Acute Leukemia | Clinical Medicine

What's up, Ninja Nerds? In this video today, we're going to be talking about acute leukemias. This is a part of our clinical medicine section. If you guys like these videos, it makes sense to you, please support us. You can do that in a couple different ways, and it really does go a long way. You can hit the like button, you can comment down the comment section, and you can subscribe. Also, we have a website. If you guys go down the description box below, click on that link, it'll take you there. On our website, we have great notes, illustrations, quiz questions, all those things that will help you that go beyond what we talk about sometimes on this lecture and I think it' be good space repetition to help you out for your exams. Go check it out. All right, let's dig in to the pathofizz. All right, so let's begin our discussion on the pathophysiology. So when we talk about acute leukemias, this is basically two different types. One is acute myoid leukemia, AML, and the other one is acute lymphoplastic leukemia or alll. Now when we talk about these, these are really disorders of hematopolesis. So we have to define what that is. So hematopoesis is basically imagine here's your bone marrow right you know the site of uh white blood cell production red blood cell production platelet production all of that's the red bone marrow so we can define hematopoesis as the site of blood cell production and that occurs where in the red bone marrow so for example let's say that I have here a bone in this bone right we'll have some red bone marrow that red bone marrow is the site of where we're going to make all our different types of cells that circulate throughout the blood the white blood cells this can be the granulite and the a granular sites. This could be your red blood cells and this could be your platelets. Question you may have is how do I take this bone marrow and make all these different types of cells? Well, that goes back to your physiology. So, you have to remember inside of the red bone marrow, there's a stem cell. This stem cell is called the hemocytoblast. So, the hemocyblast is basically like a pur potent stem cell which can make all different types of cells. That's what makes it cool. I can make red cells, white cells, platelets, all these different types. What's really cool is that this guy can differentiate. So imagine he proliferates himself and then he differentiates to become more specialized. So he's no longer going to be this kind of cell. He's going to become these two different types of cells. This one over here is called a lympoid stem cell. Let's write that out. And this one over here is going to be the myoid stem cell. We have these two cells that are different from that purotent stem cell. What's really important at this point is this is where we kind of diverge. So at this point, if there's an abnormality in this process, it's going to lead to maybe the alll. If there's an abnormality in this process, it can lead to AML. We just have to figure out where exactly in this process. Let's come down this arm first. My stem cells what can happen is they can actually further differentiate. And what happens is they can differentiate into what's called a myoblast. And myoblasts are important because myoblasts will then further kind of like change their neutrfil, become more segmented and they can become granulitic white blood cells. So again, which one's this one called? Just so I can be very very specific. Myoid stem cell to a myo blast. Now the thing here is whenever I have a myoblast, this is going to make my granulosytes. And there's different types of granular sites here, right? So we have neutrfils, we have eocinophils and here we have basophils. These are all really important because they are going to be derived from that myoblast as a whole. We call these a very specific type of white blood cell. You know what we call this one? We call these granulositic white blood cells or granulosytes. So here's what's important. A myoblast can turn into all of these different types of white blood cells. The next component here is that sometimes this myoid stem cell can also differentiate into some other different types of cell lines. I'm not going to write them down, but it can become a what? An ariththroblast. An ariththroblast can then further differentiate and become a red blood cell. So this could become a what? A red blood cell. Or it could further differentiate from this myoid stem cell and become a meggaaroblast which then eventually becomes meggaarasytes and blows up into a million pieces and becomes platelets. And then lastly this this actual myoid stem cell could also differentiate further and become a monolast and monoblast actually could go further and then turn into a monocight. So this could become a monocy. So this is your basic like physiology when it comes to hematopolesis. When we talk about this with acute myoid leukemia, the problem exists here that you have lots of myoblasts. So really this is what's happening. The bone marrow is producing tons and tons and tons of myoblasts. So that's really where this disease comes into play. You have increasing amounts of myoblast. If you really want to define it, if I were to take the percentage of these cells and how much they occupy within the bone marrow, you have to have at least greater than or equal to 20% of these cells in the bone marrow. So, I really need a lot of these things. That's a significant proportion to account for inside of the bone marrow. Now, with myoblast, the question is is why am I making a lot of these myoblast? We'll get into that, but the myo stem cell can differentiate to a myoblast. But what if I shut down the myoblast further differentiating? It no longer turns into a neutrfll. It no longer turns into an eosinaphil or a basopil. And sometimes this could even affect your monocytes as well. If that's the case, this builds up and then all this guy does is he just keeps replicating onto himself. He keeps replicating and proliferating and then what do you get? You get a substantial amount of myoblasts. When that happens, guess what? You have you have acute myo leukemia. Now, AML is interesting. With AML, there is eight subtypes. And I don't want to go through all of them because it's not as high yield as when we get into all. But we kind of say these are M0 to M7. And the most important subtype that you actually do have to remember because it's pertinent because it changes a the whole prognosis of the patient. it's a different treatment for the patient is APL and this is the M3 subtype. So the M3 subtype of AML is also referred to as acute prominitic leukemia. This is the only one that you have to remember as the subtypes and the reason why is this one has a completely different treatment and prognosis. This can lead to DIC that's worth knowing right? Absolutely. Here's a question I think I had when I was learning this topic. How in the heck would I know if a myoblast is building up inside of the bone marrow? Well, one of the things is some of these myoblasts, they seek seep into the bloodstream. And if I got a blood smear, I may be able to find these things. But the best places to take it out of the bone marrow. And when I look at these myoblasts, they have special types of markers on them. And so what we would see is when you actually look at these under the microscope, you would see these things called our rods. You see these like little these little pink structures right here? These are called your hour rods and these are an identifier. So when you see these on a bone marrow biopsy or if you get lucky and you see on a peripheral blood smear that's very specific for AML. Another thing you see all these like maroon dots all these maroon dots are a special type of like enzyme that's present really in myoblast and not in lymphoblast. You know what that's called? It's called myoparoxidase or MPO we commonly abbreviate it. So if a patient has the presence of our rods on peripheral blood smear or their biopsy if they have the presence of this enzyme when we do what's called flowcytometry that's really suggestive of AML. There's another thing I'll talk about it just because we're going to talk about it over here and I don't want you to think that they don't exist. But you see these like little blue proteins. These little blue proteins are called cluster differentiation proteins and they differentiate different types of white blood cells. There's a bunch of them and I don't think they're super worth a squeeze, but I just want you to know that they do exist. And this is CD13 and 33. If these do tend to be positive, it's not going to be super super specific for AML as compared to the mo and rods, but it is worth knowing these are identifiers of the myoblast. So I got a bone bone biopsy. I see the myoblast. I see this. I test for these things. Oh, baby, that's a myoblast. And then all the downstream consequences that can occur in this become more easy to understand. All right, we now move into the acute lymph plastic leukemia. Lymphoid stem cell. This one turned into a myoid. And look, look at all the things that could go from there. The lymphoid stem cell is not as much. It really just becomes a lymphoblast. So here we're going to have a lymphoblast. Then from the lymphoblast it then further differentiates and when it further differentiates it differentiates into what's called T- cells and into B cells. Now technically we call these Tlymphosytes and we call these belymphosytes but for right now I'm just going to write T- cells and B cells. Okay. So here's the pathway now. So we saw from the myoid you can make red cells, platelets and all these different types of granulositic white blood cells and monocytes. From lymphoid stem cells, you really only make T- cells and B cells. And if you want to go a little extra mile, it makes natural killer cells. Don't go too crazy. But the problem in this disease is the same thing. It's right here, the lymphoblast. It's not fully differentiating into T- cells and B cells. And all it does is it just keeps replicating on itself. And as it replicates on itself, you build these puppies up inside of the bone marrow. If they build up in the bone marrow to the point where there's so many lymphoblasts, how many I put there? Three. We'll do three here again. So many lymphoblasts. What's the percentage have to be? Greater than or equal to 20%. Baby, that's a lot. So at that point, that's now causing acute lymphoplastic leukemia. The next thing I need you to know is there's eight subtypes for AML. What about the subtypes for ALLL? You know, it's pretty cool. So, for this one, it's only two specific ones that I really want you guys to know about. One is going to be T cell. All right. So, watch this. I'm actually going to bifurcate this puppy. So, we're going to bifurcate this one. And when we bifurcate this, we're going to say if I have lots of these, let's say T- lymphoblasts, lots of the T-ymphoblast, I have too many of them, that can make what's called T-C cell alll T-C cell predominant acute lymphoplastic leukemia. All right, way less common. All right, way less common. Only accounts for maybe maybe 20% maybe 20% of ALLL. The more p-ominant one is when these lymphoblast, the ones that are made up here is if they're belymphoblasts. This determines a patient having B cell alll. And this one is much more common 80%. So if I tell you what's the big subtype to remember for AML, the most important one is M3 or which one? It's M3 or the APL. If I tell you which one to remember for all, it's BLLL. Here's the question. When I have to identify the difference between a a T lymphoblast and a B lymphoblast, it's different. So, for example, I'll talk about this later. When we talked about APL, it