Naveen Pemmaraju, M.D. Hello, I'm Dr. Naveen Pemmaraju, professor of Leukemia at MD Anderson Cancer Center. And today I'm happy to be joined by my friend and colleague, Dr. Fadi Haddad, assistant professor of Leukemia at MD Anderson Cancer Center, and this is the Cancerwise Podcast. We're really excited to join you today to discuss an important emerging topic in both the clinic and research, which is that of MRD, used to be known as minimal residual disease, now known as measurable residual disease. And by way of background, this is simply a monitoring tool that doctors and physicians around the world can use to more closely, and at a larger and deeper level, analyze the remission status of their patients with both acute and chronic leukemias. And so, without further ado, I want to start this session by bringing in Dr. Fadi Haddad. Really, Dr. Haddad, you've been an expert in multiple leukemias, importantly both chronic and acute. I was wondering if you could start off the discussion of MRD with telling us kind of the history, maybe using CML, or chronic myeloid leukemia, as a model, and then we'll talk about some of the other leukemia types. But take it away, Dr. Haddad.  

Fadi Haddad, M.D. Thank you, Dr. Pemmaraju, for the introduction. That's so nice to have this overview. And if you allow me before we start, I would like to present the MRD the way I present it to my patients in clinic. I usually give them the example of the iceberg. We all know the tip of the iceberg is just 10% of what we actually see, but the remaining 90% is hidden deep underneath the water. So, this is similar in leukemia, actually. When patients present to us with a disease, this is what we actually see in their blood, in their bone marrow under the microscope. But once we treat the patients, the disease will slowly, slowly go away. And many times, we look under the microscope to the blood or to the bone marrow, but we do not see any further leukemia. Does this mean that the leukemia is really gone or not? This is when we need further and deeper testing, which we call MRD testing. And those could pick leukemias at a very low level, even could pick one leukemia cell in a big sea of normal cells, 10,000 cells, 100,000 cells, 1 million normal healthy cells in our bone marrow, you can even with those tests pick up one bad or one leukemic cell. And this is what we'll be discussing today. Let me start as you nicely mentioned with chronic myeloid leukemia, CML. This disease is a disease where our bone marrow produces too much of a certain type of white cells. 25 years ago, before 2000, people used to die of this disease, but now we have very potent and new medications that cure almost 98%, almost 100% of the patients. So, it's very important when those patients receive those treatments, how should we monitor them as physicians? This is when we're going to assess for MRD. The test that we use in this type of disease is called PCR, polymerase chain reaction. This is a test that is done in the lab. Usually, we take a blood sample. It's just a simple blood draw that the patients will do and we send it to the lab, and we are able to detect if there is any CML remaining at a very sensitive or specific level. One cell of CML could be detected among 10,000 or even 100,000 of normal healthy cells. And this is very important when dictating the treatment. Once patient is treated, the patient should be monitored every three months with this PCR test, and we need to track how much the disease is improving. As long as the disease is going below 10% initially, then below 1% thereafter, then the patient is doing well and can continue treatment. If the PCR level rises beyond 10%, then this is a sign that the disease is becoming more resistant and might need a change of therapy. So, this tells you that the MRD is very important in monitoring the disease and deciding the course of therapy.  

Naveen Pemmaraju, M.D. Wow, that was a very lovely analogy. I want to make sure everyone heard what you said. Tip of the iceberg phenomenon. That's exactly what we're talking about with MRD. Again, used to be known as minimal residual disease, now measurable residual disease. And I love what you've said about CML. Not only it's academically, theoretically relevant, but as you and I know, this is what we are all doing in the clinic every day. So, it's essential what you said, not just luxurious. So, the next question now, after chronic myeloid leukemia or CML, is another area in which you're a world expert, and it's that of ALL, acute lymphoblastic leukemia. Before our time, adult leukemia, particularly ALL leukemia, actually did not, did not enjoy the same survival outcomes as, say, our pediatric colleagues and counterparts. But over the last, I would say, 20 years, especially with the pioneering work of our own chairman, Dr. Hagop Kantarjian, the outcomes in ALL for adults have been markedly better, if not cured in many cases. One of those tools, rather than being a treatment, has actually been the monitoring of the MRD as you were talking about earlier. So, can you comment on the evolution of MRD testing, maybe over the last 10 years, and with some of the newer tools that you and the team are using?  

