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CLL Leukemia Medical Experts Oncologist

Dr. William Wierda

Dr. William Wierda

Medical Director of the Department of Leukemia and CLL Center Section Chief at MD Anderson

What are the latest updates in CLL treatments? There are so many emerging options and promising clinical trials in the space. CLL patient advocate, Michele Nadeem-Baker, leads an in-depth discussion with one of the top CLL specialists out there.

, Ph.D at MD Anderson Cancer Center, who’s also Medical Director of the Department of Leukemia and CLL Center Section Chief, shares what he believes are the greatest takeaways following one of the largest blood disease conferences of the year, American Society of Hematology (ASH) 2021.

Published January 2022

What is the ASH conference?

Dr. William Wierda: Most of ASH for us is getting the details of things that we know about. We hear about. We’re able to look. 

Many of us are involved in the clinical trials so we know in real time what’s happening with the clinical trials. Some of us are on the safety and review committee for these large trials, so we do have an idea of what the presentations will be for ASH.

It’s more of getting the detail and hearing the discussion and what people are thinking about. That is what we get out of these, these meetings. There wasn’t really any abstract that was presented that was something that was completely a surprise or something completely new.  

Large CLL Study on MRD

Details of the study

Dr. William Wierda: The CLL-13 trial from the German CLL study group – that is a large trial with four treatment arms. There were nearly 1,000 patients enrolled in that study. That was a trial that compared different arms of treatment from chemotherapy therapy-based treatment.

And then the other three arms were oral small molecule inhibitor based treatments: venetoclax-rituximab, venetoclax-obinutuzimab, and venetoclax-ibrutinib-obinutuzimab. That trial, they reported results for Minimal Residual Disease (MRD). 

The poorest performer was, wait for this . . . chemotherapy.

Dr. William Wierda

And not surprisingly, the best response was seen among those patients who received venetoclax-ibrutinib-obinutuzimab. So all three drugs, although there is a bit more side effects and toxicities associated with it and the question is are there more?

But is the value of having more undetectable-MRD with three drugs and some more toxicity, better than two drugs like venetoclax-obinutuzimab, which was the next highest undetectable-MRD rate, was for venetoclax-obinutuzamab. That’s a standard treatment. That trial demonstrated that rituximab plus venetoclax was not as good as venetoclax plus obinutuzumab and the poorest performer was, wait for this, chemotherapy.

Still need follow-up

Dr. William Wierda: So I think that the trial is an important trial. We didn’t get any information, because it’s very early, about how long the remissions are lasting or what the long term follow up is with that treatment that’s going to take a couple more years. We did get data for minimal residual disease and that predicts for outcomes, remission, duration, etc. But we like to see both MRD and the follow-up data.

What is the ASH conference?

Michele Nadeem-Baker: And Dr. Wierda, what in your opinion, what were the biggest takeaways from this year’s ASH, which is the biggest conference of the year for hematologists from around the world?

Dr. William Wierda: Right. So as you say, this is our big meeting. This is where most of us present the new data. There are a couple other meetings that happen midyear around June, and we do occasionally get updated data from those meetings.

But this is our big meeting and discussion, and revealing of the detailed data around clinical trials. There were several clinical trials that were reported on. A couple of them were new reports that we hadn’t heard before, and several of them were follow up reports. 

Different classes of CLL drugs

  • BCL-2 inhibitors
  • BTK inhibitors
Small molecule inhibitors

Dr. William Wierda: Overall what they showed was that chemotherapy outcomes or outcomes with chemotherapy were inferior to outcomes for treatment with small molecule inhibitors, whether we’re talking about venetoclax-based therapy or BCL-2 inhibitor-based therapy, or we’re talking about BTK-inhibitor based therapy or drugs

Michele Nadeem-Baker: Could you explain what an example of BTK-inhibitors and of BCL-2s for our audience to understand?

BCL-2 inhibitors

Dr. William Wierda: So the small molecule inhibitors that we have are oral agents, and there are three categories right now that we have of drugs that fall into the small molecule inhibitor category: BCL-2 inhibitors, we have one. There are several that are in clinical trial.

The one that we have is called venetoclax. Very potent at eliminating disease, very potent at getting deep remissions. It’s the type of treatment that we give with the expectation of giving it for a set period of time and then stopping treatment once patients are in remission. 

Michele Nadeem-Baker: Defined treatment is a defined time as opposed to indefinite.

Dr. William Wierda: It’s a defined time – one year as a first treatment and two years as the second treatment, according to the current standard treatments that we give.

BTK inhibitors

Dr. William Wierda: The next category is BTK-inhibitors. Those have been around longer than BCL-2 inhibitors. Examples of this drug type that we currently have available are acalabrutinib and ibrutinib.

Ibrutinib

Dr. William Wierda: Ibrutinib has the most experience associated with it, and we have the most data and most patients treated so far on clinical trials with ibrutinib.

Acalabrutinib and zanubrutinib

Acalabrutinib, though, is approved. Zanubrutinib is not yet approved, but perhaps will be in the next within the next year probably. Those are drugs that are extremely effective at controlling the disease, but not as effective as, for example:

(BCL-2) venetoclax is in terms of getting the amount of disease down to the point where we’re comfortable with stopping treatment. So the best response the lowest level of disease is usually still measurable with the BTK inhibitors like ibrutinib or acalabrutinib. So patients go on that those medicines and they stay on them until they don’t work any longer. It’s more of a maintenance type treatment.

When BTK inhibitors aren’t effective

Michele Nadeem-Baker: If I’m on, let’s just say ibrutinib, it stops working. Can I go to acalabrutinib and it’ll work?

Dr. William Wierda: So if it’s not working and the disease is growing? Switching to acalabrutinib is not expected to control the disease in a meaningful way.

So both of those drugs belong to a category called irreversible inhibitors. That means they bind to BTK and they in that activate it. And the only way that the cells will the only way the cells can have a functional BTK is to make new. And so it blocks permanently the activity of BTK when it binds to BTK.

Both of those drugs bind to the same amino acid in order to do that. So if and when the main mechanism for resistance is mutation of that amino acid. So if the amino acid is mutated, then whether we’re talking about acalabrutinib or ibrutinib or zanubrutinib. All three of those are the irreversible inhibitors. They no longer bind. They’re no longer effective. 

If patients have to stop treatment because there’s a side effect or a toxicity, then yes, and if they don’t have resistance. Resistance is reflected in increase in the white blood cell count while patients are on treatment or enlargement of the lymph nodes while patients are on treatment. That’s what we that’s how we define resistance.

If that’s not happening and patients have to come off because they develop a-fib or a rash or some other reason, then it is reasonable to switch to an alternative, irreversible inhibitor, for example, ibrutinib or acalabrutinib, et cetera.

PI3 Kinase inhibitors

Michele Nadeem-Baker: Thank you. And there was a third that you were going to mention.

Dr. William Wierda: Third category of drugs are the P-I-3 kinase inhibitors. There’s two that we have currently available. One is called Idelalisib. The other is called Duvelisib. Those have a bit more side effects and toxicities associated with them, particularly Idelalisib and are used less frequently these days.

Ibrutinib, the BTK-inhibitors, and the venetoclax or BCL-2 inhibitors are extremely effective and give very good and durable disease control. You can you can switch between those two if you develop resistance. So if you develop resistance to venetoclax, for example, you can switch to one of the BTK-inhibitors and expect the response, and vice versa.

Most important considerations for CLL patients

I don’t like to think about, or talk about, or plan for chemo-immunotherapy any longer because I think it’s inferior treatment for our patients.

Dr. William Wierda
Small molecule inhibitors > chemoimmunotherapy

Michele Nadeem-Baker: What did people learn or what can patients learn from this ASH – from the the latest trials on these particular drugs?

Dr. William Wierda: I think it’s important for patients to know and to think about the fact that there are two strategies for treatment these days with the small molecule inhibitors. And I’ll talk about that in a second.

This ASH, and previous ASH meetings, have all reported out data from these large clinical trials that compare these oral drugs, the small molecule inhibitors to what has been our standard treatment, which is chemoimmunotherapy.

All of those trials show that there are new treatments, the targeted therapies BTKi, BCL-2, are superior to chemo and chemoimmunotherapy, so I don’t like to think about, or talk about, or plan for chemo-immunotherapy any longer because I think it’s inferior treatment for our patients and much more aligned with giving small molecule inhibitor based therapy. 

Fixed duration vs. finite duration treatment

I think for patients and moving that discussion a little bit further, what patients need to think about and have a discussion with their physician about is: 

  • Do I want fixed duration or finite duration treatment?  Do I want to get in remission and get off treatment and have a reasonable period of time to expect off treatment in remission?
  • Or do I want to go on a maintenance and have medication that I take every day that is extremely effective at controlling the disease? But I continue on it and there are side effects associated with all treatments, including the continuous treatment.

