All right, guys, we'll move on to the medical grand rounds portion of the conference today. And we're very excited to have Dr. Michael Keng here from the Division of Hematology and Oncology. In terms of some background, Dr. Keng grew up in Michigan and earned his medical degree at Michigan State University. He then moved on to residency out west at University of Southern California. He actually earned the trifecta there-- so voted best intern, best junior resident, and best senior resident-- before moving on to fellowship at the Cleveland Clinic, and then joined us in 2014. And really, since being here, has quickly become a leader within the department, serving as the quality director for the division, as well as serving as the director of 8 West and the Stem Cell Transplant Unit. He's also served as a leader nationally as well, serving in several roles with the American Society for Hematology and the American Society for Clinical Oncology. On the clinical side, he's become an expert in a number of areas, namely in myelodysplastic syndromes, and has spoken both nationally and even internationally on the topic, as well as building a research portfolio, serving as a PI on several studies in particular on AML. And so today we're very fortunate to have him here to walk us through the complexities of myelodysplastic syndromes with a focus on the internist approach to it, which I think could be beneficial for all of us. So without further ado, please join me in welcoming Dr. Keng. Thank you. [APPLAUSE] Thank you so much for that great introduction. Thank you for everyone coming today to listen to this presentation. My goal is just to talk about the approach to myelodysplastic syndromes, or MDS, and what to expect from treatment-related side effects and all, what a internal medicine physician may see. There's only a few studies in this presentation. It's not to focus on the latest and greatest in myelodysplastic syndrome, but really to see what you guys see on the floors a lot and also in the outpatient setting. My one disclosure is I did serve on an advisory board for Agios for a patient advisory board. The objective today is to talk about the early symptoms and recognition of myelodysplastic syndrome, approach to cytopenias, understand the diagnosis and prognostication of myelodysplastic syndrome. We're not going to focus too much on treatment, but more on the supportive care aspects of patients who undergo treatment for myelodysplastic syndrome. And here's the overview. We're going to be talking about symptoms, cytopenias, and the treatment, and future directions afterwards. So to start us off with symptoms-- So many of these patients come without any symptoms. The usual story I hear is that they are going to their primary care doctor, and routine blood work did show that there was some cytopenias, and that prompts some workup and referral. And we'll talk about the specifics in terms of the workup for the cytopenias. Sometimes they just come to the ER just due to fatigue, or just feeling bad for a few days. They thought that they had the common cold. And then after 2, 3 weeks, with the cold not getting better, they go to the emergency room, and unfortunately, was found to have low blood counts and needing further workup. Common symptoms-- really just occurs with the specific cytopenia that's present. So if a patient has anemia, they could be fatigued, short of breath, or even have heart palpitations if it's really bad. And as for neutropenia, sometimes they occur with fevers, or a prolonged or recurrent infection. And so these are things that a primary care doctor may have thought is a common cold or just a simple urinary tract infection, and then found to have specific other complications with low blood counts afterwards. And then thrombocytopenia-- they can have bruising, petechiae, or even bleeding. The most common cytopenia that does occur is actually the anemia portion. So approximately about 60% of our patients will present with an isolated anemia, and so a lot of the presentation will be focusing on the anemia portion of things. The neutropenia and the thrombocytopenia does occur a little bit less afterwards. So moving on to the workup-- and so I put together this very brief flow diagram, and we'll go through each component. First is once we hit the symptoms of cytopenia, you want to ask about the clinical history after that. If the history is not concerning for myelodysplastic syndrome right away, then work up that each individual cytopenia after that. If there's still a low suspicion for myelodysplastic syndrome, you want to treat the underlying cause. If after treatment the cytopenia has not gone away, and there's persistent cytopenias, then that's when your suspicion for myelodysplastic syndrome or a bone marrow failure becomes a little bit higher. And then that's when you would want to send a referral to hematology/oncology. Obviously, if there's any concern and needing help with the workup, hematology's always available via consult too. So to start us off are the actual symptoms of cytopenias. We already talked a part of the symptoms, but this is my definition of actual cytopenias. It's a hemoglobin level of less than 11, an ANC of less than 1,500, and platelets less than 100. That's the time when you want to start thinking there's something off about these labs, and you want to start moving forward. Next is an initial workup. A good history and physical is very important. From a history standpoint, you want to ask if the patient has had a history of cancer or a history of chemotherapy or radiation, and specifically, medications. There are a lot of medications that can cause various cytopenias, and that's something that you would want to focus on with your history. Physical exam, obviously, is important as well. You want to see if there's any signs or symptoms that's leading to a particular infection, or if there's any organomegaly. Splenomegaly