Transcription
Hey guys, it's Medicos is Perfection Alice. We are back to talk about chronic myelogenous leukemia. Thanks to the people who watch my videos on YouTube and the great people who support me on Patreon, I was able to buy a new microphone to produce better audio quality for these videos that you guys like. So thank you so much.
Chronic myelogenous leukemia: you have the 9:22 translocation; you have proliferation of all of the white blood cells except for the lymphocytes, because this is a myeloid leukemia, not a lymphoid one. So you have neutrophils, monocytes, basophils, and eosinophils that are increased in number.
Chronic myelogenous leukemia—let's break that down, and let's do it backwards. Leukemia: malignancy arising from bone marrow stem cells. Any cancer is, by definition, monoclonal—one crazy cell. Myelogenous: which means it's of the myeloid lineage of the bone marrow. As you know, bone marrow has myeloid and lymphoid lineage, so especially the neutrophils will be numerous. It's a chronic leukemia, meaning the patients are more mature, which means older patients; the cells are more mature, which means smaller in size, which means that the blasts will be few or non-existent.
Let's go back to our nice illustration here: bone marrow, myeloid and lymphoid lineage. In CML, chronic myeloid leukemia, we are talking about these guys. Let me ask you a question: Do you expect neutrophilia in this type of cancer? Yes. Do you expect basophilia in this type of cancer? Of course. Can you see an eosinophilia happen? Yes, indeed.
Chronic myelogenous leukemia is a chronic leukemia, which means a monoclonal disorder of the late stem cells. The cells are smaller, more mature, but dysfunctional. Mature doesn't necessarily mean that they are functional. Hello, it's cancer. It's a chronic leukemia; patients are older; onset is slow; cells are smaller and more mature; very few blasts—less than 10 percent. Less than 10 percent is a chronic leukemia; 10 to 20 percent is myelodysplasia, which I've talked about before; more than 20 percent is an acute leukemia. Acute equals blast. Can you guess the type of leukemia by age, roughly speaking? Yes, indeed. CML patients are usually between 40 years old and 60 years old.
CML: one of the chronic myeloid proliferative disorders, which include CML, polycythemia vera, essential thrombocytosis, and myelofibrosis with myeloid metaplasia. All of these myeloproliferative disorders have common characteristics, such as splenomegaly, reactive bone-marrow fibrosis, and they can transform into an acute leukemia, such as AML or ALL.
Risk factor for CML: radiation—not any radiation, ionizing radiation, and in high doses. The age bracket again: more than 40 years of age, usually between 45 and 55. As you know, CML represents 15% of the adult leukemia.
What's the mechanism of CML? Pay close attention, please. There is a translocation between chromosomes 9 and 22 of the proto-oncogene called ABL or Abel. This proto-oncogene translocates from chromosome 9 into chromosome 22; fuses with something called BCR, break cluster region. When they fuse together, they create BCR-Abel fusion gene. Gene makes protein after the process of translocation. This chromosome 22 is now called Philadelphia chromosome. Welcome to the great state of Philadelphia.
Let's do this again. Each cell in your body has 46 chromosomes, except for your germ cells, of course. These 46 chromosomes—23 of them come from your mommy, and the other 23 come from your daddy. So let's say chromosome 9: you have one chromosome from mommy and one chromosome from Daddy. Okay, that's why we have chromosome 9, chromosome 22, but we don't have chromosome 41; it doesn't exist. You have two copies of the exact same chromosome. Have you ever heard about a disease due to a mutation of chromosome 25? No, it doesn't exist; it's the exact same copy as another chromosome. Anyways, you have Abel on chromosome 9, BCR on chromosome 22. Then occurs a balanced reciprocal translocation. Why balanced? Because nothing is gained and nothing is lost; you have the same stuff from here to here, from here to here; nothing is added, nothing is subtracted. Reciprocal? Why? I'll talk about this in a later video, but remember: balanced reciprocal translocation. BCR-Abel fused together on chromosome 22. This chromosome now is shorter than it used to be due to that translocation. This is called now Philadelphia chromosome. We have talked about Philadelphia chromosome in acute lymphoblastic leukemia, which had bad prognosis, but here in chronic myeloid leukemia, it carries good prognosis. Yah-hoo! Got a lot of the people of Philadelphia, yeah.
So now we have BCR-Abel fusion gene—some people call it BCR-Abel 1; I don't care. You have a fusion gene. Hello, transcription; you have mRNA; hello, translation; we have a protein called BCR-Abel fusion protein. The molecular weight of this protein is 210 kDa, which stands for kilo Dalton, instead of kilogram. Kilogram is too big; Dalton is a very teeny tiny unit of mass. This protein is a tyrosine kinase, which kind of makes sense because all enzymes are proteins. This tyrosine kinase will disrupt the cell, leading to increased proliferation and decreased apoptosis, also known as cancer. Cells are proliferating, dividing rapidly, rapidly, rapidly, without death. You have cancer, and this is called an oncogene, which causes Genesis to the oncology, which is cancer-causing cancer. Uncle gene. That's why we treat CML with something called tyrosine kinase inhibitor to inhibit this crazy nonsense called tyrosine kinase, which kind of makes sense.