The challenge for the finite duration treatment is that it has to be that you have to monitor patients closely when they start on it because it’s very potent at killing the leukemia cells, and there are some risks initially that we have to monitor for.

Monitoring patients on venetoclax-based regimens

Michele Nadeem-Baker: So would this be on? Let’s just say a CLL patient like myself were to go on like venetoclax, right?

Dosage

Dr. William Wierda: Venetoclax-based. So venetoclax is the BCL-2 inhibitor. That’s the extremely potent drug. And so in order to safely start it, you have to start at a very low dose, 20 milligrams a day and you step up the dose each week. You have to be monitored each time you step up the dose.

In terms of your labs, in order to make sure you’re not having any overwhelming leukemia cell death, which can cause a lot of problems with the kidneys and with the heart, the target dose is 400 milligrams a day, so it ramps up over a month. And that’s a little bit difficult. And it does require going and seeing a physician who’s done that, is familiar with it, and understands and knows how to do the ramp up and can monitor things safely.

If you do the monitoring as it’s been recommended, it’s safe. It’s just work. Once you get to the 400 milligram daily dose, it’s very active and it’s very well tolerated. There’s not a lot of side effects associated with it.

Minimal residual disease (MRD)

Michele Nadeem-Baker: During these conferences, we always hear about PFS, progression free survival, and undetectable-Minimal Residual Disease (uMRD). What is the difference and what trials are showing the best hope for for these?

MRD tests

Dr. William Wierda: Let’s talk about first MRD or minimal residual disease. That is a test we do to determine if we can measure any amount of leukemia. We can do the measurement in the blood or we can do the measurement in the bone marrow.

It’s a very sensitive test that allows us to identify one leukemia cell among 10,000 normal cells and up to one leukemia cell among a million normal cells. So this is a way or a measure that we can check to see if we have a deep remission.

Undetectable disease is a deep remission, whether we’re talking about one in 10,000 or ideally, one in a million leukemia cells. That’s the type of response that we we’re working to get an undetectable-MRD we were working to get with chemotherapy.

Venetoclax-based therapy success

We were able to do it, but not nearly in as many patients as we can achieve now with venetoclax-based therapy. Venetoclax is much more potent and much more effective at achieving undetectable-MRD. That only tells us sort of a snapshot in time. What’s the level of disease a patient has potentially in their body?

Progression-free survival (PFS)

If a patient achieves an undetectable MRD state at the end of treatment, their progression-free survival is going to be significantly longer than if they don’t achieve an undetectable status at the end of treatment.

Dr. William Wierda

Dr. William Wierda: Progression-free survival means, basically, how long does a patient remain in a remission before the disease is growing again? That takes some time.

If we do a clinical trial and we enroll 100 patients, for example, if we’re talking about the median progression-free survival, it takes us a fair amount of time to observe a group of patients who have been treated to determine how long, on average, they’re staying in remission.

That’s kind of what we mean by progression-free survival for drug approval.  The FDA needs to see progression free survival, and we also know that if a patient achieves an undetectable MRD state at the end of treatment, their progression-free survival is going to be significantly longer than if they don’t achieve an undetectable status at the end of treatment.

So there is a correlation or relationship between MRD and progression-free survival, but they tell us different information. And with our newer treatments and our combinations of targeted therapy and finite duration treatment, we’re working on achieving as high a percentage of undetectable-MRD as we can.

We hope that ultimately translates into longer progression-free survival for a treatment. As I’m sure you understand, you can’t show that a patient’s cured if they still have measurable leukemia. So we aim to achieve undetectable-MRD state in order to show that our treatments are curative.

When is a patient considered “cured?”

I’m optimistic that we are curing some patients currently with our non-chemo treatment. Certainly, we know patients are being cured with chemo options.

Dr. William Wierda

Michele Nadeem-Baker: We hear as patients that there is no cure yet for CLL. If a patient achieves uMRD, does that mean they have a temporary cure? Or if they’re uMRD for a number of years, are they cured?

Dr. William Wierda: It means that we’re not able to detect any measurable disease. In order for a patient to be cured, meaning no more leukemia period ever to be seen, they have to be undetectable MRD, whether that’s at the end of treatment or it’s three years or five years later.

Our finite duration trials, our fixed duration trials are aimed to achieve an undetectable state historically. So let’s backtrack a little bit. I do think we are curing some patients with our treatments short of our non-transplant treatments.

For example, patients who have a mutated immunoglobulin gene who get chemoimmunotherapy, about half those patients are probably cured, meaning they have more than 10 years of no active progressive CLL. If we look at our FCR data, which is a standard chemoimmunotherapy regimen, many of those patients that I treated 20 years ago are coming back to see me and are still undetectable MRD. Their disease hasn’t come back. It hasn’t progressed. I think those patients are cured.

Can we achieve the same with non-chemo treatments? I think so. But it’s going to take more time, more follow-up, more serial measurements of MRD to show that patients who achieve undetectable-MRD state remain undetectable and also longer period of time to demonstrate that patients are not progressing.

I’m optimistic that we are curing some patients currently with our non-chemo treatment. Certainly, we know patients are being cured with chemo options. The problem is that chemo has side effects and toxicities associated with it, and we have exceptionally good treatments now with small molecule inhibitors to the point where I think despite the fact that we are able to cure some patients with chemo, it doesn’t justify giving every patient who potentially could be cured the chemo because it’s only about half of those patients.

Patients with riskier prognostic indicators

Michele Nadeem-Baker: With the ASH studies, are you seeing that? Getting to uMRD with a BTK inhibitor like an ibrutinib, acalabrutinib, zanabrutinib or venetoclax, or in combination with other drugs? Are you seeing a better chance at patients that might have riskier prognostic indicators like unmutated IGHV or 17p or TP53?

Dr. William Wierda: Right now, we’re seeing good responses for all patients independent of their risk features. If they have an unmutated immunoglobulin gene, their response is similar. If they have a 17p deletion, their response is similar to the non-17p. The challenge for the high risk is showing that they remain in remission and that their disease doesn’t come back and grow. 

If we’re talking about achieving an undetectable-MRD state, venetoclax-based therapy is what we need to give to do that. Whether it’s the standard treatment, which is venetoclax plus obinutuzumab, which is a CD20 antibody, or a newer combination, venetoclax + ibrutinib, venetoclax + acalabrutinib – those combinations, all of which include Venetoclax, are intended to get into a deep remission, undetectable MRD and time off treatment.

If we’re talking about BTK-inhibitor based therapy, unless we’re talking about combining BTK with venetoclax, BTK-inhibitor based therapy is more of a continuous treatment until it doesn’t work any longer because we know all of the BTK inhibitors are extremely effective at controlling the disease. They don’t achieve a deep remission, undetectable MRD in a notable percentage of patients so that we feel comfortable getting them off treatment.

Promise of ibrutinib + venetoclax + chemotherapy

Michele Nadeem-Baker: With a BTK like ibrutinib and venetoclax, that is potentially a winning formula for patients then. And when you add in a CD20, like obinutuzumab, is that even better than that?

Dr. William Wierda: That may be better, but there is a bit more side effects and toxicities. So if we’re talking about standard treatments, there was a trial that was presented previously and updated at ASH called the GLOW trial.

That trial is comparing ibrutinib venetoclax with chemotherapy. That trial showed improved outcomes with ibrutinib + venetoclax. About half the patients had undetectable MRD. So although it’s not yet a standard of care, it’s not been approved by the FDA, we are anticipating that it will probably be approved by the FDA as a combination therapy with the expectation of giving 12 months of combined treatment and then getting patients off treatment.

What treatments should patients be watching for right now?

Michele Nadeem-Baker: Wow. That’s nice, that patients can see a light at the end of the tunnel versus indefinite. Do you have any final words for people watching this on who are looking at treatments who are looking to go into treatment or who are on, you know, relapsed and about to go into treatment.

What should they be thinking of? I know it’s different for every patient, but depending on their risk factors, what would be the thing to look for right now or to watch for the future?

Reversible BTK inhibitor (pirtobrutinib)

Dr. William Wierda: There’s a lot of things happening in CLL. There are a lot of new and exciting drugs that we’re studying that are in early development. There’s a drug called pirtobrutinib, which is a reversible inhibitor of BTK, which you would consider giving in a patient who has developed resistance to one of the irreversible inhibitors, such as ibrutinib, venetoclax, zanubrutinib or acalabrutinib.

Pirtobrutinib is looking very promising. It’s active in patients who are resistant to irreversible inhibitors, and those remissions are lasting a reasonable amount of time. It also is working in patients who are resistant to ibrutinib and venetoclax. So we’re excited about that.

