MDS: Patient-Centered Diagnosis and Treatment

0:00 [Music] You're listening to treating blood cancers, the LLS podcast series for professionals. We will be joined by cancer experts to discuss blood cancer diagnosis, treatment, side effects management, and the importance of clinical trials. They will share their experience in treating patients and discuss strategies for optimal patient care. Let's get the conversation started. Welcome to Treating Blood Cancers, the LLS podcast series for professionals. I'm Dr. Ken Miller. I'm a medical oncologist, hematologist, and an LLS volunteer. And I want to thank all of you for joining us on this episode. Today, we're going to be talking about myo dysplasia, including diagnostics, treatment strategies, and decision

0:46 making, patient centered care, and side effect management. We're delighted to be joined by Dr. Mikuel Securus who is the chief in the division of hematology and professor of medicine at the University of Miami Sylvester Comprehensive Cancer Center. Mikuel is also the author of When Blood Breaks Down, which is a wonderful book that I want to recommend about the science of treating patients with leukemia, but also the more personal side of it as well. Muel, thanks for being with us. Ken, how delightful it is to be here. Thank you for having me. So I was a fellow many many years ago when milo dysplasia was really described by the French American British group morphologically and I'd love your broad

1:32 view 60,000 foot view first about what we know about milo dysplasia now compared to what was known then and where have the big breakthroughs been? Yeah. Well, as it happens, Ken, I was a fellow many, many years ago also, and my displastic syndrome is really different now than how it was back then. You know, back then, people were hesitant to call it a cancer. And I even had interactions with great patient advocacy groups like the Leukemia Lymphoma Society or the Alastic Anemia and MDS Foundation about whether to use the word cancer in materials that went to patients because it was so controversial. In the end, we decided to use the word because we wanted to emphasize to patients just how serious a diagnosis this can be. And also what I was experiencing in my own

2:20 clinic is patients were being told by their doctors that they had a quote blood disorder. We even published a study about this in the oncologist about what was the first word used to describe miloidisplastic syndrome to patients who had the diagnosis and really for about 90% of them it was either blood disorder or a bone marrow disorder but the word cancer or something akin to leukemia was only used about 7% of the time. So boy were my patients surprised when they came into my clinic and I started to talk to them about how we were going to use a drug like aocyitine which is a chemotherapy to treat their blood disorder. So the first step in reclassifying myodisplastic syndromes was really when the World Health Organization undertook this both in 2001

3:05 and then later of course in 2008 2016 and most recently in 2022 to emphasize the fact that now we actually refer to these diagnoses as neoplasms. We still use the MDS abbreviation but now we refer to them as my displastic syndromes or myodisplastic neoplasms. So I want to ask you about that a little bit more because it is different I at least I think between calling something a neoplasm and calling it a cancer. There is a difference. I find when I'm seeing someone with milo dysplasia, I'm still leaning toward the gentler side and saying neoclasms. But what do you do as you're talking with patients? Yeah, I

3:51 think that's a natural human tendency to want to soft shoe the diagnosis a little bit when you're looking at someone who is in his or her late 70s, 80s. Often they'll have one of their kids with them as well to accompany them to the appointment. And no one has been brave enough to use the phrase neoplasm or cancer. So the way I describe it to patients is you have my disysisplastic syndromes. I think that's still the most common way it's described. I go over what it means, how MDS arises. I talk about the fact in plain language that it's a clonal disorder and then I say, you know, you or your kids may have gone online and seen a scary word associated with it and that scary word is cancer.