really differs. They still have ALS, they still have MO, they still have these CD proteins. What really diff between APL and all the other of the eight subtypes is that APL involves pro-yoccytes which we'll talk about when we get down here. For this one, they're both lymphoblasts. So, their morphology is not really different of their structure or the type of cell and their stage that they are during the differentiation. What really helps to differentiate these is when we look inside the cell. What are these like little orange dots? These are called TDT. So it's a terminal deoxyucleotidile transferase. You you don't need to know that whole thing. Just know TDT. If they have the presence of TDT on the inside of the cell, that suggests all. All right? That's what's really important to remember. This suggests all. All right? Whereas if I said MO, that one suggests AML. All right? That's the big difference. Now, cluster differentiation proteins were not as high yield for the myoblast, but they're super high yield for the lymphoblast. So, look here. You see these on the T? They're CD2 to CD8. So, CD2, CD3, CD4, CD5, you get the point. Anywhere from CD2 to CD8 suggests a T lymphoblast. But if I have cluster differentiation CD 10, CD 19, CD 20, these are suggestive of Blymphablast. That's what I need you to remember. So the identifiers for Tlymphoblast, let's actually make sure this is very clean here. CD 2 to 8 that suggests the Tal CD 2 to 8. And if I say CD 101 1920, you would say Bympholast. All right. So we have our identifiers TDT alll CD2 to8 T alll CD 101920 BLLL. If I said which one is the most important AML subtype because it's promyo sites, you'd say APL. All right, I think we got that. Last thing I wanted to talk about is that when you get to a blast technically how when we talk about how lucapois is making white blood cells occurs you always start off with a blast then it becomes a promyoite then it becomes a miloite then it becomes a band cell and then it eventually forms a functional granular site I'm just using this as an example right for lymphoid it would be a lymphoblast a prolymphosy then a lymphocy or b whenever we go through these stages. If it's in the earlier portions of the differentiation stage here, that is acute. These are the cells that are more likely to be involved. The blast. So, this is what's really important to be remember this involves the blast. Later in these parts where the nuclei are starting to segment, they're starting to become more specific and more functional. That's chronic. So, it's not going to be as many of the blast now. You're going to have more of the close to functional, but not quite there. So, we're going to say a little bit. We're going to say less mature white blood cells because they're not really blasts. You're going to have a lot of these, but they're going to be at the later stages where they're just not close yet to being mature, but they're definitely a little bit more functional than these acute ones. The problem with this is that blast makes the progression of the disease rapid. All right? So, this is rapid progression. Whereas chronic is it's a little bit slower because these are a little bit more functional as compared to these. They're a little bit smaller. You're not going to have as much of that devastating effect. And so, because of this, this will be a gradual progression. I'm killing it. Right. Mhm. All right. So at this point we've c talked about a lot the pathophys of acute leukemias. What I need to now say is okay what in the world is causing these lymphoblasts to build up or they don't differentiate but they just keep proliferating. What causes the myo blast to not differentiate but just continue to proliferate. And then once we do that we can say what's the problem? Why is having so many of these myoblasts or lymphoblast in the bone marrow out in the blood or in the tissues a problem? So with this we talk briefly and I mean briefly about what we just said. When you go through from a myoid stem cell to a myoblast you go to what's called a promyo site. Remember I told you that most of the time if you have a myoblast and you build these up that's your AML. That's usually M0 to M7. So really whenever this builds up significantly that's going to be what's really triggering a lot of this stage for you know M0 to M7 except for so M0 to M7 AML what's the only exception except M3. I just don't want to write M012 and then all the rest of them. So that's the big thing there. But if I have lots of these, if I have lots of these. Oh man. Oh daddy. This makes the M3 AML and that is defined as APL. So at these stages what's happening is you can have lots of blasts that can make these types of problems for AML or you can have lots of promyosytes that'll make a lot of the problems for the M3 ML. AML problem is they get stuck in these stages and they never further differentiate. The question is why why does it get stuck in this proliferative stage but not in the differentiation stage and it's usually for acute myoid it's genetic. So it comes down to chromosomal transllocations and so one of them that's relatively important to remember is for APL. That's why I kept stressing that's the really important subtype to remember out of the M0 to M7. For APL, we care about a specific type of chromosomeal transllocation and it's called the 1517 transllocation. What happens is on chromosome 15 you have a PML gene. On chromosome 17 you have a raw alpha gene. This is a retinoic acid receptor receptor. What happens is you end up swapping some of that genetic data and you end up making a fusion gene. So now I have a fusion gene which here's the PML and here's the raw alpha. What do I make? I make the proyoite retinoic acid receptor alpha gene. That's what it's called. So PML R alpha gene. When you got a lot of this gene, dude, oh boy, it causes the promyoccytes to rapidly divide but never differentiate. That's the concept here. And so the big thing to remember for why I talked about acute milo leukemia, the specific subtype APL or M3 is because this one is defined as a 1517 transllocation. The other ones don't really have that. Now with that being said, in patients who have what's called tricomi 21 which is known as down syndrome, these patients have a higher risk of developing. So they're they have a higher risk of AML. Do you know how many times? 10 to 20 times. That's significant. If a patient has Down syndrome, they have a 10 to 20fold risk of developing AML or ALLL. That's pretty significant. So that's really important to remember as a potential trigger related causative factor. But basically these genetic abnormalities are basically shutting down the differentiation but triggering proliferation. Now other causes that I think are just important to quickly just check off is don't forget about chemo radiation. So chemo radiation can have that types of damaging effects and can definitely lead to mutations that are arising and that can cause proliferation without differentiation. Other ones are going to be milo proliferative disorders. So milo proliferative disorders. We talked about this in another video. So this was your ones like polyythemeia vera, essential thrombocythemeia, chronic milo leukemia and primary milo fibrosis. All of these carry that risk of converting into AML because as they proliferate proliferate proliferate you bring about the opportunity for more mutations. And even if you wanted to, I could add in another one and but I'm not going to go too crazy on this one. It's called milo displastic syndrome. So this is a disease where you have displastic white blood cells and you can have blasts that are starting to form but there's less than 20% of them whenever it converts from less than 20 to greater than 20 or greater than or equal to 20. That's the definition of AML. All right. So that's the concept here. Now for all or acute level blastic leukemia you have blast goes to a prolymphosy but it gets stuck right here so it does not further differentiate and so you don't go down this pathway and so what ends up happening is you build up these blasts right and this is what leads to your alll which could be the b type or the t type now when we talk about these these are usually going to be really important genetic causes so one of them is a sign of a good prognosis. And interestingly enough, we see this in children. So often times it's really really really I can't stress enough really important to remember that ALLL is a disease of little people. It's a pediatric type of cancer. AML is a disease of older individuals. CLLL, CML are all diseases of older individuals. But all is a pediatric disease. So because of that, you're going to see this in younger patients. So you're going to see this as our pediatrics. There's a very small percentage, very small percentage of people that can have all that could be a bad prognosis, but we see this more in adults. And this could also be due to a genetic problem. What's the difference? For the good prognosis, it's usually due to a 12 21 transllocation. like the PML raw alpha gene. I don't think it's as high yield, but you have an EVT6 gene that gets passed over to a RUNX1 gene. You're probably like, I don't know what that means. Don't worry about it. It's not that important to remember, but you get this EVT6 and you get this RUNX1 gene and I'm going to write them down, but please for the love of everything, you know, and holy, please do not memorize this. I'm just trying to give you an idea that you get this gene and this is the gene that's responsible the same way the PML raar alpha gene is there. This is the other gene that's going to kind of put the accelerator on proliferation but not on differentiation. And that's what happens. It just gets stuck here and it just keeps proliferating. This is what we would see in younger patients. This is the one that I need you to remember. This one not that common but you can see this with a 922 transllocation. You take a BCR gene, fuse it with an ABLE 1 gene. When you fuse that, you get something really, really bad. This is called the BCR Aable one. So, this is going to be called the BCR ABLE one gene. And what this does is is this accelerates your tyrroscen kinise pathway. And the tyrroscen kynise pathway is going to do the same thing that we've been talking about a million times. It's going to put the accelerator on proliferation but a block on differentiation. That's what's happening here. I already mentioned this before but again tricom 21 is just a nice little quick reminder that patients with Down syndrome what happens they carry a significant risk. Anytime you have this you increase your risk of all and AML by 10 to 20 times. That is the big thing to remember. Okay. Other causes again cheo radiation is a potential trigger here. If you cause that chemotherapy or that radiation it can cause damage to cells and if you cause that you can lead to mutations obviously. And the last one is an infection but it's a very specific one. It's called the HTLV infection. This one is only specific only for T-C cell alll. Is it really important to remember it? probably not as much just because T- cell ALLL only accounts for about what 20% but at least consider that. All right, this is our causes. So at this point we've said does a patient have AML? It's the myoblast. I got a lot of them in my bone marrow. There's eight different subtypes. The most important one is APL or is it AL? Lots of lymphoblast, lots of them in the bone marrow. Is it B or T? I now know how to identify the differences between T and B and how to know if it's a myoblast. That's very very specific on bone marrow and other special studies that we'll talk about in the diagnostic section. And then I even told you guys to remember what are the