Fadi Haddad, M.D. That's brilliant. I love how you, the historical perspective you've given. And I think MRD is gaining more and more momentum in acute lymphoblastic leukemia or ALL. If we go back just a few years ago, patients who received the treatment with ALL, we used to monitor them with a test called flow cytometry. And I believe you'll be discussing this in more depth in the next few minutes. But a lot of patients were cured by this test, flow cytometry. We test those patients using this technique, and most of them have undetectable leukemia. But six months, eight months thereafter, they have a full-blown relapsed disease all over their body and some of them unfortunately couldn't make it. Now we started questioning why those patients are actually relapsing if they do not have any residual leukemia? And then we found out a few years later that it's not because they do have any leukemia, it's because we are not able to see the leukemia that is remaining. And that's why three years ago we had a new test that came which called next-generation sequencing, or NGS, and this test can go to the deepest level of the iceberg, if I may say. It can detect even one leukemic cell that is hovering around among a million of healthy cells in your body. So, by this technique, we were able to detect very, very minimal level of disease that was previously unnoticed. And when we were able to discover those, then patients who were otherwise classified as cured are now classified as still having the disease by this new MRD test. And this tells you how much MRD is gaining momentum and is becoming more important. And those patients are now candidates to receive other treatments, maybe immune therapies or novel treatments that now can actually cure them. So, now we classify patients as being cured if they have undetectable or zero leukemia by this new test, NGS, and not by the old test flow cytometry. And I think this is a paradigm shift in the way we are treating ALL which is improving significantly the survival of our patients.  

Naveen Pemmaraju, M.D. I really absolutely loved what you just said. And again, to emphasize, what you just said is profound, Dr. Haddad. We're trying to find something that's hiding in plain sight. In other words, it's already there but we mistakenly may have thought with our previous technologies, remission, no more mother or stem cells, whatever you'd like. And what you're saying is with the better technology, deeper dive, maybe going from 10 to the minus third to 10 to the minus six, that now we can see even one cell that's hanging out that we couldn't see before. Is that what you're saying?  

Fadi Haddad, M.D. Correct, this is 100% what we're referring to.  

Naveen Pemmaraju, M.D. Unbelievable. Now as we move into another type of leukemia subtype, this is now CLL, so chronic lymphocytic leukemia. I'm starting to think about this MRD topic now in this area of the clinic. Again, a vastly different disease than the two we talked about. Median age perhaps, a little bit on the older side, more common in the Western hemisphere than in the Eastern hemisphere. But this CLL is a common leukemia. Hundreds of thousands of patients a year are walking around with this just in North America and the Western Hemisphere. What I want to ask you is, are these MRD tests available in this chronic leukemia? And how are you using it there?  

Fadi Haddad, M.D. I'm going to answer you with a very controversial answer. So, in med school, probably me, probably you, and others, up until recently, 2023, 2024, we used to say chronic lymphocytic leukemia, CLL, is an incurable disease because always patients have undetectable disease by, again, flow cytometry and other techniques. We stopped treatment a few years after the leukemia is back again. Now, by using this very sensitive test that we just discussed a couple minutes ago, the NGS, we are able to detect patients who do not have any residual CLL at a very, very deep level. It's kind of the roots of the disease are gone. And now we may be starting to say that those patients could be cured, and we can start talking about curing CLL for the first time in our lifetime, right? So... Those tests are definitely used in CLL more and more. The NGS test is used in lymphocytic leukemias, whether acute or chronic. In chronic leukemia, the utility is to monitor patients after finishing a treatment, to see after six months, one year, two years, if those patients truly have no leukemia left behind, or they still have some minimal leukemia there. But in chronic, it's different than in acute. If you have a chronic leukemia, then I may allow that you remain just under close monitoring and observation with minimal leukemia left behind because we know that in the chronic disease, usually the leukemia will put years and years before it really becomes significant to cause any life-threatening effects on you compared to acute. So, I would say more and more we're seeing this in CLL, and I think more and this will allow us to differentiate between patients who were considered uncured and now they are cured.  

