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1 K.B. Kotade et al, IJCTPR, 2015, 3(3): ISSN: International Journal of Current Trends in Pharmaceutical Research Journal Home Page: Review Article Open Access A Review on Myeloproliferative disorder K.B. Kotade* 1, P.Kadbhane 1, S.B Somwanshi 2, K.B.Dhamak 3 1 Department of Pharmacology, P.R.E.S. s, College of Pharmacy (For Women), Chincholi, Nashik Department of Pharmaceutics, P.R.E.S. s, College of Pharmacy (For Women), Chincholi, Nashik Department of Pharmaceutical Chemistry, P.R.E.S. s, College of Pharmacy (For Women), Chincholi, Nashik A B S T R A C T The term myeloproliferative disorder (MPD) was first introduced by Dr William. Myeloproliferative disorder is the general name given to a group of conditions wheree there is an overgrowth of cells in the bone marrow, often leading to increased number of cells in the blood. Myeloproliferative disorders are described according to the blood celll which is most affected. There are four types of myeloproliferative disorder that together represent around 95% of all cases. Polycythemia Vera (PV), Essential thrombocythemia (ET), Primary or idiopathic myelofibrosis (PMF ), Chronic myelogenous leukemia (CML). Uncommon types of myeloproliferative disorder together make up about 5% of cases are chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), Mastocytosis. MPD can be diagnosed by using a combination of laboratory tests and a physical examination. The treatment or combination of treatment chosen will depend on several factor including the duration and severity of disorder, whether or not you have a history of blood clots, age and general health. A mutation of a gene known as jenus kinase (JAK 2) is found in large proportion of people with myeloproliferativee disorder. The discovery of mutation in JAK2 gene is important because it has significant impact on the way myeloproliferative disorder are diagnosed and may be important for treatment in the future. Keywords: Bone marrow, Jenus kinase, Leukemia, Mutation, Myeloproliferative disorder (MPD). A R T I C L E I N F O CONTENTS 1. Introduction Causes of Myelopriliferative Disorder Types of Chronic Myrloproliferative Disorder Conclusion References Article History: Received 27 February 2015, Accepted 29 March 2015, Available Online 15 May 2015 *Corresponding Author K.B. Kotade Department of Pharmacology, P.R.E.S. s, College of Pharmacy (For Women), Chincholi, Nashik Manuscript ID: IJCTPR2525 PAPER-QR CODE Citation: K.B. Kotade, et al. A Review on Myeloproliferative disorder. Int. J. Curnt. Tren. Pharm, Res., 2015, 3(3): International Journal of Current Trends in Pharmaceutical Research 924

2 Copyright 2015 K.B. Kotade, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited. 1. Introduction The term myeloproliferative disorder (MPD) was first introduced by Dr William in 1951 to emphasize the clinicopathological similarities between chronic myeloid leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PV), and with myeloid metaplsia (MMM).Accordingly, these four disorders are currently referred as classic MPD. Myeloproliferative disorders are diseases in which too many of certain types of blood cells - monocytes, platelets, fibroblasts, red blood cells -are made in the bone marrow, the spongy tissue inside the large bones in the body where red and white blood cells and platelets are made.the chronic myeloproliferative disorders (MPD) are a group of related diseases that are characterized by neoplastic proliferation in one or more hematopoietic cell lines. Myeloproliferative disorder is the general name given to a group of conditions where there is an overgrowth of cells in the bone marrow, often leading to increased number of cells in the blood. In myeloproliferative disorder the cells in bone marrow multiply in an uncontrolled way. In contrast with leukemia, where there is an overgrowth of immature cells. In myeloproliferative disorders the cells mature with normal function, there are just too many of them. It is important to remember, that myeloproliferative disorder are chronic disease that, in most cases, remain stable for many years and progress gradually overtime [1]. The cause of myeloproliferative disorder remains unknown, although there is now rapidly increasing knowledge of some of the changes that trigger the disease. Myeloproliferative disorders are sometime described as being clonal blood stem cell disorder. This means that result from a change, or mutation, in DNA of single blood stem cells. This change (or changes) results in abnormal blood cell development, and in this case, the overproduction of blood cells.in myeloproliferative disorders the original mutation is preserved when the affected stem cells divided (proliferates) and produces a clone a group of identical stem cells all with the same defect. Mutation in dividing cells occur all the time and cells have sophisticated mechanisms within them to stop these abnormalities persisting. A mutation of a gene known as jenus kinase (JAK 2) is found in large proportion of people with myeloproliferative disorder. The discovery of mutation in JAK2 gene is important because it has significant impact on the way myeloproliferative disorder are diagnosed and may be important for treatment in the future. Finally, myeloproliferative disorder are not contagious; we cannot catch these disorders by being in contact with a myeloproliferative disorder have no family history of these disease. The longer we live, more chance we have acquiring mutations that escape these safeguards. That s why myeloproliferative disorder can become more common as we get older [2]. 