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- [00:01]
Kathy Werzer
Hello, I'm Kristen Meinzer, host of Health Matters, a Mayo Clinic podcast investigating topics big the influence of gravity and small brain eating amoeba. We talk about our health bodies and the world around us. Get off the toilet. You're gonna have hemorrhoids. So join me in conversation with some Mayo Clinic experts as we strive for happier, healthier lives. Mayo Clinic's Health Matters new episodes every other week, wherever you get your podcasts.
- [00:30]
Dr. Samir Parikh
There are a lot of efforts going on right now where the AI model will be trained into knowing what a CLL lymphocyte actually looks like, so you can even identify it earlier on without having the need to go through flow cytometry testing, etc. So I think there's going to be a huge increase in the visual appearances of these cells. And how can they be determined to be a cancerous cell versus not many
- [00:58]
Kathy Werzer
people have heard of leukemia. It's a type of blood cancer, one of the most common forms of leukemia. Chronic lymphocytic leukemia, or cll, often goes undetected in its earliest stages. In fact, up to 5% of adults over the age of 40 have a condition that could lead to the development of cll. Coming up, we'll explore how science is shifting the approach to CLL from reactive treatments to to proactive detection. That's ahead on Tomorrow's Cure, a podcast from Mayo Clinic that brings the future of medicine to the present. I'm Kathy Werzer. I am so pleased that we have three great guests with us today. Dr. Samir Parikh is with Mayo Clinic. Dr. Susan Slager is also from Mayo Clinic, and Dr. Gerald Marty is a hematologist who first defined the condition that could lead to cll. I am so pleased that you all are with us. Thank you so much.
- [01:50]
Dr. Susan Slager
Thank you.
- [01:51]
Dr. Samir Parikh
Thanks, Kathy.
- [01:52]
Dr. Gerald Marty
Thank you.
- [01:53]
Kathy Werzer
Absolutely. Well, Dr. Marty, I would love to begin with you. Let's start with can I call it a discovery that was groundbreaking? Would you share the story of your work that led to discovering and naming a condition that many of us have?
- [02:08]
Dr. Gerald Marty
In 1997, I received a phone call from Dr. Robert Vogt, Bob Vogt at the CDC, and they had been studying blood samples, doing immunophenotyping from blood samples from individuals who were part of the Superfund site exposures. These were landfills of toxic organic material that Congress had recognized seven or eight sites in the U.S. somebody raised the question that, gee, we need to do immunophenotyping on these people to see if there was any immunological abnormalities associated with this exposure. And every Superfund site also had a group of people that they could also get blood samples from that were considered normals, but not in the exposure sites. Dr. Vogt noticed three individuals who had an increase in B cells that made him think of chronic lymphocytic leukemia, cll. But there was a lack of appreciation at that time for monoclonality. If you had a B cell expansion today would just be reflux. I immediately concurred with Dr. Vogt that the immunophenotype that they derived certainly looked like it could be. All I did at that time repeated the analysis, and. And we didn't want to make a mistake. So, as I recall, at one point, we actually used three different sets of commercial reagents for kappa and lambda to be sure that we got it right. It worked out perfectly. This was definitely some type of early CLL. Dr. Faget was in Alabama. I visited him in his clinic, and I saw a patient and his son together. And the father had CLL and the son had mbl.
- [04:10]
Kathy Werzer
And mbl, we should say, is monoclonal B cell lymphocytosis. Is that right?
- [04:16]
Dr. Gerald Marty
Yes. And when I came back to the NIH with this observation and shared it with the epidemiology group, I said, I think this is the first case of familial mbl.
- [04:28]
Kathy Werzer
We, of course, are talking about the B cell lymphocytosis. Right. Do we know why these B cells start acting badly?