What are the clinical features of CML? Signs and symptoms. Sign is what you discover as a physician; symptom is what a patient complains of, which will include fatigue, weight loss, and sweating, such as any other cancer. The onset again is insidious; it's a Weiser leukemia. You can have painless lymphadenopathy; of course, painless is cancer, painful is infection. Now we can have hepatomegaly, and splenomegaly is a big deal. 90% of patients with CML have a huge spleen—I'm talking huge; I'm talking 15 centimeters or more below the costal margin. This is a big spleen. Why splenomegaly? Because it's a metastasis, and remember, leukemia is cancer; they can metastasize to the spleen, leading to a huge spleen. Be explained. You get abdominal pain; be explained. You can get infarction, why? Because the blood supply is created for a normal spleen, but now we have a huge spleen; the blood supply cannot feed this crazy insane spleen. You get infarction. When you get infarction to the spleen, you can hear a friction rub by your nice stethoscope.
There are some phases of CML. First, we have the chronic phase; usually patients are asymptomatic or have mild symptoms. This phase is very responsive to treatment, especially using the tyrosine kinase inhibitors. Most patients are diagnosed in this stage. If we do not treat them, they will go to the accelerated phase. Now they get splenomegaly, basophil failure, and we start seeing more immature cells. If we don't help them here, they go to the blast crisis, which is deadly, and I'll talk about this in the next video. Clinically speaking, it behaves like an acute leukemia. This is called transformation from the chronic myeloid leukemia into an acute leukemia; could be acute myeloid leukemia in 70% of cases or acute lymphoblastic leukemia in 30% of cases. This phase is refractory to treatment most of the time, and this is the cause of death from CML. This is so sad.
You want to go to the lab? Yes, of course. Hematology is always in the lab, so let's get a peripheral blood smear and complete blood count and see: you have normocytic anemia most of the time, except if you have folate deficiency from the rapid cell turnover, which can lead to macrocytic anemia. Rapid cell turnover will lead to increased uric acid as well as increased lactate dehydrogenase. Platelets: you can have thrombocytosis, especially in the accelerated phase and the blast phase. White blood cell count can range from ten thousand, which is normal, all the way up to six hundred thousand—a white blood cell. This is a big deal. Very few blasts—why? It's a chronic leukemia, baby. Okay. Leukemic cells can show evidence of maturation, showing all stages of development. This is different from acute myeloid leukemia, where we had lots of blasts and no maturation. You can see basophil failure; of course, they become more prominent as the disease progresses.
Let's get to a definitive diagnosis for CML by doing a bone-marrow biopsy. You will have a hypercellular marrow with myeloid hyperplasia; usually cells are more mature; that's why blasts are less than 10%. The Philadelphia chromosome is sensitive but not specific. Why is that? Because 100% of patients with CML they have the Philadelphia chromosome; it's very sensitive; it rules out the disease, but it's not specific, why? Because some patients with ALL have the Philadelphia chromosome as well, and in this case, the Philadelphia chromosome carries a poor prognosis. Leukocytes alkaline phosphatase score—the LAP tells us one thing: are these cells doing their job properly, or do they suck? In leukemoid reaction, basically proliferation of your white blood cells that occurs—kind of a normal response—you have high LAP or strongly positive LAP, which is okay. In CML, since these cancer cells, although numerous, they suck; these leukemic cells are useless; that's why you will see low LAP score. The definitive diagnosis of CML consists of cytogenetics to detect the ugly Philadelphia chromosome or translocation 9;22, which can be detected by the FISH or the PCR. Don't forget to perform the bone marrow biopsy, of course, and you can try RNA analysis to detect the BCR-Abel 1 fusion gene or fusion protein or whatever.
Please do not close the video right now; we still have to answer the case. But did you know the t(9;22) Philadelphia chromosome was first discovered in, hello, Philadelphia, Pennsylvania, by two scientists in 1960? That's why Medicos is Perfection Alice went to Pennsylvania to record a video about that. So make sure to subscribe; this video is coming soon. And if you really like these videos, would like to support the channel, please go to my Patreon page. By supporting the channel, I can make more videos, and you get early access to all of my videos, including more notes on the upcoming videos that are coming related to this topic. We'll talk about all of these, so make sure to subscribe now.
To the case: You have a 50-year-old female comes complaining of unintentional weight loss—oh, this is always bad. I'm performing an abdominal exam; you see splenomegaly. Going to the lab, you have this fish bone, which means platelet count is 600,000—this is a lot; hemoglobin is eight—this is low; hematocrit of 25—this is so low; white blood cell count of 120,000—this is so high; differential is here; neutrophils 81%—so high; and all of these are here. You can ask me; blasts are 1%—why is that? Because this is a chronic leukemia. Basophils are only 1%; normal basophil count is 0-2; 1% is kind of the upper limit of normal, but you said basophilia is expected in CML. Yes, but also I've told you that most patients are diagnosed in the first phase, the chronic phase, so basophilia is not there yet. So on the bone marrow biopsy, you have hypercellular marrow, increased myeloid-to-erythroid ratio, which means red blood cells are not numerous; however, white blood cells, including neutrophils, basophils, you know, fills, monocytes are very numerous. So this is not polycythemia, but this is a myeloid leukemia, and since the patient is 50 years of age, neutrophils are 80%; neutrophils are mature cells; immature cells are very few. This is a chronic myelogenous leukemia. This is the answer.
Second: What do you expect on cytogenetics? Trisomy 21 is also known as Down syndrome; commonly ALL. t(15;17) translocation is acute promyelocytic leukemia; I've talked about that in a previous video, and this is AML M3 subtype—again, not here. 5q deletion: we have talked about this before in myelodysplasia. Or t(9;22) translocation—the Philadelphia chromosome? Yes, indeed; this is the answer.
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