggest thing that I hear, and granted I see a lot of patients after they’ve been diagnosed by someone, gone to see an oncologist and then, come to me after, but one of the common things that I hear is that somebody has told them along the way that they have the good type of cancer, which I think is not a very helpful thing to hear as a patient because, of course, no cancer is a good type of cancer.

I think it’s important to note that CLL is one that has a lot of treatment options and usually extended survival. But I think that’s one of the most common misconceptions that I hear.

CLL Clinical Trials Explained

CLL Clinical Trials Explained from Patient Empowerment Network on Vimeo

What are the phases of clinical trials in chronic lymphocytic leukemia (CLL), and what happens during each phase? Expert Dr. Anthony Mato explains the phases, criteria for trial selection, and addresses patient fears.

Dr. Anthony Mato is Director of the CLL Program at Memorial Sloan Kettering Cancer Center. Learn more here.

See More From The Pro-Active CLL Patient Toolkit


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An Expert’s View on Promising CLL Approaches

Factors That Guide a CLL Treatment Decision

Is My CLL Treatment Working

Transcript:

Katherine:                  

For people who don’t understand how treatment approvals work, which would you give us an overview of the stages of clinical trials?

Dr. Mato:                   

Sure. I’m very involved in clinical trials at my center. There are different phases of clinical trials. And so, the way that I think about them would be – let’s focus on Phase I through III, because those are probably the most relevant ones for patients. The purpose of a Phase I trial is really to define the dose of the drug and confirm that it’s safe or not. We get very, very preliminary data about activity of the drug, but the major question that’s being asked is, “Is this drug safe?”

Phase II is – and I should also add that Phase I trials are relatively small. So, it’s a small number of patients where we’re trying to find the right dose. By the time we get to Phase II, we know the drug is likely safe. We have a lot of information about its side effect profile. We might have a hint that it’s active. And so, the purpose of a Phase II trial is to expand the size of the trial, have more patients recruited, get more information about safety but then get more information about activity.

Of course, there’s no comparator generally in a Phase II trial. So, it’s not like I’m asking this drug versus another drug. And the end of a Phase II trial, we know the drug is active, we know it’s safe. And if it appears to be active, we’re feeling confident that it may be better than a standard of care which leads to Phase III where the drug is compared directly in oftentimes what we call a randomized study to a standard of care.

So, the trial that I mentioned earlier, FCR versus FC would be a great example of a randomized, controlled trial where a new therapy would, in that case, the FCR, was compared to the old therapy, the FC.

In the more modern era, there have been several trials. I example I might mention is the RESONATE trial where ibrutinib was compared head-to-head to an antibody called ofatumumab. Patients who were enrolled were either randomized by a coin flip through a computer to one arm or the other. And then those arms are compared directly to help define a standard of care.

So, that’s kind of the basics of clinical trials, and at our center and many centers around the country, we participate in Phase I, II, and III trials trying to ask different questions that are important to our patients.

Katherine:                  

Well, speaking of patients, they’re very often fearful of participating in a clinical trial. What do you say to them to make them feel more comfortable with the idea?

Dr. Mato:                   

I mean, I think the most important thing to highlight is all of the standards of care that we’re using today, ibrutinib, acalabrutinib, idelalisib (Zydelig), duvelisib (Copiktra), venetoclax (Venclexta), these were all just drugs a few years ago that were studied in the context of clinical trials.

And so, our current standards of care are very new on the scene from clinical research. It’s very important to have a conversation with your doctor about the intent of a particular clinical trial. I think most patients are fearful of placebos or blinding where they don’t know what they’re getting, or it’s possible that they’re not getting any treatment at all.

In oncology and particularly CLL, the chances of a clinical trial having a placebo or blinding are very low. We very rarely ever participate in such studies. And so, that should provide reassurance to the patient that they know what they’re getting, they know they’re dose, their oncologist knows what they’re getting, and oftentimes, many clinical trials have mechanisms called crossover built into them. Meaning, that if you’re getting A versus B, and you get B, and it doesn’t work, you often have opportunity to cross over to A.