- [04:36]
Dr. Samir Parikh
The etiology or the genesis of malignancy is really a big question mark. I mean, I think we can postulate that there is a combination of genomic findings. And Dr. Slager will talk more about some of, you know, the heritability, meaning how much of this did I get from my parents and my grandparents versus what sort of environmental exposures I might be exposed to that may influence the risk of developing, you know, this lymphocytosis or early cancer. And we think that there is a combination of both because there isn't clearly one sort of risk factor. So it isn't only genetics. It's not only environmental, because we've seen patients who are farmers in Iowa who have, you know, worked there all their life, and they get CLL or this mbl, which is the precursor condition to cll. And then we have seen people who live in Manhattan who've never lived anywhere else who develop cll. So I think we don't fully understand it. And I tell my patients, unfortunately, I don't know why you got it because that's the first question someone asks why me? And I don't think we have a
- [05:41]
Dr. Susan Slager
clear answer why they got cll.
- [05:43]
Dr. Samir Parikh
Right, right.
- [05:45]
Kathy Werzer
How exciting was it? Do you remember back when this discovery was made of mbl, what did other physicians in the field of hematology think? Do you remember Dr. Sligger?
- [05:57]
Dr. Susan Slager
I started working with Jerry back in 2004, and we had a familial cohort that we started collecting where we had families with multiple members with cll. And any first degree relative of these CLL patients, we would screen them for mbl. And so Jerry's lab was the one that got that going for us in our cohort study. And he helped build it here at Mayo Clinic with Dr. Kurt Hanson, who also started screening for MBL in these individuals from these families. And so what we're finding from that study is that individuals that come from these CLL families, they had a high prevalence of having this precursor condition, mbl. And so that started us thinking that it's also a genetic trait similar to what you see in cll. There's a high familial relationship among members with having cll. If you have a family member with cll, you have an increased risk of getting CLL yourself. And so taking that at the earlier stage at mbl, we're starting to see a family history of cll. You also have an increased risk of the precursor condition mbl, suggesting that your germline genetics might be a contributor of developing MBL. Dr. Parikh was also saying, what about the environmental factors? You have the MBL stage of the disease, and, you know, not everybody with MBL will progress to cll. And so is it the, the farming aspect, the pesticide exposure, or is it just a genetic driver that gets you from the MBL stage to the CLL stage? But as far as the MBL stage, we don't have the large enough studies to be looking at farming, which is a very strong consistent risk factor for, associated for cll. But we can't see if it's associated with mbl. We don't have a large enough study to do that. We're finding that as a major driver of developing MBL and of cll.
- [07:51]
Kathy Werzer
Actually, is it surprising that MBL is as common as it is? I was a little surprised to see. Is it what, 5 to 10% of the population? I think that sounds like a high number.
- [08:01]
Dr. Susan Slager
8 to 10 million adults over the age of 40? Yeah. At first we just thought it was an aging phenomenon. So it just happens like, you know, gray Hair happens. It's more common. We're finding with working with Dr. Parikh and Dr. Marty, that having MBL increases your risk of other conditions, not only with cll. It's not just something you get with old age.
- [08:23]
Kathy Werzer
Let's talk about the genetic tests that are out there determine someone's risk. How have they changed the landscape when it comes to this disease?
- [08:31]
Dr. Gerald Marty
I think I would defer to the polygenetic score that Susan and her group have when I encounter it either somewhat accidentally in a family member or just a non familial individual. Basically, it's kind of the same approach that you take to mgus, an abbreviation for monoclonal gammopathy of unknown significance. You pick a period of time that you're going to monitor it. That's reasonable. Don't overdo it in the sense that the patient has to come into a medical center very often before going into the genetics and even the low count mbl. High count mbl. I think it's very important to stress the differential diagnosis of when MBL is found. I chuckle to this day that the original observation was based on an n of 3. And more importantly, each of the three individuals that had MBL, each one was distinctly different and different in the sense of a thumbprint. One of them had CLL like MBL and the other one became known as atypical MBL and the third one became known as CD5 negative MBL. What is the luck of the draw that if you were to get three individuals in that original study, the three major differences you brought up polygenic risk scores.
- [10:06]
Kathy Werzer
And I'm wondering, Dr. Slager, could you talk a little bit about that? The scoring to assess individual risk for CLL and why that's important.