2. Causes of Myelopriliferative Disorder: The JAK2 V617F Mutation: In 2005, several groups reported a single, acquired point mutation in the Janus kinase 2 (JAK2) genes in the majority of patients with Ph-negative myeloproliferative disorders. JAK2, a cytoplasmic tyrosine kinas, is critical for instigating intracellular signaling by the receptors for erythropoietin, thrombopoietin, interleukin-3, granulocyte colony-stimulating factor (G -CSF), and granulocyte macrophage colony-stimulating factor (GMCSF). Mice that are deficient in Jak2 die at embryonic day 12.5, with a complete absence of definitive erythropoiesis, a finding that underscores the vital role of JAK2 as a transducer of signals evoked by the binding of erythropoietin to its receptor. JAK2 binds to the erythropoietin receptor in the endoplasmic reticulum and is required for its cell-surface expression. When erythropoietin binds to its receptor, it provokes a conformational change in the receptor with consequent phosphorylation and activation of JAK2.63 the activated JAK2 then phosphorylates the receptor s cytoplasmic domain, thereby promoting the docking of downstream effector proteins and the initiation of intracellular signaling cascades. The JAK2 mutation in the myeloproliferative disorders is not in the germ line but, rather, is acquired. Sensitive methods demonstrate the mutation in more than 95% of patients with polycythemia Vera and in 50 to 60% of patients with essential thrombocythemia or idiopathic myelofibrosis. A substantial proportion of patients with polycythemia vera or idiopathic myelofibrosis are homozygous for the JAK2 mutation as a result of mitotic recombination affecting chromosome 9p, 6-9 but this phenomenon is rarely detected in essential thrombocythemia. The mutation is also found in a small minority of patients with the hypereosinophilic syndrome, chronic myelomonocytic leukemia, chronic neutrophilic leukemia, myelodysplatic, or acute myeloid leukemia, but not in patients with lymphoid or other cancers or in those without hematologic disorders. The presence of a mutant JAK2 in some patients with acute myeloid leukemia, especially older patients, raises the possibility that they may have had a preceding, undiagnosed myeloproliferative disorder [3]. Screening Tests: Several laboratory methods of JAK2V617F mutation detection are currently available, and one must interpret test results in the context of assay sensitivity. For example, in one of the first reports on JAK2V617F, mutational frequency in PV increased from 73% to 97% by using an allele-specific PCR assay (~3% sensitivity) as compared to direct sequencing (~20% sensitivity). On the other hand, false positive results could arise from the utilization of ultra sensitive assay systems (~0.01% sensitivity) that could detect very low levels of JAK2V617F even in healthy individuals. In general, quantitative PCR methods are International Journal of Current Trends in Pharmaceutical Research 925

3 preferred because of their potential value in measuring mutant allele burden and monitoring treatment response. Conventional DNA sequencing A PCR amplified DNA sequence of interest ( in this instance the mutated DNA region of JAK2) is processed through an automated sequencer that is based on the Sanger DNA sequencing principle. The method is semi quantitative, can distinguish a homozygous from a heterozygous pattern of mutation in the absence of mixed Clonality, and the reported sensitivity is above 5%. Pyrosequencing (sequencing-by-synthesis) The technique of Pyrosequencing is based on the detection of light signal (bioluminescence) from a luciferase reaction using pyrophosphates that are released by the incorporation of nucleotides by polymerase during in vitro DNA synthesis as source of ATP. Specific nucleotides are added stepwise to the reaction in order to determine the sequence of the DNA strand of interest that is used as a template for DNA synthesis. The method is suitable for quantitative measurements and can distinguish homozygous from heterozygous mutation pattern, and assay sensitivity is estimated at 5%. Melting curve assay A fluorescence-tagged primer that is complementary to either wild-type (WT) or mutated sequence is incorporated in a standard PCR reaction and differences in the dissociation temperature of the primer from either the WT or mutant sequence is used to differentiate between the two. In other words, mismatched binding