Minimal Residual Disease (MRD): What Does it Mean for You?

Minimal Residual Disease (MRD): What Does it Mean for You? from Patient Empowerment Network on Vimeo

Dr. Matthew Davids defines the term minimal residual disease (MRD) and explains its role in managing chronic lymphocytic leukemia (CLL).

Dr. Matthew Davids is the Associate Director of the CLL Center at Dana-Farber Cancer Institute. More about this expert.

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Dr. Matthew Davids

So, one term that patients often come across when they’re looking online that they might not know exactly what it means is so-called MRD. This stands for minimal residual disease.

And MRD is increasingly becoming an important endpoint in our trials, meaning that it’s a test that we rely on to try to make decisions about treatment in the trials. And we’re hoping that this will be a strategy that we can eventually use in regular clinical practice.

So, what is MRD? Basically, MRD is a way to look, at a very, very molecular level, at tiny, tiny amounts of the disease. And this a feature of the fact that we have very effective treatments for CLL, and so we can give various treatments, whether it’s chemoimmunotherapy or drugs like venetoclax, for example. And then we can look under the microscope in, for example, the bone marrow tissue, and we might not see any CLL cells. So, we might call that a complete remission.

But often, there’s still evidence of molecular disease left behind that we can’t see under the microscope, but we can use very sophisticated biological techniques to actually detect what we call MRD. And we find that, if there is MRD present, that patients don’t tend to have as durable of a remission compared to when MRD is so-called undetectable.

So, it’s a very important term to understand. When patients get to an undetectable MRD state, that’s a very good thing. It means that they’re likely to have a very long response to whatever therapy they had. But you also have to remember that MRD itself has its limits of what it can detect. And so, just being undetectable for MRD does not mean that you’re necessarily cured of the CLL.

And there are patients who have undetectable MRD who later do have a recurrence of the CLL. But it does help us guide the treatment in terms of knowing that patients are in a good remission, that they may be able to stop the treatment that they’re on and enjoy a long response without the need for ongoing treatment.

But eventually, for most CLL patients, the disease will come back. And we can detect that sometimes with this MRD test as well. And that’s an interesting research question ongoing as to whether we should intervene at that point to restart therapy when we first see the MRD test become positive again. And hopefully, that’s something that we’ll continue to learn about as we further explore that question in clinical trials.

Chronic Lymphocytic Leukemia (CLL) Defined

Chronic Lymphocytic Leukemia (CLL) Defined from Patient Empowerment Network on Vimeo.

What is CLL? Dr. Brian Hill defines chronic lymphocytic leukemia (CLL) and explains how it differs from small lymphocytic lymphoma (SLL).

Dr. Brian Hill is the Director of the Lymphoid Malignancies Program at Cleveland Clinic. More about this expert.

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Dr. Brian Hill:

So, chronic lymphocytic leukemia is a term that refers to a cancerous condition in which the abnormal or cancerous white blood cells are a type of B-cells with certain characteristics that are present above a certain threshold in the blood. Those same cancer cells can also grow and divide and set up shop in other organs besides the blood and bone marrow.

And that can be a lymph node, spleen and sometimes we find the exact same type of cell in a lymph node or other parts of the body. And we don’t find it in large quantities enough in the blood. And when that happens, we call it small lymphocytic lymphoma or SLL. So, people get very confused by the terminology, “Do I have leukemia, or do I have lymphoma.” And so, a lot of times there’s a reference to a condition called CLL-SLL. CLL-SLL really is one disease.

And the term leukemia or lymphoma really just refers to where is the predominant location for the abnormal cancer B-cells. Are they in the blood or are they in the tissue?

If it’s in the blood, mostly above 5,000 cells per microliter, that’s the cut off. If it’s in the blood predominantly, it’s CLL. But if those same cells are in the lymph nodes or the spleen but not above that threshold of 5,000 in the blood, then the term is small lymphocytic lymphoma. And often times that diagnosis made from a tissue biopsy or a lymph node biopsy rather through a blood test or a bone marrow biopsy. Really, these are the same disease. And even physicians who don’t practice in this area get confused about it.

And it’s important to know that they can be treated exactly the same and are interchangeable. Rarely I’ve seen a mistake be made that someone who has a diagnosis of SLL or small lymphocytic lymphoma is treated with the types of chemotherapy drugs that we would typically use for indolent forms of lymphoma.

And some of those therapies overlap. So, there are biologic similarities and clinical similarities between B-cell lymphomas and CLL-SLL for sure. But there is a lot of nuance in B-cell lymphomas, and not every single treatment that works really well for B-cell lymphoma should be used in CLL or SLL.