- [10:15]
Dr. Susan Slager
Polygenic risk scores are made up of the individual genetic variants that have been found to be associated with risk of CLL. And so right now, to date, we have identified 42 of these variants that are located across the genome. And each of these variants individually are associated with developing CLL, but not at a very strong effect. Not like BRCA1, where if you have a mutation, you most likely will get breast cancer. These variants have a small effect on your risk of getting disease. But what we found is if you combine these 42 variants into a score, everyone would have a quantitative value. And if you are at the high end of this distribution of this score, you have almost a fourfold increased risk of developing cll. And so, Ian, if you're at the low end of this score, we found that you're actually protective of developing cll. And so what we found is that there's only like 5% of CLL patients are at the low end of this polygenic risk score, and almost half of them are at the top 20 percentile. So most of them have these inherited variants. And why is only 5% of these CLL patients don't have that many inherited variants? Well, that could be that we need to identify more inherited variants, or it could be other environmental factors that are driving the disease in these individuals. And so we're finding that this polygenic risk score of these 42 inherited variants is also associated with getting MBL. So an earlier stage of the clone size, MBL is the precursor to cll. And so these inherited variants are associated with getting this clone.
- [11:59]
Dr. Gerald Marty
And.
- [11:59]
Dr. Susan Slager
And the size of the clone is much lower than what you see in CLL.
- [12:03]
Kathy Werzer
Dr. Parikh, how does knowing one's risk helpful? If I have mbl right, is early intervention needed to keep it from, if I could use the word flaring into cll?
- [12:14]
Dr. Samir Parikh
I think we have to understand that the risk of developing MBL or the risk of developing CLL is distinct from the risk of MBL going into cll, because I think there are distinct mechanisms at play. And so I think, you know, once you have identified that someone has MBL or cll, what we then try to determine is what kind of MBL is this? As Dr. Marty mentioned, different flavors of MBL, low count MBL, where the amount of these cancer cells is exceedingly small and they won't readily show up in a regular complete blood count or a cbc, if you will. And then there is what is called as the high count mbl, which is where the number of cancer cells is higher compared to low count mbl, and it'll show up on your regular complete blood count testing. And I think our approach to each of these groups of individuals is very different. So, for example, in individuals who have high count mbl, there is a much higher risk of that disease progressing to CLL over time. And so these are patients that we would see in our clinic. We would talk about some of the genetic risk markers that we would obtain to predict the risk of developing CLL, which are distinct from the polygenic risk score that Dr. Slager just talked about. And so that's a very separate group of people that we would talk about, counsel them, talk about the risk of progression, et cetera, over time. Whereas individuals who have low count mbl, the amount of disease or the cancer cells that are present is very small. And so some of these tools that we would use in individuals, high count mbl aren't really useful because our tests are being developed to actually work in an environment where very small numbers of cancer cells are present. And so I think the counseling, the approach to how we would monitor for disease progression, et cetera, is distinct in which specific subgroup of patients we are dealing with.
- [14:10]
Kathy Werzer
Are both groups, though, subject to watchful waiting? There must be some surveillance that goes on to see how things are going. Kind of a watch and wait phase of this disease, which I bet would be difficult for any patient in either group, right?
- [14:26]
Dr. Samir Parikh
Yeah, absolutely. I think watch and wait becomes watch and worry, unfortunately for a lot of people. And I think that is a real issue when we see patients, because when you tell them that, look, you have early cancer and we are not going to intervene or do anything differently, that in and of itself becomes a huge quality of life. Emotional sort of quality of life takes a huge toll. But I think that's where counseling comes into the picture. And so for individuals with high count mbl, we have developed these risks stratification tools where we obtain genomic information and many other blood tests that help us characterize the risk of disease progression over time into low, intermediate, high, and very high risk of disease progression. And then our follow up is actually tailored according to what that risk profile looks like. So in some individuals, we might say we'll need to see you every three to six months. In other individuals, it might say that, okay, we only need to see you once a year. And in some other individuals with very low risk disease, we might actually say you don't need to come see us. In hematology, in contrast, individuals who have low count mbl, the risk of disease progression to CLL actually over time is exceedingly low. And so for those individuals, there isn't really a lot of active surveillance that is necessary with respect to looking for progression of disease or progression to CLL requiring therapy. And there are other things that we need to pay attention to that we can get into, because it's not only the risk of disease progression to CLL requiring therapy. There are other things that we have to counsel patients about.
