Chronic Lymphocytic Leukemia (CLL)

foreign engineers in this video today we're going to be talking about chronic lymphocytic leukemia also known as CLL if you guys like this video If it makes sense if it helps you guys please support us one of the best ways that you guys can go about doing that and it really does go a long way is by hitting that like button comment down the comment section and please subscribe please also if you guys get a chance down in the description box below we have a link to our website where we have some amazing notes some

amazing illustrations that I truly believe that if you guys follow along with me and fill that out as we go along I really think it'll Aid in your understanding of this topic but let's get into it let's talk about CLL so CLL just like we talked about this and again at this point you should have watched all the acute leukemias my friends he should have gone over AML all and if you have I would suggest you watch CML and then this will be the last one CLL and then we'll move on to lymphomas but at

this point what you should understand when the difference really is critical is between the acute and chronic leukemias acute leukemias usually when you look at them there's an alteration in both of these leukemias chronic and acute in the hematopoiesis pathway but one of the big differences that acute leukemias they affect really close up like towards the actual stem cell component so they were affecting more of like your lymphoblast they were affecting more of your myeloblasts and they were replicating replicating and replicating but never differentiating and that's why they developed super rapidly and develop symptoms and

problems very acutely right where they wouldn't really make many functional lymphocytes or many functional granulocytes whereas in CML and CLL what happens is it starts where the myeloid stem cell and the lymphoid stem cell they proliferate and proliferate and proliferate but they do differentiate and become white blood cells they become functional or mature like granulocytes are functional and mature like lymphocytes and so that's really the big difference here so when we talk about this one again we start off with the Hamada voices probably this is what occurs in the actual red bone marrow starts off

with what's called a hemocyto blast then it becomes a myeloid stem cell which we talk about more specifically in the AML and CML lectures now what we're going to do is we're going to focus more on this side the lymphoid stem cell which will then kind of become a lympho blast and then it'll become what's called a pro lympho site and then eventually to become a lymphocyte and there's two different types there's a t lymphocyte and there is a b lymphocyte and what's really happening in this particular process is that your lymphoid stem cells are

really just kind of undergoing this excessive clonal proliferation and monoclonal kind of expansion and so what's happening is these lymphoid stem cells are kind of just replicating like bunnies making lots of lymphoblasts loss of lymphoblasts are actually replicating and differentiating becoming pro-lymphocytes and then lots of these pro-lymphocytes are actually differentiating and becoming B lymphocytes now you're probably like oh wait I know that in all there was a T Cell all and a B cell AOL because there was lots of t lymphoblasts or B lymphoblast right in CLL it primarily only affects the B lymphocytes and

so what happens is there is just these massive amounts of mature or small appearing lymphocytes particularly B lymphocytes within the bone marrow within the bloodstream and that's really what it comes down to and so this is really where the process is occurring is that you're having lots of proliferation but at each stage you're differentiating you're differentiating you're differentiating and you're making lots of fully differentiated mature small lymphocytes whereas in a l l you were replicating at this lymphoblast stage but never differentiating them into complete mature functional lymphocytes that's the big difference here my friends so

the question then comes why is there so many lymphocytes what's the reason why these cells are rapidly dividing and dividing and differentiating I don't know the answer I don't think anybody really does and that's the problem with this one is that there's really no true like underlying reason genetic problem it could be due to ionizing radiation it could be due to like certain environmental hazards but there's nothing that's really been shown and studied and actually like you know something that you can rely on to be the cause and that's really interesting so the question then

kind of comes is okay I know that I have the lymphoid stem cell making lots of lymphoblasts lots of lymphoblasts making lots of prolymphocytes and lots of prolymphocytes funneling in and making tons of these B lymphocytes but the reason why this happens not a clue what I do want you guys to take away from this one is that this is most common in patients who are usually greater than 70 years of age and that's really it is that this is most common in ages greater than 70 years old so you can be thankful that there's

not a lot to actually have to know as to why this actually happens and I'm sorry there's no true answer but and the basic pathophysiology of it is that we know that there's tons of mature lymphocytes being produced due to excessive proliferation and differentiation reason why we don't know all we know is that this happens in older individuals could be idiopathic could be environmental exposures we don't know but now let's talk about the next stages which is I've made tons and tons of lymphocytes what's the downstream effects of that in the bone marrow and in

