Facts about myelodysplastic syndrome

MD Anderson Cancer Center
Date: 11-5-12


Lisa Garvin: Welcome to Cancer Newsline, [background music] a podcast series from the University of Texas, MD Anderson Cancer Center. Cancer Newsline helps you stay current with the news on cancer research, diagnosis, treatment and prevention, providing the latest information on reducing your family's cancer risk. I'm your host Lisa Garvin. Today, our guest is Guillermo Garcia-Manero, he is a professor in the Leukemia Department here at MD Anderson and he is renowned expert on myelodysplastic syndrome which is a group of hematologic diseases. Welcome Dr. Manero.

Dr. Guillermo Garcia-Manero: Thank you.

Lisa Garvin: Let's talk about myelodysplastic syndrome or MDS. It's basically cells gone wild.

Dr. Guillermo Garcia-Manero: Well, it's a disease that traditionally, let's say 20, 30 years ago was considered almost like a preleukemia. And the reason that is that one of the many features of this disease is that it most commonly presents as a bone marrow failure situation. And by that, what I mean is that the patients may have some degree of what technically is referred to a cytopenia. That means low white count, anemia, low platelet count or combination. This disease has also a very important leukemia component where many of these patients will be in what we call a high risk situation or category that can transform into acute myelogenous leukemia. So for years, this preleukemia concept was actually used basically almost as an excuse to observe patients with MDS and don't offer really any significant treatment. Part of that was this because there were no therapies. I guess we'll be talking about that later. For the last 10 years, there's been quite a bit of an effort trying to understand better what is the natural history of this disease, what are the molecular bases for MDS, basically, what happens when you have this disease and why do you have this disease. And what we understand now is that first of all, the disease is very heterogenous. It was very difficult to make one simple categorization of this disease because unfortunately this is one of these diseases where you have multiple subsets or subtypes that are put together under this umbrella of the term MDS. And second, again, the disease has these different phases that may make the analysis even more complex depending on where you are and the stage of this disorder. But we have also learned a very important thing that is that most patients with myelodysplastic syndrome unfortunate, they will succumb to complications of the disease. So this issue that patients with MDS transform to AML and that's the cause of their death is really not correct. So a large majority of patients with MDS die from causes intrinsic to the disease itself, not truly from transformation. And that has created the total different framework for us to work and think about this disease.

Lisa Garvin: And so what is the basic biology? It's about cells that are actually being released from the bone marrow before they are mature or?

Dr. Guillermo Garcia-Manero: No. So basically, the bone marrow is an organ like any other organ in the body that has a function. And the function of this organ is to produce all the different elements of the blood. They are multiple but to make it simple is you have red cells that carry oxygen to tissues. You have white cells, there are many types of white cells, but they serve some type of defense mechanism against infection. And then you have platelets that allow your body to, you know, stop bleeding. This is an orderly process that is called hematopoiesis or blood formation. So from stem cell or several groups of stem cells, we actually don't know exactly the details of that but from some precursor cells, under different stimuli, from the outside, this organ, the bone marrow makes this different elements of the blood that is what allows you to climb on Everest if you are a mountain climber or, you know, fight an infection if you get sick, or you know, clot your blood vessel if you cut yourself. What happens in MDS is that this process is altered. And it's altered in a way that recruits the final successful generation of one of this products or multiple. So the defect is happening more in white cell formation then you maybe prone to develop infections. If you have a problem forming or creating platelets, you know, platelet count is low, then you maybe prone to bleed. And if you are anemic of course, we need some level of oxygenation in our body to carry our own functions. So you then develop complications of excess transfusion, sign of overload, things of that nature. So that's kind of like the bone marrow failure part of the disease. That is a way that many of these patients present nowadays. That is actually the most common presentation that I see in my clinic right now. People are going more and more frequently to the physicians. The physicians are using blood tests to just see what the patient is doing on a yearly basis and then they find a little bit of anemia or some degree of low platelets that are many times actually not clinically significant, but that triggers subsequent evaluation that includes this bone marrow test that we do. Eventually, this process of bone marrow failure, so in this capacity of not making the proper final product, it takes you into a situation where the cells starts acquiring and by the time in the bone marrow stem cell, starts acquiring some capacity to transform and become truly--true leukemia or a true neoplastic process. Now, in some patients there is a gradient where they start in a low risk situation where they have a little bit of low counts. And if you follow them long enough, they go on and move on into a full blown high risk myelodysplastic syndrome or acute myelogenous leukemia. But the reality is that many patients stay and only stay in a low risk situation, but we have identified here at MD Anderson that the so-called low risk disease actually is very heterogenous itself. And there are people with poor prognosis that are "in a low risk category." We could discuss that later. And there are patients that present the [inaudible] in a high risk situation. Now the question is, is it possible that 3 or 4 years earlier they could have been in some of these early phases of the disease and because they were never seen they had no symptoms? It was not detected. I don't really know. Nobody knows. But most likely, you could probably have all this type of situations where you go from low risk to more leukemia type of picture or do presented with one or the other or just stay with one.