CAR T-cell therapy

Dr. William Wierda: CAR T-cell therapy is an exciting topic. It’s an area that I’ve been involved in development. We will hear more about CAR T.

I have had many patients who have been treated with CAR T, who were resistant to standard treatments, who have had very durable remissions and who are doing very well. So for me, that holds a lot of promise for our patients – the CAR T platform. 

Bispecifics

Dr. William Wierda: The bispecifics are an area of new drugs that are in development that are very exciting, these combinations and using the tools that we have to optimize treatment to get the best outcomes for our patients. So if we have patients who are thinking about treatment, planning for treatment, getting information is very important, talking to the to the doctor about what the treatment options are.

Importance of seeing a CLL specialist

Dr. William Wierda: I assume this group, because they’re on the internet, are probably already an informed group and have an understanding of the treatment landscape and treatment approaches, but it’s important to have a discussion with the doctor.

I think it’s important for people to see a specialist, for example, who sees predominantly CLL (patients) and is aware of what’s going on. I think those of us who are specialists look forward to the opportunity ofs working with the local doctor. If we have patients who are referred to us for a recommendation, usually the referring doctors are happy to have suggestions, recommendations, and to work with us. 

I think clinical trials are important. They’re the only way that we’re going to make progress in the disease.

Dr. William Wierda
Clinical trials

And then clinical trials, I think, are important. Our clinical trials at MD Anderson are usually what’s called phase two, meaning all the patients get pretty much the same treatment and they won’t get a standard treatment like chemotherapy where they could get that with a phase three study. I think clinical trials are important. They’re the only way that we’re going to make progress in the disease. They’re the only way we’ve made made progress in treating a disease, and they’re very, very important.

Michele Nadeem-Baker: Well, thank you for all the work that that you do for CLL patients, Dr. Wierda. It’s it’s amazing how I’ve seen things, all the choices now that there are since I was first diagnosed nine years ago, and I look forward to our next conversation.

Dr. William Wierda: Great. Well, thank you for having me.

Michele Nadeem-Baker: It’s been our pleasure, at The Patient Story, and for everyone who wants to access this interview and our full conversation, please head to thepatientstory.com, where you’ll find human answers to your cancer questions. This is Michele Nadeem-Baker for The Patient Story. Have a wonderful day. 

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CLL Hematology Medical Experts Oncologist

Dr. Kerry Rogers

Kerry Rogers, MD

On Latest CLL Research & Treatments

Kerry Rogers, MD shares the latest news and opinions on treatment options for CLL (chronic lymphocytic leukemia) patients.

Lending her vast expertise and research experience as an assistant professor in the Division of Hematology at The Ohio State University (OSUCCC – James), specializing in chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL), Dr. Rogers sheds light on participating in clinical trials and the community’s efforts to move the mark in the standard of care.

Explore below for Dr. Rogers’ insights on everything from the latest in CLL treatment, decision making throughout treatment, importance, and prospects of clinical trials. Full written version below the video.


Introduction: Dr. Kerry Rogers

I currently live in Columbus, Ohio, and I’m from the Midwest, but I grew up in the Chicago area.

I have a guinea pig, and I like college football. That’s huge at the Ohio State University, but I did my residency at the University of Michigan.

Don’t tell anyone, but I went to Northwestern for an undergrad, so that’s really my football team. That’s just a bit of me.

I work at The James (OSUCCC), and I enjoy taking care of people with chronic lymphocytic leukemia (CLL) and hairy cell leukemia (HCL).

My major interest academically is on improving targeted agents for the treatment of both these diseases.

Chronic Lymphocytic Leukemia (CLL)

What is CLL

Chronic lymphocytic leukemia or CLL is a blood cancer. It’s a cancer of cells called B lymphocytes. Don’t ask me why they’re called B lymphocytes! Those are white blood cells or immune system cells that have turned into cancer cells at some point over their lifespans.

They can go anywhere in the body that the blood goes to—you can find them in the bone marrow, lymph nodes, liver, and spleen, and in the blood, because it’s leukemia.

You can make a CLL diagnosis when there’s a certain number of these leukemic white blood cells or CLL cells in the blood. You can diagnose it with a blood test, and the most common way these days that people come to be diagnosed with CLL is when their white blood count appears too high and then goes through blood tests.

Many people diagnosed have no symptoms whatsoever and are sometimes somewhat confused about going to the cancer hospital to meet with me.

When thinking about CLL, it’s also important to realize that this is the most prevalent adult leukemia, meaning more adults live with CLL than any other type of leukemia.

People with CLL can expect to live a very long time, including their natural lifespan, and not everyone needs treatment. Because of that, it’s imperative to think about how well people are going to live with their CLL.

Categories and Stages of CLL

Unlike solid tumors like breast cancer or lung cancer, where the staging is based on how far it’s spread in the body, and if it’s left the site where it developed, which could mean the patient is in big trouble, we stage these blood cancers differently. Since they go over where the blood goes, which is everywhere, we can’t use the same basis.

In the United States, the most common staging for CLL is called Rai Staging. It was developed by Dr. Rai, a very nice man if you ever get the chance to meet him.

Rai Staging
  • Stage 0: CLL cells are in the blood
  • Stage 1: CLL cells are in large lymph nodes
  • Stage 2: An enlarged liver or spleen from CLL
  • Stages3 & 4: CLL cells are on the bone marrow that has caused people to have low hemoglobin, be anemic, or have a low platelet count from the CLL
How is CLL staged?

It’s staged simply by physical exam and looking at blood counts, and many people don’t need a bone marrow biopsy for staging. Some people need it to know why people’s blood counts are low, but it’s not always necessary.

The other part was the main forms of CLL and if there’s a slow-growing or a fast-growing type.

Everybody’s a little bit different. You’ll see some people diagnosed with CLL, and they’ve had it longer than I’ve been a doctor, and they’re doing fine with it. Their white count is the same as it has been for the last couple of decades.

But there are people whose CLL isn’t moving very fast at all. Then, some were diagnosed 18 months ago, and their white count has gone from 15 to 200 over that time.

Tests for CLL

The course of the disease can be quite different in many cases, and there are some tests that we can do to help better estimate if it’s going to be a slower or faster-growing CLL.

IgHV mutational status

One of those tests is called IgHV mutational status, or immunoglobulin heavy chain gene mutational status, where unmutated usually means a faster-growing, higher risk CLL.

I’d like to think of mutated as a special, low-risk slow-growing CLL, and that’s mutating your immunoglobulin as a normal process in B cells. This just says whether or not the CLL cells did that before they turned into leukemia cells. 

FISH test for CLL

Some other tests that can help include FISH panel testing, which is just a fancy way to look at chromosomes in the CLL cells, not like the ones you pass onto your kid.

Things like deletion of the short arm of chromosome 17 or deletion of 17p can mean that we’d expect the CLL to be faster-growing, and deletion of 13q, which is part of the 13th chromosome, predicts slow-growing.

We can use a combination of these factors to guess how someone’s CLL will do.

Of course, sometimes we’re surprised. Sometimes, it looks like it will be slow-growing and it’s not, or people with some high-risk features really have an extended course but their CLL isn’t causing them any issues.

CLL in layman’s terms

One thing that really helps people that’s not necessarily fancy is knowing how to look at your own blood counts.

People get these complete blood counts all the time, and you’ll see your white blood cell (WBC) count, hemoglobin, platelets, and then below that, you’ll see a differential that tells you what type of white blood cells those are.

You always want to look at the lymphocyte count, because the CLL cells are counted under lymphocytes.

The other testing is something you do just on the leukemia cells.

It’s always very important to ask if this testing is done and what the results are so that you can know more about your CLL.

It helps you predict how much trouble you might have from the CLL in the future, the time before needing treatment, help in selecting a better course of treatment, how many treatments you might need in your lifespan, or if, at some point, a clinical trial might be appropriate for you.

The major ones are the IgHV and CLL FISH panel, which stands for fluorescence in situ hybridization. It is a chromosome analysis where they look at all the chromosomes because people with three or more changes in their chromosomes actually predict a higher risk of CLL.

They can expect to have more treatment and more difficulty with it in their lifetime. People with normal karyotype, like normal chromosomes, actually expect to have less difficulty. 

»MORE: Hear from CLL specialist, Dr. Jacqueline Barrientos

Standard CLL Treatment

Shifting Away from Chemotherapy

First, it’s important to realize that the median age that people are diagnosed with CLL is in the mid-60s or almost 70. There’s a lot of older people who might have other health conditions.

It’s always important to think about what other health conditions someone has when planning treatment.

It has been a goal in the field of CLL medicine for a long time to make sure that some treatments are appropriate even for older people in their 80’s or even 90’s with other health conditions.

But here, I’m going to talk about more of the chemotherapy for younger, fit people because I think it’ll be easier to understand in that setting.