4:37 Let me put it in context. And if somebody has a lower risk my plastic syndromes, I'll say this is more of a lower C cancer and I'm sure you have friends or family members who've had cancer and they've lived with it for years and that's what we're talking about here. But I do think for higher risk myoid disysisplastic syndromes where the median survival is less than a year and a half, we do have to be brave and put on the big boy or big girl pants and use the word cancer with our patients and emphasize to them that it's a serious diagnosis that needs serious treatment. Yeah. So, in a sense, the description that comes after the words is obviously just as important and framing it as again a chronic illness or more of a acute and life-threatening illness that it can be. Well, that's exactly right. I mean, if we soft shoe

5:24 it and say it's a blood disorder and then say and now I'm going to treat you with 7 days of aidine every 28 days or 5 days of decidabine for as long as this works for potentially the next 1 2 3 4 years. G whiz that's not going to make a lot of sense if you don't use a word to describe the seriousness of it. Also, you know, let me ask you in that framework of high-risisk and low risk, how would you describe high risk? How would you describe low risk using sort of the classifications that we're using now in 2025 from a morphologic point of view, a molecular point of view, a genomic point of view, what are the main things that make these two what they are? Sure. I think that's a great question and it's changed over time. To

6:10 be honest, I think within the MDS world, we're guilty of making this really ridiculously complicated. You almost wonder if it's job security. We're trying to confuse people. So, so they don't understand it. So, we can still be specialists in it. But it really boils down to some very basic facts. So, my displastic syndrome are characterized by cytoenias. About 80% of people with MDS have an anemia. But people can also have neutropenia or thrombocytoenia. The more cytoenas you have, the worse the MDS. That's fact number one. Fact number two is that it can be very similar to acute myoid leukemia particularly biologically like acute myoid leukemia in older adults. So blasts are important. Fewer

6:59 than 5% blasts we generally consider to be lower risk. The more recent iterations of prognostic scoring systems make a dividing line at 2% blast. So 2% or fewer blasts is really lower risk. Once you start to get to three or four or 5% blasts, you're starting to creep up there. And then more than 5% blasts, you start to get to a condition where you have a true block in differentiation just like you have with acute myoid leukemia. So blasts matter. More recently there have been attempts to start to ask the question about where we make the dividing line between my disysplastic syndromes and acute myoid leukemia. Classically that has been at 20% blasts. So once you have 20% blasts we say you have acute myoid leukemia. If

7:46 you have fewer than 20% blasts you have myoidisplastic syndromes. But really that 10 to 20% range there's not that much difference between a higher risk myoid displastic syndrome and an acute myoid leukemia. So we're still deciding where that bar is for now. I would say the standard is to still say 20% blast is acute myoid leukemia. Fewer than that is still higher risk myoidisplastic syndromes. So far I've talked about cytoenas. I've talked about blasts. The third arm to this are the genetics. So we've gotten pretty good at figuring out the genetics of myodisplastic syndromes. We have some genetic abnormalities, chromosomeal abnormalities that we associate with a good risk myodisplastic syndromes and

8:32 those can be abnormalities in minus Y, deletion 5Q, deletion 20Q. And we have some abnormalities that we associate with poor risk in my displastic syndromes. Those occur when we get the carotypic report back and we have a paragraph long of mutations, right? Someone who has a lot of mutations like that is a very poor risk my displastic syndromes and of course we associate abnormalities of chromosome 7 or chromosome 3 with poor risk. So everything else kind of falls somewhere in the middle and I'm grossly oversimplifying that but that's because we've grossly over complicated it in how we think about my plastic syndromes. So to summarize cytoenias, blasts and kotypic abnormalities those are the

9:17 things that go into the revised international prognostic scoring system. That's what we use as our quote unquote staging system for my displastic syndromes. Now MDS has become even more complicated than that particularly over the past decade as we've been focusing on molecular abnormalities and there are some classic molecular abnormalities associated with my displastic syndromes. So it is absolutely requisite that patients who are undergoing a bone marrow biopsy for potential diagnosis of myodisplastic syndromes also receive next generation sequencing panels for myoid mutations. And it's now gotten so complicated that I can't do this on the back of an envelope anymore to to calculate out a risk score. You we've got to go online.

