Myeloproliferative Disease – Hematopoietic Malignancies and Aplastic Anemia

by Paul Moss, PhD

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    00:01 Now let us move on to the second major category of additional malignant disease of the haemopoietic system, myeloproliferative disease. These are a group of conditions arising from marrow stem cells and the name suggests and tells us that these are highly proliferative disorders where we see proliferation of one or indeed more of the haemopoietic components in the bone marrow. So rather than myelodysplasia having low and dysfunctional cells in the blood.

    00:33 Here we often see increased cells within the peripheral blood. There are three major types. Polycythemia vera (PV) associated with an increase in the red cell count, Essential thrombocythaemia (ET) with a high platelet count and primary myelofibrosis where there is increased fibrotic activity within the bone marrow, bone marrow scarring really with anaemia and often very large spleen and that brings me to the slide on the right where you can see a very enlarged spleen in this patient and splenomegaly is a very common feature of all these disorders. . . one clinical clue that these all disorders should indeed be grouped together, but genetic analysis over the last three years has been very exciting and now indicates that we got a right, but putting these diseases together because they often have similar genetic basis. Let us look at the story in a little more detail.

    01:46 JAK2 is a protein that is involved in signal transduction within haemopoietic cells and it mediates the response of myeloid cells to growth factors and cytokines stimulation.The JAK2 gene is mutated in almost all cases of polycythaemia vera and in many cases of the central thrombocythaemia and primary myelofibrosis and that mutation leads to the high activity of the JAK2 gene.

    02:17 The tumor cell, belated cells can be chronically stimulated by growth factors or cytokines.

    02:28 Calreticulin mutations are usually found in patients with ET essential thrombocythaemia that do not have the JAK2 mutation. And finally MPL, which is the receptor for thrombopoietin is also mutated in a minority 5 to 10 percents of patients with ET or myelofibrosis and I think you can see if you put these three genes together JAK2, CALR or MPL, we can now explain 99 percent of cases of polycythaemia vera and up to 90 percent of cases of essential thrombocythemia and myelofibrosis. So it is a very nice story for the common genetic basis of many of these disorders. We will talk about later. This is also useful clinically because drugs that inhibit JAK2 activity are now finding a very important place in the treatment of these disorders. Let us consider them individually. Polycythemia vera, Polycythaemia is an increase in the haemoglobin concentration above the upper limit for person's age and gender and this increased haemoglobin leads to hyperviscosity, headaches, pruritus and itching. That is a really common feature, particularly after showers. The patient has a plethoric appearance.

    04:03 Just look at the top right-hand slide. The patient is very red. They may also have an enlarged spleen as you saw in the previous slides that the treatment of polycythaemia is to reduce the haemoglobin and the danger that arises from that. Ideally we want to keep the haematocrit ratio of the red blood cells within the blood volume to less than 0.45 and we want to keep the platelet count down as well to stop the risk of blood clots.

    04:36 The easiest way to do this is to just take blood from the patient venesection.

    04:43 We can also use drug such as hydroxycarbamide, which will strengthen down DNA synthesis within the bone marrow and finally JAK2 inhibitors as you will not be surprised to hear are now being introduced in this disorder to try and address the fundamental problem that is present within the malignant cells. If you are wondering what the slide in the bottom right indicates that shows somebody with gout and that can be seen in patients with myeloproliferative disease because they are producing and destroying too many haemopoietic cells all the time and the excess DNA destruction can rais ethe the level of uric acid and precipitate those episodes.

    05:31 The second major disorder within myeloproliferation is the central thrombocythemia, too many platelets.

    05:39 The main clinical problem is the blood clots and thrombosis, but actually bleeding is well which is paradoxical with the patient with the very high platelet count is the risk of bleeding. On the right-hand side, you will see a blood film and you will see typically lots of red cells as one neutrophil there and too many of those small platelets throughout that blood film. If you look carefully one or two very large platelet forms that we often see in this disorder. Now here we do not necessarily need to rush into treatment to get the platelet count down to a normal level, but we need to access the risk within individuals of developing the thrombotic disease. That will depend on the patient's age whether they have a history of heart disease, whether they are taking drugs such as estrogens, which might raise the thrombotic risk. And after assessment of the risk grip, we can use drugs such as hydroxycarbamide which dampen down blood cell production, aspirin, which reduces the function of these excess platelets or perhaps interferon, which s a natural product within our bodies.