most important genetic causes that are happening where we put the accelerator on proliferation but the brakes on differentiation. For AML the most important one is the 1517 transllocation. For all it's the 1221 rare cases 922. What's the disease where you have three chromosomes which increase your risk by 10 to 20%. That's down syndrome. That's the big things to take away from this. So now that we've done that, I want to talk about the havoc that these blasts myo or lymphoblast have on our body when they're in the bone marrow proliferating or when they're in the tissues depositing. Let's do that now. All right. So let's talk about the classic clinical findings that we see in acute leukemias. When it comes to leukemia, they have kind of a beautiful classic picture I would say that you should be thinking about. One of them is pansyenia. The concept behind this is that regardless if it's AML or alllcellular bone marrow. For AML, their bone marrow is filled with myoblast. Whereas, if it's alllast, when you have all of these kind of building up in the bone marrow, they take up a lot of space. They're pretty honky cells, right? So, they're they're they're chunky cells. And so with that being said, you're going to crowd out the bone marrow, per se. And by crowding out that bone marrow, you make less space in the bone marrow that's needed for other cells to divide and to to form, right? And so that's what usually starts to happen is because of all of this, you crowd out, we're just going to use that in quotations, per se, you crowd out the bone marrow. Now, when you crowd out the bone marrow and you make less space, what happens here is that you don't have enough space for other cells to develop, proliferate, and then form, such as our red cells, our platelets, and our white blood cells. And so, because of that, we can't push other cells out of the bone marrow into the bloodstream. So, we're not forming our red cells. We're not forming playlist. We're not forming our functional white blood cells. Now what's it called whenever you have less red blood cells? So whenever there is a decrease in the number of red blood cells and we measure this on our CBC via what? Hemoglobin. So technically the hemoglobin is what's actually going to be low, right? If we're really being specific. When you look at a CBC, you'll see that there's less red blood cells, there's less hemoglobin, there's a lower hematocrit. That might be the way that you diagnose these patients as having a form of the pansyenia the anemia portion. How does anemia though? So this is how we would define anemia, right? So we would define this part as anemia. Anemia could be a laboratory diagnosis if the hemoglobin is less than 13 in a male or less than 12 in a female. But how would they come about symptomatically? So anemia can present symptomatically based upon the presence of fatigue, palar, dysnia. These are usually classic signs. But I'd say the most common one is fatigue and palar. All right. So that's one thing. You get a CBC shows a lower red cell line. They have symptomatic that could be anemia. The next component here is what if the platelets are lower? So if you have less platelets now less platelets is pretty straightforward. It's no specific kind of like parameter like hemoglobin. It's it's the platelets itself. So if they're low, this is called thrombbo cytoenia. And this is defined as less than 150,000 platelets. When you have less of these, the symptoms is that of what platelets do. So red cells are designed to deliver oxygen to the tissues. So the reason why you develop fatigue is because of less oxygen delivery to the brain. You'll have generalized weakness because of less oxygen delivery to the muscles. You'll have palar because of less oxygen delivery which carries that reddish shoe to the skin particularly to the conjunctiva and as well as other tissue spaces. With platelets they're supposed to help you to clot and if you don't have them you can't clot. So you will bleed and so therefore the symptoms could be bleeding and usually platelet related bleeding or bruising is usually kind of a classic picture. So the bleeding is usually going to be things like gingal bleeding, epistaxis, minorio, prolonged bleeding from like a cut. So those are things that suggest a platelet disorder related bleeding. The bruising is usually in very small little blotss on the skin like pikia and pipura. All right, the next component here, this is the interesting thing. When you think about all these lymphoblasts or myoblast, they're white blood cells. They're just not mature. All right. So, what could happen is, and this is what usually can get people, you crowd out the space, which leads to less space for functional white blood cells. And the most important one that we really care about here is our neutrfils. And so, you can get less functional white blood cells. So, you can have a decrease, and I'm going to be very specific. I'm going to say functional white blood cells. And this is defined as lucopenia meaning you have a decreased number of white blood cells. What's an example again of the most important one. So most the example here that I would want you guys to think about is neutropenia. All right neutropenia when you have a decreased number of neutrfils. Now here's the problem. luccoytes. All right, they are white blood cells. When you get a CBC and you see, oh, the red blood cells are lower, the hemoglobin, the maticus lower, that's anemia. Oh, the plots are lower. Okay, that's thromocytoenia. The white cell count may not always be low. It's the amount of functional white blood cells that'll be low. Because what will happen is when you get the white blood cell count, you'll have the lymphoblast or the myoblast plus some of these functional white blood cells. Your white blood cell count could be very high. It could be normal. It could even be low. It really depends. So, it's a variable white blood cell count. What is important to know is when you look at the differential. So, the white blood cell count could be pretty high, could be normal, could be low. But when you look at the differential, and that's the key, you're going to have less of these neutrfils, basopils, and eosinaphils, but neutrfils is the most common. The reason why this is important is functional white blood cells are supposed to help you to kill bacteria and viruses and infections. And so now you can have frequent infections or fevers. This is where I want to talk about an example of why this is so important. When you have all these blasts that are taking up the space and you have less functional white blood cells that are circulating throughout the bloodstream, especially neutrfils. And how we truly define this is whenever the absolute neutrfill count is less than 500 plus a fever. This is a oncologic emergency. So if a patient has AML or all their neutrfll count when you calculate their absolute neutrfill count if it's less than 500 and they have a fever this could be a sign of a really scary disease and this could indicate something called neutropenic fever and it's actually worth remembering this. So neutropenic fever. This is the patient that if you have a patient with an absolute neutrfil count of less than 500 and a fever, you don't know where that could be coming from. And you have to assume that they have a really bad infection going on. Could be pneumonia, could be sepsis, could be urinary tract infection. You need to get blood cultures, urine cultures, all different types of cultures. Start them on antibiotics once you get those cultures and try to sus out what's going on. These patients are super high risk and they can die. All right. So with that being said, patient comes in, they present with fatigue, pallet, their CBC suggests that that's the anemia component. They come in with bruising, bleeding, their CBC suggests thrombocyopenia that suggests a part of this. They come in with variable white blood cell counts, but when you look at the differential, there's less neutrfils and they've having fevers or they're having frequent infections that accounts for that component of pansyenia. You can see this in either of these. bone pain you're not going to see as much in AML and it's going to be more common in all. So for here's what I want you to remember. I'm going to first off starting by saying that this is less common. This is more common. So less I'm sorry more common for all less common for AML. Either way the same concept exists that we talked about here before. or an AML you're getting a boatload of these myoblasts. In an alll you're getting a boatload of lymphoblasts and these things are honking big man they're huge. So because of that they're taking up a lot of space. And not only does that space factor account for less production of other cell lines, it also starts expanding the very undesirable uh tissue who doesn't really want to expand. It has to start to you know do that. So then what happens is you start experiencing a little bit of bone marrow expansion. So what occurs here? you experience some bone marrow expansion. All right? And that's just because of all these cells taking up all that space in the bone marrow. This starts to really occur. When you get a lot of this bone marrow expansion, it occurs in specific types of tissues, usually long bones. What are the most common bones to be affected here? Well, the pelvis is going to be one. So, the whole structure of the pelvis, the femur, and the tibia. These are going to be some pretty common ones. So think about any of the bones that make up the pelvis. Think about the femur and think about the tibia. These are all weightbearing bones. If you have bone marrow expansion and it starts to involve these bones, what will be the symptomatology? These are designed to hold weight. Bro, what's going to be the big symptom? The big symptoms from this is a patient will refuse to put weight to bear weight or they'll start limping because of the pain to kind of help with that process. So it could lead to a limp or a refusal to bear weight on that limb. So watch out for a patient coming in with pansyenia and symptomatology of that and bone pain with symptomatology of that should make you think of acute leukemia. But if you want to really be specific for the vignettes, it's going to be a little bit more common having bone pain with all, not as much with AML. That comes to the last type of classic presentation for these. Whenever you have AML, and it's a very specific subtype, remember I told you that I told you there's eight subtypes, M0 to M7. M3 is the most important one. I'm only going to quickly add this here that you can have M4 M5 AML which is called acute monocidic leukemia. So this is where that monoblast line is actually affected believe it or not. In this one the monoblasts actually come out here and you get a lot of these puppies here. They get pushed into the circulation out of the bone marrow into the circulation and from here these cells go and deposit into the uh m mucus membranes as well as the cutaneous tissue. When they do that they cause some interesting process to occur in the gingiva. It can actually lead to a process here called gingival hyperlasia. And with that being said, not only can that happen, but it can also cause these raised bumps, raised like red purplish bumps to appear on the skin. And this can cause an uncomfortable sight as well, which we refer to as leukemia cuts. So when whenever you have this one, you should definitely think about AML. It looks a little bit like this. If a patient comes in and they have mucaneous findings and panytoenia, which one are you leaning more to? AML. If I say a patient has pansyenia and the bone pain, refusal to bear weight or they're limping because of those bones being affected, you