Lisa Garvin: How are these--obviously, these are diagnosis that are made under a microscope by somebody, by a pathologist who really knows what he's looking at. How are patients normally diagnosed with an MDS? Are they misdiagnosed or they diagnosed with something else? I mean, how do they end up being--

Dr. Guillermo Garcia-Manero: This is a very a good question and we actually published a paper on this. I think it was last summer, because I have noticed over the years that there was quite a degree of what do we call discrepancy between the outside diagnosis and the inside diagnosis. So we calculated actually that probably we kind of declassify close to a quarter of that patients that come to MD Anderson. Now when we put out this paper, the reviewers, they really wanted us to use very astringent criteria in terms of what we call discrepancy. And I think that in the final report of that paper in blot sort of 12 percent or 15 percent, but its still is not trivial because it tells you that, you know, between 10 to 20 percent of the patients that we see, we may not actually totally agree with the outside report. And this is very important because it can go both ways. It can go down we say it was low risk outside and it was high risk here or vice versa. So you're going to be making therapeutic decisions based on those findings. And people that they thought they didn't need a therapy now within that they need very aggressive treatment and vice versa, people that came here with diagnosis of acute leukemia will say, well, we actually see very minor changes compatible with early MDS. So we see that all the time. And that's why when a patient is referred here we always try to obtain a bone marrow specimen because in a way my job is easy. I do what the bone marrow tells me. And if the source of information is not 100 percent reliable or the one that I'm used to, I'm not really giving the information that the patient require.

Lisa Garvin: Obviously, as a hematological disease, chemotherapy would probably be the most common treatment, maybe combined with stem cell or not. Is there a standard of care for MDS?