    07:03 These are actually quite useful in treating myeloproliferative disorders.

    07:09 Finally the third major subtitle myeloproliferative primary myelofibrosis and in this condition, there is proliferation of a cell within the bone marrow, which leads to fibrotic scarring of haemopoiesis and what this means is the blood production struggles within the bone marrow and tries to find another place for haemopoiesis to be established and that is often in the spleen and liver. The patient can develop a massive spleen, which enlarges even down into the left iliac, right iliac for some. The clinical problems here are of anaemia and this really very large spleen. The typical blood film in primary myelofibrosis comes under that word leukoerythroblastic. What does that mean? Just think of that word leuko white, erythro red, blastic. You see the primitive precursors of both white cells and red cells and you can see in that film there, the blood film some of these features.

    08:18 On the bottom, the cell is a nucleated red cell. And you will also see the tear drop red cells. Just look at some of those red cells in the middle of the picture and you will see the tear drop features that you see in this condition. On the top right, you will see the scarring within the bone marrow, it is full of cella but much of that is scarred tissue and that is brought out in the bottom right where we use a stain for collagen and then you can see that really come in much-affected blood production in the middle of that much damage. How do we treat this? We can get blood transfusions to support the patient.

    09:02 This is a disorder in which JAK2 inhibitors are really finding a very important role in therapy.

    09:10 Now let us move on to a different type of malignant disease and a very important one multiple myeloma. This is a malignant disease of plasma cells. The plasma cells within our bone marrow. This is very very few of them in the blood and they produce antibodies and the tumor retains these properties. It is present within the bone marrow hence the name myelo bone marrow. And again the cells produce antibodies. You will get a range of clinical problems in myeloma and I have listed some of them on the left. Increased calcium because of bone destruction, renal damage because of the antibodies, which may precipitate out in the kidney, anaemia because the plasma cells crowd out the normal haemopoiesis and bone disease because of the expansion of the malignant cells within the bone damaging normal ossification and bone formation. Let us just look at some of the pictures on the right to illustrate this. The top right blood film I do not know if you can see anything obviously different in that, but if you look carefully you will see a phenomenon called Rouleaux that is when red cell stacks one on top of the other. You can see some of the red cells lining up. That is due to the paraproteins with high levels of antibodies in the blood.

    10:44 And in the bottom you see some x-rays. What I hope you can see is the bone damage from the myeloma. Look at the skull x-ray and you will see that dark patch in the middle that is an area of multiple myeloma whereas if you look on the right on the long bones, you will see small areas of dark damage within the long bones and that is an area of myeloma as well. You can see why patients are so prone to fractures of the bone in this disease.

    11:22 The diagnosis of multiple myeloma depends on finding a monoclonal antibody in the blood or urine. This monoclonal antibody or immunoglobulin is called a paraprotein. On the top right, you will see an electrophoresis which is used to detect the sort of paraprotein.

    11:42 On the right, you can see a paraprotein right at the bottom of the screen in number 3.

    11:47 Now very often because the bone marrow is producing one paraprotein, all the normal antibodies are reduced and that, of course, leaves the patient very prone to infection. It is a characteristic feature of multiple myeloma. Of course if we do a bone marrow biopsy, we see the tumor cells and we see an excess of plasma cells. Look at the bottom right and you will see these plasma cells, very large cytoplasm and its dark nucleus. Some signs are a little bit like a . . . you can see on the left, not big cell with a grey cytoplasm in the dark purple mucosa. Those are all plasma cells. If you do radiology imaging either by x-rays or perhaps even a CT or MRI scan, we may see damage to bones and that would indicate towards that we need to treat this disease quickly. However, let me just finish off this slide with an important point. Low levels of these monoclonal immunoglobulins or paraproteins are often seen in people as they get older and if you find a low level of paraprotein without any evidence of clinical damage, then that is just called monoclonal gammopathy of undetermined significance, note the most pretty name or the shortest name, but what it means. It is stated clearly in the name, We have a normal paraprotein, but we do not know how significant it is. You do not need to treat that. However, I want one in every hundred of those patients would go on to develop myeloma every year that you follow them up.