We’ve always had some chemotherapies that could lower the white count or improve symptoms. But the mark was moved on how long people are living with CLL or survival by combinations of chemotherapies with an antibody medication called rituximab.

Fludarabine, cyclophosphamide, rituximab (FCR)

The last several decades before my time working in CLL were spent developing a regimen called FCR (fludarabine, cyclophosphamide, and rituximab). Rituximab is the antibody and the other two are chemotherapies.

Bendamustine and rituximab

There’s a similar regimen you can use in people who might be slightly less able to tolerate chemotherapy called bendamustine and rituximab. These are highly effective chemotherapies that could be given to most reasonably healthy people and can control the CLL for years.

Targeted Therapy

ibrutinib and venetoclax

It’s important to know that as a first treatment, our new targeted agents, like ibrutinib and venetoclax-based treatments, were compared to these chemotherapies and had longer progression-free survival. This is a measure of how long people are alive without their leukemia returning.

We have found that these targeted agents were actually better than these chemotherapies.

That means people lived longer without their CLL coming back after they took the non-chemotherapy targeted agents. Also, they have a different group of side effects that are generally better than chemotherapy.

»MORE: Read more about ibrutinib and other patient experiences

Choosing between Chemotherapy and Targeted Therapy

Some people choose to get chemotherapy because it’s different from these targeted agents, or they might have a health condition that makes the targeted agents inappropriate.

These days, the vast majority of CLL patients should be receiving treatment with a targeted agent and not with chemotherapy.

It’s very uncommon that you’d have to use chemotherapy to treat CLL. The one exception to that is young fit patients. IgHV mutated people and don’t have a high-risk feature such as deletion 17p can have 10 years or more of being alive with no detectable leukemia after getting FCR.

A group of younger people fit for chemotherapy treatment are those mutated and don’t have deletion 17p, called a TP53 mutation. But they might choose to get FCR because it might actually cure them.

I don’t know what else to call 10 years of being alive without detectable leukemia. We don’t usually say CLL is curable, but this is the one case where it might be.

However, there’s a lot of risks to doing FCR, like getting a different type of leukemia called acute myeloid leukemia (AML). That happens down the road due to bone marrow damage from FCR.

That is the one case where it could be very important to offer chemotherapy, especially to young healthy people that might want to do a treatment course of about six months and then potentially never need treatment again in their lifespan.

It’s not a guarantee that they’ll never have leukemia come back, but that is the one case where it’s important to think about it. But for the vast majority of other people, targeted agents are safer and more effective.

How long have the targeted agents been in use

The BTK inhibitors were developed in the last decade, and venetoclax shortly on the heels of that. When things are through phase III studies, that’s when they start being prescribed more commonly.

We—the academic centers—get to use all these drugs and people that come see us here might benefit from taking them as a participant in a clinical trial.

I’ve seen many people who did really well doing a research study to get a newer drug that later became approved. This becomes more widely available and used by general practice, hematologists, oncologists after phase III studies.

Continuous novel agent therapy vs. time-limited

For previously treated or relapsed refractory CLL once, it’s been about five years. In 2018, we had those randomized phase III studies comparing ibrutinib regimens to FCR or BR reported that ibrutinib had a longer progression-free survival, which is, again, being alive without leukemia. That really put those in very widespread use.

There is some resistance to it just because you have to take the pills for a long time. You take them indefinitely until either leukemia comes back while you’re taking them, you develop a side effect and have to stop taking them, or you have some other health condition that you have to stop.

In younger patients, compared to FCR, ibrutinib even had a survival advantage, meaning you’re more likely to be alive if you took the pills instead of FCR.

When you explain to them that, yes, it is not the first choice, most people decide that that’s better than something that has a shorter progression-free survival or doesn’t work as well.

Most people are more comfortable taking pills long term when they find out that it works better than chemotherapy.

In both people who have taken a treatment before or selecting a first treatment, there are two major standard of care options outside of a clinical trial.

Although I think participating in clinical trials is always something to consider if you can do it. I’ve seen a lot of people benefit from that. You won’t get a placebo without knowing that’s an option. From where I work, we have zero CLL trials with a placebo.

Treatment for relapsed/refractory (R/R) CLL

The two standard options are both highly effective. If patients haven’t taken either class of drugs, they’re both excellent, and you can pick based on preferences and side effects.

BTK inhibitors

There are BTK inhibitors, which are pills that target a protein called BTK. This blocks a cell signaling pathway called B cell receptor signaling. This makes the CLL cells not behave like CLL cells and die off over time.

The two main BTK inhibitors that are approved for CLL are ibrutinib and acalabrutinib. Ibrutinib is a once-daily pill. Acalabrutinib is more selective and targets pure things that ibrutinib does. It is a twice-daily pill. 

Ibrutinib and acalabrutinib are both excellent options. They’re usually given by themselves, although they can be given with an antibody medication in some cases.

Venetoclax

The other option is another oral targeted agent called venetoclax. It inhibits a protein called Bcl-2, which is an anti-cell death protein. If you block an anti-cell death protein, that’s like a double negative, and it kills the CLL cells really fast.

The problem with this drug is that it has to be started slowly so people can be monitored. It can work so quickly that it can cause tumor lysis syndrome. It is usually given with an antibody and requires monitoring. 

Venetoclax treatments are given in a shorter duration. If people are taking it as a first treatment, you give it with an antibody called obinutuzumab and take it for one year. If you’re giving it after people have already gotten treatment, you usually give it with an antibody called rituximab, and you take it for two years.

It’s whether or not they’ve taken treatment before it determines whether or not you take venetoclax for one or two years.

Venetoclax vs. BTK inhibitors

Venetoclax is like a time-limited treatment versus BTK inhibitors, which you take indefinitely till they stop working or you develop side effects and have to quit.

Some people have very strong feelings about if they want to take something and just get it done and stop, or if they’re just fine adding another pill to their pillbox. They don’t want to bother with antibody infusions. They just want to take some pills and go back to working or golfing or whatever it is they want to do.

Both are usually tolerable for the majority of patients. The ones who take long-term, obviously, for some patients have more chronic side effects.

Targeted Therapy Side Effects

Both these treatments are so effective, if you’ve never taken venetoclax or BTK inhibitors before, you can really pick based on your preference for treatment duration, and what side effects may or may not matter for your other health conditions.

btk inhibitors side effects

The main side effects of BTK inhibitors are:

  • Bleeding
  • Bruising
  • Cardiovascular side effects
  • Increase in blood pressure – high blood pressure can increase the risk for things like heart attacks and strokes. Overall, it can decrease cardiovascular health.
  • Abnormal heart rhythm called atrial fibrillation, or a-fib. A-fib is usually not life-threatening but is very irritating to deal with.

In addition, it can sometimes cause:

  • Joint aches or pains
  • Inflammatory arthritis
  • Diarrhea
  • Heartburn
  • Rashes – those usually go away or are less of a problem

Most people find the side effects from the BTK inhibitors tolerable, so they still go about their life with these things.

But for someone that has atrial fibrillation or is taking several blood pressure medications already, this might not be the best idea. People with bleeding disorders or who need warfarin anticoagulation don’t want to take this class of drugs if they have options.

Venetoclax side effects

Venetoclax, on the other hand, can cause tumor lysis syndrome at the start.  All the CLL cells die so quickly it releases toxins into the blood. That’s treatable, but if you don’t watch out, it can be life-threatening or fatal.

You actually have to start the dose low and increase it slowly. People take a low dose, and over five weeks, they increase the dose every week to get to the full dose of venetoclax, which is 400 milligrams. They have to come for at least two days in a row for blood tests or monitor tumor lysis syndrome every time.

»MORE: Cancer patients share their treatment side effects

With this monitoring scheme, it’s very safe, and people developing tumor lysis syndrome can get that treated usually with medications. Things seem to go very well for people, but it’s a lot of hassle to do that.

To protect people from tumor lysis syndrome, they have to stay hydrated. People who have heart failure, take diuretics or have kidney impairment, which could make tumor lysis syndrome more common and more dangerous, might not want to go this path just because that’s a greater risk to their health.

Once people are at the target or treatment dose of venetoclax, it actually seems to have fewer chronic side effects than the BTK inhibitors. Some of them include diarrhea, lower neutrophil count or neutropenia (neutrophils are infection-fighting cells).

People can sit down and look at their health conditions. If they have severe kidney impairment, they probably want to take a BTK inhibitor. If they have abnormal heart rhythm problems, they would want to take the Venetoclax.

It’s a decision you make together with your treating physician.

I sometimes see patients considering their options for first treatment who ask me right off the bat, “Which one should I do?”

I say, “I don’t know, we just met. I need to ask you some things about you, and then I can tell you what you might want.”