10:05 If you do a search on IPSS- M M for molecular, you'll have a very easy to use calculator where you plug in information about a patient's blood counts, a patient's age, kotypic abnormalities, and molecular abnormalities. and it will now kick out a score that tells us whether a patient is lower risk or higher risk. Higher risk is a positive score, lower risk is a negative score with the IPSSM. So let's take it to the next step. There is a group and I can think of patients in my practice who would be defined as low risk. They have let's say some morphologic changes. They don't have a I'm thinking of one woman in particular, no cytogenetic abnormalities, but a few things on fish.

10:53 We talk about a watch and weight approach or supportive care. Sure. What's the state of therapy? The state-of-the-art now for someone like that. Let's start with higher risk MDS. If a patient has a diagnosis of higher risk MDS, I believe we need to start treating that patient immediately. And the reason is, as I mentioned before, if the median survival is less than a year and a half, we have to start therapy to try to prevent that MDS from going into acute myoid leukemia because the rate of transformation is so high with higher risk MDS, but also to prolong someone's overall survival. The only level one evidence we have in higher risk MDS for treatment is with the drug aocytoine

11:38 where there is a randomized trial the ASA1 study in which patients with higher risk MDS received ascocadine or conventional care regimens on that study patients who received ascetine actually live longer significantly longer than when they received conventional care regimens. So that's why it's so important first of all to start by figuring out does someone have lower risk or higher risk MDS to know how urgent it is to start therapy. So with higher risk MDS our goals of therapy are to try to prolong overall survival prevent transformation to acute myoid leukemia and provide somebody with a better quality of life maybe by improving their blood counts with lower risk MDS. No prospective randomized trial has ever demonstrated that

12:24 intervening with a drug is going to allow someone to live longer. So if I'm not allowing somebody to live longer with a drug with lower risk MDS, the only thing I'm adding to that person's ability to feel better is to minimize their transfusions or maximize their quality of life. Right? So if somebody with lower risk MDS has a really good quality of life, let's say they had an abnormal blood count, their primary care physician recommended they go to a hematologist. the hematologist did a bone marrow biopsy and lo and behold, they have lower risk MDS but never would have known it otherwise. The only thing I'm going to add to that person if I try to treat them are side effects to a

13:09 drug. Yeah. Exactly. Right. So those are the folks we follow with active surveillance and it may be that I see somebody every 6 months. It may be that I see them every month depending on where on the spectrum of lower risk MDS they fall. So really getting down to some nitty-gritty ariththropoadin loose patter again what are some ways to decrease transfusion burden for example so if somebody doesn't yet need blood transfusions if their platelets are pretty good sometimes I make the joke they're good enough for government work right they they get the job done they may not be perfect but they get the job done they haven't had recurrent infections and there's nothing we have to do once someone's hemoglobin starts to drop particularly as it gets closer

13:56 to eight. A hemoglobin of eight is generally our transfusion threshold for lower risk myodisplastic syndromes. A lot of people will use a hemoglobin of seven because of the studies that have been conducted in the hospital where there's no difference in outcome if people are transfused at a hemoglobin of seven or nine. But those studies were conducted in patients who were in intensive care units. It's not the same population as our older adults who are outpatients. So good point. transfusion threshold of eight is generally what we use in the MDS community. So once a person starts to get down towards 8, 7.9, 7.8, they're going to start to feel it. Particularly since these tend to be older adults, and that's when we start to think about initiating therapy. We

14:42 can start off with a blood transfusion. If a person needs a blood transfusion every 2 or 3 months, and I have a couple patients like this, that's probably not too bad a quality of life. But once my patients start to need a blood transfusion more frequently than once per month, they start to complain about it a lot. It becomes a burden to them to have to come to the infusion center to get that blood. And that's when we start to think about initiating therapy. An easy first step in initiating therapy are ariththropois stimulating agents. Yeah. Now, it doesn't take an MDS nerd like me to know that if a patient has a skyhigh EPO level already in their serum, an EPO level of 700, a thousand, and they're already starting to require blood transfusions, giving them