dissociates at a lower temperature. The method is semi quantitative with a 1% to 10% reported assay sensitivity. Allele-specific PCR There are several different methodologies that utilize allelespecific (AS) primers, in the context of both qualitative and quantitative platforms. One such assay is very sensitive (0.01%-0.1%) and involves the use of a mutation specific forward primer that results in the amplification of only the mutated sequence that is detected by capillary electrophoresis.23 Another AS-PCR method, referred to as amplification refractory mutation system (ARMS; reported sensitivity of 1%-2%), uses two primer pairs to specifically amplify both WT and mutant DNA sequence in a single reaction. In general, AS-PCR methods are suitable for quantitative measurements on a real-time PCR platform, using either genomic DNA or cdna [4,5]. 3. Types of Chronic Myrloproliferative Disorder: Myeloproliferative disorders are described according to the blood cell which is most affected. There are four types of myeloproliferative disorder that together represent around 95% of all cases. 1. Polycythemia Vera (PV). 2. Essential thrombocythemia (ET). 3. Primary or idiopathic myelofibrosis (PMF). 4. Chronic myelomonocyte leukemia (CML). Uncommon types of myeloproliferative disorder together make up about 5% of cases. These include: 1. Chronic neutrophilic leukemia (CNL). 2. Chronic eosinophilic leukemia (CEL). 3. Mastocytosis[1]. 4.1 Polycythemia Vere: Introduction of PV: Polycythemia Vera (PV) is a myeloproliferative disorder characterized by overproduction of red blood cell (RBC) although white blood cells (WBC) and /or platelets can also be increased in many patients. Normally the number of red cells in blood is controlled by the growth factor erythropoietin (EPO).When there is not enough red cells erythropoietin is released from the kidney, where it is made. As the number of red cells increases, the erythropoietin level falls and red cell production slows. In polycythemia Vera the red cells grow even when EPO level are low. The reason for this was discovered in 2005 when it was found that most patients with polycythemia Vera had an abnormal or mutant JAK2 protein. JAK2 is part of the signal used by EPO to make the cells grow. The mutant JAK2 causes the red cells to grow whether EPO is present or not. Polycythemia vera (PV), a myeloproliferative disorder with a poorly understood pathogenesis,1 predominantly affects people in the 6th decade of life, but nearly a fifth of the patients are diagnosed with PV before the age of 50[6]. Pathophysiology: The primary defect involves a pluripotent stem cell capable of differentiating into red blood cells, granulocytes, and platelets. Clonality has been demonstrated through glucose- 6-phosphate dehydrogenase (G6PD) studies as well as restriction fragment length polymorphism of the active X chromosome. Erythroid precursors in PV are exquisitely sensitive to erythropoietin, which leads to increased red blood cell production. Precursors in PV are also more responsive to cytokines such as interleukin-3 (IL -3), granulocyte-macrophage colony-stimulating factor, and steel factor. Myeloid and megakaryocytic elements are often increased in the bone marrow (Fig 2). More than 60% of patients have endogenous Megakaryocytes colony unit formation. Increased red blood cell production in PV leads to an increased red cell mass and increased blood viscosity. This in turn can lead to arterial or venous thrombosis, bleeding, or both. The haematocrit is directly proportional to the number of thrombotic events. Investigators have demonstrated a reduction in cerebral blood flow in patients with haematocrit between 53% and 62%. An increased platelet count can also contribute to bleeding and thrombosis. Although platelet aggregation abnormalities exist in most patients, these abnormalities do not appear to correlate with the risk of bleeding or thrombosis. Increased production and breakdown of blood cells can lead to hyperuricemia and hyper metabolism[7]. Signs and Symptoms of polycythemia Vera: Fatigue, general malaise. Trouble breathing. Intense itching after bathing in warm water. Stomachaches. Purple spots or patches on skin. International Journal of Current Trends in Pharmaceutical Research 926

4 Nosebleed, gum or stomach bleeding, or blood in urine. Throbbing and problems with vision. High blood pressure. Blockage of blood vessels. This may cause heart disease, stroke or gangrene(tissue death) of arms and legs[7]. Diagnostic criteria: Full blood count: People with polycythemia Vera have a high red cell count with a correspondingly high hemoglobin level and haematocrit, due to the excessive production of red cells. A raised platelet count and raised white blood count is common finding. In most patients the diagnosis is confirmed by JAK2 mutation. The JAK2 testing is done on a regular blood test and is positive in nearly all cases. Another finding that helps to confirm the diagnosis of polycythemia vera is an enlarged Spleen. Red cell mass: Measurement