In simple terms, can you explain what chronic lymphocytic is?

 It’s a leukemia, which by definition means it's in the blood and in the bone marrow because inside your bone marrow is where all your blood cells are made. As you heard from the title, it's a chronic leukemia. There are acute leukemias, but this is a chronic one that people can live with for many years.

There are two main types of cells – myeloid cells…(and lymphoid cells). This one is a leukemia of lymphoid cells, hence the name chronic lymphoid leukemia.

That’s really not known. In most cases, there is an association with Agent Orange, so sometimes Vietnam war veterans who develop CLL, that is considered a service-related injury. But in the vast majority of people who have CLL, we don't actually know why they develop CLL and that's a very active area of research.

Are there any particular signs and symptoms that individuals can look for?

The most common way that CLL actually gets diagnosed is (through a) routine physical. That’s because, in the vast majority of cases, most people at the time they developed CLL actually don't have any symptoms.

So, they tend to be having a routine blood count or as part of let's say a pre-op. Sometimes in people who are going to have knee replacements, I've seen this where they have a pre-op blood test and their lymphocyte count is high and they have no symptoms at all.

They can, however, present with lymph nodes – meaning an enlarged lymph gland just like you can get an enlarged lymph gland in your neck when you have an Infection. Those lymph glands can swell up somewhat from CLL. Now, they're generally not painful but if, say, a man is shaving or something like that they might notice “Oh what's this?” So, sometimes people do notice lymph nodes.

It's unusual that people have a lot of symptoms when they first present, but in someone who had chronic fatigue or night sweats, it's always good to get a routine blood test. Although there's many other reasons why people can have fatigue other than CLL.

There’s slow- and fast-growing CLL. What’s the difference between the two?

In most people, the disease is slow-growing. Again, that's why it's chronic. There are few people who have more fast-paced disease. And how can we predict that? Well we predict that by looking at some prognostic factors in terms of looking at certain things in the patient’s cells. For example, we look at if there are any chromosome abnormalities, various proteins in the cell called zap70 or CD38. We look at a variety of things inside the cell to try and predict is this going to be a slow-moving disease or faster.

To give some perspective on what fast-growing CLL is, it is someone who maybe is asymptomatic at the time they get diagnosed but within let's say a year or so is already requiring therapy. That's what we would consider fast moving in chronic lymphocytic leukemia.

We see approvals for CLL in tandem with small lymphocytic leukemia (SLL). Can you explain what SLL is and why we see this?

So they're really pretty much the same disease, which is why as you said you see drug approvals generally for both. The difference is in SLL, which stands for small lymphocytic lymphoma, you notice it doesn't have the word leukemia. So, the difference is that those patients don't have blood involvement. So, they can have enlarged lymph nodes. In fact, if you take a lymph node biopsy from a patient with CLL or SLL, you wouldn't know which disease they have because the lymph nodes are exactly the same disease. You only know because of the semantics. If you know what their blood counts are, if they're leukemia or lymphoma.

Patients with SLL can have bone marrow involvement. It's not just necessarily lymph nodes, but by definition they don't have a peripheral blood involvement. So their peripheral blood counts look relatively normal but the disease is essentially the same disease. It's either just not in the blood or is in the blood and essentially they respond to the same treatments.

What would you say is your biggest piece of advice for a patient who is diagnosed with CLL?

 I would say this to anybody who's diagnosed with a serious disease like cancer: I would see my oncologist. Talk to them about the plan and then I would get a second opinion at a major referral center or with a real expert in the disease. Part of the reason for that is that, although as leukemias go, CLL is common compared to what we call solid tumors, like tumors where you have a mass, it's much rarer. So most people that are in private practice may have a couple of patients with CLL, but generally not very many. So they don't have a lot of experience with it. You do want to talk to your oncologist about the plan first because not only would I recommend they get a second opinion at a major center or with an expert in the disease but it's good to know what your oncologist is proposing as a plan so that you you can then discuss that with the expert. If the expert says that's exactly what I would do, then you can feel even more confident when you go back to your physician. It’s really important and I don't think that's specific for CLL. I would say that for or any kind of a disease that can really impact your life.

Understanding the Basics of Chronic Lymphocytic Leukemia

Can discuss the tests that are conducted in newly diagnosed patients and moreover which tests patients should be asking for?