and hepatomegaly are actually very-- sorry, and lymphadenopathy are very rare in myelodysplastic syndromes. So when you see lymphadenopathy and organomegaly, those are patients that you want to have something else on your differential other than just pure myelodysplastic syndromes. And next will be a complete blood count. For us in hematology, a complete blood count with differential is very important because I want to see what other cells make up that white blood cell count total. And then a peripheral smear would be very helpful as well. So on the right hand side of the slide here-- I'll show them with the mouse. Maybe the mouse doesn't show up here, but you can see that there are normal white blood cells. And then this red blood cell here with the arrow is a immature cell, and it's dysplastic because there's a nucleus inside and a little extra material within the cytoplasm. Over here, you have a white blood cell and with a little bridge in between. That's also dysplastic as well. If you see any abnormal cells that are concerning for dysplasia, then that's something that you want to quickly get over to a hematologist/oncologist as well. If there's one cytopenia, I think that it's perfectly fine just for a primary care physician to start and initiate that workup. My rule of thumb is if there's two or more cytopenias, there's something else that's typically going on. And if it's not something very readily noticeable, like medications, then you would like to get this patient over to a hematologist quickly because then a bone marrow biopsy would be warranted. So we talked about the symptoms and before, about the clinical history. The clinical history aspect, which I already mentioned, is if a patient has a history of chemotherapy or radiation, or if they're on some sort of immunosuppressive medications. You want to see if there's any significant exposures to chemicals. The one that we're most concerned about in myelodysplastic syndromes are a history of benzene. This is a lot of exposure. Just being a hair dresser or having your hair dyed is not enough. That's my most common question I get asked. You actually have to work at like a tire factory or a plant for many years and actually have had direct skin exposure to these chemicals. Next, if you do see a Vietnam War vet, exposures to Agent Orange has been linked to myelodysplastic syndrome and acute myeloid leukemia, so those patients I would have a high suspicion of some bone marrow failure. Congenital conditions-- those who have a primary bone marrow failure, like aplastic anemia, PNH, or those that have like Fanconi's anemia-- most of these patients would have already been plugged up with a hematologist earlier. But if you're seeing them for the first time, these are things that you'd want to be concerned about for myelodysplastic syndrome. And lastly, is if you have multiple cytopenias-- like I said, two or more-- or if you see dysplasia on a peripheral smear, these are patients that have a high risk. And like I said earlier, if you have a high clinical suspicion, what you want to do is just get the patient over to a hematology oncologist. If not, then you could start proceeding to the workup. So on this next slide here, I've listed out the big differentials that you want to think about in this specific workup-- just follows with each thing. So on the top left here, we have neutropenia. The main ones to think about are nutritional deficiencies. Those include B12, folate. Really bad copper or zinc deficiency can also lead to pancytopenia, not just neutropenia itself. So those are in your differential. Autoimmune disorders and medications can all lead to neutropenia. Next, thrombocytopenia-- the big one that I actually neglected to put on this slide was actually pseudothrombocytopenia. A lot of times when a platelet count is clumped in the blood tube, it can actually lower a platelet count, and so you'd want to actually resend this platelet count if you see suspected platelet clumping on a peripheral smear. Platelet disorders like ITP or TTP are always big ones that we see in the hospital that a team calls us to get consulted on. DIC due to infection is something that will lower your platelet count, and there's common consults, especially from the ICU, from concern for the thrombocytopenia. Infection and medications are probably the two biggest things that can lead to thrombocytopenia. Infections do include HIV, and the hepatitis B and Cs are very, very common to lead to thrombocytopenia. So these are the things to really keep on your radar. I really highlighted the anemias because, like I said, the majority-- the first presenting symptom is likely an isolated anemia for our patients with myelodysplastic syndrome. So if you guys remember in the MCV, we can split that up to microcytic, normocytic, and macrocytic anemias. And so MDS commonly causes a macrocytic anemia, so that's listed down here, and then the differential includes the nutritional deficiencies again. Again, that's the vitamin B12, folate, and zinc, and copper. What you also want to watch out for is patients who have substance abuse, like alcoholism. Those who have bad liver disease can also have a macrocytic anemia. Those who have a lot of reticulocytes in the peripheral smear can also have a falsely increased MCV, and those who have hypothyroidism, and medications. Medications like HAART therapy for HIV can really increase your MCV, and also those chemotherapy agents, like hydroxyurea and TKIs, can also increase your MCV. So those are pseudo-macrocytic anemias, but those are things just to keep on your radar. All right, so moving on to epidemiology and staging, so the formal definition is MDS is a heterogeneous clonal hematopoietic disorder derived from an abnormal multipotent progenitor cell. It's characterized by a hyperproliferative bone marrow, dysplasia of cellular elements, and ineffective hematopoiesis. My