the blood and in the tissues all right my friend so now we get to talk about the next component here which is again we have a patient who has CLL and with this problem they have this excessive expansion monoclonal proliferation of massive amounts of lymphocytes when they have all of these lymphocytes that are kind of in their bone marrow what are some of the negative Downstream consequences that can occur well one of the big things here is that you are having lots and lots of lymphocytes that are being produced here and what starts happening is

is that over time some of these bees lymphocytes some of them are mature but they may be not as not as competent as I would actually like to say so yes in this particular process what may actually happen is you make lots of mature so you actually increase the number of mature but let's call them slightly less Inc slightly less competent so we'll call them incompetent B cells or lymphocytes so because of that because you get a lot of these like lymphocytes that are mature appearing but they're not as competent as they should be one

of the downstream negative consequences of that is that you make plasma cells from these lymphocytes some of these lymphocytes are supposed to convert into plasma cells and so then you get decreased competent plasma cells and then if your plasma cells are not completely competent then they aren't able to produce things like what antibodies so now if they aren't able to produce antibodies that means that you will have less antibodies being produced and this is called hypo gamma globulinemia and antibodies are supposed to be able to bind onto pathogens viruses bacteria tag them to be eaten

by what the right way of blood cells activate the complement system just really enhance the inflammatory reaction and clear pathogens from the bloodstream but now if I can't actually do that and I have less of these actual gamma globulins present now the downstream negative consequences of that is that I have a high risk of infections because I can't tag these pathogens and enhance the destruct destruction of these pathogens and so now the downstream consequences of a high risk of infections and these infections can look various different ways so what are the ways that they can

present they can present with pneumonia they can present with urinary tract infections they can present with cellulitis so these are the downstream things that can actually have a high degree of mortality in some of this patient population so that's one interesting type of effect you will make a lot of these lymphocytes and they will look mature but they may not be as competent and as functional as normal produced lymphocytes and that's the important thing to remember the other thing is that you have to remember it's just like in acute acute leukemias when you have all

of these actual lymphocytes that are being produced they start kind of crowding out the bone marrow a little bit not as much as in compared to like you know whenever you have a patient has CML They Don't Really crowd out the bone marrow until they start getting into the accelerated into the blast phase but this one's kind of similar they produce so many different types of lymphocytes that these are enough to kind of crowd out the bone marrow a little bit and because they crowd out the bone marrow they can drop all the other cell

lines so you can actually drop your neutrophils you can drop your red blood cells and you can drop your platelets and the reason why is there's less space and less nutrients available for these cells to be able to be produced and so you drop other cell lines which is just like you would see in AML and all so what could I see out of this I could see neutropenia less white blood cells particularly the ones that really help with fighting off infections and so now if there's less neutrophils there is a high risk of infections

promoting pneumonia UTI cellulitis other opportunistic infections the other thing is that there's less red blood cells and I end up with anemia and this can present with power this can present with dyspnea and this can present with fatigue and then the last one is you could have thrombo cytopenia and with thrombocytopenia this could actually cause bruising which can look like petechi eye it can look like uh ecchymosis it can look like peppera or it can actually cause full-on bleeding to be present gingival bleeding epistaxis GI bleeding Etc so look for anemia neutropenia and thrombocytopenia and

so this is interesting because you're like well this wasn't the same in CML and you're right it's not in CLL though there is enough crowding of the actual bone marrow to cause these particular types of problems I'm afraid so now we have to talk about the next component here which is when we have a lot of these lymphocytes that are actually in the bone marrow they're replicating and they're going crazy and then they start pushing themselves into the bloodstream what are the downstream kind of consequences from that so similar to all we already talked about

this they do have other cell lines being affected right so they can potentially see some neutropenia they can see some anemia they can see some thrombocytopenia now the other thing that's really interesting with this one and they don't really have a lot of bone pain that's a big thing that actually helps to differentiate CL from Al as well but nonetheless one of the big things that when you get a lot of these actual leukocytes particularly lymphocytes so they're going to have like a crazy lymphocytosis so they will have an insane lympho cytosis now we see