I think these are really important, and the discussion is very similar for people picking a treatment that has taken before but never taken either of these classes of drugs before.

»MORE:Learn more about the process of clinical trials from one program director

Clinical Trials

Triple Therapy (Ibrutinib, Venetoclax, Obinutuzumab)

We always like to make treatment safer and better for our patients. So we had a study combining the BTK inhibitor ibrutinib, venetoclax, and an antibody, obinutuzumab, as a treatment for one year.  It’s ongoing in follow-up, but everyone in this study has completed treatment.

When you give more drugs together, you get more side effects. It’s not a surprise, but the nice thing about this is it’s one year, and now we’re seeing how long people remain in remission at the end of that one year of treatment.

So far, we’re at about three years of follow-up, and it looks very good.

We’ve treated people with both relapsed/refractory CLL and people taking this as a first treatment. Several other studies are going on for BTK inhibitor and venetoclax combinations. We expect the response rates to be very high, but we are excited to know how long people remain in remission with this.

We hope to learn with longer follow-up who might most benefit from this combination and who’s going to stay in remission longer than with other things.

I’m just super excited that we really move the mark and get regimens into the standard of care in CLL and are able to do a randomized phase III trial, where you sign people to treatment in your treatment.

Again, there’s no placebo here, and usually, you know which one you’re getting to, after you randomize. You don’t know when you sign up, but you know before you get treated.

There are two ongoing studies, one through the Eastern Cooperative Oncology Group, or ECoG, and one through the Alliance. Those are both US Oncology Cooperative groups that do studies conducted on hundreds of sites across the US. They are both randomizing patients to ibrutinib and obinutuzumab.

You take the antibody for a limited time, but the ibrutinib indefinitely, and then the three-drug combination, ibrutinib, venetoclax and obinutuzumab given for a fixed duration. You don’t take it forever, and they’re looking at progression-free survival.

One study is for younger individuals, one’s for older individuals. They have a few small differences, but that’s mainly what they’re looking at.

»MORE:Read more on FDA approvals of clinical trials

I am excited to see over the next several years how that turns out, and I’ve also treated several people in that study who were really excited to participate in it.

You have to emotionally think it’s okay to be randomized, but a lot of people thought it was fun. They were like, “Oh, great, I’m going to get one of two great things, and I don’t have to pick.” 

Metrics for these studies

When you pick a new standard, you compare standard treatment, which in this case is ibrutinib and obinutuzumab, to an investigational treatment, which is that three-drug combination.

The main goal is to determine progression-free survival: how long people are alive without leukemia and if one’s longer or shorter than the other. That’s a measure of how effective these things are.

Some studies use the overall response rate, but these drugs are so effective that they don’t really work out CLL because everyone responds to these things, which is great, by the way.

Then, when we look at the patients in the study who had high-risk features, low-risk features. Then we see how our high-risk patients did compared to high-risk patients with the other treatment. 

For ibrutinib, some people have their leukemia come back while they’re still taking it.

Determining resistance to treatment

We have some neat studies going on at our institution and some other institutions across the country, looking at how we can identify who’s developing resistance to ibrutinib before they actually get sick.

We can look at mutations in BTK, which is the protein that binds at the drug binding target. Once people develop mutations in BTK, in particular spurts, we know that the drug will stop working.

We’ve offered them clinical trials to add a second drug like venetoclax to reduce this resistance and see if we can keep the leukemia from relapsing and be healthy for longer.

The CLL Community is looking at adding a second drug to people who are on ibrutinib and doing well. Remember, I said that ibrutinib, and actually, acalabrutinib II, which is the other BTK inhibitor, changed the way the CLL cells work and behave, but it doesn’t actually kill them off.

Lots of people still have CLL floating around, which is why we think they need to keep taking those drugs. We’re wondering if people can have another drug added to it to just knock out those residual leukemia cells. That way, they can be in off-treatment remission. If you do that, then they won’t be on it long enough to get resistance ideally.

Importance of clinical trials

It’s always good to know what your standard options are, and what your clinical trial options are.

For people who haven’t taken BTK inhibitors or venetoclax, those are good standard options. For people who are resistant to both those, usually clinical trials are your best option.

You always want to know what drug is being studied, how the study is going, who’s been in it, and what your doctor expects from the study.

Misconceptions about clinical trials and “placebos”

In cancer trials, you would know there was a placebo because you have to sign a consent saying there’s a placebo. But it’s usually considered unethical to give people who need cancer treatment a placebo.

It will explain if it’s randomized and what are the treatments that you would be getting. A lot of studies, especially the ones we have, are studying very new treatments. Sometimes they’re studying the dose of the drug.

You should know exactly what drugs you’re getting. It can feel really weird but you should consider your options.

With the state of cancer research these days, we actually have a very good feeling that these drugs are going to help patients before we give them to patients. Many of them have been studied obviously in the lab using CLL cells; cell lines have been studied in animal models of CLL.

We don’t start trials with new drugs until we’re fairly confident that it will help people. I’ve seen many patients benefit from drugs that they wouldn’t be able to get just because they’re not yet approved.

If anyone’s considering it and unsure if they have someone they know in the CLL community or peer support for someone that’s been in a clinical trial, it’s always good to talk with people who have done it just because the individual benefit to doing something like that can be significant.

People always tell me, “Oh, I feel like I’m your guinea pig.” I’m like, “Oh, you should be so lucky to be my Guinea pig, you know what that thing’s lifestyle is?” I was like, “My personal guinea pig is not an experimental animal. It’s my pet, has a super nice lifestyle. People would love to be my guinea pig.” 

But really, people aren’t guinea pigs as much as you think. If you’re considering a research study, make sure you get to ask all the questions about what the drug is and why being in this study might benefit you or others, and your doctor should be able to answer those questions for you.

Up and Coming New Treatments

CAR T cell therapy

CAR T-cell is exciting. It’s still investigational for CLL, but I’ve seen it help a subset of patients, especially those that are resistant to these drugs I’ve been talking about. It can be very powerful for select people, but it is a hassle to do, and it is still investigational.

For people who have very good, other treatment choices, it’s usually not something we run to as a first treatment or even a second treatment. But it can be great for people that need that.

Reversible BTK inhibitors

The things that I’m excited about are some drugs that are hopefully going to move up to benefit more patients. We’re always trying to make treatment safer, more effective.

There’s reversible BTK inhibitors. Ibrutinib and acalabrutinib bind BTK at the same site and bind it irreversibly, meaning forever.

Reversible BTK inhibitors bind at different sites than the two approved ones and bind and unbind BTK, which seems to limit some of the side effects.

Also, for some reason, these drugs can work in people who are resistant to the BTK inhibitors, which you expect ’cause they bind to it at a different site but can work in people resistant to BTK inhibitors and Venetoclax. They seem to be very well tolerated.

A reversible BTK inhibitor such as LOXO-305 (pirtobrutinib) is now under study. LOXO-305 is the one that’s the furthest in development, and they just gave it a direct name.

It’s just exciting when I go to professional meetings to see what new types of drugs are being developed in CLL or things like cyclin-dependent kinase inhibitors that are coming back into play. These drugs, either alone or in combination, are likely to benefit patients.

Again, we keep moving the mark more and more towards safe, highly effective treatment, and it just keeps getting better.

New drugs with new mechanisms, drugs with the same mechanism but in a different way—these are the way we move the mark in CLL.

It seems to have fewer side effects, not no side effects. Anyone that tells you there’s are no side effects is lying. You never get anything for free or don’t do anything. But, that, and also because the mechanism is different from the irreversible BTK inhibitors, it can be used in resistance.

If someone takes ibrutnib until their leukemia comes back while they’re taking it, taking acalabrutinib isn’t going to work because they have the same mechanism. But taking a drug that binds the same protein but with a different way of doing it can work after your resistance.

This allows people to take two BTK inhibitors before moving on to a drug like Venetoclax or other treatment options. They’re just really effective, especially in people with really resistant CLL. It’s not just that there are fewer side effects, but also they seem to work great, which is awesome.

Treatments for Hairy Cell Leukemia (HCL)

Hairy cell leukemia vs. chronic lymphocytic leukemia

I love talking about hairy cell leukemia, which is another chronic B-cell leukemia. It also has very long survival rates, but it has some different features than CLL.

Unlike CLL, it’s very rare. It’s not very common to have people diagnosed with hairy cell leukemia.

HCL Treatments
Purine analogue chemotherapy

Over the last couple of decades, purine analogue chemotherapy was developed for hairy cell, and it’s actually spectacularly effective for the majority of patients.

People can take a single course of purine analogues and be in remission for decades sometimes. But there’s a group of hairy cell leukemia patients who don’t get decades of remission from purine analogues, or aren’t able to take them for other reasons such as side effects.