would say more likely all. How do we really iron out other complications or presentations of these two types of leukemia? Let's do that. Now when we talk about these alll acute lymphoplastic leukemia in a perfect world you know you may have a patient who comes in and they present with pansytoenia and maybe just some bone pain you make that diagnosis but oftent times patients come in a lot sicker and it's important to be able to realize these presentations and to consider them because they may come in with some kind of like non-specific stuff and it leads you to the diagnosis of AL. What are those things? One of them is lympadenopathy. I like to think about this easily. Um so lymphocytes love to deposit into lymphatic tissue. So whether that's nodal tissue like lymph nodes or extra nodal tissue such as like liver, spleen, other different areas of the body. It's very common for lymphocytes to deposit into these tissues. So lympho blastic leukemia is going to involve more organ involvement whereas acute miler leukemia is going to kind of really reside within the bloodstream. That's where it's really going to do its kind of problems. And I think that's really important to remember and it may help you to sus out these two types of disorders and their complication presentation. So lymphodenopathy you get a lot of these myoblasts right I'm sorry lymphoblast you're pumping these things out of the bone marrow into the bloodstream when these lymphoblasts get into the bloodstream they go and deposit into the lymph node now you have these lymphoblasts depositing here and they're going to cause enlargement of the lymph node that's called lympodinopathy how would that present usually it's going to be painless enlargement of lymph lymph nodes. And what's the most common ones to be affected? Well, it could be the cervical lymph nodes, right? These are definitely common. The axillary lymph nodes are very common. The superclavvicular, the inguinal lymph nodes, and sometimes it can even get into the mediainum. But I'd say the big thing about this one is it's kind of diffuse. It can hit a lot of different lymphatic tissue. Cervical, axillary, inguinal, superclavicular, mediainal. That's one way that we can think about this. Here's another thing. This chunk of lymphocy, the lymphoplast, they get deposited in here. They also pump out cytoines. And so when they pump out cytoines, they pump out things like interlucan one and tumor necrotic factor alpha which trigger the hypothalamus and cause fever, chills, things that kind of like are periodic and sometimes we can call this B symptoms. So if a patient comes in with fevers, chills, fatigue, malaise and on top of that lymphatinopathy, painless lympadinopathy, you think about lymphoma, consider all. All right. All right. The next one is a paddle splinomegaly. Same concept here. Your bone marrow is pumping out these lymphoblasts into the bloodstream. And these lymphoblasts when they're getting pumped out into the bloodstream just like there's getting pumped out here, they can go and they can deposit into the liver and they can deposit into the spleen. When they do that and they deposit into these kinds of organs, they're going to cause the organs to get larger and this is going to lead to hpatosplenomegaly. HPA splenomegaly. One of the biggest things to remember is that your right side is going to be occupied right upper quadrant liver, left upper quadrant, spleen. It's going to push everything in the middle. What's right here in the epigastrium? The stomach. So the stomach is commonly compressed. So you get stomach compression. What's the stomach supposed to do? Don't you dare say, "Oh, it breaks down my food, bro." It does. Yes, but it's supposed to accept food from the esophagus. If I compress the stomach, I make it smaller. Whenever food and fluids come into it, it stretches and it's going to stretch a lot quicker and it's going to reach that point where you're going to be fuller. It's kind of like acting like you have a buriatric surgery essentially like you did like a a lap band or you did a vertical sleeve gasterectomy. It's the same concept. I wish I had that sometimes. But this scenario is going to cause early satiety. You're going to feel full. Again, I wish I knew what that felt like. Sometimes I eat like pizza or the the the the sink like a rat. But hey anyway let's keep going. So we have a battle splenomegali when these patients have these big enlarged livers of big enlarged spleens. Sometimes it can be palpable but the biggest presentation is early satiety or abdominal fullness. If you actually happen to get images of these it would look a little bit like this. Okay. So we've seen now if a patient comes in with lympadinopathy they come in with a paddlomegaly pansyenia bone pain you're thinking alll let's add another thing now lympadenopathy and pylonomegaly these can all be seen in any type of alll cell alll which one's more common so this last thing you only see in T-C cell alll so let's add that here this is only son of a gun this is only in t- cell alll only in T A L. And let's actually box this so that you guys remember this is the only thing that you'll only see in this one and you won't see in B cell all and it should make sense. Bone marrow is pumping out what lymphoblast. How do you identify it's a T lymphoblast versus B lymphoblast? It's got the TDT but it's got CD2 to CD8 for T. CD1019 20 for B cell. Just a little seeing if you guys remember from here these tly lymphoblast they go and they deposit into the thymus. This right here this is this is your thymus. So now you're going to get thyic enlargement bro when that thing get big. It has mass effect. So then it's going to lead to a mass effect. All right that mass effect is it means that it's going to push on structures nearby. Let's pretend where's my green marker? Here it is. Let's pretend the thymus gets bigger and it enlarges and compresses this little brown tube. What's that brown tube that I'm smashing on? The esophagus. So, if I compress the esophagus, all right, so if I hit the esophagus, what would that look like? That would cause dysphasia, difficulty swallowing, right? What if I compress this other guy? So now it's good. A little green goo going here, branching out into this guy. What's this? The trachea. So now I'm compressing the trachea. What's that going to look like? Well, it's going to decrease air flow. That could lead to dysnia. And in worst cases, it may even cause strider, which is that really loud sound that you hear during inspiration. So, they can be short of breath or when they take a deep breath in, it sounds like they're really trying to squeeze air through a tiny little hole because the diamond is compressing on it. Here's the scary one though. The scariest part of the mass effect is if you compress the SVC. So if you compress the SVC. So now imagine here that this guy goes over here and it starts compressing on the SVC. Are you going to be able to get good venus return into the right atrium? Now no blood's going to back up from the superior vennea into the brachiosyphalics into your internal jugulars into your subclavians. What's going to happen? These patients can get real sick. So they can have if it backs up the J. So let's say it backs up. So it'll cause backup into the internal jugular vein. So the internal jugular vein that's going to cause face and neck swelling. If it backs up via the subclavian veins, that's going to cause chest and arm swelling, right? because you're going to be causing blood to back up and that's going to cause the kind of enlargement of the veins and on top of that it's going to enlarge the soft tissue. So they'll look like they have a big swollen face, big swollen neck, swollen chest and arms and it even gives a bluish kind of like a light tinge of bluish discoloration to it. This is usually again what we would see here. So it's going to cause compression. So, you're going to compress this. So, you're going to uh squeeze on the internal jug of the vein, squeeze on the subclavian vein, and you're going to get all this swelling. Now, here's what's really important. This can actually become an emergency if an SVC syndrome you get so much backflow. So if you get backflow of internal jugular vein, this can lead to impeded venus drainage from the brain. You know the brain has the sinuses which eventually drain into the uh sigmoid and then the internal jugular vein. Well, if you got a compression of the super venne, it's already backing up. That's going to cause poor venus drainage because blood's supposed to go from high to low pressure. But now you have the outflow which is what's going to come out of the brain into the internal jug of the vein. It's high. That's going to cause blood to back up. intraranial pressure can go up. So this could lead to an increased intraranial pressure. Oh no, that's not good. The second thing is it could back up the internal jugular vein and what happens is it kind of flows into these collaterals near the larynx. Those get enlarged and the larynx can get adeus. If your larynx gets adeus, dude, you can't get air flow into your airway. That's terrifying. So sometimes it can even cause luringial edema in these scenarios. This is emergency bro. This is you. This can cause respiratory distress. This can cause them to herniate. In those scenarios, you got to get these patients and get a stent in that vessel and open it back up. Sometimes it's not common, but if you compress the superior vennea enough that you can't get blood into the right atrium, you could even cause hypotension. But you see it more because it actually starts to really compress the heart like a tamponot effect. But that's not as I worry about these two big ones here. All right. So, we see this as being a pretty big concern here, right, with T-C cell all. Well, is there anything else? Yeah. So I had a patient when I um I was I was in the neuroscience ICU. young patient was diagnosed with all and she ended up having signs of menial leukemia because what happens is this disease sometimes man it can be so rapid and so aggressive that they can pump out these lymphoblasts and these lymphoblasts they have sanctuary sites the testes it's rare it's a rare finding but it can go to the testes a higher likelihood of a sanctuary site um is it can go to the meningis and it can deposit so here I'm going to show these like little black dots here this is the leukemic cells depositing to the meningis they'll create like a meningial reaction now. So it's going to get like inflamed. So if you have an inflamed meningis now that's going to be called menitis. They can get symptoms of menitis. Dude it's just terrible. So that what's that going to be? Well the biggest symptoms is headache right that's one thing because when you involve the meningis you affect the trigeminal nerve. You can also cause nausea and vomiting. You can also the meningi spread down into the neck. So you can also get neck pain or nucal rigidity. We'll put EG nucal rigidity and you can even involve the cranial nerves. So you know cranial nerves three, four, six and even the second nerve uh can actually be affected and so you can even get cranial neuropathies cranial nerve pauses. The most common is going to be cranial nerves two, three, four, and six. So you can get dipopia and blurred vision and papa edema. These are characteristic findings of menitis. How do I know if it's leukemic related? You would need to do an LP. So I'd actually have to do an LP test the cerebral spinal fluid and look for that LP to show me cytologology of the leukemic cells. So another thing I would need here is I would actually have to do an LP. So I'd actually have to take and do a lumbar puncture because again the meninges you have that subacoid space right