of the total red cell mass was previously necessary for making a diagnosis of polycythemia Vera. However, with the availability of the test for JAK2 mutation in most cases it is no longer needed. Polycythemia Vera is diagnosed when the red cell mass is 25% greater than the average normal expected value. This test is now mainly used when the hemoglobin is high and the JAK2 mutation is negative. Bone marrow examination: A bone marrow biopsy is not always necessary in patient with polycythemia Vera. However, when performed, the bone marrow is abnormal with increased number of normal cells. Fibrosis or scarring of bone marrow may be prominent, especially if the disease has been present for number of year. Iron stores measured in bone marrow may be depleted since iron is being used to make more and more red cells, and iron absorption is reduced. Bone marrow aspirate and biopsy: A procedure that involves removing some marrow for examination in the laboratory. The biopsy is small core of bone is taken under local or occasionally general anaesthetic, from the back of the hip. A sample of bone marrow and soft inner bone is withdrawn or aspirated for testing under a microscope. Other tests that may be performed: Blood tests: a. Serum vitamin B-12 level-which can be high b. Uric acid level-high c. Erythropoitin levels-low d. Coagulation studies to see if your blood is clotting normally e. Blood oxygen level-usually normal but if the oxygen is low it points to a cause other than PV for the high haemoglobin. Other examinations: a. Chest X-ray to rule out lung disease. b. Abdominal ultrasound or CT scan to rule out kidney disease and measure the kidney and liver size [4,7]. Treatment for polycythemia Vera: The goal of treatment for polycythemia Vera is to reduce the number of cells in the blood and help to maintain a normal blood count. The treatment or combination of treatment chosen will depend on several factor including the duration and severity of disorder, whether or not you have a history of blood clots, age and general health. Venesection: Venesection is a procedure in which a controlled amount of blood is removed from bloodstream. This procedure is commonly used when people are first diagnosed with polycythemia Vera because it can help to rapidly reduce high red cell count. In process similar to a blood donation, mls of blood is removed, usually from a large vein in front of elbow. The procedure may need to be repeated frequently at first, usually every few days, until haematocrit is reduced to the desired level. After this need to have the procedure repeated periodically, for example at monthly intervals, to help maintain a normal blood count. Many people with polycythemia Vera also need other treatments in addition to (or instead of) venecection to help control their blood count. Chemotherapy: Myelosupressive (bone marrow suppressing) drugs are commonly used to reduce blood cell production in the bone marrow. These drugs are commonly used for people with a high platelet count, complication due to blood cloting or bleeding, or symptoms of an enlarged spleen. They are also used for some people who are unable to tolerate Venesection or whose disease is no longer responding to Venesection. The most commonly used Myelosupressive agent is a chemotherapy drug called hydroxyurea. It is particularly useful in controlling a high platelet count in older patient and therefore reducing the risk of thrombosis. Hydroxyurea is taken in capsule form every day. As hydroxyurea is a chemotherapy drug, it can affect fertility. Most people who take hydroxyurea have very few side effects but a small number of people do not tolerate it well. Hydroxyurea can increase the number of minor skin cancer in people with sun damaged skin. Rarely, people taking hydroxyurea can develop ulcer around their ankles. Another less commonly used chemotherapy drug is busulphan. This drug is taken in tablet form. Interferon: Interferon s is a substance produced naturally by the body s immune systems. It plays an important role in fighting disease. In polycythemia Vera, synthetic interferon is sometime prescribed for patient to help control the production of blood cells. Interferon s is usually given three times a week as an injection under the skin using a very small needle. A weekly injection is also now available and is becoming more widely used. Side effect of interferon s can be unpleasant but they can minimized by starting with small dose, and building up to the full dose over several weeks. The main side effects are flu-like symptoms such as chill, fever, aches, pains and weakness. Aspirin: Aspirin has been shown to significantly reduce the risk of thrombosis in people with polycythemia Vera. It is usually given to all patients with polycythemia Vera unless there is a reason not to give it. Aspirin works by preventing your platelets from clumping together to form harmful blood clots in different parts of your body. Aspirin can irritate the International Journal of Current Trends in Pharmaceutical Research 927