New drugs (cladribine, pentostatin, vemurafenib)

The hairy cell community has been working on new drugs for this group of hairy cell leukemia patients who aren’t expected to benefit from purine analogues like cladribine or pentostatin.

There are a couple of drugs in this area that are available and FDA-approved for people. But vemurafenib, which is not approved for hairy cell leukemia, has been very well studied. It can be used in people with hairy cell leukemia with a BRAF mutation which is found in the majority of people with classic hairy cell leukemia.

But there’s still a need for new drugs for this group of patients as those drugs don’t cover everybody.

We have actually conducted a phase two study of ibrutinib. It’s been FDA-approved for four different cancers. We’ve studied it in hairy cell leukemia, in a group of patients who aren’t expected to benefit from purine analogues.

People who have been previously treated or people with a variant of hairy cell leukemia have been found to have a very long progression-free survival. Around 73% of people are alive for three years without their leukemia returning. 

The response rates don’t look quite as high, but that’s probably the response criteria we were using. You can really see how many people benefited by looking at progression-free survival.

It’s definitely a really important treatment option for people with this rare leukemia that aren’t expected to benefit from therapies like Purine analogues.

I think we published those results in a journal called Blood recently so that other doctors could find them and think about using that for their patients with a hairy cell that might need something beyond purine analogues.

Prognosis and findings so far

The prognosis for hairy cell, in general, is quite good. Most people can expect to finish their natural life span. Some people die of infection and rarely will someone die of leukemia. 

Before purine analogues, survival was actually expected to be a couple of years, and not a couple of decades. When people don’t benefit from purine analogues, usually, they take more treatments, and their lifespan can be shortened by this. It’s still possible depending on what treatments you get to live for years.

It’s not like people had a very, very short survival, but certainly not the decades you’d expect from people that really get a lot of benefit from purine analogues, and other treatments like vemurafenib which is usually given for a fixed duration. Their relapse-free survival, or roughly how long it is before the leukemia returns in the majority of patients, is less than two years.

With this ibrutnib study, people are still alive without their leukemia returning for three years. Almost three-quarters of them are really quite good.

The study has been open since 2013. Some people have been in it a really long time, and I look forward to continuing to see how it benefits those patients. Some people are obviously quite sick and had taken 8 or 10 treatments before being in the study and probably wouldn’t be doing very well if they hadn’t been in a research study.

It’s also a nice example of how participating in a clinical trial can benefit people, because folks with hairy cell leukemia would not have had access to this if they didn’t decide to be in a research study.


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Categories
Calquence (acalabrutinib) CAR T-Cell Therapy Caregivers CLL Hematology Ibrutinib (Imbruvica) Leukemia & Lymphoma Oncologist Venetoclax Zydelig (idelalisib)

Dr. Tim Fenske

Tim Fenske, M.D., M.S.

Chronic Lymphocytic Leukemia (CLL) Treatment

Dr. Tim Fenske is a hematologist-oncologist who specializes in cancers like lymphoma, leukemia, and CLL/SLL (chronic lymphocytic leukemia/small lymphocytic lymphoma). In this interview with The Patient Story, Dr. Fenske describes the basics of CLL and latest treatment options, including immunotherapy and targeted therapy.

  • Name: Tim Fenske, M.D., M.S.
  • Role: Professor, Medical Oncologist, Researcher
  • Experience: ~15 years
  • Hematology/Medical Oncology
    • Cancer Center – Froedtert Hospital, Moorland Reserve Health Center
  • Associate Professor
    • Medical College of Wisconsin
  • Fellowship
    • Hematology/Oncology – Washington University – St. Louis, MO (2002-2005)
  • Approach with patients: Education & including patient perspective

Patients who are nervous about a clinical trial typically say things like, “I don’t want to be a guinea pig.” The thing is, that’s not really the case. In most trials, you will not be the first person to have taken a drug. There are very few scenarios in which the patient would be the first.

Tim Fenske, MD, MS



Introduction & CLL Basics

Can you introduce yourself?

My name is Tim Fenske. I am a part of the faculty at the medical college at Wisconsin University in Milwaukee where I’ve been practicing for about 14 years. My practice is focused on lymphoma (Hodgkin’s, non-Hodgkin’s) and leukemia.

I came to medicine from the research side of things. I had spent several years doing lab research and became very fascinated with the immune system and the idea of bone marrow and stem cell transplants as well as immunotherapy as ways to treat cancer. That’s how I got interested in this field.

Then, after all the years of training, residency, and fellowship, I ended up as a specialist in blood cancers with my research area being more focused on clinical trials and testing new agents.

What is CLL? Is it leukemia or lymphoma?

With CLL, they actually call it CLL/SLL. That’s a way to make the distinction that it can present in different ways. There’s a leukemic presentation where there are a lot of cells in the blood, and then with SLL it’s more of a lymphoma where they have enlarged lymph nodes and not a lot of cells in the blood.

The distinction for CLL is a certain number of cells in the blood. You can have enlarged lymph nodes with CLL, but if you just have the lymph nodes and not so much the cells in the blood, that’s gonna be called SLL. The cells themselves look the same. The diseases are the same. It just has more to do with where the cells are living.

»MORE: Learn more about CLL →

What is the difference between leukemia and lymphoma?

The short answer is leukemia means you have cancer cells circulating in the blood. Lymphoma is when you tend to have the cells in lymph nodes or other organs that are part of the blood system like the spleen.

There are, of course, exceptions. You can see lymphoma show up in just about any organ. Leukemia can present as almost like tumors in the blood.

The most common scenario is that leukemia is circulating in the blood and there are detectable cancer cells in the blood. Whereas a straight lymphoma is when the cells aren’t so much detectable in the blood, but they’re in the lymph nodes.

Testing & Treatment

What determines when someone with CLL will get treatment?

In many cases you can wait. We check a lot of biomarkers and run a lot of tests on patients when they’re first diagnosed. We run chromosome tests, protein stains, mutation analyses, and things like that. Those things are useful for predicting prognosis.

Within patients with CLL, there are some who have a more aggressive form of the disease and can’t do watch and wait very long. There are others who won’t get treatment until five or 10 years after they were diagnosed.

These biomarkers are reasonably good at predicting whose disease is going to be a slow mover versus a fast mover, but they don’t actually tell us who needs treatment at that moment. These biomarkers are more for giving us an overall idea of how the disease is going to go: fast or slow.

The actual decision to treat or not treat is based on more basic things like whether or not the patient is anemic or has a low platelet count. Other symptoms might include fevers, drenching sweats, weight loss, extreme fatigue, or pain from enlarged lymph nodes.

Those kinds of things would influence a decision of whether to treat or wait.

What are some of those biomarker tests?

There’s something they do on the immunoglobulin gene called a gene mutation analysis. That’s a little confusing. The normal counterpart cells that CLL cells come from are called lymphocytes.

Those cells go through a normal maturation process as part of the immune system. In that process, there’s a normal mutation process that happens.

A cell that’s further along in the B cell development pathway will have these mutations, and a cell that’s not as far along won’t have those mutations.

It’s a way of assessing how far down the B cell development pathway that cell got before it turned into a CLL cell. It’s not a mutation that drove the cell to be cancerous. Those are different.

Immunoglobulin mutation analysis has been a good way to cluster patients. If they’re mutated, they have a better prognosis as it turns out. If they’re unmutated, those cases tend to be a little harder.

Then there’s a panel we do called a fish panel. It looks for structural abnormalities in the chromosomes of CLL cells. One of the things we look for is chromosome 17p. That’s where the p53 gene resides. If that is deleted, that’s been shown to be associated with a less favorable prognosis in CLL.

If you have a deletion of part of chromosome 13 and that’s the only abnormality, those cases actually do better than normal. There’s another abnormality they look for in chromosome 11. That’s associated with adverse prognosis as well. So, the fish panel is another way to risk-stratify patients. It doesn’t necessarily influence the treatment, but it tells us what risks there are.

Why do genetic testing if it doesn’t influence treatment?

Some of those studies like with p53 and others, a lot of that data was generated years ago using treatments that were not as good as what we have now. It’ll be interesting to see if those risk assessments will still hold up nowadays with some of the new treatments. We’ll see. What used to be a really high-risk group may not be as bad as it used to be.

Newer Options

Can you talk about some of the new treatments?

Chemotherapy drugs are small drugs that block something that any dividing cell has to do, so that would be how it copies its DNA, unwinds its DNA, how one big cell physically separates into two smaller cells. All the proteins and enzymes that makes that machinery work, those are the things that chemotherapy blocks. 

Rituxan is a big antibody molecule that’s much larger than a chemotherapy drug. It sticks on the outside of the cell, and it flags it to your immune system in a number of ways.