- [15:59]
Dr. Gerald Marty
I feel quite strongly about this aspect of the discussion. There are two things, perhaps three things that are more clinical, if you will, and not so much related to the theoretical aspects of the genomic calculations. Those three things, these are almost incomprehensible to me how mbl in the sense of its relationship to cll, can be associated with two striking clinical things. And one of it is the increase in infections of infectious disease in MBL and also the increase in second primary tumors. Both of those are well known characteristics of cll. In fact, as I marvel to this day that even though we have this well known disease state of common immunodeficiency disease, which I think probably CLL is a prime example, I don't see any thinking being applied from that field to cll, which I think would be helpful.
- [17:09]
Kathy Werzer
You mentioned an increase in infectious disease and increases in primary tumors, and I'm wondering, is there a genetic overlap between mbl, cll, melanoma, multiple myeloma, lymphoma, those other sorts of diseases? Is there a genetic variant that someone inherits that increases the risk of these other diseases?
- [17:30]
Dr. Susan Slager
Yeah. So across the lymphoma subtypes, there's many lymphoma subtypes, but the more common ones are like diffuse large B cell lymphoma, follicular lymphoma, even multiple myeloma. There are common genetic inherited variants that are similar across these lymphoma subtypes. And then you mentioned skin cancers, melanoma, for example. There's also genetic similarities between what we see in CLL and what we see in melanoma or even non melanoma skin cancers. Just by having cll, you have an increased risk of getting skin cancers and non melanoma or melanoma skin cancers. What hasn't been done well is to see those individuals who ultimately developed a melanoma. How much is it driven by treatment? How much is it driven by their prior, their genetic predisposition, that they already had some of the melanoma inherited variants and that maybe that wasn't enough to trigger to get melanoma, but it was. The CLL therapy, for example, was enough to get it over the hump that they ultimately developed melanoma. And so that's an active area that needs further research.
- [18:40]
Dr. Samir Parikh
Hi, I'm Dr. Bill Maurice from Mayo Clinic Laboratories. Curious to learn more about healthcare innovation.
- [18:45]
Dr. Susan Slager
I'm Dr. Bobbi Pritt, host of Answers
- [18:48]
Dr. Samir Parikh
from the Lab, a podcast that explores
- [18:50]
Dr. Susan Slager
trends and innovations in laboratory testing and clinical diagnostics.
- [18:54]
Dr. Samir Parikh
New episodes drop twice a month. You can subscribe on your favorite podcast app or visit mayocliniclabs.com to learn more.
- [19:02]
Dr. Gerald Marty
Are you trying to become a better human? Well, the Human Optimization Project is an exciting new podcast offering for Mayo Clinic which aims to help you do exactly that. We're all struggling to balance the need to perform and do more while simultaneously maintaining our wellness. In the Human Optimization Project, we're focusing on 10 key domains of human performance to help people achieve more, improve well being, and become the best humans they can be. If that sounds like what you're looking for, search for the Mayo Clinic Human optimization project on your favorite podcasting app.
- [19:42]
Kathy Werzer
Do you three wonder what AI and machine learning could do? Could they examine variants of unknown significance in genetic tests and make them significant if the machine learning is used maybe to predict resistance to therapies, that kind of thing?
- [19:58]
Dr. Susan Slager
Absolutely. AI is being used in a whole bunch of different ways and novel ways, and whether or not some of them pan out to being something that we can replicate and validate and make sure it's a true finding as opposed, it just opens up new ideas and how to understand these variants of unknown significance. A lot of the inherited variants for CLL are in regions that are not coding. They don't make a gene, they're not part of the gene region in the genome. And so what are they doing to increase your risk of getting cll? Now, we haven't used AI in that case, but we did look at other genomic approaches to try to understand that these variants are residing in the genomic regions that regulate genes nearby or maybe a little further down the stream. And so they, they kind of help turn on and turn off the gene expression, but they don't actually reside in a region that makes a gene, if you will.