15:28 exogenous EPO probably isn't going to work. Their body's already cranking out a lot of EPO. Yeah. If on the other hand you have a patient who has an EPO level that's less than 100. So higher than upper limit of normal for labs which is usually around 25 but lower than 100 the likelihood that that person is going to respond to EPO is actually pretty good. You're probably getting into the range of about 50 to 75% chance that it's going to work. So giving EPO as a first step is a great idea. Now with MDS we don't give the same doses that we would to a patient who has renal failure. Patient with renal failure may get 10 or 20,000 units of recominance humanized ariththropotin every week for somebody with MDS that's going to be closer to 60,000 units per week per week for

16:14 recominant humanized ariththropotin if we're using darbapotin the US study actually used 500 micrograms every 3 weeks and then if patients didn't respond after about 12 weeks you give it every two weeks just to comment that I mean it's a very well-made point that the real dosing is not the right dosing for MDS. Yeah. I mean, I'm glad you're emphasizing that also, Ken. So, one of the referrals where where I look like a rock star, but I'm not such a rock star is patients not responding to EPO from their doctor who's giving 10 or 20,000 units a week, right? I come up with the magic of giving 60,000 a week and all of a sudden their hemoglobin smart. So, I think EPO is a great starting point. You mentioned loose patter. There

16:59 have been a couple of randomized trials with loose powder and loose patter has a couple of indications on its label. One of those indications is for upfront therapy of patients who have transfusion dependent anemia with lower risk plastic syndromes. Now in this study patients were enrolled if they had ring citeroblasts or an SF3B1 mutation. SF3B1 mutations are almost a synquin non for ring cider blasts or if they didn't and on this study upfront therapy with loose patter led to a transfusion independence response rate lasting 12 weeks or longer of about 60% compared to about 31% for patients who got ariththropois stimulating agents and the duration of that response was

17:45 actually over 2 years. It was pretty impressive. It is. But the caveat to this trial is that almost all of those the improvement in response to loose patter over ariththropes stimulating agents was driven by patients who had ring ceterlasts and or SF3B1 mutations. So they were true rock stars. They had this incredible different rate of transfusion independence with loose patter versus orthropois stimulating agents. But when you looked at those patients who didn't have ring cider blasts or didn't have an SF3B1 mutation, the response rates to ESAs or to loose patter were about the same. So my approach to these patients if they don't have ring cerblast and don't have an SF3B1 mutation is it's dealer's choice.

18:33 You can start with an ariththropois stimulating agent and then when that stops working or if it doesn't work you can then consider going to loose patterin. second line for those patients who do have ring cider blast or an SF3B1 mutation you can certainly start with loose patter and then consider ariththropesis stimulating agents as a second line although we really don't have a lot of data about the effectiveness of ESAs following loose patter so we used to look at ring refractory anema with ring sitter blast that group even as you know some were puradoxy responsive the reason I bring it up is what is there in particular about that biology that makes it a sort of its own subset. Anything about the molecular biology? Yeah, Ken, that's a

19:20 great question and one that I don't think we really know the answer to. I I wonder if it has something to do with iron transport mechanisms because it is different in patients who have ring cider blast. That's why they have the rings compared to those who don't. But we really don't know. Uh and you could certainly make the case and say as you reflect over the past 20 years of treatment of MDS you could say well wait a second those folks with ring sitter blast seem to do better with every therapy is there really something special about loose patter versus not the answer is I don't know what I do know is there's a randomized trial that shows that those folks with ring citar blast sure do seem to respond better to loose patterep than folks who don't have ringitar blast you ask you about because we've talked some about low risk and what I would call supportive care. You made a very good point about I'll use my own words

20:07 which is if it ain't broke, don't fix it or or at least you know do no harm. The there's an intermediate group who are probably not on the very verge of developing acute leukemia but have some blasts and they have cytoenias. Let me ask you about one group in particular who have neutropenia. there let's say some anemia or thrombocyopenia but where neutropenia is the biggest issue how do you manage them use chronic antibiotics is a growth factor in a sense a no no that's how I've learned it but what are your views yeah there are a tricky population there are some patients with MDS about 6% have an isolated neutropenia so it's relatively rare often we'll see neutropenia in combination with other cytoenias as you say as patients start