like greater than like 5 000 cells per like millimeter cubed of blood is really the way that you look at it but that's a pretty you know alarmingly high amount when that happens one of the big things is that maybe some of these cytokines that are released from these lymphocytes like you may see things like interleukin-1 tumor necrotic Factor Alpha they may help to be able to trigger your hypothalamus to kind of turn on that thermostat a little bit higher and so it may kind of trigger like these low-grade like fevers and it may trigger

like these night sweats potentially as well so these are some kind of constitutional symptoms that you may potentially see associated with that high lymphocytosis we talked about this in CML so in female they had that crazy leukocytosis like in like sometimes in the 200 thousands and so some of those cytokines can be released as well and that may trigger this process the next thing is that you can actually have some of these lymphocytes get deposited into the lymph nodes and when they do that you can form something called lymph adenopathy and this is an interesting

kind of term um so remember we said in all they get lymphanopathy lots of lympho blast deposit into the actual lymph nodes the same thing you can call these lymph nodes that deposit into the lymph a lot of these lymphocytes that deposit into the lymph nodes and cause them to get a little bit bigger lymphadenopathy but with that terminology comes a little slight additional terminology so we say that CLL is really a massive amount of these lymphocytes within the bloodstream and the bone marrow but when it actually causes a lymphocytosis and a lymphadenopathy so CLL

plus a lymphadenopathy that's actually called something else we call it small lymphocytic lymphoma so we actually technically give this next name called small lymphocytic lymphoma which is where these leukemic cells kind of deposit into the lymph nodes and cause lymphadenopathy that is called small lymphocytic lymphoma now sometimes this small lymphocytic lymphoma can kind of cause a really really scary hard kind of like core of lymphocytes to kind of really become a scary high-grade tumor when that happens it can cause something called a Richter transformation and with a Richter transformation what you get is you get

that small lymphocytic lymphoma which is basically CLL lymphadenopathy but what happens is it transforms into a high grade lymphoma and so what happens is you actually get we're going to kind of use these synonymously CLL or SLL starts to convert into what's called diffuse large B cell lymphoma this is a high grade neoplasia a high grade lymphoma very very nasty type of disease and this is another big high yield thing that differentiates CLL from all okay so lymphadenopathy Richter transformation we also can see some constitutional symptoms fevers and night sweats potentially from a predominant lymphocytosis

the other thing is that these kind of lymphocytes can deposit into the liver they can deposit into the spleen and when they do that they can cause something called hepatosplenomegaly which you also saw in what other disease you also saw this one in all you only see split omegaly in CML and you don't really see any hepatible omegaly at all in AML okay with the hepatosphonomegaly what could be some potential features that they present with they may present because it's taking up a lot of space your liver is getting bigger pushing on the stomach and

the small intestine spleen's getting bigger pushing on the stomach and some of the small intestines because of that it's going to cause decreased kind of like digestion decreasability of kind of eating and so you may have nausea vomiting you may have poor appetite or anorexia you may feel full very very quickly see there may be a sense of what's called abdominal fullness so these are potential things to watch out for the last one here is that you'll notice that as you get a lot of these like matures of a lot of mature but very little

competent lymphocytes so B cells some of these gain the capacity to produce unnecessary antibodies that like to attack our own tissues son of a gun right and these are called Auto antibodies Auto antibodies and what happens with these dang Auto antibodies is that they like to go and attack other tissues of the body and so what they'll do is they'll attack our red blood cells and their attack are platelets so now here we're going to draw like a red blood cell here and when you attack the red blood cell it's actually nasty in effect and

then you can also attack over here we'll draw the platelet so this comes up with now a different name what's interesting though is that when these Auto antibodies attack the red blood cells and they attack the platelets it causes these to start kind of like lysing ripping and kind of getting destroyed and what happens is this leads to a drop of the amount of red blood cells because you're cutting and lysing them open we call this autoimmune hemolytic anemia and then when you bust open these platelets and destroyed them this is called ITP immune thrombocytopenic

purpura now what's important to remember is that you may see this in patients who have CLL but another kind of Golden Nugget that you don't want to miss and they may ask you on the exam is a combination of autoimmune hemolytic anemia ITP in the presence of CLL is often referred to as Evans syndrome and I don't want you guys to forget that so don't forget that one as well the last potential thing that you could see I'd say It's relatively uncommon but if you get a large number of lymphocytes you have to really have