you would be trying to tap into that and take some of that cerebral spinal fluid off and that would show me what it would show leukemic cells. So it show me lymphoblast and that presence of lymphoblast with the findings of this would be enough for me to say okay this patient can have meninja leukemia. We never want this. We never want this. So you know what we do whenever a patient has all this is what happened to this young patient. She had to get intratheal chemotherapy. So she was diagnosed with ALLL but we have to prevent the leukemic cells from spreading to the meningis and so we'll put in omia reservoirs or we'll do lumbar punctures and squirt in the chemotherapy to prevent those leukemic cells from infiltrating that. That's why it's really important to remember this. All right. Okay. The last complication now I want to preface tumor lis syndrome can occur in both all and it can occur in both AML but we see it more common. So here I want to write this down. You can see this. It's more common in all, but you can see it in AML. The concept behind this is that again your bone marrow is pumping out the lymphoblasts. When you have these lymphoblasts, right? And and what we find is that in patients who have all they tend to have what's called hyperlucytosis, like crazy crazy crazy high levels of white cell counts. So they can have very very high luccoytosis. We call it hyperlucytosis. All right. Problem with that is that creates a tumor burden. Imagine I have 450,000 white blood cells. Could you imagine that's a high tumor burden where if these cells for some reason decided to die? In other words, I trigger the initiation of chemotherapy. What is chemotherapy supposed to do? It's supposed to kill these cells. So that's what I want to do is I want to stimulate these cells to die. But when I do that, they pop open and release all their super super important contents like phosphate, like potassium, like uric acid and we see the presentation of tumor lysis syndrome. That's why when a patient has all and we start chemotherapy we need to monitor for this and prevent this from happening. So hypercalemia what we know about this from cardio from renal is that this has a very profound effect on the cardiac system particularly the electrical activity and so what we may see is we may see arhythmias or we can see the classic ECG changes and this is what they like to to test on uh for the exam. What's your uh ECG changes that I need you guys to remember? Let's let's highlight them. What's the first presentation you always remember? Go up this way, down, and back. So up is your peak T-wave. Second, as you go back, the prolong PR interval down you flatten the Pwave. Back to the right, you widen your QRS complex. From here, if this progresses, it can become a sine wave and break down into VIB or ASY. Can you imagine how dangerous that is? So when we have a patient who gets chemotherapy, they have all we like to put them on telemetry where we constantly monitor them for any ECG changes or arhythmias. What kind of arhythmias can they develop? I just told you they can have brada cardia. So they get brada cardia or they could have cardiac arrest. So they can go into cardiac arrest. This could be asy or vib or they could also develop brada cardia particularly a blocks. So they can develop like a first degree, second degree, third degree AV block. So this is important thing to remember. So we got to watch out for this. Now hyperasemia is where it kind of gets scary. So whenever you got lots of uric acid, right? This uh let's represent it with this like this blue dot here. These little blue this is this is your uric acid. When these little guys get over here and they move across the glomemeilus, what we see is that these little sons of guns are super toxic. They're nephrotoxic. They get into these cells here and they can induce a nasty toxicity and they cause damage to the proximal tubular cells. So now I'm going to have what is this called? Acute tubular necrosis. So I'm going to have acute tubular necrosis. That's I just stimulated that by these toxic uric acid crystals. Now what happens is when these cells die, what do they what do they do? Do you guys remember? They start sloing off. So, let's imagine here I start breaking up this cell. And what I'm going to do is I'm going to start shedding off sloing off some of that tissue. As I sloth off the tissue, such an interesting word, sloth. As I sloth off that tissue, what do I do? I obstruct the flow of urine. Can you filter things across if all the pressure is built up in that tubes and in the capsule? No, you can't filter this. Look at this. All this is going to be inhibited. Your GFR is going to go down faster than you can ever imagine. And because of that, what's going to happen is this is called an obstructive uropathy. So what is this called? This is going to cause obstructive uropathy. So obstructive uropathy due to those nasty cells and that's going to again cause a drop off in the GFR. an abrupt one. All right? Because you're going to build up the pressure. You're going to build up the pressure in the capsule and that's going to impede the net filtration pressure. Now, GFR determines the way that we clear metabolic waste. My GFR is going down. Am I going to clear metabolic waste? So, if I'm impeding this process where things are supposed to be filtered or secreted, now this process is impeded. So, I can't filter and I can't see creep because these cells are damaged. Bro, that's terrifying because now my creatinine can go up and that's really what determines the incidence of an AKI. That's really whenever it goes up acutely, that's determines what an AKI is. I can also see the potassium, the water, the protons, and the ura go up. So, what if my potassium goes up? That's hyperlemia, bro. Wait a second, Zach. They're already at risk for hypermia. Exactly. That's why this is such a disaster whenever you have these two together. The other thing is that the water can go up. So, they can develop hypervalmia. They can get volume overloaded and then they can also build up their protons. They can get acidotic. And then lastly, if the ura builds up, it can cause uremia. And these are the concerns, right? So I'm not going to write those out, but again, hyperalemia, hypervalmia, acidosis, uremia. It's really important to remember that that's the presentation of an acute kidney injury. So an ATN is the way that these patients will present with what we would define as an AKI, an acute kidney injury. This is why this part is super critical to identify. The last thing is so if a patient comes in, they got kidney injury, they got hypercalemia, and they got um a history of all, some chemotherapy, and then another thing you check their fossil levels. Fossil levels are through the roof. You know what the problem with phosphorus is? You don't really think about it doing very much. One thing it does do is it binds free calcium. So, it loves to bind that free calcium. If you got a lot of this sun to gun and it binds up the free calcium, what's going to happen to your calcium levels? It's going to go down. Might have less ionized calcium, bro. Ionized calcium is important because high calcium blocks sodium channels. Low calcium doesn't block the sodium channels. These things are going to fire like a son of a gun. These neurons are going to go absolute ham bone and they're going to fire and fire and fire. What's that going to present as? Neuromuscular irritability. What's that called? Tetany. I could come in with shave tech sign, triso sign, what else? Peroral paristhesas, seizures. It's pretty terrifying. The whole point of really identifying tumor licis syndrome is that whenever a patient has this and they're getting treated, you monitor these things. And there's a pneummonic. I don't know if it's great, you may hate it, you may love it. I think it at least gives me a basic idea of the contributing factors. I like to remember puke all in caps and then calcium and lowercase that phosphorus is elevated, uric acid is elevated, potassium is elevated. So this these two elevated, calcium is lower case, it's decreased. May help you a little bit to at least remember that these are the the four characters that are the problematic issue in tumorlyis syndrome. Okay. Now that we've done that, let's see what's the big presentation for AML. All right, so now we move on to the complications of acute myo leukemia. Now it's really important to remember that for acute myo leukemia, can you get tumor lis syndrome? Absolutely, you definitely can. All right, so in acute myo leukemia, they can get tumor lis syndrome. All I wanted to emphasize is that you see it more commonly for all. The reason why I'm doing that is so that they present it in the boards. They're going to utilize that concept that it is more common in ALLL. All right. So, don't forget that. With that being said, we're going to talk about luccoasis and DIC because that's the two big complications that you see in acute mild leukemia. Can you see luccoasis in all? You can. You definitely can. It's just it's more common in AML. Let's talk about these. So, luccoasis, what is this? This is basically um a concept here where you see it in AML, they pump out lots of these myoblasts, right? So you're going to get lots of these myoblasts. Now remember I told you that these account for white blood cells. So when you get a CBC and you get a white count that's like you know 300,000 these are accounting for that. So the more myoblasts you have the higher that white cell count is going to be. The higher the white cell count the more incidence of luccoasis you're going to have. At what point in the bloodstream when you do a CBC when these guys get into the bloodstream at what point are you concerned about luccoasis? We get concerned about luccoasis whenever the white blood cell count is greater than 100,000. At that point we start saying that okay there's so many myoblasts here in the bloodstream that what it could actually do is is it could do a couple things. One is it could decrease the uh it could increase the viscosity of the blood. So you're going to increase blood viscosity and then that's going to start causing little occlusions. these like little white cells, they can start kind of like shoot and they get stuck in all of these like microvasculare. And so then what's going to happen is you're going to get microvascular occlusions. So now look at this. If I get these white cells and I have so many of them that they flow through here and they start kind of accumulating here and they get stuck in these like smaller micro vessels. Blood which carries oxygen is supposed to be moving through this to these tissues. Am I going to be delivering oxygen to these tissues now? No. As a result, there's going to lead to decreased O2 delivery. That decrease in O2 delivery because of these white cells plugging up the microvasculare can then present with organia. And the reason why is if I start stimulating organia, this can present in different organ systems. For example, let's pretend these tiny little white cells get stuck here in the microvasculare of the MCA or in the microvasculare of the ACA or in the microvasculare of the PCA or the microvasculare of the vertebrate. You get the point. They're clogging up these areas, decreasing oxygen delivery. It could be to the point where it causes mild symptoms, sometimes headache, dizziness, right? But the scariest fact is if it causes enough blood flow to be reduced to the brain where they start having neurological deficits, but they can it's only transit. They go back to their normal status. What's that called? A TIA. So in mild cases, it could be just a headache and uh dizziness. That could be the most mild scenario, but it could get