20:55 to slouch towards intermediate and higher risk MDS for patients who have an isolated neutropenia or where the neutropenia is the predominating cytoenia the very first thing I do and and we've heard this this this phrase in medicine before when we say to each other don't just do something stand there right the opposite of what you hear in the movies where they say don't just stand there do something in medicine the hardest thing in the world is to not do something is is I watch those patients over time to try to figure out if they have a functional neutropenia. So the blood counts may be low, but we've all seen these folks who have neutropenia where they get an infection, all of a sudden those neutrfils rise and they they have a good response to to to an insult, right? So

21:42 if I have a patient who's neutropenic, but they're not getting infections and I follow them for 6 months, a year, a year and a half, then once again maybe the best thing to do is is nothing is just watch them over time. Sure. If I have patients who get recurrent infections, I will start to introduce prophylactic antibiotics. I do not use growth factors to stimulate the neutrfils though. I think it's a pirick victory. I think we're convincing ourselves that we're making something better by raising the numbers. I don't know that we're improving a functional immune response. Got it. Yeah. Thank you. So then the question is what do you do with these folks? What happens when they do start to get infections? And that's when we start to think about hypomethylating agents. There's a dirty little secret in drug development and MDS and that is

22:28 that if 80% of patients have some degree of anemia, drug development is going to focus on anemia. That's the market share. So you don't have drugs that are focusing on isolated neutropenia or isolated thrombocytoenia. So what we wind up doing for these folks is to introduce hypomethylating agents. So the same drugs that we use for higher risk MDS although there's a study in which we participated for the MDS clinical research consortium where we showed that giving less is more. So instead of giving 5 days of decidabine or 7 days of aocyadine maybe 3 or 5 days of asicetine or 3 days of decidabine is enough. Got it. Very interesting and appealing because again we're treating a group with cytoenias with drugs that are somewhat milosuppressive.

23:14 Right. Exactly. Particularly with lower risk MDS with higher risk MDS again we're slouching towards a much more serious disease. And biologically we're looking at something that is almost acute myoid leukemia. Even if you look at the molecular characteristics of these diagnoses, higher risk MDS is very similar to acute myoid leukemia. And maybe someone with higher risk MDS has on average three molecular mutations. Someone with secondary acute myoid leukemia has four. So we literally see in the biology how higher risk MDS becomes secondary acute myoid leukemia. Let me ask you about evolution from MDS into leukemia. What do we know as a field about how that occurs? Are the

23:59 repair mechanisms gradually deteriorating? What have we learned? I've done some translational research from the clinical translational research looking at the genetics of myoid malignancy. So I really think about it from a genetics perspective and then I also have a background in epidemiology. So I throw in some statistics into it. Right? So stochiastically MDS evolves over years or decades. How do we know that? We've got two levels of evidence to say that. The first is an epidemiologic study. There was a a publication in JCO from the Atomic Bomb Research Institute where they found they have incredible detailed information about where a group of people were standing in relation to where the atomic bomb was dropped on

24:44 Oroshimar Nagasaki and based on that they've actually calculated the doymmetry of their radiation exposure and what they found is that these folks who were exposed to the atomic bomb when compared to people in Japan who weren't exposed to the atom IC bomb have 17 times the likelihood of developing MDS in the 1970s,8s and '90s. Remember the atomic bomb was dropped in 1945. Yeah. So a very long So you're saying that process has been going on for 40 years. For decades, right? For decades. So that's epidemiologic evidence for my claim. The biologic evidence for it are the work that we and others have done particularly people like Lucy Godley