 Thetests that we usually are going to do once the diagnosis is made are to look at prognostic factors. What I mean by that are tests where you're looking to try and predict how people's disease is going to progress because this is a cancer where we don't necessarily treat at the time it's diagnosed because many patients can live many years and be totally asymptomatic with CLL but they often want to have some expectation for the course of their disease. There are a number of prognostic factors. FISH is one and that stands for fluorescent in situ hybridization and it's just a test to look for common normalities that are seen in CLL cells. We also sometimes look at levels of certain proteins in the cell like CD38 or zap70. We do a test called beta2 microglobulin and then we have another test we do that looks at what's called IgVH mutation status. The IgVH is a gene inside the CLL cell in about half of patients. All of those together can help us predict disease progression.

Now there are some people who will argue well if you're not going to use the test to make treatment decisions do you even really need to get them at the time of diagnosis and the simple answer is it really depends on how comfortable the patient is not having those results or do they really want to get those results because it is true that if you've already decided the patient's asymptomatic and you're planning to carry out a watch-and-waitstrategy, you might not need the test because you're not acting on them.

You need them, in particular the chromosome test as well as a mutation status, if you're going to treat and that's because there are some abnormalities, for example, a chromosome abnormality called 17p deletion where those patients do not respond at all well to chemotherapy. So, if you knew that that abnormality was there immediately that would no longer be an option for therapy. So, it's very important that we get them at the time of therapy.

The other important point is the chromosomes can change so even if we have a patient who got tested when they were newly diagnosed for the chromosome analysis and then three years later they've progressed enough to warrant treatment, it's very important to check the chromosomes again. The mutation status does change and so not only do we need to repeat them at the time of therapy initiation but if we treat a patient and they stay in remission for a couple of years and then the disease recurs, it's also important again before initiating treatment to check the FISH at that time.

We also have another test looking for what's called a p53 mutation. That's different from the immunoglobulin mutation test and the reason that's important is the two groups that we never want to give chemotherapy to are those with the 17p deletion and those with the p53 mutation. Those are really crucially important to be tested basically any time a patient is going to get treatment.

Cancer treatment over the last decade has expanded exponentially, but in particular with CLL, how has the initial treatment for this disease evolved?

It has evolved and that's because up until really just about five years ago all of our treatments for CLL were chemotherapy based either with mild chemotherapies that we might use in older patients with a lot of comorbidities who might be failure or somewhat more aggressive chemotherapies that generally produce longer remissions but are better tolerated by younger patients. I would still say there is a role for chemotherapy but we certainly have moved further and further away from it because we now have what we call the small molecules, which are not chemotherapeutic agents.

They are agents generally which will interfere with a protein function inside the CLL cell and by interfering with that function help kill off the cell. They're generally oral. It doesn't mean that they don't have side effects but the side effects are different than chemotherapy and in general these novel small molecules are very well tolerated, particularly in older patients who have much more difficulty with chemotherapy so we have still have chemotherapy as an option. But now we have three small molecules which have been approved to be used in CLL up front. (Imbruvica [ibrutinib]) another similar drug called (Calquence [acalabrutinib]) and another drug called (Venclexta [venetoclax]). In some cases, we give these drugs with an antibody treatment and in some cases we don't. There is another class of drugs called the PI3K inhibitors that are oral agents, and there's two drugs – (Zydelig [idelalisib]) and (Copiktra [duvelisib]) – in CLL, but those are only approved for patients whose disease has recurred. We have three small molecule options in the upfront setting for initial therapy.

There are a fraction of patients who still would be good candidates for chemo but all of them can be considered standard in that all of them have been FDA approved to be used as an initial therapy.

Does chemo-immunotherapy still have a role in treatment?

Yes, Ishould clarify what i said about chemotherapy. I actually meant chemo immunotherapy. So what is the distinction there? Basically all of our chemotherapy regimens are given in combination with an antibody. So an antibody is not chemo, it's a protein that's designed to sort of latch onto the CLL cell, kind of like a lock and key, and when it does that it helps the chemo kill the cell. The chemotherapies that we use in CLL, the three main ones are calambisol, which is a really mild one and can be given by mouth. And then two intravenous ones bendamastine and fludarabine. All of those are given in combination with antibodies.

So really chemotherapy by itself is gone. Over the years, it has evolved to be chemo immunotherapy.

What are some exciting drugs or combination regimens that are in the pipeline?

Well we have exciting ones that we can use right now. I mentioned we have ibrutinib, we can use a calibrate which can be given with or without antibody and we have venetoclax, which is usually given with an antibody called (Gazyva [Obinutuzumab]) and those are producing really great results. They’re very new. For example, (Calquence [acalabrutinib]) only had an approval within the past year. (Venclexta [venetoclax]) and (Gazyva [obinutuzumab]) only had a frontline approval in the past year and a half.

