Chronic Leukemia – Leukemia

by Paul Moss, PhD

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    00:01 Now let us turn to the second major subset of leukaemias. We move from acute leukaemia into chronic leukaemia and I will start with chronic lymphoid leukaemia. This is the most common leukaemia in many societies. Interestingly not all societies because there seems to be a genetic predisposition to CLL. That is more common in those of Caucasian and Asian origin. CLL develops from the accumulation of a clone of B cells, which you can see on the blood film there in the bone marrow in the blood and in the lymph nodes. On that blood film, you will see many lymphocytes. You will see many purple smears and indeed very cells are lymphocytes, which have undergone destruction during the preparation of the blood film. Smear cells are a characteristic feature of CLL.

    01:06 Now the B cells in CLL are very interesting. They have a number of unusual proteins on the surface, unusual for B cell. I have put two there, CD5 and CD23 and it is the presence of those proteins that we look for when are making a diagnosis of CLL in a patient who has too many lymphocytes within the blood. Now, CLL is quite slowly progressive.

    01:41 It developed over many years and now from 90 percent of patients are diagnosed with CLL simply because they have blood taken for another reason. They may go for a health check or they may go as the doctor saying that I feel quite so well or dizzy or whatever it is, a blood test is done and we notice that there are too many lymphocytes. So it can be what we call an indolent disease slowly progressive and not needing any treatment. Indeed, treatment is generally only started when the patient needs it. We call this as a watch and wait policy.

    02:22 So when do patients need treatment, if they develop anaemia, when the CLL crowd out the normal cells and the bone marrow and lead to anaemia or perhaps when the lymph nodes in the neck swell up and cause problems or the spleen, which can also be involved.

    02:48 So it may seem unusual that we make the diagnosis of leukaemia, but don´t treat it. But certainly results from several years ago showed that if one treats too early, you can actually have a worse outcome than watching and waiting. What about the treatment of this condition? Over 30 years, doctors have been studying different combinations of treatment for CLL and at the current time, a combination of chemotherapy with injection of an antibody targeted against the B cells through CD20 is a standard treatment. So younger patient would get CD20 specific antibody with more intensive chemotherapy and all the patients will get an antibody with perhaps less intensive chemotherapy and those are effective in the majority of patients although they are never in themselves curative. The disease always has the risk of coming back and these combinations of chemotherapy and antibody are usually given for around 4 to 6 courses perhaps every month if possible and the patient may well obtain a remission for several years before they need treatment again. But in fact in CLL as in many areas of haematology, there has been some interesting new developments and tablets have recently been developed that specifically target B-cell receptor signalling that are very effective in CLL. There are two major pathways that we can inhibit mentioned on the slide, BTK Bruton's tyrosine kinase and PI3K delta, PI3kinase delta subunit.

    04:51 These are two proteins, which are involved in signalling when a B-cell sees its antigen through the immunoglobulin on the cell surface and they send survival signals and proliferative signals to the tumor cell and tablets, which block those signalling pathways lead to the death of the CLL tumor cells. Now these have only been around for 2 or 3 years, but they may well come to represent the new standard of care in chronic lymphocytic leukaemia and now drug studies are being designed and started which compare chemotherapy with oral medication.

    05:40 Finally a fourth subset of leukaemia, chronic myeloid leukaemia. This is a relatively rare disorder but is seen in people of all ages and is remarkable because we know so much about its etiology and it lead to the introduction of a new treatment that is changed our approach to cancer. In many cases, it is caused by a translocation. This was the first translocation to be identified in cancer called the Philadelphia chromosome between chromosomes 9 and 22. Just look at that cartoon on the right and you will see those pink chromosomes. On the left of those pink diagrams, you will see the normal chromosome 9 and below it the normal chromosome 22. But if those break at ABL and BCR, they can stop that genetic material and lead to those pink chromosomes on the right, 9q+, 22q-. Now, what is fascinating about this translocation is it leads to the formation of a new protein, a fusion protein that is shown in the top right? BCR and ABL come together to form a new fusion protein only present within the tumor cells. As you will see on the right-hand side of the diagram, this protein encodes an enzyme, which has tyrosine kinase activity and this tyrosine kinase activity is overactive within the tumor cells and through a range of mechanism that leads to proliferation of this myeloid cell and generation of the leukaemia and as you will see, it drives the bone marrow to access proliferation of the myeloid compartment. The clinical features of CML reflect that myeloid proliferation. Let us look down the left-hand side first of all splenomegaly often you will see a very large spleen under the left-hand side of the ribs and patients with CML. Fevers, sweats and indeed gout because the patient is making so many cells and also many of these cells are dying and gout interestingly is precipitated by the formation of uric acid from DNA of cells that have been broken down. Let us look now on the right-hand side. You will see on the right the particular blood film of the patient with chronic myeloid leukaemia. Lots of neutrophils, but also earlier and more primitive cells that we should not see in the blood, promyelocytes and myelocytes and in those two tubes, we see the startling feature of CML that we see in some patients, very high numbers of leukaemic cells. Let me explain. On the left-hand side of those two tubes, you will see normal blood. It has been placed in the centrifuge and the bottom of the red cells or the top is the plasma and in between those two, there would normally be a very thin layer of white cells sometimes known as the buffy coat whereas in the right-hand tube, you can see that enormous white area that is the huge buffy coat of the malignant white cells within the blood of this patient. So if you ever wanted to see an example of how leukaemia really does mean white blood that is a typical picture.