25:30 University of Chicago looking at germline mutations that lead to myoid malignancies. So I myself had a patient who invited his identical twin in to meet me as well both of whom had MDS in their 60s and we uncovered that they had a germline mutation in the DDX41 helilicase abnormality. So those folks were born with something that didn't rear its ugly head morphologically until they were in their mid60s. Again, decades of evolution. So now let's turn this to your question about the evolution of MDS to acute myoid leukemia. You get one mutation probably at some point when we're younger and we see this in folks with chip, right? Clonal hematopois determined potential where we see that rise in people who have these mutations

26:16 we associate with myoid malignancies. You know, it starts when we're younger in our 40s and 50s, but really starts to take off in our 60s and 70s. Right? That's mutation number one. Add to it something in our environment. Maybe it's somebody who smokes. Maybe it's somebody who got radioactive iodine for thyroid cancer or radiation for prostate cancer or chemotherapy or radiation therapy for breast cancer or lymphoma. That adds mutation number two, maybe mutation number three. Then you have cells that have already shown a proclivity to develop mutations that are inherently unstable and more likely to develop that fourth mutation and that's when you're getting from MDS to acute myoid leukemia. Yeah. Let me ask you some questions about the host because I have found it interesting. Well, obviously that there's patients

27:01 who are treated let's say for leukemia and go into remission and do well. There's people that don't and this is obviously moving more into the leukemia side. It could be high-risisk MDS as well. Is there any known difference in terms of immune surveillance since this is a time when obviously as clinicians we're very tuned into immunotherapy? Sure. Another great question. So there are data showing that patients who have autoimmune conditions are more likely to develop my displastic syndrome. Right? So it is definitely an immune disysregulation problem. And we have data from patients who have alastic anemia which is a T- cell mediated bone marrow destruction process who obviously have more of a proclivity for developing myodis plastic syndromes and you can see

27:47 them develop mutations over time. So there is an immune surveillance problem I think that is more predominating in a subset of patients with myisplastic syndromes that also describes why drugs like antiy globulin work in about a third of patients with lower risk MDS so fascinating right it is but let's get to your question about imunotherapy and cartisel therapy why the heck hasn't that worked then in patients with my split it's been a real dud. It really has been and and I think that's because particularly as we move towards higher risk MDS, I don't think it's the immune surveillance problems that are predominating. I think then you're getting much more into a clonal process

28:34 where you need a damaged hematopoetic cell precursor to be either corrected or removed and more blunt instruments like chemotherapy, hypomethylating agents are going to be more effective. Got it. any new insights since demethylating agents became available, at least the way I've described it, to patients or to internal medicine colleagues, is that we're unsilencing certain genes that are favorable. Is that the case or is it more complex or different? When I talk to patients about this, because they'll ask me, how does this drug work? I think there are three ways that it works. One is exactly what you're talking about where we talk about these CPG islands on tumor suppressor genes, right? said methyl groups are added to tumor suppressor genes. They turn the tumor

29:20 suppressor genes off. Therefore, the genes don't suppress the tumor. Hypommethylating agents or DNM T DNA methyl transferase inhibitors are protecting those tumor suppressor genes from methylation allowing them to be transcribed and thus allowing suppression of the tumor. That's mechanism number one. Mechanism number two is as differentiation agents. So we have these cells in MDS and in acute myoid leukemia that are stuck at immature stage of development and this is helping march them along so that they eventually become like mature neutrfils. Mechanism number three is directly cytotoxic. So when we see people who are treated with hypomethylating agents we sometimes see a little bit of all of this occur.