most common question I get is, MDS is a pre-leukemia, so therefore it's not a cancer. Unfortunately, it is a cancer. It is something that needs to be treated with a hematologist and so that we can help better with survival and quality of life. To break this really clunky, really distorted definition down-- so what really happens? So the cells become abnormal in shape and size, and that's the dysplasia that you'll see. This happens mainly in myeloid cells, so you see this in your red blood cells, white blood cells, and platelets. Cells don't work well, so you have ineffective hematopoiesis. And then because of that, you have resulting cytopenias, which are the low blood counts that we talked about. We'll discuss a little bit later, but there is a risk that the patient, if not treated, can develop or transform to acute myeloid leukemia. It's very rare that you would transform to acute lymphocytic leukemia, but I've seen that happen. And in general, as the disease progressed, the bone marrow, also, function declines, and that's the problem that we're dealing with. So this is a pictorial version of what I just talked about. In a healthy bone marrow, you have your hematopoietic stem cells. These lead to lymphoid and myeloid cells, and this is what you'd normally see in the periphery. However, in myelodysplastic syndrome, what happens is that you have problems with intrinsic, extrinsic factors leading to defects to these cells. And you actually have, instead of normal hematopoiesis, you get these immature precursors that form. These are these blasts, these leukemia premature cells that actually are concerning for us, and that helps with the diagnosis. And due to these blasts that form, you have peripheral cytopenias and a hypercellular bone marrow. Hypocellular bone marrows do occur with myelodysplastic syndrome, but that's very rare. It occurs in less than about 5% to 7% of the time, and those patients often get a diagnosis of aplastic anemia. So one thing to think about is that it's confusing because you think of low blood counts having a hypocellular bone marrow. This is the case where you actually have hypercellular bone marrow because your bone marrow's trying to work hard to compensate for all these defective cells. That's why you have a hypercellular bone marrow. A few fast facts is that MDS typically is diagnosed in the elderly. The median age of diagnosis is 71 years of age. It occurs in men more than women, and the primary causes are 80% to 90% of the time. Primary just means it's just de novo. It just happened. It's bad luck. As you age, you accumulate more and more mutations. And as your immune system's not able to fend these mutations off, you actually have issues with de novo MDS. The secondary causes, meaning from radiation or cancer, occur in about 10%, 15% of the time with radiation and DNA alkylating agents. And this leads to a exposure that's prolonged, so it occurs five to seven years after the radiation or DNA alkylating agent was actually given. For those patients who received a topo II inhibitor, less than 5% of the time, you will have a MDS that occurs relatively quickly after the exposure-- one to three years afterwards. So that history is really important. It's what type of cancer they've had and what type of chemotherapy or radiation has occurred in the past. These two slides were borrowed from one of my mentors, Dr. [INAUDIBLE]. So we talked about some of these environmental exposures. Next, antecedent acquired hematologic disorders-- these are prior bone marrow disorders that can lead to development of myelodysplastic syndrome. Listed here, aplastic anemia occurs in about 15%-- sorry, 15% to 20% of patients with aplastic anemia can get into myelodysplastic syndrome. And those with PNH can also develop myelodysplastic syndrome afterwards as well. The big one for a congenital disorder that I just point out for residents on service is basically Fanconi's anemia. That's the big one to remember. There are a whole slew of other congenital marrow failure things that are more rare that can lead to myelodysplastic syndrome or acute myeloid leukemia, but the big one is Fanconi's anemia. This is a Venn diagram of basically all the myeloid disorders together, and MDS kind of ties everything together. The reason why MDS sometimes is misdiagnosed or diagnosed late is because of how tricky and how similar they are with other disorders. So you can see that there's a lot of overlap between even aplastic anemia, myeloproliferative neoplasms, and there's specific overlap disorders that are occurring in between. And so this is why a bone marrow biopsy is just so important, and to the residents, is that we often repeat bone marrow biopsies when a patient just had one a few weeks or months ago. The reason why is that we do want our hematopathologist to read them because it's important that a dedicated pathologist who knows hematology, especially the myeloid disorders, can verify and make sure that the actual diagnosis is correct because each one of these do have different treatments and prognosis. This is not for you to read, but just for you to know that the NCCN, the National Comprehensive Cancer Network, has put together myelodysplastic syndrome guidelines. They go with initial evaluation to first- and second-line therapy. We already talked a lot about everything with-- if you suspect a cytopenia, and you want to think about myelodysplasia, there's a lot of things that you want to think about, meaning the history and physical, and to rule out all secondary causes. So how do you make a diagnosis? A bone marrow biopsy is absolutely needed. What you would need in the bone marrow biopsy is both the aspirate and the biopsy. The aspirate is the liquid component, and the biopsy is the solid core. From the aspirate itself, what we really want to look at is the amount of blasts that are present. Blasts are those-- remember what I said. Those are