Then you’ve got these newer, more targeted agents like Ibrutinib, Venetoclax, Acalbrutinib, Idelalisib, and many others in development. These are smaller drug molecules that go inside the cells. Instead of blocking something that any cell has to do, they tend to be more selective. They target enzymes that are more active in CLL cells.

We’re in this new era where we have these novel or targeted agents. That really started about 10 years ago with Ibrutinib and more recently we’ve had Venetoclax. Before that, we really only had chemotherapy and Rituxan, which is more of an immunotherapy drug.

Ibrutinib

Ibrutinib blocks an enzyme called bruton’s tyrosine kinase or BTK. This is an enzyme that does play a role in normal B cells, but it’s a very important enzyme in CLL cells, too.

You don’t get all the same chemotherapy side effects. It’s a highly effective way of treated CLL. It does still have possible side effects, but it does a good job.

Venetoclax

Venetoclax works in a different way. It works on a pathway of proteins. When you have cancer, the problem can be that the cells are growing too much or that they don’t die when they’re supposed to die. CLL, in large part, sees cells not dying when they’re supposed to, so they’re accumulating. Venetoclax blocks a protein and turns a death signal back on in the cells, triggering apoptosis. That’s just a fancy term for programmed cell death. It restores the cell’s ability to die.

Idelalisib

Then you’ve got this other class of drugs called PI3 kinase inhibitors like Idelalisib. It blocks a different enzyme in the cell.

Acalabrutinib

Recently, we’re seeing second and third drugs in each of these categories. So, at first we had Ibrutinib, and now we also have Acalabrutinib. It isn’t technically approved for CLL yet, but it’s probably going to be approved in the coming year. It seems to be more selective for BTK than Ibrutinib. We believe that some of the side effects from Ibrutininb are due to what we call “off-target effects,” so in theory, Acalabrutinib might have a more favorable side effect profile.

What is the difference in side effects with these drugs versus chemotherapy?

You don’t lose your hair, typically you don’t have as big of a drop in blood counts, and in general you don’t see nausea and vomiting. So, with these targeted agents, you don’t have typical chemo side effects, but they can still have side effects.

For example, Ibrutinib can cause rashes, diarrhea, heart rhythm disruptions, muscle and joint aches, and things like that. About 20% of people wind up having to come off of these drugs because of some side effects. It really depends on the person.

Do you see chemotherapy becoming a thing of the past?

Targeted agents are definitely where the field has moved. For several years there was a debate about which patients should still get chemo.

Really, in the last year based on some recent studies, most experts in the field agree that there’s very little if any role for conventional chemotherapy in the frontline for CLL.

Maybe in the third or fourth line, you might start to think of some chemo. It’s going to be very rarely used moving forward.

There are some newer immune therapies like CAR-T cell therapy that are on the rise too. We never really did a whole lot of stem cell transplants for CLL, but we used to do some. Those numbers are going down. We still get an occasional patient where it makes sense, but that’s not very often.

When is CAR-T cell therapy a viable option for a CLL patient?

It’s not approved as a treatment for CLL yet. It’s something that would be done in the context of a clinical trial. That being said, there are three main classes of targeted agents. There are BTK inhibitors like Ibrutinib or Acalabrutinib. There’s Venetoclax. Then there’s the PI3 kinase inhibitors like Idelalisib.

If somebody has had all three of those classes and they’re still having problems with their CLL, that’s somebody we should be thinking about putting in a CAR-T trial.

Other Advice

How do you handle patients who have questions about holistic or alternative treatments?

In the old days, the doctor told the patient what to do, and the patient did it no questions asked. Doctors these days try to be more collaborative and take the patient’s perspective into account. That can be kind of tricky when the patient is bringing in all sorts of things they read on the internet.

As a doctor, you want to be respectful of the fact that it was important enough to the patient that they brought it up, but at the same time, a lot of these things don’t have nearly enough scientific evidence for us to recommend them.

Diets, supplements, fasting, and things like that are brought up a lot. We don’t have enough good scientific data to support a lot of that.

It’s not to say that those things are worthless; it’s just that we don’t have enough data.

Diet is a big one. For every one special diet that someone is touting, there are hundreds of others saying the same thing. All we can do is give people generalizations of healthy diet, exercise, stress management, support systems, good sleep, and all these things people know to be doing anyways.

I think some patients get frustrated because they just want some simple answers and things they can do. I try to walk through that with them. If a patient is really set on a certain supplement or something, I have our pharmacists look at it and make sure there’s nothing harmful that would interact with their other treatment.

I make sure it would be safe for them to take, and then I’ll tell them as far as I know, it’s okay for them to take it, but we can’t always know for sure how something is going to affect them.

Do you have any advice on clinical trials?

A lot of patients are not very well informed about clinical trials. It’s on the doctor to educate them.

Many people seem to think that trials are a last resort after there’s nothing left for them to try. That’s not true.

There are all different kinds of trials. There are phase 1 trials which means you could be getting a really new drug. Ibrutinib, Venetoclax, and all our new drugs were a phase 1 trial at some point. If patients hadn’t signed up for those trials, those drugs wouldn’t have made it to market. Those patients’ willingness has helped a lot of people.

Then you have trials where we’re testing out how we use drugs and maybe using them in a new combination. It really depends on where a patient is in their disease.

Patients who are nervous about a clinical trial typically say things like, “I don’t want to be a guinea pig.” The thing is, that’s not really the case. In most trials, you will not be the first person to have taken a drug. There are very few scenarios in which the patient would be the first. Like I said, many trials are looking at drugs that have already been approved and just tweaking how we use them.

Getting the word out about being involved in clinical trials is important because it not only pushes the field forward, but it also could give patients access to cutting edge therapies a little sooner.

Do you have any advice for newly diagnosed patients?

First of all, try to understand your disease as well as you can. A lot of people think leukemia is just one thing or lymphoma is just Hodgkin’s or non-Hodgkin’s. Within non-Hodgkin’s, there are about 50 different kinds.

So make sure you understand your disease process and how it’s normally managed so they have an idea of what to expect.

If a patient has something that’s less common, it never hurts to get a second opinion from a specialist who sees more of that disease. We have people who live in more rural areas and don’t want to drive two or three hours when they want treatment.

I understand that, but they could see that specialist every once in a while in addition to their local doctor. That specialist can collaborate with their local oncologist in many cases.


Thank you Dr. Fenske!


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Provider: Northwell Health (NYC)
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Oncologist: Specializing in myeloma and other blood and bone disorders
Experience: 35+ years
Institution: Berenson Cancer Center
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Categories
Calquence (acalabrutinib) CAR T-Cell Therapy CLL Hematology Ibrutinib (Imbruvica) Medical Experts Northwell Health Cancer Institute Obinutuzumab Oncologist rituximab (Rituxan) Venetoclax

Dr. Jacqueline Barrientos

Jacqueline Barrientos, MD

CLL Treatment

Hear from experienced CLL specialist, Dr. Jacqueline Barrientos, who talks through what CLL is, treatment options, and the trend of drug research.

  • Name: Jacqueline Barrientos, M.D.
  • Role:
    • Associate Professor, Oncology Research
      • Feinstein Institutes for Medical Research
    • Associate Professor, Division of Hematology and Medical Oncology
      • Northwell Health
    • Principal investigator
  • Experience: ~15 years
    • Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY
    • Clinical Fellow
    • Associate Professor, Karches Center for Oncology Research, Feinstein Institutes for Medical Research
    • Associate Professor, Division of Hematology and Medical Oncology, Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell
  • Approach with patients: Finding the therapy that gives the best outcomes and quality of life

Many times, people don’t really want to know about it and just want to listen to their doctors. The field is changing so quickly that I think the most important thing you can do is to be an advocate for yourself.



Introduction

Can you introduce yourself

My name is Jacqueline Barrientos. I’m an associate professor of medicine at the Zucker School of Medicine in New York on Long Island. I work at the Northwell Health Cancer Institute’s CLL Research and Treatment Program.

Why did you get into oncology

We are making so many advances so quickly. I went into oncology because I think that chemotherapy will be a thing of the past for many cancers and especially in the blood.

If you know what is driving the cancer, then you can just target that driving factor, and you don’t have to affect the other healthy tissues. It’s amazing what we’ve been able to accomplish in the last 10 years.

People who had a very difficult cancer to treat can now just take a pill and go on with their life and not even have to spend hours getting an infusion.

It’s just amazing to see it, and it’s very rewarding to see patients living longer lives and have very small side effect profiles from these new drugs.

What is CLL

Is CLL leukemia or lymphoma

The disease has its two components. It’s called chronic lymphocytic leukemia because it has two parts. On one hand, there’s the blood cancer part. It’s a disease of the blood. That’s the leukemia.

On the other hand, you have enlarged lymph nodes. The way that these cancer cells live and proliferate is by going to the lymph nodes. Once they grow in the lymph nodes, then they go back out into the blood.