Clinical trials in CLL are the reason why there’s been so much innovation over the last several years, the reason why we can talk about six and seven approvals of drugs within half a decade.

And many of the drugs that we have at our centers will likely become standard of care in the near future. So, it gives us access to important drugs a little bit in advance of when they might be available for patients through FDA approval. So, it a lot of hope; it’s a lot of innovation. And the major message I would say to patients is don’t think of a clinical trial is for when all options have run out, but oftentimes there are great trial options that are aiming to improve the current standard of care in the frontline and also the relapsed/refractory settings.

Katherine:                  

What’s involved in patient participation in clinical trials?

Dr. Mato:                   

Well, the process is called informed consent, and so, if you’re interested in a clinical trial, you have a conversation with your oncologist to review the study, the schedule, the screening procedures. If you’re interested, you sign an informed consent and then begin a process of doing some testing, oftentimes scan, blood work, EKGs, bone marrow biopsy, to try to identify whether or not you’re a good candidate for the study.

Clinical trials are often more rigid than standard of care meaning you have to follow a strict schedule. You have to report everything, side effects, or successes related to the clinical trial. And oftentimes, a clinical trial is performed at the particular center that you signed the consent. And so, if you came to our center at MSK, odds are you would have to have treatment at our center in order to participate in that trial.

Once you’re enrolled on the trial, you’re on a strict schedule. You work with the physician and a research team, often a nurse directly who specializes in clinical trials to help ensure that you’re monitored appropriately and that the trial is successful for the patient.

An Expert’s View on Promising CLL Approaches

An Expert’s View on Promising CLL Approaches from Patient Empowerment Network on Vimeo.

As chronic lymphocytic leukemia (CLL) research continues to expand, new and promising treatment approaches have emerged. Dr. Anthony Mato shares information on developing therapies, including inhibitor, immunotherapy, and antibody options. 

Dr. Anthony Mato is Director of the CLL Program at Memorial Sloan Kettering Cancer Center. Learn more here.

See More From The Pro-Active CLL Patient Toolkit


Related Resources

 

Is My CLL Treatment Working

Factors That Guide a CLL Treatment Decision

CLL Clinical Trials Explained

Transcript:

Katherine:                  

Let’s get into developing research. Let’s get into developing research and what it can mean for patients. What new approaches are showing promise?

Dr. Mato:                   

Wow, that’s a loaded question, because there are so many possible answers. There are new versions of the current standards of care, different classes like BTK inhibitors or PI3K inhibitors which have the potential to be very active but better tolerated.

So, that’s one big group of new agents in development. There are several agents in development that appear to be effective in the setting of resistance to the current standards of care. There are classes of immunotherapies that allow us in different ways to use the immune system of the patient to fight cancer directly, so not necessarily targeting the cancer cell but targeting the immune system to make it do its job to filter out the cancer.

There are new antibodies in development. And that’s just a little slice of what’s in development for CLL and new combinations of course of the current standards of care which when put together could be even more effective. So –

Katherine:                  

What about – oh, go –

Dr. Mato:                   

Sorry. I was just going to add that so many different possibilities available that not every center can participate in all of these types of research, but it’s amazing for patients to know how many different new options are in development that maybe even better than the current approaches.

Katherine:                  

Right. What kind of side effects might be involved with the emerging treatments? What might people expect?

Dr. Mato:                   

That’s a hard question to answer, because the purpose of the clinical research is to help define the side effects associated with these newer drugs. And so, while we have a hint from early data or from Phase I data what a side effect profile might look like for a new drug, part of the consenting process is to help gather information not only about a drug’s activity but also about its side effect profile.