those premature leukemia cells, and anything greater than 5% or anything less than 20% clinch the diagnosis of myelodysplastic syndrome for us. Complete blood count with differential because you want to see if there's a cytopenia, and lastly, the karyotype. The chromosomal analysis is extremely important because it really helps us with risk stratification and prognosis. Lastly, a MDS FISH panel and flow cytometry is important, especially if we are not able to see blasts there just with our naked eye with the smears. And this is becoming more and more important, which is next generation sequencing. There are a lot of specific mutations that help with prognosis and our new inhibitors are being developed. It's more developed in acute myeloid leukemia at this time, rather than in myelodysplastic syndrome, but over time, I believe that this is a next area of future drugs and clinical trials. OK, so this sums up everything of what we talked about-- the cytopenias plus decisive criteria, which is the dysplastic cells, or the blasts that are present, abnormal karyotype. That, in addition to ruling out all your other causes for cytopenias, will make the formal definition of myelodysplastic syndrome. All right, in regards to milestones for MDS characterization and treatment, all this is just trying to show is that myelodysplastic syndrome's a relatively new diagnosis. It occurred in the 1980s for the first time by the French-American-British classification. And in 2016, the WHO revamped and reclassified different parts of MDS, and these are the new revisions. So what they look at is how many lineages are dysplastic, meaning is it just with the platelets, white cells, or red cells, or if there's multiple lineages. Ring sideroblasts are specific-looking red blood cells that does have a good prognosis with. And then lastly, how many blasts that do occur. Excess blasts-1 and -2 are other classifications that are there. The one thing for residents would be the myelodysplastic syndrome with isolated deletion 5q. That's the one thing that we actually have a targeted therapy for at this time, and that's the one that I will be spending a little bit of time to talk about, and that medication's lenalidomide. So this is the old scoring system, but I think it's good just to point out the three things that we look at for scoring systems is the bone marrow blast-- the percentage-- the cytogenetics, and how many cytopenias are present. You get a score. You plot them down. And the score ranges from low to high risk. And you can see that the median overall survival really can go from years to less than half a year without any treatment. And I like this graph here because it compares the two. So we have non-small cell lung cancer overall survival curves here. This is stage I here, and stage IV is the very bottom red line. And I plotted MDS overall survival low risk up here and higher risk in this purple underneath. So you can see stage-for-stage MDS risk prognosis is the same as non-small cell lung cancer. So it's something serious, and we want to get patients treated quickly. So once the patients are diagnosed, urgently, a referral over to a hematologist or stem cell transplant's very important. Now, since 1997, in 2012, there has been a new classification that occurred, and I'm putting this up here just for reference. You can see that now, instead of a few cytogenetic abnormalities that are listed, you can see that how many things are divided out very carefully. So it now goes from very good to very poor. So this is why a bone marrow biopsy, that initial one with cytogenetics, is so important for us, not only for diagnosis, but also for prognostication. So again, the variables, like I said, went from very good to very poor for the DNA, the cytogenetic mutations. Blasts here are now even sparsed out even more, from less than 2%, to 2% to 5%, to 10%. And I like to just point this out. To differentiate between less than 2 to 2 to 5 just takes a very fine eye, and it takes a, in my mind, a specialized hematopathologist. And that's why bringing the patients to someone who practices myelodysplastic syndrome is so important. And then the specific cytopenias are listed out instead of clumping them together, and now the new risk groups go from very low to very high. The median survival without treatment can go from 8.8 years to about half a year. OK, so prognosis made easy-- all I say is that if you're very low or low, you are considered my lower risk prognosis group. If you're in the very high to high group, you're in this higher group. What is missing in this section are those patients who had that intermediate, and we just don't know what to do with these patients quite yet, and that's something that's being studied, I believe, now. OK, so like I promised earlier, I'm not going to be focusing too much on treatment. But more about the principles of treatment and what you'll see from an internal medicine standpoint is that the key principle is that myelodysplastic syndrome is unfortunately not curable. Not every patient will have a complete response, and the only cure that we have right now is an allogeneic stem cell transplant, so a transplant from someone other than from themselves. So I work really closely with the stem cell transplant team so that once the patient is in remission, or as close to it as possible, if he or she is eligible and would like to, stem cell transplant is the answer. So our goals can shift here. So unlike, I would say, testicular cancer, where a cure is always almost the goal because of how highly curable it is-- so sometimes we go from actually getting just 100% cure, and getting the patients through every line of chemotherapy, what we're trying to do is we're moving to improving quality of life, and I'll try to minimize the amount of toxicity. There are many things that can be possible even in someone in their 60s or 70s, so just because you're 60 or 