Dr. Guillermo Garcia-Manero: That's a very good question. Basically, because the disease is so heterogenous, as we we're talking earlier, we really try to target the specific therapies for specific subset of patients with the information we have. So the stem cell transplantation can cure a fraction of patients, but it has risks that are inherent to this type of approach. So then you have to calculate the risk benefit. So for instance, it's clear that patients with what we call low risk disease do not benefit from early transplantation. That doesn't mean they may not be educated about this because they may need that 5, 6 years later. Patients with high risk disease appear to have a benefit with transplant, but transplant is a way to consolidate the disease. And then the question is how do I take and that's actually my job. Patients do transplant. And then the other issues that because this is a disease of older individuals, maybe on age are on 70 to 75 years of age, the reality is that transplant is only uses in a small minority of patients just because this older individuals are either not interested or they are not free to go to transplant or they may not have appropriate donor. So what are the non transplant approaches? We divide this into risk situations. So for instance, if you have an alteration of chromosome 5 and you have anemia, you have low risk disease, this are drug called, the thalidomide that works very well in this group of patients. But probably the standard right now for majority of patients is the so called hypomethylating agents. There are two of them. One is called 5-azacytidine, the other one is called decitabine. They have been shown, particularly is azacytidine randomized clinical trial to improve survival. We have a lot of experience with decitabine here, and it also has giving us very positive clinical results. The reality is that they are really not curative. So they are not drugs that you can say, "I'm going to take this for 6 months and then the disease is going to be gone." So these are chronic therapies. And there's a lot of questions in terms of how you integrate this cytotoxic therapy. So we called this hypomethylating agents in reality are low or not very toxic forms of chemotherapy and are not maybe what the public thinks in terms of what chemotherapy is. How you integrate these approaches with the stem cell transplant. And there's a subset particularly the younger ones that may be candidates for type of therapies that we use in acute leukemia that these are very high dose, very intensive type of approaches. But that is usually or commonly used when we want to basically take patient to transplant fast. But they are not optimal. None of this approaches that we have are really drugs that we can say patients going to live a normal life or is going to live the total life that he or she was supposed to have before they were diagnosed with this disease. So instead for a small group of patients that's probably are cured with transplantation, our compounds, for a long survival, they decrease transfusion needs, they improved quality of life. So these are good intervention, don't get me wrong, but they are chronic. And one of the things that we're seeing now is that eventually, most of our patients will lose the benefit that they had if they had that response. So that's problem, what we call resistance or failure. But now that we have a lot of experience with these compounds, we're saying. So what we do here at Anderson is actually trying to develop no combinations, trying to improved on some of this "standard of cares" either by using new drugs, new combinations, or now actually in the time of, I guess genomics, trying to identify new alterations that we could target and you know, maybe improved outcomes from particular group of patients.

Lisa Garvin: And also isn't a part of your research trying to detect which cases will become acute or actually morphed into AML? Do you have--are there markers? Is there's something your looking at to do a predictive?

Dr. Guillermo Garcia-Manero: Yes. So that's an important question. Actually, a lot of our emphasis over the last 3 or 4 years and it may sound kind of, you know, simple but has been very important, has been to define better what the actual history of the patient with MDS is because this had not been really well studied in the past. So we probably are one of the groups that have put more energy on describing actually simple questions like what causes death in these patients. In this--as I mention earlier, in this so-called group of patient with low risk disease. When you have the experience that we have here by seeing a lot of patient in the clinic, you know, you realize that patients have very different trajectories if you follow that. So we build models that allows us actually to predict an early patient that is 1/2, a very poor prognosis. And this is very important because, for instance, we never thought or discussed this concept of early intervention in leukemia because the idea was you either have leukemia or you don't have leukemia. But now we're starting to learn actually that in MDS and probably other leukemias like chronic lymphocytic leukemia, et cetera, we could develop tools to actually do this early--not detection, through this early prognostication. So then you can say, "Well, you look wonderful. You have low risk disease," but with some degree of certainty, we believe you may get very sick from this disease in 12 months or in 15 years. And then the 15-year person is like you don't need to come here or I can see you in 5 or you don't need anything, but maybe this patient that is going to get sick in 12 months from now actually wants to start on a preventive type of approach. And we are really working hard into developing this type of tools where we can say these are patients that may not be treated in the community because they have low risk disease and they probably--statically, they have never been shown to really benefit from many early intervention, but the models predict that they are not going to do good. And this is a very important framework for us because now we can start saying, "Can we treat the disease earlier?" That is interesting because solid tumor oncologist know this for like a hundred years, you know. You preferred to have an early stage little tumor than, you know, metastasis disease. We never thought in leukemia like that. These models are actually putting this a little bit in perspective that we think is important.

Lisa Garvin: Great, thank you for being with us today.

Dr. Guillermo Garcia-Manero: Oh, thank you for the opportunity.

Lisa Garvin: If you have questions about anything you've heard today on Cancer Newsline, contact ask MD Anderson at 1877-MDA-6789 or online at www.mdanderson.org/ask. [Background music] Thank you for listening to this episode of Cancer Newsline. Tune in for the next podcast in our series.