5 lining of the stomach which can result in pain or discomfort in the stomach, causing nausea, heartburn or loss of appetite. Taking aspirin with food or milk may help prevent this. In addition, many people are prescribed enteric-coated aspirin that allows the drug to pass through the stomach and into the intestine before dissolving. This helps to reduce the risk of stomach upset. Anagrelide hydrochloride: Anagrelide hydrochloride (anagrelide or Agrylin ) is a drug used to reduce high platelet counts in people with polycythaemia Vera and essential thrombocythaemia. However, studies have shown that hydroxyurea is more effective in most patients in reducing the risk of complications - thus anagrelide is used only in people who do not tolerate hydroxyurea [8]. Essential Thrombocythemia: Introduction: Essential thrombocythemia (also called primary thrombo- cythemia), a disease that results in the overproduction of platelets by the bone marrow, generally affects people over 50. (Elevated numbers of platelets can also occur as a result of infection, iron deficiency, and other secondary causes.) Platelets, also known as thrombocytes, prevent bleeding or cause it to stop. High numbers of platelets can result in increased blood clotting or sometimes increased bleeding. Essential thrombocythemia (ET), is a chronic myeloproliferative disorder characterized by a high platelet count. It originates from a pluripotent stem cell. ET generally shows a slight female preponderance ( ). The median age at diagnosis is 60 years although there is very wide range of ages in which the disease can appear (18-90 years).approximately half of the people are asymptomatic while the other half have vasomotor, thrombotic or hemorrhagic disturbance [1]. Pathophysiology: The proliferative of megakaryocytic is primarily caused by clonal stem cells, as confirmed by enzyme and genetic analysis. Megakaryocytes progenitor cells in ET are hypersensitive to the action of several cytokines, including IL-3 and IL-6, and possibly thrombopiotin. This lead to increase platelet production. There is controversy regarding spontaneous Megakaryocytes formation in ET. Thrombopoietin and its associated receptor pathways do not appear to be involved in the development of ET. Increased platelet count in ET are associated with increased thrombotic and hemorrhagic complication.decreasing platelet count in EET can decrease thrombotic complication.high platelet count are associated with acquired von Willebrand disease resulting from the adsorption of von Willebrand multimers onto platelet mambranes.a reduction in the platelet count is associated with correction of the defect and cessation of bleeding. Qualitative abnormalities in platelets themselves are also likely to contribute to the increased risk of thrombotic and hemorrhage complication in ET, because reactive thrombocytosis is not associated with an increased risk of thrombosis or bleeding, even with high platelet count. Platelet aggregation studies in ET are often abnormal. Signs and Symptoms of essential thrombocythemia:- Heart attacks or stoke. Headache. Burning or thrombing pain, redness, and swelling of the hands and feet. Gastrointestinal bleeding or blood in urine [6]. Diagnosis and treatment: The diagnosis of essential thrombocythaemia is made only when other causes of a raised platelet count have been excluded Diagnosis: Full blood count: A persistently raised platelet count is the most common sign of essential thrombocythaemia. Under the microscope the platelets may be abnormally large. Fragments of Megakaryocytes, the cells from which platelets are released, may also be seen in the blood film. Around a third of people with essential thrombocythaemia will also have a mildly raised red cell and/or white cell count. Jak2 and other mutation: A mutant form of JAK2 can be found in about 50% of patients with essential thrombocythaemia. This is the same mutation found in most people with polycythaemia Vera. About 5% of patients with ET have a mutation in a different gene, the MPL receptor - which is the receptor or thromboparetin (TPP) the growth factor for platelets. The result of these changes is that platelet production continues even when the body has too many platelets. Bone marrow examination: In essential thrombocythaemia the bone marrow is usually found to be overactive, similar to polycythaemia Vera. An excess number of abnormal Megakaryocytes is a common finding. Cytogenetic and molecular analysis of blood and bone marrow cells may be carried out in the laboratory to help confirm the diagnosis. Other blood tests may be done to check general health and how well kidneys, liver and other vital organs are functioning[9]. Treatment: People at high-risk of thrombosis, a chemotherapy drug called hydroxyurea in combination with low-dose aspirin is often used as first-line treatment. Hydroxyurea works by suppressing the function of bone marrow and therefore controlling platelet production, while aspirin prevents platelets from clumping together and forming harmful