Naveen Pemmaraju, M.D. That's phenomenal. And you're also reminding us that testing MRD can be practice changing because on the research side, which you mentioned earlier, which is profound, want to make sure our viewers caught this, is that it may help us with early intervention, may help us with preemptively changing a therapy, when maybe in the older model, we'd have to wait for full blown or overt relapse or progression. So, maybe I just wanted to comment on that with you. As these reports become more and more complex, you mentioned the patient journey. What's a way to explain once again to folks about MRD, Dr. Haddad, maybe alluding to what you said earlier, but just one more time how to explain this to folks?  

Fadi Haddad, M.D. So, it's try, is trying to find a needle in a haystack. One leukemia cell remaining left behind in your blood, in your bone marrow unnoticed is like a hiding spy and once the surveillance is gone this seed that is hiding behind will slowly, slowly grow back and then will cause trouble. So, MRD are tests that can help us detect any seed that is left behind, so we are able to completely eradicate it from its roots and tell the patient you are officially cured.  

Naveen Pemmaraju, M.D. Well, that's brilliant. That's brilliant, I've never heard it put that way. It's a detective, a spy, an elite operations team that you send in to try to find every last cell. Never heard anyone say it that way, that was brilliant.  

Fadi Haddad, M.D. Now that we spoke a lot about NGS, about PCR, about maybe more lymphocytic disease, let me come back to you. You're a world expert in myeloid disease. You've led many, many efforts in acute myeloid leukemia. You are the leader of the BPDCN program in our group throughout the world. You have led to the approval of many drugs in this space. How can you comment on the MRD, the minimal residual disease testing in the myeloid space? Let us start, maybe, by flow cytometry tests and acute myeloid leukemia, how can you define that? How do you use it in clinical practice?  

Naveen Pemmaraju, M.D. Well, thanks, Dr. Haddad. You're right. And as we turn the lens now to acute myeloid leukemia, maybe first AML, as you asked me, what a revolution we've seen in the treatment of this disease. I would say that about 25,000 Americans a year are diagnosed. So, considered a rare blood cancer, but unfortunately, a very life threatening one. Five-year survivals for many of our patients, these are averages. They're statistics. They can vary from patient to patient but overall is less than 50% of our patients are expected to be alive with this disease at five years. That's historical. We're rewriting those textbooks. So, a deadly disease, a life-threatening one. As you said earlier in your discussion, if any tool or test can help you and me find even one cell earlier, faster, deeper, better than before, that's a potential victory for us and our patients. And in so doing, the evolution is in front of our eyes. As you mentioned, the first one I would say is the PCR and the flow cytometry tests, as you said. Unfortunately, many of these AMLs don't have a specific protein to follow. Maybe one in particular might be the core binding factor AML or the acute promyelocytic leukemia, APL. So, those will have a certain protein that you and I can follow in the clinic. Most of them won't have that, and so we've been using flow cytometry. Our pathologists may not appreciate this analogy, but at least in the clinic we do, which is maybe it's a side scatter of light. You're trying to look for light patterns on the cells. It's called gating, and the flow cytometry picks that up. So, you can find populations and side populations of leukemia cells that the traditional tests were not picking up, mainly by the human eye. And so, maybe that goes down to 10 to the minus two, minus three, maybe at the most 10 to minus four level. And that's been helpful. If you're positive at the end of therapy, maybe the end induction, the first therapy, or at the of consolidation, maybe it helps us to, as we talked about earlier, preemptively change the therapy. Add to the therapy. Move to an immunotherapy. So, that's flow cytometry and AML, very powerful. We use it in the clinic every day. Now, what's kind of exciting to you and me and for our patients and families, is what you just mentioned on the lymphoid side. High level, going down to the millionth level, if you will, 10 to the minus six, and those NGS, next generation sequencing assays, aim to try to get deeper. One of these Invivoscribe assays is trying to help us with a high sensitivity NPM1 and FLT3. And again, those are a certain percentage of our patients that will have AML. So, can you take a life-threatening big cancer and chop it up into subdivisions, if you will? It may be dozens at the end of the day, but if each one is five to 10% of those patients, maybe we'll be able to have a personalized test for each of those. That's what we're trying to develop, and that's already in the clinic. That's not science fiction or 10 years from now. The question will be, I think, about cost, availability. Can these results be used and replicated around the world for practice-changing decisions? I think that time is coming very soon.  