- [20:58]
Dr. Gerald Marty
I recently had the opportunity to speak with Dr. Hansen and we discussed the role of AI in flow cytometric analysis. When AI is added to this system, what it has made possible is the length of time that it takes for a technician to do all of the gating that's required to figure out these subtypes. 45 minutes. AI can accomplish that analysis in the length of time that you cough. And I think that as we get deeper into this, I think we're going to find, if we just take the fish, cytogenetics, if you will, unmutated and mutated, and the stereotype, the number of possible subgroups that exist from that kind of information I think is only going to increase.
- [21:53]
Dr. Samir Parikh
One of the most common ways by which CLL is diagnosed, or mbl, you go to your doctor's office, they run a blood test, you see a cbc, which is a complete blood count, and you look at what is called as a white cell count, which is typically increased. And then, you know, most of the time there is a reflex where there will be someone who will look at a slide and say, okay, there is an increase in the lymphocyte Number and generally speaking, to confirm a diagnosis of CLL and to know or mbl to know that these lymphocytes are, you know, a clonal process, meaning it's a cancerous process versus if it's a reactive process. So you could have the influenza infection or any other infection and your lymphocyte number may go up and then the number comes down once you've recovered from the infection. So I think it is critical to be able to find this thing relatively easily. So unless you run a flow cytometry study with all the things that we just talked about, it's not easy to differentiate between what is a cancerous lymphocyte like an MBL or a CLL clone versus a reactive lymphocyte because of an infection that you may be dealing with. And I think this is where AI will come in because there are efforts going on right now where the AI model will be trained into knowing what a CLL lymphocyte actually looks like. So you can even identify it earlier on without having the need to go through flow cytometry testing, etc. So I think there's going to be a huge increase in the individual appearances of these cells and how can they be determined to be a cancerous cell
- [23:27]
Dr. Gerald Marty
versus not right on target. About how the diagnosis of MBL differentiating from reactive lymphocytosis and early mbl. One of the four posters dealt with this issue. I don't know what the end value is of the cases of lymphocytosis that they have picked up on the CBC and have been able to do flow cytometry. And the majority of the lymphocytosis is surprise, surprise, B cells. But here's the caveat that just upsets me. They're all, the majority are all high count mbl. I think at the level that we're able to detect, it is high count mbl. I think from a research standpoint, an investigative standpoint, it would be nice if we could detect more of low count mbl. Susan can probably address more of the population.
- [24:16]
Dr. Susan Slager
The biggest barrier would be is flow cytometry. It takes 45 minutes for a tech to do the cell sorting and analyses. And so if AI can speed this up, maybe we can do it in larger population cohorts. So we're fortunate. At Mayo Clinic we have a cohort of over 10,000 individuals that we screen for MBL. But it's a very laborious process to do that. MBL screening with flow cytometry and maybe we can use this AI technique that I'm hearing about to make it a little bit faster. But it's still very expensive and it requires cells to be banked. And most of the biorepositories around the world do not have banked cells. That's very expensive to store that way, as opposed to DNA, which is very easy and inexpensive to obtain and store. And so at Mayo Clinic we've been taking these cells that we've banked and we've been using flow cytometry to screen for mbl. And so a barrier is that that's very expensive, time consuming, and not always feasible without having the right biospecimens. So if we're able to do either speed up the flow cytometry process or have a new, new AI approach that can just read the DNA and say, oh, this person has mbl, you know, that would open up new avenues for research for mbl, especially at the low count MBL stage.
- [25:42]
Kathy Werzer
It sounds like then early testing, equitable access to early testing is also a challenge. Am I hearing that correctly?
- [25:49]
Dr. Susan Slager
Most of the time, low count MBL is not usually identified in the clinic. It's only through research that we identify a low count mbl, which is the more common condition for MBL, as opposed to the high count mbl. And so most people don't even know they have low count MBL unless it's through a research process.