clots in body. Anagrelide hydrochloride (anagrelide or Agrylin ) and interferon may also be used. Studies have shown that hydroxyurea is better at reducing complications than anagrelide and is usually preferred. Those people at lowrisk may be treated using low dose aspirin, or an equivalent drug alone. They usually have a very good outlook with no difference compared with the general population. Plateletpheresis Very rarely, if platelet count is very high and have symptoms of clotting or bleeding, platelet count will need to be reduced quickly to prevent further complications. In these emergency situations, excess platelets can be removed from your bloodstream using a procedure known as Plateletpheresis. During this procedure a portion of blood is passed through a special machine called a cell separator. The blood is drawn from a cannula (plastic needle) placed in a vein in one arm. The machine spins the blood very quickly and removes the excess platelets. This is a continuous process. While platelets are being removed the International Journal of Current Trends in Pharmaceutical Research 928

6 rest of blood is being returned to via another cannula, placed in other arm. Plateletpheresis is usually carried out in hospital. It usually takes about two hours to complete [10]. Primary and Ideopathic Fibrosis: Introduction: Myelofibrosis was first described in 1879 By Gustav heuck. Older terms include "myelofibrosis with myeloid metaplsia" and "agnogenic myeloid metaplsia". The world health organization utilizes the name "chronic idiopathic myelofibrosis", while the International Working Group on Myelofibrosis Research and Treatment calls the disease "primary myelofibrosis". Eponyms for the disease are Heuck-Assmann disease or Ashman s Disease, for Herbert Assmann who published a description under the term "osteosclerosis" in It was characterized as a myeloproliferative condition in 1951 by Dameshek. The Leukemia and Lymphoma Society describes myelofibrosis as a rare type of blood cancer, manifesting as a type of chronic leukemia. Primary myelofibrosis (also called idiopathic myelofibrosis or agnogenic myeloid metaplasia) is a disorder in which normal bone marrow tissue is gradually replaced with a fibrosis scar-like material. Overtime, this leads to progressive bone marrow failure. Primary fibrosis is a rare chronic disorder diagnosed in an estimated 1 person per 1oo ooo each year. It can occur at any age but is usually diagnosed in between age of years.in about 50% cases there is mutation in jak2 gene [11]. Pathophysiology: Clonal studies have demonstrated as a stem cells origin. The clonal proliferation of hematopoietic stem is believed to produce growth factor that lead to the fibrosis of the bone marrow. Initially, the bone marrow is hypercellular, but normal hematopoiesis is diminished as the bone marrow become fibrotic and patient becomes pancytopenic. Because of this, the extramedullary hematopoiesis occurring in the liver and spleen causes these organs to enlarge [11]. Signs and symptoms: Many symptoms are attributable to the pancythopenia associated with myelofibrosis. Pancythopenia occurs as a result of decrease hematopoiesis and splenic sequestration. Most patients are anemic and feel short of breath and fatigued. Thrombocytopenia and neutropenia can lead to hemorrhage and infective. Other Conventional system include symptoms include anorexia, weight loss and night sweats. The WBC and platelet are counts might increase initially but typically decrease as the progresses. The blood film display a characteristic leucoerethroblastic picture caused by crowding out of normal hematopoietic element by fibrosis in bone marrow. Patient might complain of abdominal discomfort and decrease appetite because of splenic and hepatic enlargement resulting from extramedullary hematopoiesis portal hypertension and jaundice can occur as a result of increased hepatic blood flow [12] Diagnosis: Full blood count: People with primary myelofibrosis often have varying degrees of anemia when diagnosed. When examined under the microscope the red cells are often described as being teardrop-shaped. Higher than normal numbers of white cells and platelets may be found in the early stages of this disorder, but low white cell and platelet counts are common in more advanced disease. Bone marrow examination: It is not always possible to obtain any samples of bone marrow fluid using a needle and syringe (bone marrow aspiration) due to the marrow fibrosis. This is known as a dry tap. The bone marrow trephine biopsy typically shows abnormal fibrosis of the marrow cavity. Cytogenetic and molecular analysis of blood and bone marrow cells is also carried out under the microscope to help confirm the diagnosis [12]. Treatment: A chemotherapy drug such as hydroxyurea may be used to reduce an enlarged spleen. In some cases, the surgical removal of the spleen (called a splenectomy) may be considered, especially if your spleen has enlarged so much that it is causing severe symptoms. A splenectomy may also