a ton and ton a ton of lymphocytes lots of like antibodies and proteins and things like that that are abnormal these can really kind of clog up lots of proteins and lots of cells make the blood very viscous so when you have increasing cells and you have increasing proteins this increases the viscosity of the blood and whenever you increase the viscosity of the blood it can produce this rare situation called hyper viscosity syndrome and the primary way that these patients present is with a headache but that's really hard because a lot of patients can present

with headaches and this is a rare occurrence so what you'd have to have is a certain degree of clinical Gestalt to really find this you would have to have a severe headache and crazy high lymphocyte levels to really have a suggestion of hyper viscosity syndrome so now at this point let's now move on to the next step which is how do we diagnose this I'm afraid so now we can talk about the Diagnostics of CLL so we have a patient who's coming in seven years of age or older coming in what kind of features of

maybe some lymphanopathy maybe some fever some night sweats maybe they also have potential features of some other problems like a paddleston omegaly and then also you get some blood work done you find some anemia could be due to two things could be due to decreased space from lots of lymphocytes or autoimmune hemolytic anemia you can see some thrombocytopenia due to autoimmune effects or it could be to decrease space you may see some effects of some crazy lymphocytes on their actual CBC with again more of a predominance that lymphocytes are super high with all the other

leukocytes you may see a drop in the neutrophils as well and then higher risk of infections because of the hypogama globinemia and less neutrophils being produced and then again you may also potentially see the hyper viscosity syndrome not as common but if you think about this a CBC with peripheral blood smear would be a Gateway kind of test to really help us to have a high degree of Suspicion so with this what I want to do is I want to look to see okay will I have any effect on my red blood cells my platelets

my kind of other granulocytes or white blood cells and then the lymphocytes all of these things are going to be affected I can see low red blood cells low platelets I may see some problems with my neutrophils so there may be a plus or minus low neutrophils and then on top of that for the lymphocytes I'm going to see a massive amount of these lymphocytes so what are some of the downstream effects I can see low red blood cells what is this called anemia this could be due to decreased space from lots of lymphocytes proliferating

or it could be due to autoimmune hemolytic anemia how do I differentiate this one this one you'll have to have features of hemolysis LDH will have to be elevated haptoglobin will have to be low and the direct antibody or Coombs test will have to be positive that's one way I also have low platelets this could be due to decreased space but it could also be due to ITP which was due to the auto antibodies and what's the combination of IDP and Iha our autoimmune hemolytic anemia is called Evan syndrome I also may see potentially low

neutrophils this may progress with increasing risk of infections and there may be increasing number of lymphocytes and with these lymphocytes they're mature appearing but they're less functional and because of that there may be less antibodies being produced so because there's less antibodies and less functional neutrophils or less neutrophils in general you have a high risk of infections pneumonia UTI skin infections Etc the other thing that's really interesting is that when we look at this we can do something called a peripheral blood smear and what happens is when we take these lymphocytes and we put them

onto a peripheral blood smear they do not like being on a peripheral blood spray they actually get smushed and they pop open and then what happens is they form these weird cells called smudge cells I'm not even kidding it's what we call them smudge cells if you see SMUD shells I want you to think about this crushed little lymphocytes it's literally you take the lymphocytes they're so fragile when you put them on the slide and try to get the smear going it'll literally just kind of like pop and rupture open and they look like these

things called smudge cells if you were to get some lymphocytes though you should see a lot of mature appearing lymphocytes small mature appearing lymphocytes and that's really what you would get off of your CBC with a peripheral blood smear so look for evidence of high amounts of mature pairing lymphocytes low neutrophils low platelets low red blood cells the next thing is what about a bone marrow biopsy would this actually be helpful believe it or not not really it's actually not super useful and it's not super diagnostically definitive either the reason why is is it's great

for all it's not great for a CLL because the reason why is if we take a chunk of the bone marrow you know what we're going to see we're going to see an increasing number of small mature appearing lymphocytes and that may be helpful because when you see this you think CLL if you saw a ton of large immature appearing blast cells almost greater than 20 percent lymphoblast then you would start thinking about AOL so this is way more helpful for all and not as helpful and useful and diagnostically definitive as in CLL now if