30:06 Sometimes we don't see a lot of difference in cytoenia. Sometimes we see patients become profoundly cytoenic to these drugs and we see that cytoenia occur in different weeks of a four-week cycle. And so I think that's where you're seeing the kind of which of those mechanisms of attack are actually predominating. Wow. In very interesting and subtle I mean in many ways to accept someone who's seeing this all the time in a large number of patients. So thank you. Let me ask you about a patient and I'm interested in your thinking process. So I'm seeing a woman now who's 78 years old in fairly good health not a lot of coorbidities but not robustly in good health in terms of just general lifestyle and abilities. She has high

30:54 risk MDS. She's got about 15% blast. She's got one of those paragraphs of cytogenetics as you described it and she's really very high risk. I have been treating her with aocyadine and we're maybe four months into it. I can't say there's been any big change. But how do you think through the care of a patient like that? What is the role for transplant? So what we've learned from a bunch of randomized trials that we've conducted looking at combination therapies is how critically important it is. I can't emphasize this enough. How critically important it is to maintain the dose and the schedule of the hypomethylating agent during the first four to six cycles of therapy. And we

31:40 learned from a variety of trials the North American intergroup trial where asicetadine was compared to asocyadine and lenolyomide or aocitine plus the histone dioetyl inhibitor verinistat. We learned this from the asicetadine versus plus heavonet trial. We learned it in this from aetine versus a asicetine plus sabatamab trial which is immune therapy that patients who didn't get enough dose who had dose delays who had dose reductions didn't do as well. So let me give you one example of this. On the North American intergroup trial, when we looked at the number at median number of weeks that patients received each of these arms, patients got aocyadine alone for a median of 26 weeks, right? So

32:28 we're talking about 6 months. Patients got lolenolyomide for about 25 weeks, pretty close. But they got asocedine vernistat only for 20 weeks. As a result, the response rates were lower for Asocusadine and Verinist, but they were artificially lower. Yeah. Right. They hadn't gotten enough drug. And when we actually looked at overall survival, there was a trend towards an improvement in overall survival in patients who got aine and ferinist. So if they had just stuck with it longer, we may have seen a significant survival advantage to that drug combination. Yeah, we used that information and applied it to the ASocidine and Pebbanetistat trial. Pvonetistat is a NED 8 activating enzyme inhibitor. On that study, we had very

33:14 strict language. You are not allowed to dose reduce. You are not allowed to dose delay. You're not allowed to alter this at all without speaking to a medical monitor. And then the medical monitor was instructed, don't let them alter anything. What we found was something really interesting. If you look at the original studies that led to ASocytine's approval, the CR rate was 17%. And that has been repeated over and over again, a CR rate of 17% for ASocytine. On the PvNet trial, the CR rate to aocitine monotherapy was 32%. Wow. Wow. So it almost doubled. Yeah. when we were really strict about keeping patients on the right dose and the right schedule for the first 4 to 6 months. That's probably my biggest piece of

34:00 advice to treating anybody, including your 78-year-old patient with excess blast to maximize the chance that the drug's going to work. Got it. Got it. And in terms of transplant, there are a number of trials now, most of them decision analyses or high-tech statistical voodoo that goes into this that have shown that when we treat patients with higher risk MDS upfront with a bone marrow transplant, we maximize their survival. The opposite is true in lower risk MDS. That we maximize the survival in someone with lower risk MDS if they undergo a transplant after they've already been exposed to a bunch of different types of therapies. You've mentioned adding a variety of different drugs to the demethylating agents. Where do you see things going in

34:46 terms of the new clinical trials and what are some of the things you're excited about? Yeah. Well, so I've dedicated a lot of my career to looking at combination therapies and MDS and it has been a frustrating career, but I have not given up on it yet. Okay, good. So we are waiting for results of a randomized trial that combines aocyadine and venettolax versus monotherapy in patients with higher risk MDS. This combination has already been approved for patients with acute myoid leukemia. And so you would think gee it should work in higher risk MDS but MDS is trickier to treat than acute myoid leukemia with a lot more problems with cytoenias. And that's where you have the bone marrow failure aspect to a diagnosis for my displastic syndromes. We are expecting the results to be

35:31 reported out later in 2025. We've been waiting now for years. If that study is positive, it will be the first combination therapy approved for the treatment of MDS. If that study is negative, I will bet you a nickel there going to be a lot of caveats to it and subgroup analyses and someone's still going to try to tease out some positive aspect to it. For now, I am really not giving that combination off label unless I have a younger patient who has a blast percentage that is scarily close to 20%. So, they already essentially have acute myoid leukemia. Yeah. Other combinations are being explored. I think one exciting area is thinking about targeted therapy. IVA sit which targets Idh1 mutated MDS. It's a very rare subtype of MDS has been