Not to Worry! Your Guide to Watch and Wait

Not to Worry! Your Guide to Watch and Wait from Patient Empowerment Network on Vimeo.

 Watch and wait, or active surveillance, often feels like watch and worry to CLL patients. Dr. Brian Hill provides a comprehensive guide to the period of time before CLL treatment begins and shares approaches for managing anxiety.

Dr. Brian Hill is the Director of the Lymphoid Malignancies Program at Cleveland Clinic. More about this expert.

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Dr. Brian Hill:

So, watch and wait is the term that’s referred to for not actively treating a patient with CLL after the diagnosis. As many people probably out there watching know, the diagnosis of CLL is often made incidentally or accidentally through routine laboratory tests that are done for some other reason.

Maybe they are going to have surgery. Or maybe they are going to have just a primary care checkup. And blood count shows too many white blood cells. And everything else is fine. The patient feels normal. There’s no symptom. But it leads to a referral usually to a hematologist who then does more testing and makes a diagnosis of chronic lymphocytic leukemia. The word leukemia is very scary because it often conjures up images of acute leukemia which is a disease that can make people very sick very quickly.

We’re taught in much of medicine and in much of cancer that early diagnosis and early treatment is very important. And it is very important for many conditions – breast cancer or we’re taught let’s get our mammograms.

And have an early detection and immediate treatment to cure the breast cancer. Similarly, colon cancer – get your colonoscopy, get your diagnosis sooner rather than later. And have surgery so you can have a higher likelihood of a cure. In the case of chronic lymphocytic leukemia, it’s never been shown despite multiple attempts over many decades, that treating someone with CLL is – earlier, is going to impact the outcomes and the big picture. But we do know that treating CLL earlier can lead to more side effects earlier.

So, in other words, if you feel fine and your blood counts are just a little abnormal, and there’s not compelling indication to treat, we can safely observe patients until an indication for treatment exists. And what I tell patients is that if we treat today, the treatment will work.

If we treat tomorrow, the treatment will work. And if we treat in five years, the treatment will work. So, there’s – we have very good evidence that delaying treatment until you need it does not compromise the likelihood of the treatment working. So, it’s a little bit of a different mindset from other types of cancer where we are taught to treat early and immediately. So, a lot of times people will call it watch and worry instead of watch and wait, and there’s a lot of anxiety about that.

Again, their diagnosis has the word leukemia in it. It can be a very scary time. And it takes a little bit of trust to be convinced that you don’t need to be treated just because you have it. And that’s often times when we do get second opinions if the first hematologist/oncologist says it’s okay to watch it and wait. We don’t need to treat. A lot of the time people then seek another opinion to confirm that’s accurate. And in most cases – I would say 90% of the time when I’ve had a second opinion for a patient who’s been recommended to watch and wait, I typically concur with that recommendation.

So, during watchful waiting or – I like to call it active surveillance because it’s not that we aren’t doing anything, we are surveilling or monitoring. And the two things that we monitor are symptoms and blood counts. So, it sort of begs the question that many people ask which is, “If you are not going to treat me now, when will you treat me? When will I need to be treated?” And the first indication – the first thing we look at is symptoms. So, if you have symptoms of significant fatigue to the point where you are really having a difficult time functioning.

Or if you have drenching night sweats that wake you up from night and make you change your nightclothes. Those type of symptoms would push us to treat. So, those are the things that are being asked of patients at their regular follow up which is usually every two or three months initially.

And sometimes can be spaced out to every four to six months if things are stable. But usually during the first year you want to be checking on folks every two to three months. Weight loss would be another symptom to look out for – sort of unintentional weight loss. The other thing we monitor is the blood counts. So, with a simple CBC or complete blood count, we can see what is happening with the white blood cell count which may and often goes up.

And a lot of folks focus on the white blood cell count and its trajectory and how that is rising. Some people’s white blood cell count can fluctuate. Others can stay relatively flat. And some people do have a continued rise on the white blood cell count. The white blood cell count in and of itself is not the final reason to recommend treatment.

But with time, as the white blood cell count goes up, we sometimes see the other numbers going down. And actually, the other numbers going down are the ones that are more important. Those numbers are – the red blood cell count measurement which is usually measured by hemoglobin concentration or hematocrit. And then the other is the platelet number. So, if either the hemoglobin or the platelet number gets below threshold, those are typically indications for treatment.

So, during this period of observation or active surveillance – watchful waiting, whatever term you choose. This can go on for years.