we've done the CBC with peripheral blood smear CA crazy lymphocytosis how high I I wrote it over there let's actually write it again this has to be sometimes lymphocytes have to be greater than 5 000 cells per millimeter cubed of blood so if I see a high lymphocytes I see low platelets I see low red blood cells plus or minus maybe a low neutrophils or a neutropenia I don't need the bone marrow biopsy to really help me and then I get the peripheral blood smear and I see smudge cells or increasing small mature lymphocytes I

think CLL especially if you've got a crazy lymphocyte count and some of the other features what I would consider as an immuno phenotyping I don't even think that this is crucial as well but it may help Amino histochemistry not super applicable here but what is maybe applicable is this flow cytometry and so when we talk about this there's all and then there's also CLL and pretty much the most common cell of the lymphocytes to be affected is the B cells 80 of them is in present in B cell all and pretty much CLL it's only

the B lymphocytes that are being affected so when we do this we look at flow cytometry we're trying to take those antibodies tagging specific cluster differentiation proteins that are present on the actual lymphocytes and when you tag them it'll give you specific proteins that are very indicative of a particular type of cell in this situation if it's a B cell all you're looking for very specific ones and oftentimes this is things like cd10 cd19 maybe even cd20 but for B cell for the CLL the most important differentiator is cd5 and you can also see some

similarities cd19 cd20 there's even another one called cd23 so you see some degree of similarities here right but what's the big one that kind of like Telltale here cd5 for CLL and cd10 for B cell all that's a really important thing because it may be somewhat helpful in differentiating these two if it really is confusing but it shouldn't necessarily be because oftentimes you can get a lot of information just from your CBC prefer blood smear the other thing is that there is no need for genetic studies you want to know why because if I do

a cytogenetic study there is no specific chromosomal abnormality or genetic disease that's been Associated remember we went through the causes there was I didn't write anything down for any genetic disease any chromosomal translocation or anything like that because there hasn't been any identified for CLL so it's not actually helpful to do any cytogenetics or PCR testing immunohistochemistry there's nothing really specific there as well what I would say is CBC with peripheral blood smear in a differential is helpful and then you can consider the bone marrow biopsy and then a flow cytometry may also be useful

oftentimes these additional tests will just be helpful in kind of assisting in the diagnosis just like we said in all they also have a paddle splenomegaly so all has a pathophone omegaly CLL has a paddle spinal negatively and CML only has splenomegaly there's no hepatosplenomegaly at all and AML but if we wanted to find hepatosphonomegaly we could do an ultrasound of the spleen or the liver or the you know the right upper quadrant or we could do a CT of the abdomen to find that and then if I wanted to see a lot of these

leukemic cells a lot of these like I'm sorry these lymphocytes that were present in the lymph nodes I could do a lymph node biopsy and I could actually take a look at these cells and look to see if they look like small kind of mature appearing lymphocytes versus lymphoblasts so some of the big things and also what's another thing for lymph node biopsy if I take this I could also help me to find out is there any diffuse large B cell lymphoma which was what due to what process the CLL converting into diffuse large B

cell phone is called Richter transformation so that's another important thing to be able to identify so at this point we should have diagnosed CLL now the question is how do we treat it all right my friend so now we can talk about the treatment of CLL so in this situation one of the ways that we determine the treatment is we look at what's called their classification system and really it's the Rai classification system it's the way we actually help to determine the degree of severity of a patient's CLL which will determine their degree of treatment

and that's a really really important thing so this is pretty high yield I do want you guys to remember this so we have rei0123 and 4. and obviously as we go this way the more severe the CL L CLL is the more likely we're going to be a little bit more aggressive with the treatment on these ends so let's go through this the first thing is you have REI 0 what is this indicative of so really the key thing for CLL that we've kind of picked up is a persistent lymphocytosis greater than 5000 per millimeter