    13:41 When myeloma does develop and we have clinical problems that we must treat, how do we go back treating it? This remains a very difficult condition to cure, but treatment has improved a lot in recent years and the median survival now can be up to 7-10 years. Now younger patients will have chemotherapy and I will talk to you about the sort of drugs we use in a minute followed by an autologous stem cell transplant. What do you mean by that? In that procedure, you take blood from the patient, which contain stem cells and you can freeze it down which then allows you to give the patient to high dose of chemotherapy and then when the blood is trying to recover, you can put in the stem cells as you are previously frozen to support the regrowth of the blood compartment. So it allows a very intense chemotherapy to be given and that hast been shown to improve survival. All the patients normally tolerate that approach and so they tend to have chemotherapy alone. Sometimes after the chemotherapy you may wish to get maintenance treatment with the drug such as lenalidomide and we will talk about that in a second. On the right, I have shown you the picture of the skull x-ray.

    15:03 On the far right, you will see an MRI magnetic resonance scan and I hope that if you look at the vertebral column, you will see that one of the vertebrae is damaged there with the tumor. That is very common in patients with myeloma.

    15:20 Let us talk about some of the drugs that we used in myeloma. There are a wide range very interesting agents.At the top there I have put a drug called Velcade or bortezomib.

    15:32 It is a drug that inhibits the proteosome. That is part of our normal cell that breaks down proteins within the cell, very effective agent. Secondly I have grouped together lenalidomide, thalidomide and pomalidomide, Thalidomide I am sure you have heard of. These drugs have a similar mechanism of action on myeloma is one of the most effective areas for their use and they are used in many many drug measurements. Dexamethasone steroids often used in myeloma and melphalan classic . . . agent. They are still used in some patients with myeloma and are often used for preparing people for an autologous stem cell transplant.

    About the Lecture

    The lecture Myeloproliferative Disease – Hematopoietic Malignancies and Aplastic Anemia by Paul Moss, PhD is from the course Hematologic Disorders. It contains the following chapters:

    • Myeloproliferative Disease
    • Polycythemia Vera
    • Essential Thrombocythemia
    • Primary Myelofibrosis
    • Multiple Myeloma

    Included Quiz Questions

    1. Lymphoma
    2. Polycythemia vera
    3. Essential thrombocythemia
    4. Primary myelofibrosis
    1. JAK2
    2. CALR
    3. MPL
    4. NF1
    5. MEN1
    1. Signal transduction
    2. Signal initiation
    3. Signal transcription
    4. Signal elimination
    5. Signal re-entry
    1. Calreticulin
    2. BRCA
    3. NF1
    4. MEN1
    5. CFTR
    1. Fever
    2. Headaches
    3. Enlarged spleen
    4. Pruritus
    5. Plethoric faces
    1. Serial blood removal
    2. Venesection
    3. JAK2 inhibitors
    4. Hydroxycarbamide
    1. Interferon
    2. Cyclophosphamide
    3. Methotrexate
    4. Vincristine
    5. Vinblastine
    1. Fibrosis of the bone marrow
    2. Necrosis of the bone marrow
    3. Production of red blood cells in the liver
    4. Enlargement of the spleen
    5. Decreased red blood cell lifespan
    1. Hypocalcemia
    2. Decreased renal function
    3. Clonal proliferation of plasma cells
    4. Anemia
    5. Lytic bone lesions
    1. Rouleux formation
    2. Anemia
    3. Proliferation of plasma cells
    4. Tear drop cells
    5. Leukoerythroblastic blood picture
    1. Serum electrophoresis
    2. ELISA
    3. Western blot
    4. Peripheral blood smear
    5. Nephlometry
    1. Plasma cell inhibitors are given to patients with Monoclonal gammopathy of undetermined significance
    2. There is a low paraprotein level in patients with Monoclonal gammopathy of undetermined significance
    3. Patients do not show any signs of clinical damage in Monoclonal gammopathy of undetermined significance
    4. Patients with Monoclonal gammopathy of undetermined significance can progress to multiple myeloma
    1. Vincristine
    2. Melphalan
    3. Lenalidomide
    4. Bortezomib
    5. Dexamethasone

    Author of lecture Myeloproliferative Disease – Hematopoietic Malignancies and Aplastic Anemia

     Paul Moss, PhD

    Paul Moss, PhD

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