- [26:10]
Dr. Samir Parikh
There are two distincts. So we've talked about low count MBL and high count mbl. And so the other way of thinking about this is low count MBL is population level mbl. So you don't know that you have it. It's only when you ask people to volunteer and you test their blood and you find these very, very small amounts of cancer cells. On the other hand, high count MBL individuals come to clinical attention and they are the clinical mbl, so to speak, because they've got gone to a doctor's office and they've gotten a blood test that shows that there is an abnormality in the blood count that leads to additional investigations and high count mbl. So I think the research questions and the focus of what we want to do for both of these populations is very different because I think there are ethical questions. For example, right? I mean, we know that There are roughly 8 to 10 million individuals in the US who have low count MBL. They don't know that they have it. We have the potential to test it with all the tools that we talked about. Is that something that we should consider or not? I mean, you know, what are the clinical implications of having low count mbl? So I think these are research questions that I think are critical. You heard about the increased risk of infections, the increased risk of other cancers, etc. You know, if I have low count MBL and if I know that I have a higher risk for some of these other cancers, for example, melanoma, is there a moral imperative for us to work on identifying these individuals and talking about this risk? And so I think these are, these are unanswered questions. And we struggle with this because we don't see these people with low count MBL in the clinic because there is no mass screening for these sort of conditions that is currently available or even recommended. But these are initial findings from our large screening study of close to 10,000 individuals. I think we need to build on that, need to understand the clinical implications to be able to better counsel our patients.
- [28:09]
Kathy Werzer
Dr. Slager, you were the one that did that incredibly large epidemiological study, right? Do you start testing the population that donates blood?
- [28:20]
Dr. Susan Slager
Well, we do try to screen as many people as possible. The people that we've been screening are local, tub, Mayo Clinic, and so that we have access to their medical records. And then we can see what happened before they were screened and what happens after them. So we can see if they develop melanoma or if they develop another type of lymphoma or they go on to develop in cll. And so that's the beauty of our cohort, is that they are people that go to Mayo Clinic or the regional facilities that we have access to their medical records. And so touching on what Dr. Preek was saying about the ethics of telling these individuals that we found that they screened positive for mbl, especially the low count. The counterbalance is, you know, if you tell them, they're going to ask, well, what do I do about it? So our study shows that you have an increased risk of serious infections, including Covid and pneumonia that results into hospitalization, but you also have an increased risk of developing lymphomas and melanomas, and so getting infections. Well, wash your hands. That would be, that would help you protect your increased risk of getting infections for, for skin cancers. Well, it's already well known to wear sunscreen or wear clothing to protect your exposure to UV radiation. And so there's nothing that we would change per se. But as far as your clone, your MBL clone, growing from low count to high count to cll, we don't know how to stop it. And that's, that's the, you know, the concern about telling these individuals with low count mbl, it's like, well, there's nothing we can do about it right now. Still at the research phase.
- [30:01]
Dr. Gerald Marty
Busy healthcare professionals. This one's for you. Find Mayo Clinic talks on your favorite podcasting app or visit ce mayo.edu podcasts to learn more. Every week we share succinct, rough, relevant and practical medical insights tailored for healthcare clinicians that you can immediately apply to your practice. Each episode covers common health issues seen in a primary care practice shared by Mayo Clinic experts.
- [30:39]
Kathy Werzer
So I wonder what's on the horizon that really excites all three of you when it comes to moving the needle on detection treatments? What, what's out there? We talked about AI, obviously. Is there something else out there? Advanced genomics, novel cellular therapies, Anything that's on the horizon that is really igniting you?
- [30:58]
Dr. Samir Parikh
It's the boring stuff that's actually exciting in a way because we've talked about, you know, the clone and how can we target the clone and how can we get rid of the clone. And I think that is in and itself an important thing. But I think it's the immune milieu or the immune microenvironment around it that I think is far more important that you know, we don't pay enough attention to. And I think altering the immune microenvironment in a very early stage, low count MBL or high count MBL individual might actually prevent some of these immune related complications that are a far bigger risk to them. So you know, the risk of infection, risk of other cancers. So can we alter the immune microenvironment? And so there are already efforts that are ongoing. For example, exercise, you know, can we offer an exercise, a structured exercise intervention that can alter the immune microenvironment to prevent cancer from, from getting worse. I mean, already we have seen in a cohort of study with patients who were treated for colon cancer where random allocation to exercise versus no exercise, people who got exercise actually live longer compared to people who did not. This is the first time we actually saw some results like this in the cancer world. So we all know exercise is important, but this was the first time we actually saw that it made a difference. So can we do something similar in our patient population? Similarly, what role does diet play? There are early indicators in a similar sort of condition called mugus monoclonal gammopathy, which is another precursor hematologic malignancy, where a plant based diet may be actually slightly better in reducing the risk of disease progression. We don't know if something similar is applicable to mbl. So I think again, there is a lot more that we can learn and apply from things that are very basic that we can hopefully adapt and make it easy for our patients to hopefully not have the immune related complications that we fear more, rather than the clone getting worse and needing CLL directed therapy in the future.