Cube to blood has been kind of the big kind of a kind of our overarching theme so that's the first thing so what I want to see is I want to see the presence of lymphocytosis if that's present that's at least going to be REI 0 but let's say they have nothing else the next thing I said that was really really important is they have a lymphocytosis so now we're going to go into the next kind of classification system the next thing is that I told you lymph nodes are always affected and CLL or all

so I will see lymphadenopathy involvement then I go to Rai two so now I have a persistent lymphocytosis and I have a lymphadenopathy so what was that called whenever you have CLL plus a lot of lymphadenopathy it was called small lymphocetic lymphoma but then the next thing here is the other organs hepatosplenomegaly so then if they have some hepatosplenomegaly that's the next organ to be commonly affected in CLL so the same thing rei3 the lab lymphocytosis they will have lymphadenopathy they will have hepato spleno megaly and then the next thing is that they could have

anemia this is usually not the anemia associated with uh autoimmune hemolytic anemia so I need to make sure that you remember this is not autoimmune hemolytic anemia this is the anemia due to decreasing space from rapidly developing lymphocytes really important my friends then the last effect here is you have a lymphocytosis right so you have to have a lymphocytosis fclo you have to have a lymphadenopathy then if you have the hepatosplenomegaly we have a lot of organ involvement and then we said after apatosphonomegaly you have to have anemia to be REI 3 the last one

which is again not autoimmune hemolytic anemia the last one is thrombo cytopenia and it cannot be ITP so you're probably like okay Zach how in the stink am I supposed to remember all this the next thing is if the patient is REI 0 1 and 2 and they're asymptomatic so we'll kind of put this as like this we'll put a symptomatic r a i zero one two you do nothing you do nothing you observe these patients so what I want you to remember is this is observation it's better to avoid any kind of treatment process

for these patients if the patient has symptomatic Rai 1 and 2 1 or 2 then you should consider treating these patients then you will consider treatment of these patients then you can do treatment and this is usually chemotherapy which we'll talk about in a second the last component here is if the patient is REI three through four regardless if they're symptomatic or not symptomatic so r a i doesn't even matter if they're symptomatic or asymptomatic three or four these patients will also get treatment with chemotherapy so this is an important thing to be able to

remember so it seems as though as if you kind of get REI 3 4 you go to treatment chemotherapy if it's REI 1 and 2 and you have some degree of symptoms like what kind of symptoms well if you have any kind of severe problems such as maybe at this point you start kind of getting like features of a paddle splenomegaly right or problems associated with lymphadenopathy or the lymphocytosis is causing other kind of Downstream effects these are big things to be able to remember now the question then comes okay we're going to treat these

patients with chemotherapeutic agents what are we going to treat them with the agents that we generally give for these patients is it depends so if they are younger they'll get a specific treatment and if they're older they'll get a specific treatment regimen so for the younger ones we do uh kind of like a three-part regimen and three-part regimen here is actually it's three particular drugs so these three drugs I want you to remember is flu derabine so flu derabine the other one is called cyclophosphamide so cyclophosphamide and the last one is called rituximab these are

the three treatments if you guys do forget them the way I remember them is fcr so fluderabin cyclophosphamide and rituximab for the younger patients for the older patients these tend to respond better to a specific drug called abrupt to nib abrupt nib okay so you might be okay Zach how am I supposed to remember all of these chemotherapeutic agents for AML all CML CLL really when it comes down to it for the chemotherapeutic regimen in AML it wasn't like a ton it was really the primary things that you saw within that was with cytarabine and

the other one was Ida rubus and or Donna rubison for the all that was the C vad right and so for the C vat it was the cyclophosphamide VIN Christine asparaginase there was also the dexamethasone in the donorubicin the other thing for AML what I think was more important is to remember the actor of the all trans retinoic acid and arsenic trioxide was the really big thing to remember that was for the APL subtype for CML it's always tyrosine kinase inhibitors and then for this last one for CML remember fcr fluderabin cyclophosphamide rituximab for the

younger patient population and then abrupt nib for the older patient population if they fail if they fail the chemotherapy so they fail chemo then what we do is we move them to the next step which is a bone marrow transplant and that's usually an option for every single type of leukemia if they fail the normal chemotherapeutic regimen or immunotherapy whatever it may be my friends in this video we talked about CLL I hope it made sense I hope that you guys did really enjoy it and as always thank you love you until next time [Music]

foreign [Music]