And it can be associated with anxiety. So, trying to do things to cope with managing anxiety is important. Other things that many people are interested in are – is diet. So, do we know of a particular food or food group that we should focus on? Or is there something we should avoid? And the short answer to that is that many – it’s a difficult topic to study. As you might imagine, diet can be so varied around people. And in a typical week the average person eats so many different types of foods that it’s difficult to focus in on one particular thing.

What we can say is that in general for health, clearly fresh fruits and vegetables are the best source of nutrition. And also, are best for your health.

Avoiding processed foods and processed meats and other foods that are high in saturated fats is probably important in general for your health. Although we can’t say specifically that it’s definitely going to make an impact in the white blood cell count or the trajectory of the CLL. In terms of supplements and natural products, many people are interested in this topic. And again, it is a difficult one to study. Some of the natural products out there are purified forms of things from plants and other ingestible herbs and so forth.

But the problem is, is that if you take any component – even if it’s natural occurring, take it in large quantities it can lead to other problems. There was a well-known study from – that studied the impact of green tea extract on the white blood cell count.

And if you took large quantities of green tea extract, it seemed as if it did sort of lower the white blood cell count a little bit. But some people also had abnormalities of their liver function as a result. So, I don’t recommend green tea extract. And I instead say, “If you like tea and you want to drink green tea, I think that’s probably fine.” But I wouldn’t do it in excess. And just maybe try to incorporate it into a balance diet otherwise.

Overwhelmed By a CLL Diagnosis? Key Steps to Take

Overwhelmed By a CLL Diagnosis? Key Steps to Take from Patient Empowerment Network on Vimeo

CLL advocate Dr. Brian Koffman, outlines key steps to take following a chronic lymphocytic leukemia (CLL) diagnosis.

Dr. Brian Koffman is the cofounder, chief medical officer, and executive vice president of The CLL Society.

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Dr. Koffman:             

When somebody’s starting their CLL journey, there is some advice that I’d like to give people. The first is take your time. CLL rarely needs to be treated as soon as it’s diagnosed. You have time to learn about the disease, to familiarize yourself with the disease, and that learning is an iterative process.

You go over and over stuff, and eventually, this incredibly foreign language full of acronyms and medical talk becomes more familiar to you, and you feel more comfortable with it. But, it’s very overwhelming at first, but it’s not like some acute leukemias and other kinds of cancer, where they’re gonna see you on Tuesday and book the start of therapy on Friday. In CLL, that almost never happens. So, the first thing I would say is take a deep breath, under-react, and accept that you’ve got some time to make that decision.

The second strong piece of advice I would give people is to get an expert on your team. I can’t emphasize that enough. CLL is a rare cancer that the treatment paradigms have shifted radically in the last couple years, and they’re continuing to shift. And, if you’re not taking advantage of those changes – and, the research shows that in the community, patients are still too often getting inappropriate or less-than-optimum care compared to what’s happening in academic research centers.

You wanna get into their Rolodex file. You wanna be in their system so if a crisis happens three years down the line, you’re not a new patient trying to get an appointment. You have them in your system.

A third point that I’d make is to insist that you get appropriate testing before each and every treatment of your CLL. “Test before treat” is one of our mantras at the CLL Society because CLL tends to evolve over time, and not some – most, but not all of the prognostic and predictive factors can change over time, and those factors can be very influential in terms of saying, “This therapy will work, that therapy won’t work.” It’s critical that you know that, and if you knew it a year ago, it may be different now, so it’s critical to insist that your doctor do the appropriate predictive and prognostic testing.

We outline that on our website in our “test before treat” section in terms of what tests you need to have done. Take your time, get an expert, and get tested before treatment.

So, one of the questions I get asked is how can people learn more about CLL?

So, you can – some people like to learn online. has highly curated, medically reviewed articles that can help people from the beginning move forward. Leukemia and Lymphoma Society has useful resources on their website and has pamphlets that can help. Lymphoma Research Foundation is another. The Patient Empowerment Network offers you resources, listening to CLL experts and other CLL patients.

Going to support groups – you can often learn from other patients’ experiences. There’s nothing like meeting another patient and finding out what they’re like in that journey, especially if you’re two months into the journey and they’re 15-20 years into the journey. That can be incredibly helpful for you to see what their personal experience was in doing that. So, and also, there’s educational forums – for example, at the CLL Society, we have a dozen educational forums across the country every year – that give people an opportunity to learn from experts at places like the National Institutes of Health, Dana-Farber, MD Anderson, UCSD, and the Mayo Clinic.

So, we usually have one that isn’t far away from people to be able to go to if you wanna do your learning live.