70 years old doesn't mean that these patients need a straight to hospice or supportive care, but it takes an honest conversation with the patient so that they understand what is entailed with their treatment. So this is a pictorial diagram that I'm trying to sum up treatment, and so over here on the very top is if you go from being asymptomatic to symptoms. And so as you become more symptomatic, your bone marrow reserve starts decreasing, and then your transfusion threshold starts increasing. On the y-axis here is your prognostic scale, scoring risk. If you're a low risk versus the very high risk, your survival starts decreasing as you start having increasing amount of blasts. And so just general principles here-- observation is a very valid and very key thing that we can do. If you're a low risk, and you're not symptomatic and not needing any transfusions, we can observe these patients and to see how they are. If they need growth factors afterwards, that's also available. As we start getting to more and more decreased bone marrow function, we could start developing more and more mutations. And if that occurs, we can develop-- going into more specific, higher intensity treatments, like a hypomethylating agent-- the two that are approved in the United States are this azacitidine and decitabine-- investigational agents like clinical trials, and then those who are very close to acute myeloid leukemia can undergo specific intensive induction chemotherapy, and also followed by a stem cell transplant. So very briefly, anything from observation to stem cell transplant is a potential treatment option for our patients with MDS. Age alone should not exclude a patient from active therapy. The big thing that I tell all patients and all primary care docs is that blood counts will get worse before they get better, and active therapies require time, and time is in a period of months, not just weeks. It takes about four to six cycles of four to six months before we know if an active therapy is working, and they will go through a lot of side effects during that time. So we just have to support patients through that. And strategies, proactive management, with the patient and the primary care doctor is very important for us. This is just a flow diagram of low-risk disease here, and just for the interest of time, I'm just going to be mentioning these briefly. There are trials for each one of those, but these are for a different presentation. But if you don't have any treatment transfusion needs, and you have a good quality of life, observation is very doable, and I do follow these patients approximately every four to six months just for blood count routine checks. If they start to have isolated cytopenias, then we could talk about transfusions. In the US, we do give packed red blood cells and platelets. Granulocyte transfusions are very laborsome. It's not very helpful at times, and I've only given this once in fellowship, and the patient was not doing well to begin with. So these are something that we don't actually do here for routine MDS patients. Growth factors are something that are available here in the US too. We have growth factors for all three cell lines-- the red cells, white cells, and platelets. And if you have an isolated anemia, these growth factors can be helpful. Moving on, a growth factor for the red cells-- all I'm just putting down here is trials have been shown with different combinations, but a single growth factor-- the relative response rate could be as high as 40%. And so this could be a very good treatment method for someone who just got diagnosed with MDS. Lenalidomide is something I just did want to touch base on, especially with this deletion 5q. It's been studied in the setting of deletion 5q and non-deletion 5q. For patients that do have that deletion 5q abnormality, the transfusion independence can be about 61%, so it's huge. So that's why that karyotype in the very beginning, for us, is very important. And the transfusion independence can stay in approximately 2.2 years, so that's why that deletion 5q is such a important thing that we do follow up on. In patients that do not have deletion 5q, that response is not as high as the 61% that we talked about. It's about 26%, so it's still something worth trying. And the duration of response is about a little bit less than a year at 41 weeks. So it's still something with minimal side effects other than just injection. It's something that we can consider for patients with-- sorry, not to inject. It's a oral pill, so it's something that we can consider. The biggest thing that we want to watch out for, for those who are on lenalidomide, is the two cytopenias. It's the thrombocytopenia and the neutropenia. Those who have the deletion 5q abnormality has a greater chance for both of these cytopenias, so that's the one thing that we do want to be careful about and monitor patients as they're on lenalidomide. Moving on to thrombocytopenia, we already talked about specific growth factors. And those who have multiple cytopenias, something like immunosuppressive therapy with ATG is a good option for patients. This is something that has a response rate for approximately 31% and can have a median duration for about 16 months, so a little bit over a year as well. So for immunosuppression, age is the single most strong variable for response, and those who have other autoimmune issues will likely do best with ATG and immunosuppressive therapy. One thing I do like to focus on that I get a lot of questions about is the risk for transfusion and iron overload. And so with this does show is that patients with transfusion independence do do better than patients who are transfusion dependent, no matter whether you're good-risk or intermediate-risk myelodysplastic syndrome. And you could see that the more red blood cells that you need, the shorter year overall survival may be. And so the common question I get