worse, right? It could then progress to a TIA where you have transient eskeemic attack or it could go all the way to the point where you develop a true infarct of the brain. Here's an infar. Right? That's the scary concept here. So I could actually infarct this tissue if I'm not giving enough oxygen supply. It could start off where it's just headaches. Right? That could be the first symptom. Then it could then progress to a TIA. Worst case scenario, it can progress to a CVA. So this is usually in the order of how it may progress. Sometimes they may go straight to a stroke. It might just be too bad. So that's one thing. The second thing that I need you guys to think about is it could also kind of plug up the flow out of the retinal veins. So imagine I olude the retinal veins. Well, retinal veins are supposed to bring blood out of the retina here. But now that's going to be impeded because I got this occlusions here. If I olude that all this blood proximal is going to start building up. These retinal veins are going to get big as a son of a gun. Look at these. Look at these things. Look at this. These things are getting huge. That's going to cause dilated retinal veins. If you get dilated retinal veins, the problem with that is that you cause a back pressure in the retina. And that back pressure, the issue with that is that it can cause hemorrhages to form within the retina. So sometimes this may cause what? It may cause retinal hemorrhages. Now another thing that's really important to remember is that you have the optic disc. That's where like your retinal artery, the retinal vein kind of through that area and even have the optic nerve. Sometimes when these retinal veins get super engorged and dilated, they cause the enlargement of that optic disc. That's called papadeema. Papaladeema. When you have this, when you have papadema, that's one thing that may cause the blurred vision. Retinal hemorrhages could cause blurred vision. These are the big things to remember. So often times with this type of presentation, one of the big ways that these patients may present is they may present with that blurred vision. So this could be the fundoscopic findings, but this could be the symptomatology of those fondoscopic findings. So watch out for that. Could they be presenting here with blurred vision? That's the big thing to remember. The other one here is that sometimes these little white cells can plug up the pulmonary arteries. Could be in like the more distal ones, but it could plug up these pulmonary arteries. What are these supposed to do? Well, blood's supposed to go from the right atrium to the right ventricle to the pulmonary arteries to the pulmonary capillaries where we deliver oxygen. I mean, where we actually pick up oxygen at the alvoli, drop off CO2. Now, because of that, you're going to get a decrease in the gas exchange at the alvoli. So, you're going to get a decrease in the alvolar gas exchange. If you don't exchange those gases, you're not going to be able to have a good oxygen. So, you're going to end up with what's called hypoxia that may be evident on the patient's SPO2. Or they may come in with dysnia because of the hypoxia. They may come in with an increased respiratory rate to compensate for their hypoxia. They may be working hard to breathe to compensate for their hypoxia. These are the things that you want to be looking for. So because they can get microvascular occlusions in their pulmonary circulation, they can present with hypoxic respiratory failure or dissant due to their hypoxia. They can present with neurological deficits in worst case scenarios and they can present with blurred vision due to the fundoscopic findings. All right, man. That's luccoasis, right? And again, luccoasis is a pretty severe one. Now, here's what's interesting. So you you're probably asking, okay, Zach, I feel like you said back there that all can have hyperlucytosis. So wouldn't all lead to luccoasis more likely than AML since their white counts tend to be higher? You would think that. But what we found is that there may be other alternative reasons, and this is what's interesting, as to why AML develops luccoasis more than all. It may not just be the elevated white count alone. It may be something else present that we just don't know yet. But for now, white counts greater than a thousand with symptomatology is luccoasis. Which one do you see it more commonly in? It's going to be more common in AML, but you can see it in all. All right, cool. Next one. DIC. This one you're only going to see in AML, but again, it's specific. It's only in a subtype. Remember, mediaal masses are only found in uh TALL. Well, in DIC, you're only going to see that in APL, which is the M3 variant of AML. So, it's only going to be in APL. Now, if you remember with APL, the bone marrow is going to be pumping out a lot of these. It's not the blast. What was the big difference? You had that fusion gene, the PML procinoic acid receptor alpha gene that was in the processes. So, these are going to be your proylotes. They're like one stage after the blast. So, you're going to have a ton of these little sons of guns. Now, promyocytes are dangerous. And the reason why is they secrete lots of chemicals that these blasts don't usually secrete. And so, when they get into the bloodstream, when they infiltrate into the bloodstream, these are disastrous, dude. So, for example, they can release things like tissue factors. So remember tissue factor that's something that activates the extrinsic pathway because it binds with factor 7. It can also release all these different types of coagulation factor activators. So it can activate other coagulation proteins. So the whole point here is that you're releasing certain things that are going to do what? Trigger the coagulation cascade. So I'm going to increase the clotting proteins or I'm going to increase my clotting cascade with this concept here. So these little promyioytes are sons of guns. They release tissue factor. They release these activators of the coagulation cascade and that pumps up my clotting cascade activity. Now if I have clotting proteins, what do I need in order to bind to the actual vessel first to start a clot? I need platelets. So I need platelets present to be able to help that process. So what happens is the platelets will start sticking to the endothelium. When the platelets stick to the endothelium that activates other coagulation factors and these coagulation factors will then start again triggering that fibbrin mesh to form. So pl start the primary hemostatic plug and the coagulation cascade leads to the secondary heistic plug. Either way, the combination of these two are what I get to form these micro throi. So now what ends up happening is in DIC I get widespread micro throi. These widespread micro throi can lead to organ eskemia. But here's the problem. Here's where it really gets bad. When you use these clotting proteins, and I'm talking you you make a lot of these things, dude. You make clots all over the place. You consume your clotting proteins, you consume your platelets. So what ends up happening here is you end up with two effects because of the consumption of platelets and the consumption of clotting proteins to make all these throi. What ends up happening? So I increase the consumption of pllets. I increase the consumption of my clotting proteins. What does this do? The problem with this is I have these micro throi, but now if I have a little nick in my uh vessel here, I won't have the platelets or the clotting proteins to stop the bleeding. So now, as a result, these patients can have clots and they bleed. That seems paradoxical, Zach, but that's what happens here. So, they can get bleeding. This could be in the form of what? Echimosis, GI bleeds, brain bleeds. This could be uh prolonged bleeding after surgical procedures, oozing from IV sites. The list goes on and on and on. But this is usually bleeding that's going to be presenting because of the consumption of platelets and the consumption of clotting proteins. So, if I have a new nick, I can't stop that. All right, that's interesting. So, a patient can have thrombi and they can bleed. That is kind of interesting. But here's what gets worse. The promyosytes, not only do they release these things to cause the clotting cascade, which eventually gets consumed that causes bleeding. But they also release something called, so here's my promyite. They release something called a nexin 2. Now, don't go too crazy. All I want you to know is that it's basically increases the activity. It leads to increased activity of plasmine eventually. Now plasmine if you guys remember helps to break down fibbrin and fibbrinogen. And so what it's going to do is it's actually going to break down some of the clots. And so it's going to lead to the breakdown of fibbrin and fibbrronogen. This starts breaking up clots. Dude, what's that going to do? That's going to further worsen the bleeding. Oh my gosh. So, not only do I have thrombi that are forming because of the consumption of the plates and the clotting proteins, but I end up consuming them, I have less of them to stop myself from bleeding. And then on top of that, these dang proyoytes, they release things that break down clots. So what do I end up doing any even more? Again, I trigger more bleeding. That's why this is disease is super super super scary and it's something that you have to be able to recognize. Now the next concept here, okay, we have patients that bleed and they have clots. But here's another thing. When you make these micro throi, right? You know who um just unfortunately get the brunt of this sometimes? Here's all these micro throi. Red cells are just a little bit too big. So when they run through these micro throi, they get shredded to pieces. It's terrible. And when they get shredded to pieces, they make these like weird shredded up cells. And what are these called? These are called shisttoytes. So these patients will have shistytes. The only way that you can truly see shistytes is you look on a peripheral blood smear if the patient has anemia. So they can get anemia and they can have the presence of shistytes. So one of the ways that we truly diagnose a patient having DIC is they'll first start with bleeding, skin bleeding, echimosis or petiki or they can have prolonged bleeding from surgical sites, they have GI bleeds, they have uh brain bleeds, they have oozing from IV sites, all these different things. Either way, they're bleeding. And on top of that, we get certain types of labs. First thing I do is I get a CBC and I show that my platelets are low. So, what would I see on my labs? My labs are the key thing here that helps me to make the diagnosis. So, yes, it's not just the bleeding, but there's certain labs. One thing is I'm going to because of the consumption, I'm going to have less platelets, right? So, my platelets will be low. I'm going to rip up my red cells. So my red cells are going to be low. So I'll have a lower hemoglobin. All right. If I look at the peripheral blood smear, I'll have shistytes on the peripheral blood smear. If I look at because I consume my clotting proteins, I can't now stop myself from bleeding. What happens to my coagulation labs, my PT, my PTT? Those all go up. So I have an increased PT and PTT because I'm making clots all over the place. What's one of the things that tells me if I have a heavy clot burden? D- dimer. So D-dimer will be elevated. And because I have consumed so much of my fibbrin and fibbrinogen because I'm breaking down the clots, what happens to my fibbrronogen level? That goes down. Do you see why I break this down? that precipitates bleeding but it also lowers your fibbrronogen. So then you have a low fibbrronogen. These are pretty much