36:18 approved by the FDA. People are typically using it after a patient has been exposed to a hypomethylating agent and that hypomethylating agent has failed that patient. I think increasingly we're going to start to see targeted therapies added to aocytoine for patients with MDS acknowledging that these are still very rare subtypes of MDS. Already we're starting to think about the SF3B1 mutated patients, those with ring citerlasts as being a potential quote target unquote for drugs like loose patter though both you and I have discussed how we're not really sure that that's targeting a patient in a special way. But I am excited about the future as we finally teased apart a lot of the biology of MDS, what drugs we're

37:03 going to be able to apply to treating it. Very nice and very exciting. And I have to say, you know, thinking back again to 30 years ago, what was Milo dysplasia and what is it now? I want to reflect back on something you said earlier which has been meaningful to me in the past half hour. In a sense, the study you mentioned about maintaining dose or dose intensity in MDS is a reminder that it's a cancer. Y and therefore not calling it what it is really has harm beyond just not being as truthful as we might be. Completely agree. Completely agree is so important in communicating to our patients the seriousness of a diagnosis of particularly higher risk MDS. Lastly, just ask you as an author because you've

37:48 written about some of your patients with leukemia, but if you were to do a second book or another book because I know you've written other things, but if you were to do another book on MDS, how might it be different than the first book on leukemia, what stories might you want to share? So I am actually working on another book, something that's a little broader than MDS, focusing on cancer and identifying what's truth in cancer and what are fallacies in cancer because I think there's a lot of information that's great out there about cancer. And I think there's a lot of misinformation as well and we hear this from our patients. They've, you know, hear things like, gee, I should be avoiding eating anything with sugar in it because sugar feeds cancer, right? That's one of my favorite ones. So I am working on that. And you know, I love to

38:34 include anecdotes about my patients, of course, in a completely hypocmplant way. Of course. Yeah. Because we learn so much from them and it helps us with how we investigate cancers like my displastic syndromes and make other people's lives better. I have some terrific stories from my patients about their occupational exposures, which you never know unless you ask. I think you have to be a naturally curious person and ask how one of your patients has lived his or her life. Yeah. And that's why when we talk about medicine being a privilege and the insight we get to our patients, it's not just empty words, but we only get to experience that privilege if we make the effort to explore our patients lives. And I've written about

39:20 some of these folks have these incredible stories about how their MDS may have arisen. I recall one patient who talked about how he was in the Navy and was sent down in a naval warship during the Cuban missile crisis and he talked about how hot and humid it was as they were, you know, approaching Cuba, of course, cuz it's in the tropics and how the only place he could sleep was in the cool, dark hull where he would lie down right next to one of the nuclear missiles. Wow. Well, well, so you can imagine that exposure may have been mutation number one. Yep. Yep. Yeah, I got it. Wow. That is an interesting story. Yeah. I think we're very fortunate to be able to get to know people in this way and part of the joy of medicine of being in the healing

40:06 profession. Yeah. Like that we are. Yep. Absolutely. So again, this is Dr. Ken Miller. I have to say this has been such an interesting topic and discussion. What a pleasure to meet and talk with Dr. MueL Sicurus who is the chief in the division of hematology and professor of medicine at the University of Miami's Sylvester Comprehensive Cancer Center and the author of When Blood Breaks Down. Muel, thanks so much for being with us. Ken, what a pleasure and a joy it was to be here with you. Thank you for inviting me. Terrific. Thank you. And I want to thank all of you for listening to this terrific episode. For a listing of all of our healthc care professional continuing education activities, podcasts and healthc care professional resources, please visit

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42:23 professional continuing education activities by visiting lls.org/ce. Let's keep the conversation going. Until next time, [Music]