be considered if have an increased need for blood transfusions. It is less helpful for those who have low platelet counts. Small doses of radiotherapy to the spleen can also be given to reduce its size. This usually provides temporary relief for about 3 to 6 months. Bone marrow or stem cell transplants using a sibling or unrelated donor can be successful at curing patients with myelofibrosis. They can be a good option for younger patients with advanced disease. However, transplant is not commonly recommended and the decision to proceed to transplant needs to be considered very carefully. There are considerable side effects from the treatment and in some cases there can be complications that may be fatal [12, 13]. Chronic Myelomoncyte Leukemia: Introduction: In patients with chronic myelomonocytic leukemia (CMML), the body increases its production of monocytes (a type of white blood cell) and has difficulty producing normal numbers of other types of blood cells. CMML is classified either as a myeloproliferative disease or a myelodysplatic syndrome and its treatment depends in part on how it manifests itself, but often entails blood transfusions and sometimes oral or intravenous chemotherapy to control the disease [14]. Pathophysiology: CMML was initially characterized as a myelodysplatic syndrome because of the associated dysplasia and cytopenia in some patient s myeloproliferative features (increased myelopoiesis). High peripheral monocyte count s are often associated with pericardial, pleural, synovial, and ascetic effusions, as well as hepatomegaly and splenomegaly secondary to tissue infiltration by monocytes[14]. Sign and symptoms: International Journal of Current Trends in Pharmaceutical Research 929

7 People with this disease often have symptoms of anemia headache, pallor and may develop abdominal pain due to enlargement of the spleen. Some have a low white blood count or a low platelet count, and therefore are susceptible to infections. Common symptoms and signs of the disease include fatigue, weight loss, fever and night sweats, splenomegaly, and hepatomagely. Serositis is another CMML characteristic, but relatively infrequent, disease feature and might involve the joints (arthritis), pericardial (pericarditis and pericardial effusion), peritoneum (ascites). The bone marrow is often hypercellular with granulocytic proliferation, as predominant feature. Dysplasia is usual and may involve 1, 2 or all myeloid lineages[15]. Chronic Neutrophilic Leukemia: Introduction: Chronic neutrophilic leukemia (CNL) is characterized by mature neutrophilic leukemia leukocytosis with few or on circulating immature granulocytes, monocytes, or basoplilia. Affected patient usually have splenomegaly, and bone marrow histology reveals granulocytic hyperplasia without evidence of dysplasia or substantial reticulin fibrosis. By definition, patient with CNL features Right shifted neutrophilia with less than 5% immature granulocytes. Signs and symptoms: Fatigue is the most common presenting symptoms. Other reported symptoms include weight loss, easy bruising, bone pain, and night sweats. Most patients have palpable splenomegaly. Diagnosis and treatment: Treatment options may include the use of chemotherapy drugs such as busulphan or hydroxyurea, which are given in tablet or capsule form. These drugs are used to control the high white cell count[4,16]. Chronic Eosinophilic Leukemia: Patients with eosinophilia have an abnormally high number of eosinophils, a type of white blood cell, in their blood. Eosinophilia is not a type of cancer but it often occurs in reaction to something else in the body. High levels of eosinophils indicate that the body may be reacting to an allergen or parasite, or to substances produced by the cells of cancers such as Hodgkin s disease and chronic myeloid leukemia. Thus, eosinophilia is most commonly a reaction to a disease process rather than a specific disease itself. Blood eosinophilic that is neither secondary nor clonal is operationally labeled as idiopathic. Hypereosinophilic syndrome is a subcategory of idiopathic eosinophilia that requires documentation of both a target organ damage and an absolute eosinophile count of ⁹/L or higher for at least 6 month [1]. Signs and symptoms: The presence of eosinophilia-associated tissue damage, including cardiomyopathy, gastroenteritis, cutaneous, hepatoslenomegaly, and either cytopenia and cytosis. An HES phenotype with episodic angiodema, urticaria, fever, weight gain, and elevated levels of serum IgE, IgM, and polyclonal γ globulin is associated with a relatively benign, corticosteroid-responsive disease (Gleich syndrome). Diagnosis and treatment: This is often a difficult diagnosis to make. While a simple blood test will demonstrate that high numbers of eosinophils are present, it is often difficult to find out what the cause of this is. Eosinophils are increased in the blood in allergic reactions, in response to some infections (such as intestinal worms), related to abnormal lymphocytes, or due to a