Some patients present with only the enlarged lymph nodes and no evidence of leukemia in their blood. Those people are called SLL patients, which is like a sub-sub-type. They present a little differently, but it’s the same disease.

»MORE:  Learn more about CLL→

CLL Treatment (2020)

Why is it important to see a specialist

It’s very important to see a specialist when you’re dealing with CLL to ensure that the physicians can make decisions based on a patient’s markers. 

What are important genetic markers to test for

There’s a marker called 17p deletion. That’s a very bad mutation. It not only tells you that the disease will be more aggressive, but it also does not respond to chemotherapy. Even new targeted therapies that are now being used still see these patients relapsing fairly quickly. 

Less than 10-percent of patients will have 17p deletion at the time of diagnosis, but over time, people can develop it. It’s kind of like clonal selection. Because the therapy is not curative, the cancer tries to come back, and when it does, it becomes more aggressive over time.

That’s why some patients stop responding to the treatment. One of the reasons a patient may stop responding to the drug is because their cancer can actually develop a mutation to it. 

There’s another group of people. 90-percent of patients don’t have 17p. What do we do with them? It all depends on other markers. 

Another important marker is called IgHV mutation status. This is a gene mutation of the heavy chain of immunoglobulin. There’s a test that’s not widely used, but we use it here. As a patient, I would want to know my status. You can be either mutated or unmutated.

Mutated patients usually have a very slow-growing disease, and on average, they don’t require therapy for the first eight years after their diagnosis.

If you are not mutated, most people require therapy within the first three years. It’s more aggressive. When treated with chemo, these are the patients that will have a shorter time in remission compared to mutated patients.

With mutated patients, you can give them chemo and immunotherapy, and more than 10 years later, they will still be in remission. You can essentially “cure” them.

When does a CLL patient need to start treatment?

The majority of patients present with abnormal blood counts. The normal maximum number for white blood cell counts is 10,000. Many patients present with 20 or 30. Over time this number can increase to even 40, 60, or 100. There is no magic number at which we decide to start therapy.

We monitor and when patients show symptoms like anemia, low platelets or painful enlarged lymph nodes, then we’ll start therapy.

Usually, enlarged lymph nodes are cosmetic. You may notice them because they’re there, but if they don’t cause pain, we won’t usually start therapy because the treatments can often have more toxicities than the disease itself. 

How does a specialist decide on a course of treatment?

If a patient has the 17p deletion marker, they need to be on a targeted agent like ibrutinib, which is a Bruton’s tyrosine kinase (BTK) inhibitor.

It doesn’t kill the cells, but it tells them to stop surviving and proliferating so eventually the cells start to die, but it doesn’t work immediately. You have to take the drug every day. 

We just published some data comparing that drug against the best chemo regimen. The big winner was ibrutinib. Even in younger people, the best therapy is a targeted agent. Not only in patients with 17p, but with other markers as well. 

For unmutated patients, we stay away from chemotherapy.

We only do targeted agents. Right now, category guidelines in the United States say to give you ibrutinib. It is frontline for young people and older people. 

New Drug Research

What research is being done on ibrutinib?

There have been attempts to improve the outcomes of ibrutinib because it’s a wonderful drug. The problem is that it’s a drug you take forever, so of course, you can develop side effects.

One common side effect is high blood pressure, so you can also wind up having to take an anti-hypertensive. The other side effect you can have with Ibrutinib is joint pain. Even if you’re young, it can be debilitating for you.

There are other drugs that are like second generation Ibrutinib that are being tested against it that we have found may have less toxicity as far as joint pain. One such drug is called acalabrutinib.

It’s only approved for mantle cell lymphoma right now (start of 2020), but it has been announced that it met a primary end point against chemotherapy in terms of refractory disease, so at some point this year it will be approved for CLL as well. 

Is acalabrutinib the only drug for CLL working through a clinical trial or are there more?

There’s another one called venetoclax. Venetoclax is a BCL-2 inhibitor. It’s very different than ibrutinib and acalabrutinib. It’s an apoptotic drug. Apoptosis is the process by which your cells die.

What it does is once it’s in your body, it tells your cells to die. The main problem people have had is tumor lysis syndrome. That is a medical term for when your counts of cells drop so quickly, that it overwhelmed your kidney and renal function. Patients will wind up needing support because their potassium can go up really high or they will need fluids.

In order to minimize the toxicity, we start patients off with a small dose of 20mg. Then they will go to 60mg a week later. Then 100, 200, and 400. Over a process of five weeks, you end up getting to the target of 400mg.

The drug used to only be approved for 17p deletion patients. Recently, it was approved for use in combination with rituximab, a monoclonal antibody, for people with relapsed disease. Now, based on new research from the Germans, it’s been approved for frontline in combination with obinutuzumab for anyone over 65. 

The beauty of that combination is that you only have to take it for a year, and four out of five patients will still be in remission two years later. Plus, it’s not chemo.

What usually happens with approvals is they start with relapsed/refractory, then older people or 17p deletion, and then they approve a drug or combination for everyone. 

Are stem cell transplants a viable treatment option for CLL patients?

The problem is that the drugs we have for CLL are so good, and the toxicities from a stem cell transplant are so high. We use it only as a last resort.

There’s another type of therapy in clinical development right now called CAR T cell therapy, and it’s really interesting. Your T-cells have the important job of fighting infection.

What they do is they take out your T cells, re-engineer them to recognize leukemia cells, put them back into the patient, and the T cells expand. Now you have an army of T cells who can attack the CLL. 

By itself, it really didn’t have good outcomes. When you combine it with ibrutinib, it’s another therapy that works really well. It’s just one more therapy that people are thinking might be better than stem cell transplants. Even though it’s risky, it’s something I would do before I did a transplant. 

With transplants, you might be dealing with chronic graft vs. host disease, some skin issues, GI tract problems, or eye problems. There are a lot of things that can go wrong.

Sure, you can be alive, but it’s not a good way to live. With lots of these drugs we have now, many people can live a normal life and practically forget they have CLL. 

Are these new treatments safer than chemotherapy in terms of risk for infections?

With ibrutinib, we’ve seen a little bit of neutropenia, but it’s usually later on rather than right up front. It doesn’t correlate with high rates of infection at this time. There have been some reports of severe fungal infections, but it’s in patients that have a high use of steroids.

It’s important to not take steroids with ibrutinib. 

With Venetoclax, it can cause neutropenia. What we do sometimes is sometimes we cut down the dose to 200mg and still see the same clinical activity as we would with the 400mg. 

There are some people who are young whom I see. If they don’t have any issues or fevers, I don’t do anything even though they live with the chronic neutropenia. It’s a different kind of neutropenia than you would experience with traditional chemotherapy approaches.

Many of these new drugs can cause neutropenia, but the rate of infection is not higher than what we would expect from other drugs. The rate of severe infections is around 15-percent rather than 50-percent with chemotherapy. 

Final Words of Advice

In your mind, what would have to happen to find a cure?

We’re working towards a cure. We’re working on new targets. The problem is that it’s a blood disorder, and your blood is everywhere. Sometimes, the CLL is able to hide in some special places. All it takes is one tumor cell to come back and reproduce.

We’re working towards eradicating minimal residual disease (MRD). Many of these drugs have improved these outcomes, but we’re still not at 100-percent.

We can achieve complete remission, but not MRD negativity. By that I mean there’s no evidence of the disease, but there’s still at least one cell hiding somewhere in the blood. We have to find a target.

We’re looking for another one. Right now, we have a couple. One is B cell receptor inhibition. The other is DIABLO process pathway. There are a couple of new targets in clinical development. 

When I started in the field, people with 17p deletion only had on average two years of life left. Now, these people are living a decade longer. It’s amazing to see that. 

What advice do you have for someone who was just diagnosed with CLL?

The most important thing is you need to educate yourself. It is very life-changing. You’re going to live with this for the rest of your life. Many times, people don’t really want to know about it and just want to listen to their doctors.

The field is changing so quickly that I think the most important thing you can do is to be an advocate for yourself.

We did a registry just to see how doctors were testing markers. Less than a third of doctors within the community and even academic centers were testing for 17p deletion or igHV mutation.

It’s really sad because many of these patients who are getting chemo shouldn’t be getting chemo. 

If they are unmutated or have 17p deletion, chemotherapy will not work for them. It’s very important to educate yourself so you know if something doesn’t feel right. 

Go get the second and third opinions. In some cases where you are not like your typical patient, your doctor might not have seen some toxicity or side effect before and won’t know what to do, but maybe some different doctor has seen it before and knows what to do.

It’s always good to feel comfortable with your doctor and not be afraid to ask questions. 


Thank you Dr. Barrientos!


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