is, should I give patients a iron-chelating agent? And so what I talk about is-- let me just skip for the sake of time here-- are the guidelines that have been published by the NCCN and the MDS foundation is that the iron-chelating agents are something that are expensive. And they take time to work, and they do come with a lot of GI side effects. And so my rule of thumb is that you need to have had a significant amount of transfusions, namely, over about, I would say, 40 units per year or a serum ferritin level of greater than 1,000. They have to be lower risk, and they have a life expectancy of greater than a year. So if you have a very high risk patient that we expect them to transform soon, or their prognosis is very poor, to start an iron-chelating agent is not going to make a difference to save them from the iron overload symptoms. Those symptoms do take a while to have end-stage organ manifestation, so we want to make sure that we're using these agents in the right setting. Those who are candidates for allogeneic stem cell transplant who are diagnosed in the lower risk setting, those are ones that I will consider a iron-chelating agent earlier just because I want to preserve their organ function as best as possible for those who are considered stem cell transplant candidates. This is for higher risk patients. The big breakdown is those who desire or not desire stem cell transplant. Those who do not want stem cell transplant could be placed on a hypomethylating agent, which we talked about earlier. And those who do want a stem cell transplant-- this is who I do get referred over to a stem cell transplant physician to get a workup for a donor identified as quickly as possible. To talk about a hypomethylating agent, this is my last trial I'll be actually talking about because I think that this is the largest [INAUDIBLE] medication that's been approved for myelodysplastic syndrome, which is azacitidine. Azacitidine was studied about a decade ago. And what they looked at were patients with higher risk myelodysplastic syndrome, and they were randomized between by days of azacitidine compared to conventional care regimens, which is best supportive care, low dose cytarabine, or standard chemotherapy as physician's choice. And upon this, what this did show was that patients who received Vidaza, did have a much improved overall survival of about 24.4 months compared to the 15 months with physician's choice. And with improvement, they had improvement with all markers, meaning the erythroid, the platelets, and the neutropenia. You can see here that the neutropenia is the one that has the least amount of improvement. So this is what we see currently is that a patient may be doing very well on these hypomethylating agents, but the neutropenias, what I commonly see that is lagging behind, or it does not improve. And so those are things that-- infection's the common thing that we just have to be very concerned about. This just looks at the adverse events, and the biggest ones that we see are the cytopenias that are listed all up here and febrile neutropenia compared to the best supportive care. OK, so this is just a repeat slide just saying that MDS is not curable, and what we really want to do is focus on allogeneic stem cell transparent if possible. If they are not interested, then it's to really focus on not just overall survival, but it is quality of life and minimal toxicity. OK, so this is a pictorial diagram of what's happening when a patient is receiving treatment, and I really want to focus on this for the remainder of the presentation. It's just because when I work closely with primary care physicians, there's concern that the counts look so much worse than when we started off with. We need to stop therapy right away. So what happens is before treatment, your blood counts are starting to drop as myelodysplastic syndrome is progressing, and normal cells are crowded off. And so you could see there's a decline in your bone marrow reserve. As treatment starts, your treatment's cleaning out the marrow. It's cleaning out both normal cells and bad dysplastic cells at the same time, so you're going to get a big drop in your counts. And so this is actually a patient of mine earlier, and you could see that this is their baseline neutrophil count. And so we started treatment in the two- to three-month mark. You could see that, man, their neutrophils dropped well below 50% of what they started off with. And they stayed low for quite some time, up until-- for this patient particularly-- about three months. And after treatment is started, and the patient starts to respond, normal marrow function starts occurring. And then the platelet count starts-- not platelet, I'm sorry-- the neutrophils count starts increasing, as shown in the graph here. And then once the counts are-- and the marrow function's completely normal, then what happens is you start developing resolution of your other blood counts. The neutrophils, like I said, are the hardest ones to recover from. And this is the ones that we time and time again will see that patients will kind of hover at a 60% of their baseline neutrophil count, and that's what we just are left with. Everything else, like platelets and red cells, do recover quite nicely. And this is the big gap that I like to work with patients and primary care physicians about is to try to figure out what early toxicities can occur and discouraging a patient from actually stopping therapy. If you stop therapy in that second or third month part, all the patients that really have gained are just the side effects. They have not reaped any rewards, so unfortunately, we really want to get them through that hump. And waiting for blood counts to occur really involves partnering with a primary care physician. And so things that we want to do is supportive care. Supportive care does involve both red cells and platelet transfusions. So even if they