In terms of the horizon, we're kind of on the horizon right now because these treatments have only been approved in the past year or so and we expect them to produce very durable remissions. I can't even tell you what the average remission is going to be other than I know it's going to be based on years. Thisis how our treatments have expanded. You said exponentially, but just within the last year and a half, we've gone from having one small molecule to having three of them at our disposal.

What do patients have to look forward to in the future?

 Well there are other interesting molecules that are in development. There are CAR Ts, which I think most patients have heard about. There's not yet a CAR-T cell therapy approved by the FDA in CLL.

There's something else called bi-specific antibodies, which are very interesting molecules because what they do is their antibodies that bind to the target. So in this case, the CLL cell. Butthen they also bind to the patient's own Tcells and what they actually serve to do is to redirect the patient's own T cells, which is a component of their immune system and get it to attack the CLL cells. So, kind of like CAR T, but using the patient's own t cells with a drug or an antibody that we give them.

There's also a class of drugs called antibody drug conjugates. We don't have one yet in CLL and the idea behind that is you take the antibody which again binds to the CLL cell, but on the other end of the antibody is essentially a toxin or a poison. But you would not be able to treat the leukemia because it would make them sick, but because you give it attached to the antibody it only goes into the cell that the antibody is binding to. So you actually direct that poison right on to the CLL cell. That’s another very interesting class of drugs where we yet don't have any available in CLL. So even though we have these new great drugs, we have all these other classes which also may lead to subsequent therapies for CLL.

The Future of Frontline Therapy in CLL

Should patients be getting retested if or when their disease recurs?

There are some tests that we should be repeating anytime we're considering a new treatment, that includes the FISH test which looks at chromosomal abnormalities inside the CLL cell as well as an important protein abnormality called the p53 mutation. A p53 mutation is a gene that can be mutated and the reason it's super important to know about these chromosomes and the p53 status is that those patients should never receive chemo or chemo-immunotherapy because they don't respond very well to it. But even with the small molecule therapies that we have nowadays, patients with those abnormalities can do better on one drug than another. So in other words, it's important to know that because it may affect the physician's choice of treatment.

Outside of testing, are there other factors that should be considered when it comes to determining the next line of treatment?

When you have treatment options, which we do nowadays, you want to look at the side effect profile. If you have a patient who has a history of atrial fibrillation or an irregular heart rate…maybe in that patient you want to go towards one of the other drugs. (Venclexta [venetoclax]) can cause tumor lysis so someone with a high-volume disease maybe you would be a little bit more cautious about using that. So you want to look at the side effect profile.

The other thing that's important is that for some of these small molecules, the length of time that the patient is on the drug is different. So what do I mean by that? With (Imbruvica [ibrutinib]) or (Calquence [acalabrutinib]), the drug is given indefinitely. So once the patient starts on it they just continue on it unless they have a side effect which makes them stop or unless x number of years later the disease starts to come back and is then resistant to the drug. With venetoclax-based therapy, the regimen that's approved for relapse is venetoclax with the antibody (Rituxan [rituximab]) and that's a time limited therapy. So the rituximab is given for the first six months only and then the venetoclax is given daily for two years. So that treatment actually stops at two years and that may or may not be important to the patient if they have a time-limited therapy and that may or may not be important to the patient in terms of whether continuous therapy is a problem or time limit is more attractive.

We all know that in the states with oral agents there are copays and so in some senses having a limited time duration might be attractive. On the other hand, there are some patients who say well wait a minute if I'm responding to the drug you're going to stop it anyway and they don't like that idea so they actually would prefer to have an indefinite therapy as long as they're tolerating it and it's working.

So, I think you have to look at the side effect profiles of the drugs, that they're different durations of time and then what the patient preferences might be or what's most important to them.

All of the drugs approved for frontline therapy are also approved in the relapsed setting. That could also be how you factor in what you're going to use in relapse. So obviously if I gave a ibrutinib a patient up front and maybe five years later the disease is starting to come back, well clearly it's resistant to ibrutinib so I'm going to move on to something else. All of the drugs that we have in the frontline we have in relapse now.

We do have some drugs in relapse that are not approved for frontline and those are PI3K inhibitors and there's two of those drugs. (Zydelig [idelalisib) is one which is given in combination with the antibody rituximab and then (Copiktra [duvelisib]) is the other which is given as a single agent. Both of those can be options for relapsed disease but are not options for frontline therapy.