- [33:02]
Dr. Susan Slager
The other aspect is, okay, so we found, we have 1500 individuals that we found that we have MBL and some of them were getting serial samples on them and were screening and looking at is there a change in their clone, in their MBL clone, is it growing, is it saying the same? They most, most of the time they don't go away once you have it, it pretty much stays there. And so who are these individuals with this low count MBL who's going to progress? And so is it the immune microenvironment that Dr. Parikh was talking about or are there other genomic features? We just had a paper that came out in Blood Cancers Journal looking at other genomic features that are in the blood that I've identified individuals with MBL who have increased risk of progressing to lymphoma. So now the ethics is, are those the individuals that we are. We should be telling, hey, you have other features in your blood, not only the mbl, but you have your germline genetics, you have this other, it's called clonal hematopoiesis in your blood. And plus you have mbl. And so you have kind of all three characteristics that are strong factors for developing not only cll but other lymphomas. Are those the biomarkers that we should be then screening to determine who's at risk for progression as opposed to, yes, you have mbl, but you don't have these other features. And maybe, you know, we don't have to see you again or we don't have to share the research results because we're just not finding you're a low risk individual for any of these outcomes that we've been studying.
- [34:33]
Dr. Gerald Marty
In the 2023 IWC lll meeting in Boston, I think it was made quite clear and dramatically that in terms of overall survival in patients with cll, that it has reached the point where age matched sex match controls, patients with cll, particularly the treated population, have the same overall survival. So now if you have a clinic of CLL patients, if you're successful and you have an ideal population, your clinic now is essentially one of minimal residual Disease mrd. But guess what? You still have the problem of infections and you still have the problem of secondary tumors. Now let's go back to the other end, which is, you know, low count mbl. And how can we detect it earlier and with methods that are not as expensive as multicolor flow cytometry. We see so much now about This1 abbreviation TDNA. Circulating tumor DNA or the liquid biopsy in the setting of cll. What can we learn from the circulating tumor DNA in the setting of cll? Can we go before low count MBL and find circulating DNA? And then in my mind, that way of thinking leads to the concept of nodal mbl. Samir, you hit it right on the nose. I mean, microenvironment now is the golden shining diamond, if you will, in this area. How are we going to biopsy that first node that's involved with nodal mbl? How will you know which one it is? And then can you imagine the human subjects committee review that's going to be required to, you know, very carefully using imaging and ultrasound to micro dissect that lymph node.
- [36:33]
Dr. Samir Parikh
That's where AI will also come in the picture. Right. Because we have such excellent AI models in radiology now where if you go back historically, you can say, okay, someone got a CT scan for an unrelated reason, they went to the ER because they had a, you know, kidney stone, for example, and then they saw a lymph node eventually, which was biopsied, that turned out to be, you know, nodal mbl. Like you're talking about, what were the characteristics of that lymph node compared to the thousand other lymph nodes that were enlarged but never turned out to be nodal mbl. Right. So you can then start making those comparisons. So you can train a model and then apply it subsequently in the future and say, okay, well, you know, this is unlikely to be nodal MBL versus this is likely to be something of significance.
- [37:21]
Dr. Gerald Marty
And that would be basically nodal versus reactive. Although I think you probably wouldn't get nodal reactivity. Although nodal has to come before diffuse, right?
- [37:31]
Dr. Samir Parikh
Correct. But at the same time, you know, you get a vaccination for some reason, and many people have enlarged lymph nodes. That is a reactive lymph node, and it's not a nodal MBL of any sort. So certainly those things can happen. And I think with where AI is going, if it is trained properly in a good data set, then I think it can be replicated and validated in a different data set.