characteristic for DIC. Okay my friends at this point we've talked about acute leukemas with respect to the patho the causes the classic findings the complications. Let us move on to the diagnostic approach. Putting all of this together is really the key right because we've talked about a lot. So if I see a patient who comes in with potentially fatigue and palar I want to think about anemia. If I see easy bruising and bleeding, I want to think about thrombocyopenia. And I hear that, oh, they've had a couple infections this year and they've had frequent fevers, I want to think about neutropenia. These things are telling me the sign of pansyenia. And I can get a little bit more specific. And if they say anything about bone pain or having difficulty bearing weight or limping, I think alll. And if I hear mucinous lesions on their manifestations of their physical exam, I'm thinking AML. So, okay, I want to prove the panytoenia and I want to look to look at the specific type of cell in the blood in the bone. So I get a CBC. I'll get make sure it's with a differential so I can tell the types of white blood cells and then I get a peripheral blood smear to get an idea of what's that the actual cell in the blood and see if it can help me determine if it's lymphoblast or myoblast. So if I do the CBC with diff and I see that they got pansyenia all those cell lines are are low that would support these symptoms. And if I see they have lots of blasts on their differential oh okay cool that tells me that these are definitely more of the acute types of features. This could be an acute leukemia. I have to look at the actual blood smear and say, is it lymphoblast or myoblast? So, if I look and I see lymphoblast, that's very helpful. When you kind of look at a blood smear here, you can kind of see I have a lot of red blood cells here. When I zoom in, look at all these. These are tons and tons and tons of lymphoblast. And when you really zoom in here, you can kind of notice, oh yeah, wow, these are very large appearing cells with a very large nucleus and large cytoplasm. This is characteristic of my lymphoblast. Now it doesn't guarantee that the patient has um alll. The reason why is this is just in the peripheral blood. I actually have to confirm that this is in the bone marrow. So I would have to follow up and get a bone marrow biopsy. But let's say that I move to the next step which is all right. I have another patient who has a differential that shows pansyenia. They got increased blast. Maybe they have mucaneous lesions. And when I look at their blood smear I see myoblast with our rods. And so when I zoom in on this portion here I see oh wow this is definitely a really huge nucleus. Oh, what's that? That's our rods. Our rods. Oh, that was always associated with acute milo leukemia. Again, not a guarantee, but it's very, very likely. The only way that I can prove all of this is I got to get a bone marrow biopsy and send that sample off, look for those CD proteins, look for the TDT, look for the mo and really figure out, is this a lymphoblast or is it a myoblast that's in the bone marrow causing all of these problems. So if I see greater than equal to 20% lymphoblast on the biopsy, boom, it's all I got it. If I got greater than equal to 20% myoblast on the biopsy, boom, it's AML. But then the question is with with all is it T or B. That's where the flowcytometry and imuninohystochemistry comes in. If I do that and I see CD10, 19, 20, and TDT, ah dude, that's the Bly lymphoblasts. And if I see, oh, it's CDT but CD2 to 8. Oh, that's the Tlymphoblast, right? And then you know what we can actually say is I can get cytogenetic studies which really look at the types of mutations or chromosomeal transllocations. And remember there was two 1221 922. If I got 1221 that's for pediatrics it is good prognosis. And if I get the 922 the Philadelphia chromosome that's in adults that's bad prognosis. That's also something that we can do from this study because it helps to guide kind of our treatment progression. Now with AML there was like eight subtypes. Again, you can actually look at these on the biopsy and kind of get an idea. If you really wanted to know specifically though from those um which type, again, you could do the CD13 and 33, but the MO is the really big one. If you see myoparoxidase that's actually present on their uh flowcytometry or their heisty chemistry from a myoblast from their bone marrow biopsy, it's AML. What you could then do is take it a step further and get the cytogenetics. Why? Because I want to look for one specific chromosomeal transllocation. Remember 1517. If I find the 1517, what was that associated with? Come on, spit it out. APL. All right, that was the PML raar alpha gene. All right, fusion gene. All right. Now, what if I have a patient coming in with complications like some scary ones that we talked about? We talked about a lot of them. Let's put it together. So, if they come in with these oncologic emergencies, per se. So, I see stroke symptoms. So they have he maybe there's some dizziness some TIA they have some focal deficits they have shortness of breath they have hypoxia and I get a white cell count and it's greater than 100 thousand they have hyperlucytosis and organic eskeeia symptoms that's luccoasis if I hear menitis symptoms headache nausea vomiting nuclear rigidity some cranial nerve pauses what am I thinking I'm thinking menitis but I'd have to prove that by getting an LP to see the leukemic cells if I have face neck arm swelling and in worst case scenario their intraanial pressure is high so they're neurological deficits or they're having respiratory stress from lingial edema. I'm thinking SVC syndrome, right? Especially the T- cell ALLL. And if I hear coagulopathic bleeding, so I hear that they're having a lot of hem hemosis, echimosis, bleeding from IV sites or from catheters, they're having uh a lot of these problems, I'm thinking DIC, especially with APL. And if I hear that their creatinine bumped up significantly, they're having um arrhythmias that are showing PT waves and prolonged PR intervals and dropping of their P waves and widening QRS complexes. I'm thinking about the hyperc calmia factor. And if I hear that gout flare and the AKI, I'm thinking about that uric acid that's causing a lot of these diseases, especially we see this in all. This one AML, ALL, T-C cell, and APL. Now we can really thoroughly evaluate all this and this is kind of an initial stuff. You can get coagulation studies and you can extend that out. We can get a PT, PTT, we can get an INR. We can look at fibbrronogen. We can look at a D-dimer. All this is trying to do is prove this uric acid. I'm trying to prove if there is potentially um especially with combination with a CMP. If their uric acid's high, their potassium is high, their phosphorus is high, calcium is low. I'm looking for tumor lysis syndrome. CT chest with IV contrast. I'm trying to see if the SVC is compressed. I'm looking for SVC syndrome. And a loop a lumbar puncture is looking to see if there's leukemic cells that support menial leukemia. So again, a lot of this is really putting it together. So it technically lucosis is a clinical diagnosis. You need a white cell count, a greater than 100,000 hyperlucytosis, and es schemic symptoms. That's the diagnosis. Then if I hear that a patient is having some menitis symptoms, I get a lumbar puncture comes back negative for really any kind of disease like bacteria or viruses or fungal. But when I throw off cytologology from tapping in there and it comes back positive for leukemic cells, it's meninja leukemia. If I get that CT with IV contrast coming through here, the chest and I say, "Oh my gosh, there's a big goober here and it seems to be, oh, that's the SVC. Look at it. It's tiny as can possibly be. That's probably my superior venneava syndrome." And if I have a patient who's bleeding and then I look and I get their PT and their PTT and it's elevated, they got a low fibbrinogen, a high dimemer, and add on that other thing, they have thrombocyopenia, they got shista sites on their blood smear, that's really supporting that DIC picture. All right. And then lastly, if I hear a patient has, you know, arrhythmias, they're having high potassium on their CMP, high uric acid when I test that, their phosphorus is high, their calcium is low, and they maybe got a recent dose of chemotherapy, I'm thinking about tumorlyis syndrome. All right? So, this is really a very comprehensive approach in that sense. But before we treat the disease, we should treat some of these acute complications. And we talk about this in a lot of different systems, but it's always good to have overlap because you'll remember it when it's actually necessary. So in tumorlyis syndrome, the problem here is that you get a lot of these crystals, the uric acid crystals, and they can really cause a lot of damage. And sometimes there's not a lot of evidence, but you can try and really fill their vascular system to flush some of these uric acid out um and pres prevent the actual precipitation of them, which can worsen kidney injury. So it's always good to maintain good IV fluid resuscitation just to avoid volume overload. The problem with tumor lis syndrome is the uric acid. You want to try to lower that as much as possible because if you go back to your kind of biochemistry whenever these cells pop open they release purine nucleotides that can convert into hypoanthine and xanthine and then to uric acid. Uric acid is the problem. This is the one that kills the kidneys and causes that nephrotoxicity. Right? So we have enzymes that help in these process. Oxidase helps to make this step and it also helps in this step. Well, if I had a drug theoretically that could inhibit zanthinoxidase like alopurinol, what I may be able to do is reduce the uric acid because it's going to inhibit these steps and so I'll end up with like less uric acid potentially, right? And that's less nephrotoxicity. Problem is is that it's only going to inhibit what kind of like in a in a degree it's inhibiting uric acid formation in a patient who has tumorlyis syndrome and they already have uric acid out there. It just prevents further uric acid, but it doesn't actually reduce that already present uric acid. And so that's why it's really only good at decreasing uric acid before it's formed. That's why it's more of a prophylactic therapy. Whereas rasburease, this is actually better in a acute scenario because what rasbase does is let's say that uric acid's really high and I give them a drug that actually can convert uric acid into a very less toxic form that can be easily excreted from the kidneys. there's no nephrotoxic effect. That would be great because I convert a lot of that deadly stuff into the less toxic stuff. That's where raspberase comes into play. It actually helps to convert uric acid into alenon which can be excreted very nicely and it doesn't cause any defrotoxicity. That's the benefit of raspberase. So we use this in an acute event and this is more of a prophylactic event. But IV fluids should be given no matter what if we're concerned about this. All right. Now with luccoasis the problem is we got tons and tons of white blood cells. We got to lower them. So acutely what you'll probably be doing is two therapies up front. That's at least what up to date supports which is hitting them with hydroxyurora. It's a cyto reduction agent. So it hits the bone marrow and shuts down the production of mostly a bunch of different cell lines, red cells, platelets, and white cells. Problem is is it kind of takes a little bit of time. So it's good as more of a a chronic and preventative or prophylactic effect. Uh but when you need to rapidly remove white cells, this is really the thing that you want