Fadi Haddad, M.D. Wow, that's phenomenal what you're describing. So, if we heard it correctly, now AML is not a single disease, you're saying?  

Naveen Pemmaraju, M.D. Exactly.  

Fadi Haddad, M.D. It's a variety of disease according to what genes each patient has. And you're mentioning those new techniques can actually detect those genes at a very sensitive level?  

Naveen Pemmaraju, M.D. You could not have said it better. In the 1970s, AML was only understood by what one could see with the human eye under the microscope. That was called the FAB, or French-American-British classification. AML M0 to M7, based on the size and shape of the cells, it was a very helpful and still used today system, but it's been supplanted by what you said, which is now we know the chromosomes, that's called cytogenetics, the molecular features as you just nicely delineated, and the flow cytometry features. In fact, so much so, that in the latest WHO and ICC, the major classifications, you can subdivide AML into dozens of diseases just simply based on what you said, the chromosomes and the molecular. And you can even upgrade a quote-unquote lower grade myeloid neoplasm up to AML on the basis of what you've said. So, the molecular genes not only help with diagnosis, so what's the, what is the entity, prognosis, how am I going to do with this? But also monitoring long-term, even when you thought someone was in remission, but oop, as you said, hiding in plain sight. Maybe not so. Maybe we can intervene.  

Fadi Haddad, M.D. That's brilliant. And Dr. Pemmaraju, you've always been a visionary in this field. So, if you may allow a couple of questions, how do you see the field moving forward in rare disease maybe, maybe in acute myeloid leukemia with MLR rearrangement? We know that we have newer therapies now, the Menin inhibitors, or the BPDCN, which is your niche, your field of expertise. Can you comment on potentially newer MRDs in the years to come?  

Fadi Haddad, M.D. Oh, great, great question, Dr. Haddad. So, first in AML, which we were talking about, you nailed it. When I look at the field, you have these mutations which are actionable. So, IDH1 and 2 make up a certain percentage, let's say 10 to 20% of AML. Then you tack on FLT3, which may be up to a 30% of the AML then NPM1, which maybe up to 30 to 50% of AML. So, each time we make an assay, that helps us to monitor that particular subset. But you mentioned the hottest, most emergent one. That's KMT2A, or MLL. This is being pioneered by our colleague, Dr. Ghayas Issa, around the world, and what's happening here is three things. You just said it, and I think this is exciting. One: can you take a really, really rare subset of leukemia that was previously not forgotten, it was just untargetable, undruggable before, and now you have a target? So, that means you have to check for it, and there has to be an assay. We've developed that. Two: you have to have a successful group of drugs that actually target that. That's what we're starting to see. The first one has been approved with four or five others in active investigation. And then, as you said, can you now monitor that assay where it goes down to either zero or close to zero, as you showed us in CML? And then the fourth one is what you're talking about. The visionary is, okay, that number is not going to zero, but that correlates with relapse of the disease, worse outcomes, and I can intervene with XYZ. That's the future, that's where I see this MRD going. As I look forward after AML into the more rare disease niche areas that I specialize in, BPDCN is one, Dr. Haddad, that stands for blastic plasmacytoid dendritic cell neoplasm. A long word, which basically says a very specific type of cell, in this case, the PDC, plasmacytoid dendritic cell, is mutated or aberrant, leading to a cancerous process. This rare leukemia is quite unique. It's a hybrid disease because it affects the skin, bone marrow, lymph nodes, and even the central nervous system. So, it's unusual compared to the other leukemias, and you're right. Even though we haven't yet finalized an MRD, we borrow from the more common. So, ALL, AML, the ones we've mentioned together. But because it involves the skin and the central nervous system, I envision an MRD assay perhaps if you'll allow, for each organ system. Can there be a skin MRD, a CNS MRD? And again, these modalities that you and I know, flow cytometry, NGS, et cetera, and can we standardize and hybridize those so that they're the same around the world? That I see as the future, and then can we make an early intervention that matters to the patient?  