started off with not needing transfusions, patients will need transfusions. Sometimes it's as much as once or twice a week, so it can be very disconcerting for a patient. Antibiotic prophylaxis is important as well. I commonly start patients both with antiviral prophylaxis for HSV and antibacterial prophylaxis if their neutrophil count drops below 500. If a neutrophil count stays below 100, I do have concern for fungal infections, and those patients are placed on antifungal prophylaxis. Setting expectations appropriately-- I put this on here as very last, which is dose modifications and delays. In the first three or four, cycles, I try to stay on time unless there's a life-threatening infection or something that I have to delay a patient for. Because I expect these cytopenias, and I expect these side effects, stopping and delaying the next round of treatment, to me, it's not going to be helpful. And actually it's doing the patient a disservice, so I try to stay on time as much as possible. The next slide just kind of goes with a patient that has been published, and it nicely shows what happens with blood counts. As you can see that, when treatment is started here, you can see that the hemoglobin drops, and it drops pretty rapidly after the first few cycles. And then after a cycle 4, and after stem cell transplant, you could see that their red cells do increase. Their platelets are in this kind of orange color, and you can see that after treatment's started, your platelets do drop. And it does increase after cycle 3, and then after stem cell transplant, your platelets do increase. Lastly, is this neutrophil count, your white blood cells, and you get say that things do stay awfully low. And after stem cell transplant, you do get that boost upwards. And so if a patient can get to stem cell transplant, that is my main goal and focus for myelodysplastic syndrome. Lenalidomide was that other medication I did talk about, and you can see that hemoglobin can respond upwards. And your platelets do drop initially, and they start normalizing as well. But the big thing that really just doesn't improve that well is just your white blood cell count. So those are the things that we just have to be really careful and cautious about is the risk of infections and complications due to a neutropenia. This is a subgroup analysis of that study that I'd showed about azacitidine. The reason why I bring this up is that these are patients who are over the age of 75, and these are traditionally patients that may not be given much of a chance because they're older. And what I do really want to focus on is that their grades of cytopenias and fatigue really start increasing compared to best supportive care after cycles 1 and even 3 and 4, but afterwards, things start improving after you get past the first few cycles. And so this is just even showing you that, even in older folks, if we can help them through those first four to six months, we can really get patients on the upwards trend in improvement. Obviously, this does involve a really-- goals in care conversation earlier with our patients. And when I see a new patient before I start new therapy, this is exactly the conversation we have is that you have to be willing to give this a try for about four to six cycles. And are you willing to go through all this? Because you will feel worse before you get better, and there are a risk of side effects when your counts are so low. The next few slides are just actually for reference, and I believe we had talked about them, so in interest of time, I'm just going to skip them. This just talk about managing neutropenia. We already talked about monitoring blood counts and prophylaxis and recognition of infections. Thrombocytopenia-- you may just need platelet transfusions and just carefully monitoring medications that can also lower your platelet count. And injection site issues-- sometimes these patients get growth factors or injections with the hypomethylating agent, and they can cause localized pain, bruising, or bleeding. And that's something just to watch out for too. For just my last few minutes here is to talk about some clinical trials and a future direction is that we really do have to do better for this disease because what happens is right now, our gold standard medication is a hypomethylating agent, which is that Vidaza and decitabine I talked about. But if you do fail that medication, you can see how poor your overall survival is-- is that your overall survival after that is about 5.6 months after you've failed that therapy. So a lot of research right now is going on in this particular area is that how do we make that first hypomethylating agent better, whether to combine it with a different therapy, or after you've failed that therapy, what additional therapies are available? Here at UVA, we have several trials that we're looking at this. We are looking at an HDAC inhibitor, which is that pracinostat. What is shown is that early start of this combination has led to increased complete response rates, and therefore, we can get patients faster to stem cell transplant. There's a NEDD8 activating enzyme inhibitor, pevonedistat. Our trial's opening up in about a month. Rigosertib is being used in the relapse setting, as well as ipilimumab, which is a immunotherapy agent. All right, gene mutations are very important for us, and the only reason why I bring this up right now is because everything for us in myelodysplastic syndrome is unfavorable except this SF3B1. And so basically, last year the NCCN put in-- these are all the potential mutations that we do know about. The only one, like I said, that's favorable for us is that SF3B1 mutation. So these are all clinical trials that are being studied at are all these particular agents that can target a specific gene mutation to see if we can have help. And as you can see, not one patient is the same compared to the next patient. You