to do is add on lucaperesis. So lucaperesis basically you're going to remove the blood from the patient right which has all of these heavy amounts of the blast in this case since we're talking about luccoasis we're talking about AML all right so we want to remove a lot of those and then what we want to do is we want to centrauge it to separate it onto layers and then we're going to get our red cell layer our buffy coat layer which contains the platelets and the white cells and then you're going to get your plasma all I want to do is get rid of those white cells all of those excess myoblasts and as I do that I can give back the blood to the patient that I have, you know, I don't have any need to to actually remove like their plasma and their red cells and their platelets. So that's the goal of lucaperesis is to rapidly reduce it. So we do that a lot when they're severely symptomatic. All right. Now DIC a lot of it's really just supportive. If a patient has a low platelets and they're bleeding, you give them a platelet transfusion. If they have a low hemoglobin, you can and they have again potentially in this scenario we wait for at least less than seven, we'll transfuse them with the pack red cell. If they have a bleeding and they have an increased PT and PTT, you can give them FFP. The thing about DIC with acute leukemas, especially APL, is we actually do have a specific treatment and it's called all trans retinoic acid, often times abbreviated ATRA. And the cool thing about this drug is if you guys remember the 1517 transllocation makes the fusion ankop protein or the fusion enco gene, which makes the fusion encoin. And this put the differentiation block on those promyocytes and said you can't convert into a neutrfil or an eosinaphil or a basophil. And so that was the problem. So you build these things up. What if I had a drug like all transretinoic acid which basically what it does is it takes and actually adds ubiquitin onto this fusion protein. When you ubiquitinate something often times it tells proteosomes which are things that break down proteins to say oh I see something. Let me eat it. And it goes through and it rips that thing apart. Now you don't have any of the PML or R alpha. If I don't have this, is it going to be able to put a differentiation block anymore? No. Guess what? These things differentiate. And when it differentiate, it actually can, funny enough, if you give this sometimes it can cause differentiation syndrome where you make too many of these neutrfils, but that's not neither here nor there. It can make a lot of these neutrfils which converts them. And so now you have less risk of a lot of the problems that comes with APL like DIC. And so that's one of the benefits of this drug. Intrathealcylup therapy with methtoresate is really the stand hold therapy as prophylaxis in patients with the diagnosis of ALO. We can access their cerebral spinal fluid which can have contact with the meninges as it flows across it via an omia reservoir. So we can take and we inject the medication into this right into their cerebral spinal fluid right into a ventricle or we can access their cerebral spinal fluid via the lumbar puncture and inject that medication right in there as well. again it'll come into contact with the meninges and it'll get rid of a lot of those leukemic cells or at least prevent them in a way from forming there. So we often times do this as prophylactic to prevent that with the diagnosis itself. But if the patient actually has infection which is confirmed via LP or not infection but the infiltration of leukemic cells we have to give pretty high doses and a little bit longer than desired. All right SBC syndrome really a lot of the times it comes with treating the underlying disorder. So if you have a tumor in that area, sometimes you may have to just do chemotherapy um and some radiation therapy and some steroids. Usually the radiation and the steroids are the big thing up front, but that's going to be in a patient who doesn't have severe emergent symptoms because steroids are going to take some time and so are the radiation therapy. If a patient has high ICP or lingial edema with respiratory distress, we ain't got time to do that. We got to put a stent in and keep that thing patent so we can get blood flowing in. So often times we'll put a stent in to just keep it open and then we'll hit them with that chemo, radiation, steroids to kind of debulk the tumor and decrease it in size so we have less compression. You're treating the underlying disorder that way. So that's a lot. So how do we kind of put it all together? Well, if I said that I got a patient who comes in with luccoasis, what do you do up front? Well, luccoasis, I'll do hydroxyhea first, right? Especially if that white count's really high. It may take some time. So what do I want to add on? Especially if they're really symptomatic, I want to add on luciferis because it's going to rapidly drop that white count, reduce the further disease. If I hear menial leukemia prophylactically with the diagnosis of ALL, I do intratheal chemotherapy, right? But if they end up with a diagnosis from an LP and they have menial leukemia symptoms, I got to do high high doses. If I SVC syndrome, I just want to know are is it an emergency with high ICP, lingulade edema, hypotension. If it is stent, if it's not, then what do I do? I say, okay, I'm just going to go ahead and get them ready, schedule them with radiation oncology, get them some chemotherapy, but particularly radiation therapy and steroids along with chemo. shrink the tumor and that should help with that process. All right. If I hear that the patient has DIC, I'm gonna support them the best I can. If they have platelets that are less than 50,000 and they're bleeding, I'm going to give them a platelet transfusion. If they have hemoglobin less than seven, I'm going to give them a packet cell infusion. If they have high PTT, PT and they're bleeding, I'll give them FFP. But again, a lot of it's supportive. But if they have APL, I have a specific treatment that's all transretinoic acid. And then lastly, if a patient has tumorlyis syndrome, we want to know is it acute? So, do they have the puke calcium symptoms? If they do, IV fluids to really reduce a lot of further kidney injury, maintain good uimmia, and what is the one that reduces uric acid after it's already formed? Raspberase. All right. And then after that, you can again say, okay, the patient I given them raspicase, but they unfortunately they it sustained so much damage to their kidneys and they ended up with hypercalemia. they ended up with worsening acidosis. They ended up with hypervalmia and uremic symptoms. What do you do? You dialize them like you would any AKI patient that progresses that way. But if it's a prevention, this is not a patient who has acute tumors syndrome, but they have a high pre uh like a high risk or a probability of developing that, you do IV fluids to keep them euimmic, but you give alopurol to decrease the formation of the uric acid if it forms. Okay. So, let's move into the actual treatment of the underlying disease. Treating leukemia involves obviously chemotherapy. And so when we talk about acute lymphoplastic leukemia, obviously it comes with its plethora of complications that we talked about managing, but we also have to consider the treatment of the actual underlying disease. And so when we think about this, we think about something called the CAD regimen. And so this is really consisting of a couple different chemotherapeutic agents. One is going to be cycllophosphomide. The other one is venristine. A is adriomyc also sometimes referred to as docar rubicon and dexamethasone which is a type of corticosteroid. And so we're basically giving these to kind of reduce a lot of those leukemic cells in the bone marrow especially if that patient does not have a 922. What's the most common for acute lymphoplastic leukemia? If it's a chromosomal transllocation it's 1221. Right? So this is going to be the CAVAD regimen for most of those patients. However, if the patient does happen to have cytogenetics that support the 922 transllocation, we actually target the BCRABLE which actually targets your tyrroscen kinise receptors. And so we're going to give them tyrroscen kinise receptor inhibitors and that is going to be things like a mat nib per se u and any of your nibs. Those are going to be the ones that are going to be targeting that bcable fusion gene. All right, particularly at the tyrroscen kinus receptor point. Now obviously with the goal um of that the disease is that you have a hemocytoblast or a myoid stem cell or lymphoid stem cell with acute leukemas that are not differentiating and they're just building up. And so what if we replaced a lot of our stem cells, our hemocytoblast or the actual lympoid stem cells with normal stem cells. And if we replace those normal stem cells, they won't have these genetic predispositions with the 1221, the 922, the tricom 21, all of these mutations that they've encountered. You're giving them normal stem cells that can differentiate and proliferate into normal red cells, normal white cells, normal platelets, etc. All right, that would be the goal, but we only do this in patients who really have that high risk. They're they're basically on chemotherapy and they potentially are suitable for getting a bone marrow transplant. Now with acute milo leukemia, it's really citabine and donor rubicon are going to be the drugs of choice that we will actually target to kill these leukemic cells. Now all transretinoic acid is the really important one that I talked to you guys about in DIC. The reason why is you're giving them supportive treatment but you're treating the underlying disease with all transretinoic acid. We also there's been a lot of literature that suggests using arsenic triioxide in combination. This is another drug that you can give. So again the kind of question that you'll get on treatment of acute milo leukemia is probably going to be more pertaining to this one. All transinoic acid is really really helpful but there is becoming more literature to support the combination of both of these especially in those high-risisk patients with APL. Again the concept behind this is that again you're trying to remember that with that 1517 you're getting that fusion gene. And they're getting that fusion ankop protein and that puts the block on differentiation. If you give them these medications like atra ultrans retinoic acid it ubiquitinates this fusion protein which kind of sets it up to get degraded by proteosomes. Arsenic triioxide can also help in that process. But if you get rid of the PML raw alpha fusion protein you basically say hey no more differentiation block and now the cells are allowed to proliferate and differentiate and you now have normal neutrfils. And that's the goal. Now lastly, as with again any acute leukemia, replace the stem cell because if I can replace that myoid stem cell with a normal stem cell that doesn't have mutations or any kind of chemo radiation that damaged it or myop proliferative neoplas or miloisplastic syndrome that are present. I'm giving a normal stem cell that's capable of differentiating into our normal types of granularytes. And that's the ultimate curative goal. Again, you're doing this in patients who you're treating with chemotherapy and maybe they're not getting a little bit better. They're high risk of continuing to get worse if you don't kind of do something if they have the proper candidacy and they're fit for a transplant. So, my friends, that covers acute leukemia. I really hope that you guys liked it. I really hope that you enjoyed it and learned a lot. And man, I love you guys. I thank you guys. And as always, until next time. [Music]