Fadi Haddad, M.D. That's brilliant what you're just mentioning because we only think about the new test. We look at about positive results that we see at big centers, big trials, but they may not always translate into clinical practice. So, what I think the cons of those techniques, particularly flow cytometry or cytogenetics, is as you nicely mentioned, they need expertise. They are dependent on which lab they are being performed, and which pathologist is actually reading those tests. I would say the pros is the new tests that are being available such as the NGS, such as the Invivoscribe or the other tests that we mentioned that are very specific can go deep into the iceberg to say, say if the roots of the disease are still here or not. Those are becoming more and more standardized and those are becoming more centralized in either one lab or very few labs across the country. So, this tells you that whenever you have a patient with, with those disease, you just send the specific test to a centralized lab. You just ship it across the country, across the states, and then you will get one result where you can be confident that this result is actually correct and true because all the data, all the tests from all the country are centralized to that single location or to those few single location. This is similar to what had been done in Europe and other countries. So, I think by centralizing the testing, you improve on the results, and number two, you reduce the cost. And many of those tests are actually approved by the Food and Drug Administration, FDA, then subsequently reimbursed by insurance companies. So, I think the more we do that, the more they will be readily available for community practice. They will be reimbursed. They will be, I would say, better standardized, and they will slowly, slowly replace the old techniques that are dependent on centers and and physicians.  

Naveen Pemmaraju, M.D.  Wow! You blew my mind away with that because you nailed it and you also mentioned something that I want to say back to you and out loud. This is a multidisciplinary item, this MRD testing. So, what I mean by that is what you just said. I want to draw it out. We are the clinicians we're the face, perhaps, if you will, of the team but it takes a whole team to make an MRD test happen. The pathologist and the pathologist's team is the critical juncture. So, shout out. You and I talk to our superstar hemepathologist, Dr. Sonam Loghavi, Dr. Rashmi Kanagal and the team. But it's really the, that's where it starts. So, I think the journey of the MRD, which I didn't think of, is so important. So, hospital leadership committees, very important because let's face it, this does take some money and resources. Folks need to attend the meetings to see some of the things we mentioned have only come out in the last few years. Then the pathologist team with their techs, technicians and all their folks have to have the right machines, the right assays. What's the cost? And then what you said is important. Even if a community may not have access, do you have the ability to send out? That's what you just mentioned, right? Send out the MRD test to a bigger center. Maybe that consolidates costs but still helps. And then does your clinical team have access ability? To then intervene on it, right? My goodness. So, there's like five or six steps to this MRD and it underlines how multidisciplinary it is. Maybe one last question, Dr. Haddad. Something that we don't know much about right now but I think will be important for us is in some of these diseases like myelofibrosis, MPNs that you and I care about and specialize in, post-transplant, there are some situations where we don't have a defined MRD to follow but there are publications, New England Journal and others, showing perhaps molecular bonding, where do you see some of these fields going? How does one think about MRD in the next five to 10 years, maybe in areas that don't have a defined MRD? I'll give you that easy question.  