So, when we consent a patient, there is a little bit of an unknown about side effects, and we have sometimes very limited information that we can share about the activity. So, it’s not easy to just group these together and say these are the newest side effects to worry about. That’s really the purpose of the studies that I’m mentioning and the general idea of clinical research.

Katherine:                  

And that makes sense. How is research into the genetics of CLL providing a better understanding of how a patient’s individual disease may behave?

Dr. Mato:                   

Well, just a few years ago, the basic genetic studies for CLL included just a few chromosomal markers that we could easily or sometimes not so easily test. At our center, for example, and it’s not unique, we’ll be able to look at the over 400 different mutations associated with hematologic malignancies. The more information we get, the more we realize that although under the microscope a CLL cell may look like another CLL cell, biologically, they’re very different.

They’re driven by different genetic mutations, and knowledge of those pathways that are important for an individual CLL will oftentimes, will hopefully in the future guide how therapy is selected for patients.

Is My CLL Treatment Working?

Is My CLL Treatment Working?  from Patient Empowerment Network on Vimeo.

During chronic lymphocytic leukemia (CLL) treatment, specific blood tests and diagnostic measurements are examined to gauge a patient’s treatment response. Dr. Anthony Mato details the specific criteria that are assessed while monitoring a therapy. 

Dr. Anthony Mato is Director of the CLL Program at Memorial Sloan Kettering Cancer Center. Learn more here.

See More From The Pro-Active CLL Patient Toolkit


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An Expert’s View on Promising CLL Approaches

Factors That Guide a CLL Treatment Decision

CLL Clinical Trials Explained

Transcript:

Katherine:                  

How do you monitor to see if a treatment is working, and what if the patient doesn’t respond to any of the treatments?

Dr. Mato:                   

Yeah, so, we response criteria, and so, they’re largely very simple measures. We perform a physical examination before and after treatment to see if the lymph nodes and spleen are decreasing in size. We measure the white blood cell count to verify that it’s going down. We look for normal parameters of normal functioning bone marrow like improvement in the hemoglobin or the platelet count.

So, those are some of the measures we use, and we put them together. And of course, just asking a patient how do they feel, do they feel better, are the symptoms that were associated with the CLL improving, and if the answer is yes, that would be considered responding disease. We also sometimes do measures like CAT scans to measure internal masses or internal lymph nodes and a bone marrow biopsy to verify that all the CLL cells are gone.

So, that’s the basics of a response assessment, and we also venture now into a new territory called MRD, or minimal residual disease, where we’ll be able to look beyond the traditional response assessment. Sometimes, it measures at a measurement of one in a million cells to verify that there’s no evidence of CLL present. If a therapy’s not working, fortunately – well, first I’ll say that with the modern therapies that we’ve already mentioned, response rates exceeded 90 percent.

So, it very, very infrequent that we have a patient where we pick the appropriate therapy where it doesn’t work for them. But if one is not working, then we do have measurements of resistance, and we can try to tell why a therapy maybe not working and switch them to an alternate class. And oftentimes, that will solve the problem.

Katherine:                  

Dr. Mato, you mentioned the term MRD. What does that mean?

Dr. Mato:                   

It stands for minimal residual disease. That’s using technology like flow cytometry or PCR or sequencing to take a deep look in the bone marrow and the blood for the presence or absence of CLL.     

So, when I perform a bone marrow biopsy, a pathologist with their eyes might count one hundred cells. With MRD testing we could look at 10,000 or 100,000 or 1,000,000 cells to see if there’s any CLL present, much more than the human eye or the human brain could process.

Factors that Guide a CLL Treatment Decision

Factors That Guide a CLL Treatment Decision from Patient Empowerment Network on Vimeo.

When making a chronic lymphocytic leukemia (CLL) treatment decision, several factors come into play. Dr. Anthony Mato explains how he partners with patients to find the best fit for their specific CLL.

Dr. Anthony Mato is Director of the CLL Program at Memorial Sloan Kettering Cancer Center. Learn more here.