have different cytopenias, different comorbidities. So a lot of work is being done in this area, including here at UVA. So concluding remarks-- this is the review of what we talked about. If you identify a cytopenia, go through a detailed history and physical, workup a single cytopenia, and if that does not resolve after your treatment, then there's a higher suspicion for myelodysplastic syndrome. If there's multiple cytopenias that you know, an earlier referral is helpful so that we can rule out myelodysplastic syndrome with a bone marrow biopsy. Lower risk disease really is just trying to adjust the specific cytopenias. Higher risk disease is to try to get treatment started immediately and to get a patient over to stem cell transplant. So I just want to thank all of you guys for your attention. Thank you for the Hematology/Oncology Division for everyone's help. And definitely, thank you with the internal residents and the department because I know that you care for our patients a lot on 8 West, 8 Stem Cell. It's been a very busy service, and we really appreciate all the great work, medical care you're doing for us with our patients. And obviously our patients and families-- we wouldn't be here without them. So thank you for your attention. [APPLAUSE] [INAUDIBLE] very nice review [INAUDIBLE] understanding the rational approach to cytopenias is critical [INAUDIBLE]. I wondered if you could just say a few words about CHIP. It's gotten a lot of attention lately. [INAUDIBLE] relevant [INAUDIBLE]. So what Dr. Williams is talking about is this phenomenon known as CHIP. And so CHIP stands for Clonal Hematopoiesis of Indeterminate, or of Potential significance right now. And so what happens is that sometimes a genomic panel is sent on patients for other reasons, or because there's some cytopenia that's noted, and that big long list of the gene mutations that were presented-- some of them can be positive, right? And what we know to do with each one of them is still up in the air right now. We know that there's some very bad ones that can kind of clinch a diagnosis, and we have some good ones, where we can have some targeted agents for. But a lot of it is just a big unknown right now. We do know that patients with CHIP that we do want to monitor them a little bit more carefully. There are prognosis issues that there are-- it's tied with some cardiovascular diseases right now. And actually, Krista Isaac is actually looking at that as her fellow project-- is to see if knowing these earlier-- what we need to do, whether we need to have earlier cardiovascular intervention, whether we need to do more follow up from a hematology/oncology standpoint. But from an MDS standpoint, what we do know is that we do want to follow these patients more carefully. It's almost like they had a prior exposure of some sort that we just don't know about, and what happens is that they have a more or a increased way or, I guess, a risk to get to a myelodysplastic syndrome. There was a recent paper published by Dr. [INAUDIBLE] actually that looked at this on CHIP. And what he found was that his patients, on average, with CHIP identified, maybe 5, 10 years down the road, there is a potential for myelodysplastic syndrome or overt acute myeloid leukemia. So those are patients that we are monitoring very carefully. [INAUDIBLE] thing about Roundup [INAUDIBLE]. [INAUDIBLE] Right, so we do know that exposures are-- it gives you an increased risk for a myelodysplastic syndrome. The big one that I focus more on, like I mentioned earlier, is the benzenes and also Agent Orange. But Roundup-- I mean, just a little exposure here and there just-- I've used Roundup before to kill something in the distant past. I mean, I don't think I'm at increased risk for myelodysplastic syndrome. But if you are constantly with the chemicals, not using protection, and actually are getting that direct exposure-- and it's years of exposures-- that's what I'd be a little bit more concerned about. I mean, I've had hairdressers who use those dyes without gloves on every day, and they're not at increased risk for myelodysplastic syndrome. So those are all exciting things I think just for us to hear more about, and maybe there will be more ties to that in the future. Good point, John. Dysplastic cells-- are they just monoclonal, or are they polyclonal? [INAUDIBLE] What therapy? [INAUDIBLE]. CAR T-cell therapy? Yeah. Yeah, so the question was whether these cells are clonal or polyclonal. Most of the time they are clonal. They all derive with just one abnormal signal, but things could change very rapidly, and that's why frequent bone marrow biopsies are very important. Because although you can start off with one clonal mutation, and you see one thing that's noted, further bone marrow biopsies have shown if you progress with your disease, you can actually gain more mutations out. And so it can become-- you can achieve other mutations issues. For CAR T-cell therapy, we're still trying to identify the uses of that in myeloid malignancies right now. So CAR T-cell therapy or other more of these T-cell-related therapies are used a lot in our lymphoid settings, and multiple myeloma-- I think they're looking at a specific protocol-- lymphomas, and ALL, Acute Lymphocytic Leukemia. But it's being studied in AML right now. I don't believe that there is an active trial right now with myelodysplastic syndrome, so we'll have to see. That is an area that I know will be looked at in the future, especially if you've failed a stem cell transplant in the past, so-- [INAUDIBLE] I've seen some cells do, but it's not every cell. And so the early-phase trials with immunotherapy, like nivolumab or ipilimumab, have not been that exciting to be honest with you. Single agent have not work, so they're looking at different combinations with that hypomethylating [INAUDIBLE]. Great question. All right-- Thank you. Thank you. Yeah. [APPLAUSE]