What are some exciting trials going on in the relapsed/refractory setting?

There are a lot of trials looking at new agents in the relapsed/refractory setting because the presumption is that the patients going on those kind of trials may be going on them because they've exhausted some of their more standard options, which are the drugs we're talking about. So sometimes these drugs have new mechanisms of action.

Bi-specific antibodies, for example, where the antibody binds to the CLL cell but it also binds to the patient's Tcells and re-engineers the T cells to attack the CLL cells, those are very interesting. We don't yet have any in CLL, but there are those agents in clinical trials.

We have antibody drug conjugates where an antibody is attached to a poison. The patient receives the antibody, but if they got the poison they would be very sick. The poison is only directed into the cell to which the antibody binds so it goes right into the CLL cell. There are also combination regimens in both the frontline and relapsedsettings. So combining, for example, ibrutinib and venetoclax or combining duvelisib and venetoclax, looking at whether the combinations are even better than the single agents.

And there are new drugs in these categories. I mentioned that there's two BTK inhibitors, ibrutinib and acalabrutinib. There’s actually a third one (Brukinsa [Zanubrutinib]) which is in clinical trials that could lead to an approval in relapsed CLL.

In the PI3K drugs I mentioned, idelalisib and duvelisib, umbralisib is also in trials actually in both the frontline and in the relapsed population. That one probably I would say of all the drugs we're talking about is the closest to having approval in CLL, which we could see probably next year.

Very much so. There's no doubt that the novel agents or the small molecules have increased the lifespan of your average patient with CLL. It was on the order of years even when we only had chemotherapy or chemo immunotherapy. But it's clearly much longer now because we can go from potentially sequencing one drug and then if that stops working move to another drug. So there's absolutely no question that survival for CLL patients is much better than it was 10 years ago.

So with that, what do patients with relapsed/refractory CLL have to look forward to moving forward?

Even longer life spanbecause I'm mentioning all these noveldrugs that are in clinical trialsincluding CAR-T cell therapy, which most patients have heard of. We have a novelclass of agentsand the mechanisms of resistance to the drugs that exist hopefully will be very different with a totally different mechanism of action, which leads us to assume that some of these drugs that have a whole new mechanism of action. They are still likely to be effective

a different mechanism of action in the cell has managed to figure out how to become resistant to that.

Living with CLL as a Chronic Disease

Can you break down how a clinical trial works?

 So, CLL clinical trials come in a lot of different flavors. They can be trials of new agents, completely novel agents, that don't yet have FDA approval and they can be drugs that are next generation. So, for example, we have a BTK inhibitor, but another company might think that they have a better BTK inhibitor. Sometimes there are combinations of drugs. So there are trials right now, for example, combining (Imbruvica [ibrutinib]) and (Venclexta [venetoclax]), two agents that have been approved separately, that have really great activity in CLL. There’s another trial combining venetoclax with (Copiktra [duvelisib]), a different category of drugs.

I think a lot of people sometimes have the misconception, particularly in leukemia, that they're anxious about maybe participating in a clinical trial because of placebo. I don't think I've ever seen one in CLL in patients who need treatment where there's any kind of assignment to a placebo. I think that intimidates a lot of people.

…I think it's important for a patient to consider a clinical trial, particularly with the novel agents if they're available because, for example, if we think about the fact that ibrutinib completely changed the landscape for CLL, it's really been a total game changer. It was a small molecule that was approved. If you consider how long it takes to get a drug FDA approved, and that one by the way went really fast, what that means is that people who are on the clinical trials actually have access to the drug years before that drug becomes FDA approved. So it can really get you access to novel, great drugs before they're even out there for the rest of the community to use.

We also have to keep in mind that clinical trials are very important because that's the only way we get new drugs. Every drug that is approved by the FDA had to be tested and usually in more than one clinical trial. Usually the first trial looks for the appropriate dose and the second trial looks at how well people respond, and then when we go to what we call phase 3 those are what are the randomized trials where a patient is randomly assigned to what's usually considered the standard of care or the newer drug. There's all different places along the way where we have to accumulate that trial data before it goes to the FDA for approval. That’s why people who happen to get on a great drug can have years of early access to it before it even gets approved.

We have to remember that clinical trial participation is so important because as I said no drug can get approved without clinical trials so if there are no clinical trials, we don't have any new drugs.

You mentioned misconceptions about clinical trials. Are there other misconceptions we can negate about clinical trials?