See More From The Pro-Active CLL Patient Toolkit


Related Resources

 

An Expert’s View on Promising CLL Approaches

Is My CLL Treatment Working

CLL Clinical Trials Explained

Transcript:

Katherine:                  

So, with all of these options, how do you then decide which class might be right for an individual patient?

Dr. Mato:                   

Well, you think about the patient. You think about their medical history, their comorbidities, their preferences, and then you try to focus on their disease biology, their genetic factors, their molecular factors, and also what therapies they’ve had. So, if I had a patient who had ibrutinib (Imbruvica) previously, I’m not going to give them acalabrutinib if they were resistant, for example. So, it’s not just one thing. It’s multiple things that have to be taken into account in order to make a decision.

And, of course, for me as an oncologist, the hardest part is that there have not been many trials comparing the newest therapies to one another. So, I can’t tell you what’s better ibrutinib or acalabrutinib (Calquence) by a head-to-head comparison. I can’t tell you whether you should start with ibrutinib before venetoclax (Venclexta) or venetoclax before ibrutinib not because we’re not very interested in having those studies performed. But they have not been performed at this point in time.

The only thing I can tell you based on prospective data from a head-to-head comparison is that we do have direct data comparing acalabrutinib which is a BTK inhibitor to idelalisib (Zydelig) in the relapsed/refractory setting. And by all measures, acalabrutinib was better tolerated and more effective. So, we have some very early head-to-head data but not as much as we need in order to make these decisions for patients.

Katherine:                  

How are side effects taken into consideration?

Dr. Mato:                   

Well, all of these drugs although they are targeted, and they’re oral, and they’re relatively easy compared to chemotherapy are not without side effects. And so, each of these classes have their own unique side effects. BTK inhibitors can be associated with increased bleeding risk or atrial fibrillation or infection. PI3K inhibitors can be associated with lung or liver or colon damage. BCL-2 inhibitors might be associated with lowering of the blood counts and infection risk or something called tumor lysis syndrome.

So, we try to, if you had a side effect to one, not pick a drug with the exact same side effect profile, for example. And we also think about medical history for patients. So, if I had a patient who was on blood thinners and has poorly controlled atrial arrhythmia like AFib, I might not start them on a BTK inhibitor. If I patient who has active Crohn’s disease or ulcerative colitis that’s poorly controlled, I might not start them on a PI3K inhibitor. And if I have a patient who’s near dialysis because of chronic kidney disease, and I’m worried about further tumor lysis syndrome, I might not start them on a BCL-2 inhibitor.

So, you kind of weigh a patient’s medical history, their prior therapies, and their response and toxicities, and then make a decision on what’s the best fit for patients.

Katherine:                  

Well, what kind of testing is involved to make sure you have the best approach?

Dr. Mato:                   

Well, there are several tests that we think about using or we do use, and they’re mostly genetic and prognostic tests. And so, what we like to do is look at the CLL cells beyond looking at them under a microscope to try to identify the genetic markers that drive the biology of CLL. So, for example, if I have a patient who has deletion 17p which is one of the more feared chromosome abnormalities, I know right off the bat chemotherapy’s not a good fit for that patient. But I can do quite well with a BTK inhibitor like ibrutinib.

An Overview of Current CLL Treatment Approaches

An Overview of Current CLL Treatment Approaches from Patient Empowerment Network on Vimeo.

What chronic lymphocytic leukemia (CLL) treatments are available now? Dr. Anthony Mato reviews treatment classes and explains how they work to combat CLL.

Dr. Anthony Mato is Director of the CLL Program at Memorial Sloan Kettering Cancer Center. Learn more here.

See More From The Pro-Active CLL Patient Toolkit


Related Resources

 

Factors That Guide a CLL Treatment Decision

Is My CLL Treatment Working

CLL Clinical Trials Explained

Transcript:

Katherine:                  

To help patients understand more about the types of treatment currently available, let’s review the treatment classes and discuss how they work to fight CLL.