- [37:56]
Kathy Werzer
We've done episodes in the past about Mayo Clinic's pre cure initiative. And I'm wondering with the population data that we've talked about here today, how is that leverage that data leverage in this precure initiative for cancer prevention?
- [38:09]
Dr. Samir Parikh
There are several initiatives going on within Mayo Clinic, but a major one, as you pointed out, is a precure initiative is to try and identify cancer early so we can fix it early. And I think there are a number of initiatives across both the solid tumor world. So when you for example, are dealing with pancreatic cancer and also within the liquid tumor, where are the hematologic malignancies? And one of the examples was a study that Dr. Slager led, you know, that led to a very deep and a greater understanding of MBL in the general population. And so I think what our next steps are that we are trying to address, how can we better capture this data in our general patient population that we are seeing? If you do have a patient who has a diagnosis of either low count or high count MBL and they wish to be seen, we now have a special clinic called the Hematology Precursor Clinic where patients could be referred and they would have all of these additional testing that can be accomplished to try and better understand the risk of disease progression. And, and how can we better address some of the emotional needs of these patients and eventually how can we tailor early intervention in a specific subset of high risk individuals and even talk about therapies that may be directed towards, as we were discussing the immune microenvironment. And so I think this is not just looking at how do we better identify these patients but how do we get them to a place where they can meet with an expert group of clinicians who are dealing with this patient problem and then get the necessary additional testing done and then interventions. And so I think this initiative is a division wide and a three site cancer site across the Mayo Clinic sites both in Florida and in Arizona as well, in addition to Rochester. And so hopefully this will set the stage for us to be able to deliver the kind of care that we hope that we can provide to our individual patients with mbl.
- [40:04]
Dr. Susan Slager
Whether or not we include individuals that are at the low count stage in this pre cancer clinics is still the big question. Would it help them or does it cause more anxiety?
- [40:16]
Kathy Werzer
Because it is so difficult, isn't it? You're not sure next steps? Will something happen? I can see where that would be an emotional burden to carry.
- [40:26]
Dr. Susan Slager
Yeah. You know, some of the CLL patients have talked to me saying why did you tell me I have CLL when I'm not getting treated. And so MBL is even in an earlier stage. High count MBL is an earlier stage in the cll and low count MBL is an even earlier stage. As Dr. Parikh was saying, the Precur initiative is to identify those people who are at risk. And the only way to do that is to continue to study and identify the features that we could develop treatments for or identify who's at risk.
- [40:55]
Kathy Werzer
Final question for Dr. Marty. Because you shape the field, I'm wondering where you'd like to see it go in the next five to ten years.
- [41:02]
Dr. Gerald Marty
Two things still to pursue this cell of origin coo. And then with all of this information that we have and with the tremendous clinical improvements that have come with so called targeted drugs, targeted reagents, double and triple treatment. If we could define, as Susan was mentioning earlier, those individuals with MBL that are definitely going to progress, I have
- [41:31]
Kathy Werzer
greatly enjoyed our conversation. Dr. Parikh, Dr. Slager and Dr. Marty, thank you so much for your time.
- [41:37]
Dr. Susan Slager
Thank you.
- [41:38]
Dr. Gerald Marty
It's been a pleasure. Thank you.
- [41:39]
Dr. Samir Parikh
Yep. Thank you so much, Kathy. Appreciate it.
- [41:42]
Kathy Werzer
Tomorrow's Cure is a production of Mayo Clinic with production help from the podglomerate. Be sure to follow Tomorrow's Cure wherever you get your podcasts. I'm Kathy Werzer. Thank you so much much for listening. Hi, it's Kathy. If Tomorrow's Cure has opened your mind to the innovations and technology shaping the future of medicine, we'd love your help in spreading the word. Please take a moment to rate and review Tomorrow's Cure. Whether you're listening on Apple podcasts, Spotify or your favorite app, your feedback helps others find these discussions and discover how breakthroughs in healthcare are becoming reality. Tell us which episodes or ideas resonated most with you, what surprised you, or what you're hoping to hear more of? Thanks for listening and for being a part of Tomorrow's Cure.