Essential Lab Tests for CLL Patients

Essential Lab Tests for CLL Patients from Patient Empowerment Network on Vimeo

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Dr. Danielle Brander provides an overview of essential lab testing for chronic lymphocytic leukemia (CLL) patients and discusses which tests should be repeated over time.

Dr. Danielle Brander is Director of the CLL and Lymphoma Clinical Research Program at Duke Cancer Institute. Learn more about Dr. Brander here.

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Dr. Brander:               

So, there are additional laboratory tests besides the genomic or the prognostic markers that patients should have at the time of diagnosis. One that all patients have is a test called the flow cytometry, and that is done often for CLL patients on the peripheral blood. It may also be done on the lymph node or the bone marrow. And this is a profile of the surface of the cells that help your pathologist and your oncologist to confirm that this looks like CLL.

So most patients when they’re told of the diagnosis will have this either from the blood or it’s found on the lymph node. Notably, it’s not required in all patients, and most patients, in fact, to have a bone marrow biopsy at the time of diagnosis unless there’s a concern about other blood counts being low, and it’s not clear why that is going on.

Most of the other tests besides the prognostic genomic genetic markers that we talked about such as FISH, or IGHV, or TP53 are routine tests. So patients will have a repeat blood count, and this should be a blood count with a differential of the white blood count. CLL is a problem of a type of white cells called lymphocytes. So on the differential of the types of white cells you’ll see the lymphocytes are usually marked clearly elevated. But the differential also makes sure that there’s no low other white blood cells such as neutrophils, which are important in fighting bacterial infection.

It’s also a good idea to have at the time – and most patients will – a baseline chemistry, which include the kidney and the liver function. Though definitely not common, some patients can have involvement of CLL of the liver or kidneys.

This is pretty rare, especially around the time of diagnosis. It’s helpful to have those baseline tests. It’s also helpful because the median age of diagnosis of CLL is usually the early 70s, and so a repeat of the baseline kidney and liver function might find other chronic health problems that are important to know moving forward.

Some of the other tests, baseline labs, are more patient specific, and might need follow-up. For example, if the blood count revealed anemia, which is a low hemoglobin or hematocrit, the cells that carry oxygen, your treating team might want to order additional tests for anemia and make sure that the anemia isn’t due to something totally unrelated to the CLL such as iron deficiency or B12 deficiency, etc. So, there might be additional lab tests depending on the additional screening tests that are obtained at that time.

One other test that I’ll – or two other tests that I’ll mention at diagnosis, 1.) Is immunoglobulins, mostly for patients that have had a problem with recurrent infections because patients can have low antibody levels associated with CLL, even if it’s not been treated. So, your team – if recurrent infections have been a problem – may check for those antibody levels, those immunoglobulin levels. A second test that can be helpful at baseline is a test called SPEP or serum protein electrophoresis, which looks for extra proteins in the blood. And again, this can be seen with CLL and other lymphomas, and especially depending on patient’s symptoms, your physician, and treating team might want to obtain those labs.

Again, there are good resources online including the NCCN, CLL and leukemia patient-specific sites that might give a better outline beyond what we can cover today of tests that might be helpful in your specific case.

There are labs and tests in CLL that are repeated over time. Two of the common ones obtained at baseline, the complete blood count and the chemistry, will usually be repeated at every visit after diagnosis for patients not being treated at the time of diagnosis. They’re part of the monitoring, so every three or four months after you’re diagnosed when you see your oncologist and you have an exam, your history of how you’ve been doing, and labs taken, the white count and the chemistries are all to be followed with time.

At the time of treatment, there’s often additional tests that might be done depending on the type of treatment you’re receiving to make sure you don’t have a specific risk for recurrent reactivation of infections, for example. So the testing might change at the time of treatment. And specific to the prognostic biomarkers, the genomic or genetic testing of the CLL that we mentioned, some of them are repeated with time and some aren’t. The FISH, which is obtained at the time of diagnosis is recommended to be repeated. If patients have treatment, the CLL goes into response, and then relapses because the FISH testing can change with time.

The IGHV mutation status, however, as long as it was felt to be an adequate appropriate sample, is a characteristic of the leukemia that doesn’t change with time and would not be repeated. Similar to FISH, it’s a good idea to test the TP53 at the – not always at the time of diagnosis, but before treatment to make sure there’s not TP53 mutation.

But then similar to FISH, if the CLL goes into response and relapses, it’s advisable to repeat the TP53 as that can change as patients have different treatment options and they both help to, as mentioned, inform the first treatment. They’re also helpful to have in mind as patients are being followed on treatments because some patients have a higher risk of the treatment to stop working, for example, if there are higher-risk genomic changes.