Well, and let’s start with chemo. Some patients are probably familiar with the term FCR. What does that stand for, and how does work?

Dr. Mato:                   

Sure. FCR is a name for three chemotherapies that are combined together.

So, this is fludarabine, cyclophosphamide which are two cytotoxic chemotherapies combined with the monoclonal anti-CD20 antibody rituximab (Rituxan), so two traditional chemos plus an immunotherapy called rituximab that have worked together synergistically and have been quite effective over a prolonged people of time for treating patients with CLL. FCR was originally developed at MD Anderson.

But a very important CLL trial called CLL8 confirmed that FC plus rituximab was better than FC by itself, so a trial that demonstrated improvement in progression-free survival but also in overall survival advantage. And so, this became the standard of care more than a decade, and it has been a very common chemotherapy combination for patients.

Katherine:                  

What about monoclonal antibodies? How do these treat CLL?

Dr. Mato:                   

Great question. So, right now, we have several monoclonal antibodies that are approved in CLL.

They all target the same cell surface marker called CD20. And so, the way antibodies work in general in these patients, in our patients is that we identify a cell surface marker. In this case, it’s the protein CD20, and these antibodies are able to target that specific cell surface marker, bind to it, and in a way act as a flag for the immune system to destroy these cells.

So, an antibody like rituximab may be able to destroy a cell directly, or it may flag the cell to be destroyed within the immune system within the spleen, for example. So, different mechanisms of action but it’s a targeted therapy because it focuses on a specific protein that’s largely expressed on the cancer cells relative to other cells within the body.

Katherine:                  

There are also a variety of inhibitor treatments. What are they, and what exactly are they inhibiting?

Dr. Mato:                   

Yeah, so the kinase inhibitors are probably some of the most important drugs developed for CLL to date.

And we have different classes. One group would be BTK inhibitors which stands for Bruton tyrosine kinase, another would be PI3K inhibitors. Another class would be a BCL-2 inhibitor which is a little bit different. Essentially, the way to think about inhibitors are that they identify key molecules within a cell that are very important for either cell survival or cell signaling. These are the molecules that tell cells to either migrate or to hone in on a particular area or to amplify signaling to allow them to survive.

So, a drug like ibrutinib (Imbruvica) or acalabrutinib (Calquence), which are BTK inhibitors block this BTK signal and interrupts a very important survival signal in the cell, kind of causes it to go haywire in many ways, and then allows those cells to slowly die over time. PI3K inhibitors like idelalisib (Zydelig) or duvelisib (Copiktra) do the same. They block a very important and parallel signaling pathway to BTK that cause a very similar effect.

And then venetoclax (Venclexta), which is a BCL-2 inhibitor works a little bit differently. So, CLL cells are very primed to actually die except that there are signals in place that block that process called apoptosis, and so venetoclax blocks the blocker of that signal, sort of inhibits the inhibitor to cell death and allows that natural process of cell death to occur in CLL cells.

And so, they’re kind of targeting different pathways, but they’re able to stop the cell in a way. This is very different than cytotoxic chemotherapy like the FC which targets all dividing cells. Here we’re targeting cells where those particular enzymes are most important.

Katherine:                  

Do inhibitors need to be taken indefinitely?

Dr. Mato:                   

That’s a great question, and that’s something that we’re still working out. Right now, BTK inhibitors and PI3K inhibitors are all given as continuous therapies. That’s not to say that they couldn’t be stopped, but they haven’t been studied in a way that allows us to stop them. So, there’s not a lot of evidence to support that.

 BCL-2 inhibitors, venetoclax, were studied as either as continuous therapies or as what we call a time-limited therapy, either 12 months in the frontline or 24 months in the relapsed/refractory setting. And so, they can be given for a fixed-duration period and then stopped.