    09:55 Now, the treatment of chronic myeloid leukaemia is one of the fascinating areas of medicine.

    10:04 Imatinib is a drug that was designed specifically treat chronic myeloid leukaemia and it can specifically block the BCR-ABL protein. You can already see how exciting that is because that fusion protein is only in the tumor cells. It is exactly the sort of drug that we have been looking for when it comes to specifically affecting the tumor cells as opposed to chemotherapy.

    10:34 It is highly effective and simple oral medication can control the disease in most cases.

    10:42 Now it is true that the disease can get resistant in some cases or the patient might perhaps be intolerant of Imatinib, but there are now several new drugs, which also inhibit BCR-ABL in different ways and indeed some evidence that they may be more effective than Imatinib as a first line of therapy. So there are many trials now seeing if these different drugs are effective at different stages and to bring about a more rapid and complete control of CML. But the treatment of this disease has been transformed. Treatment is now monitored by looking at the percentage of the BCR-ABL messenger RNA in the blood and so we will see patients in the clinic perhaps every three months and will see how rapidly we are killing off the tumor with the tablet combination. If it is not quickly enough, we will switch to another agent, which is more effective. The success with Imatinib has changed the general approach to treatment of cancer and many types of cancer now even the common sorts, lung cancer, breast cancer we are starting to look away from the old fashion chemotherapy, which affects many rapidly dividing cells and we are looking into the genome of the tumor cell finding the specific mutation that cause that cancer and looking for tablet that can specifically block that and that is how cancer will be treated in the 21st century.

    12:34 So In summary, leukaemia can be classified into four different subtypes. Now each of these four is very different and you need a very thorough diagnostic approach to making right diagnosis of the subtype and I hope that you have seen and enjoyed from this talk that these leukaemias are treated by a variety of therapies, chemotherapy antibodies and drugs that inhibit signalling pathways. As is often the case in hematology, the development of these drugs has led to improvements in many areas of medicine.

    13:14 Thank you very much for watching.

    About the Lecture

    The lecture Chronic Leukemia – Leukemia by Paul Moss, PhD is from the course Hematologic Disorders.

    Included Quiz Questions

    1. Suspected on a routine blood test
    2. The patient develops indigestion and examination shows a greatly enlarged spleen
    3. Life threatening infection
    4. Severe bleeding
    5. Patient notices some swollen glands in the neck
    1. Tyrosine kinase inhibitor
    2. All-trans-Retinal
    3. Mercaptopurine
    4. Vincristine
    5. Bleomycin
    1. CD 5+ and CD 23+
    2. CD 3+ and CD 15+
    3. CD 10+ and CD 20+
    4. CD 5+ and CD 21+
    5. CD 8+ and CD 21+
    1. BTK
    2. WT1
    3. p53
    4. PTEN
    5. K-ras
    1. Calcium pyrophosphate
    2. Gout
    3. Massive splenomegaly
    4. Fever
    5. Sweats
    1. Smudge cells
    2. Increased prolymphocytes
    3. Cells with basophilic stippling
    4. Cells with nuclear inclusions
    5. Increased myeloblasts
    1. Preparation artifact causing rupture of the fragile cytoplasm of cells
    2. Swelling of the cells causes rupture of the fragile cytoplasm of cells
    3. Pressure from the surrounding cells causes rupture of the fragile cytoplasm of cells
    4. Accumulation of the mutations causes rupture of the fragile cytoplasm of cells
    5. Self destruction by apoptosis leads to rupture of the fragile cytoplasm of cells

    Author of lecture Chronic Leukemia – Leukemia

     Paul Moss, PhD

    Paul Moss, PhD

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