Fadi Haddad, M.D. Well, I'm gonna give you a not so easy answer. So, what I think, and maybe some people would agree and won't agree, I think in the next five to 10 years, we will have artificial intelligence, AI, taking over the field of MRD, specifically in those disease that are so rare, that are so complex, and where you do not have any standardized testing for those type of disease. Because we have all the tests available. None of them apply to exactly the clinical scenario you mentioned, myelofibrosis, post-transplant. So, the effort of the pathology community and the leukemia expert is to gather all those cases, put them into a model, get AI to look into all of those 1,000, 10,000, 100,000 cases and come up with a model that can be as accurate if not even more accurate than the human eye to tell you if the disease is here or not. So, that's, that's how I see the future moving forward.  

Naveen Pemmaraju, M.D. I mean, just brilliant. I am blown away by that because you yourself are becoming expert in these technologies including AI, social media. I just want to emphasize how smart that is because some of our blood cancers are so heterogeneous, so impossible to even standardize that we as humans may not even agree on what those are or worse, we may miss it. So, what a great use of AI. One could picture a project exactly what you said. Can you give your AI a thousand cases of X, train it on those thousand cases? Here's what a potential MRD looks like. Here's, what it doesn't look like. Here's what disease overt progression looks like. Here's what remission looks like. Then you then you go to a validation cohort of another thousand and another thousand until you're ready for prime time. And another issue that you bring up is using non-invasive means. Currently, right now, most MRD assays are either at the tissue-specific or bone marrow level. But we should say one great breakthrough, as many of these are available through the peripheral blood, right? So, that's, that's great. But what you're envisioning is even one step more. And a world where we have non-invasive MRD testing based on algorithms from AI. You just blew my mind away. That's amazing. I think the question for you, the last question then, is what would you say about how does one factor in MRD testing into the future of research in the non-myeloid, non-lymphoid leukemia. So, a couple of them that we didn't mention here, aplastic anemia, PNH, some of these have a defined factor to follow, but as you know, most of them don't. Do you envision that we can have an MRD for every single subtype of leukemia?  

Naveen Pemmaraju, M.D. That's a tricky question. I'm not sure that we actually could have an MRD for all type of disease because some disease we need to be old school and just look at what the tissue is telling us. Because as you nicely mentioned at the beginning, to be able to track a disease, you need to have at least a marker, a barcode, a protein. But what if you don't have any of those? Then you will not be able track it and you need to go old school, old fashioned and put this piece of tissue or that piece of bone marrow under the microscope and just look at it by the eyes of an experienced pathologist, then you can say if the disease is getting better or worse.  

Naveen Pemmaraju, M.D. What a great way to sum up, and I totally wholeheartedly agree, that MRD is a great tool, likely not to replace the traditional morphologic pathologic, but to add to it, to be synergistic too. So, we may close by saying that MRD, minimal residual disease, or measurable residual disease, is an adjunct tool that augments, helps, improves our patient care in both the acute and chronic leukemias, rare and common. And then as you and I kind of had a nice discussion here that it potentially in research venues, both the existing technology and with the help of AI and computer technology, may expand the horizons for thinking about early intervention and new therapies. Dr. Haddad, I have to tell you, as always, when I meet up with you, I love talking to you, but you just blew my mind away several times during this. So, I hope the viewers out there got something out of this.  

Fadi Haddad, M.D. Thank you, Dr. Pemmaraju, for this interesting discussion. I hope it was helpful, and hopefully when we do it next time, we will have more updates and maybe all what we said today is going to become controversial.  

Naveen Pemmaraju, M.D. Well said. Thank you so much and thanks to everyone for joining us on the Cancerwise Podcast. For more information or to request an appointment at MD Anderson, call 1-877-632-6789 or visit MDAnderson.org. And thanks for listening to the Cancerwise Podcast from MD Anderson Cancer Center.