Some people have the anxiety that you're experimenting on me. Well we don't like to call it experimenting, but yes you can think of it as the fact that you are testing out a drug that hasn't been given to a lot of people, especially in the phase 1 part of the trial where you're looking for the dose, you’re one of the first people on the trial. So you would be one of the first people ever to get that drug. If you're on a phase 2 trial, where you're looking at response…then people did get it before you and that's why it's moving forward to phase 2. By the time it gets to phase 3, where you're randomly comparing it to standard of care there's plenty of knowledge. So you are going into a trial to get something that might not be a drug or combination that you can get outside the trial, but hopefully that's something that will benefit you and then benefit society as a whole if it leads to subsequent approval of that drug.

How can patients learn more about clinical trials if they're interested?

 There are some really good websites that are run for patients with CLL and, of course, the Leukemia & Lymphoma Society is a great one that really helps to match up patients with trials in their area. This is one of the issues with clinical trials, that it's probably easier for patients in larger metropolitan areas to participate than it might be for someone who lives in a really rural area where they're not that close to their medical center. They have to be able to get there. There are certain trials where the larger centers will partner with smaller practitioners. For example, there are major academic centers but then there are affiliated, much smaller centers that participate in those trials, too. So, cooperative group trials are particularly easier for patients to have access to because of their design and you don't have to come to one of the say four centers that's doing that trial. So that can be really helpful.

There are a number of different sites that can be really helpful in trying to identify trials, particularly in a certain region for a patient…Some of the treatments, particularly if it's an oral agent that the patient takes themselves and can actually be administered at home. In those kind of trials, the patients do have some back and forth to the trial center but much less than if it's a drug that actually has to be delivered at the trial center.

There are a variety of different possibilities even for people who don't live in in highly populated metropolitan areas to potentially have the possibility of participating in a clinical trial.

What is the best way for patients to join a trial or find out if they are eligible?

Generally, you can get some information from your doctor or online by looking at the website that the government runs called clinicaltrials.gov, where they will list the eligibility. For example, if you're looking for a therapy for your patient who has relapsed and you look on at the trial on the website, it says no prior therapy but right off the bat you know whether your patient is going to be eligible or not.

If you look eligible on paper that doesn't mean you will be eligible. What do I mean by that? I mean the eligibility may tell you that somebody who has to have lymph nodes that are less than 5 centimeters and then you go to enroll on the trial and you have the CATscan done and your lymph nodes are too small, I’d say it doesn't guarantee you eligibility because some of the testing that would be done in conjunction with seeing if you're a candidate for that trial might then exclude you. So in other words, you sign the consent for the trial, it sounds interesting to you but then because you don't meet some of the criteria you can't get treated. You often will have to go there to know for sure if you can participate.

I would say my biggest piece of advice for people looking to consider a clinical trial is to bring somebody with them. You want to bring a caregiver, a loved one, a spouse, a friend, somebody who can help you because it's very overwhelming particularly if you're relatively newly diagnosed right with the cancer and now you're hearing the details of a clinical trial. We know very well that it's hard to process all that in a doctor's office, particularly when you're hearing a lot of information about a trial in order to make a decision about whether to participate. It really helps to have a person there with you who can also ask questions for you or ask questions that you, the patient, didn't think to ask.

I would take notes also because it's amazing how much people forget the second they leave the doctor's office. It has to do with the sheer volume of information that might have been delivered to them in a 30-minute time frame. So I think it's really good to take notes.

The other thing I think is good to do is write down your questions before you go and bring them in for the same reason you're a bit overwhelmed in the office or the doctor starts telling you something about the trial and you’re a little confused and you stop to ask the doctor some questions about what they've just told you and then the question you had in your mind right before that is gone because you can't remember it. So I think it's a great idea to write questions down. And i think it's a great idea to bring somebody with you who can not only help you ask the questions but process the answers later on when you're not in the doctor's office.

Understanding Chronic Lymphocytic Leukemia | CURE^® Speaking Out

Understanding the Basics of Chronic Lymphocytic Leukemia

The Future of Frontline Therapy in CLL

Living with CLL as a Chronic Disease

Joining a Chronic Lymphocytic Leukemia Trial

Latest News

Understanding Chronic Lymphocytic Leukemia | CURE® Speaking Out

Understanding the Basics of Chronic Lymphocytic Leukemia

The Future of Frontline Therapy in CLL

Living with CLL as a Chronic Disease

Joining a Chronic Lymphocytic Leukemia Trial

Latest News

Understanding Chronic Lymphocytic Leukemia | CURE^® Speaking Out