myeloproliferative disorder. In some people mutations that affect the growth of eosinophils can be detected by a blood test. Treatment: The natural course of chronic eosinophilic leukemia can vary considerably between individuals. The disease may remain stable for many years, even decades, or it may quickly progress and transform to an acute leukemia. Because of this, the most appropriate treatment for each patient is decided upon on an individual basis. Treatment may include corticosteroids, chemotherapy drugs such as hydroxyurea, and interferon therapy. Some patients may respond to a newer drug called imatinib mesylate, most often used in the treatment of chronic myeloid leukemia. A stem cell transplant may be considered in selected cases [17]. Mastocytosis: Introduction: In patients with systemic mastocytosis, the mast cells (cells involved in allergic reactions) are present in excess numbers. Mastocytosis can be present only in the skin (cutaneous mastocytosis or chronic urticaria), but in systemic mastocytosis increased numbers of mast cells are present throughout the body, including the gastrointestinal tract and the bone marrow. Mastocytosis is a disorder that results from the overproduction of mast cells, in bone marrow. These cells accumulate in the blood, spleen, skin and other body tissue. Excess number of mast cells release large amount of histamine and other substance collect which can cause allergy-type reaction in affected tissue. There are two main types of Mastocytosis: 1. Cutaneous Mastocytosis: Only affecting the skin, this is most commonly seen in children, and has a good prognosis, often resolving at puberty. 2. Systemic Mastocytosis: More common in adult, this affects bone marrow and other tissue, including the skin [1]. Signs and symptoms: Constitutional symptoms: fatigue, weight loss, Sweating and fevers. Skin symptoms: Itch, Urticaria and dermatographism. Systemic symptoms: a. Release of mast cell granules, b. Abdominal Pain, c. Flushing, d. Fainting, e. Headache, f. Rapid Pulse, g. Cough and shortness of breath. Musculoskeletal problems: International Journal of Current Trends in Pharmaceutical Research 930

8 Including bone pain, Osteoporosis, Fractures, joint and muscle aches. Diagnosis and treatment: The diagnosis of Mastocytosis can be made on skin or bone marrow biopsies, and by measuring the blood level of tryptase, an enzyme released by the mast cells. Treatment decisions tend to be made on an individual basis and may include chemotherapy in tablet form and/or interferon therapy to help control the overproduction of mast cells in the bone marrow. Many cases of Mastocytosis in adults have been shown to have a mutation of a protein called KIT, which is a growth factor for the cells that causes them to keep growing. New drugs that block this mutant protein are being developed and may prove useful for treating Mastocytosis [1, 18]. 4. Conclusion Myeloproliferative diseases are a heterogenous group of disorders characterized by cellular proliferation of 1 or more hematologic cell lines in the peripheral blood, distinct from acute leukemia. In this regard the most exciting development concerns a novel jak2 somatic point mutation. The discovery has provided guidance for to focus for additional pathogenetic studies and development of in reduced side effects. 5. References 1. Myeloproliferative Disorders - a guide for patients, families and whanau, nz/page/213v 2. A Tefferi. Classification, Diagnosis and Management of Myeloproliferative Disorders in the JAK2V 617F Era, American Society of Hematology, 2006, 81(4): C James, V Ugo, JP Couedic. A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature, 2005, 434 (7037): Pascal mossu. Diagnostic value of serum erythropoietin level in patient with absolute erythrocytosis, Haematologica, 2004, 89: JV Jovanovic, A Ivey, AM Vannucchi, E Lippert, EL Oppliger, B Cassinat. Establishing optimal quantitative-polymerase chain reaction assays for routine diagnosis and tracking of minimal residual disease in JAK2-V617F-associated myeloproliferative neoplasms: a joint European Leukemia. Jul 17, RL Levin, M Wadleigh, J Cools. Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell, 2005, 7(4): A Tefferi, LA Solberg, MN Silverstein. A clinical update in polycythemia vera and essential thrombocythemia. Am J Med, 2000, 109(2): B Gunnar. Adverse effects and benefits of two years of anagrelide treatment for thrombocythemia in chronic myeloproliferative disorders. Haematologica, 2004, 89: therapeutics. Patients are at risk for thrombotic and hemorrhagic events. They are also at risk of developing secondary acute leukemia from their underlying disorder, as well as from their treatment. Though myeloproliferative disorders are serious, and may pose certain health risks, people with these conditions often live for many years after diagnosis. 9. G Finazzi, T Barbui. Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia, 2008, 22(8): AM Florena. Value of bone marrow biopsy in the diagnosis of essential thrombocythemia. Haematologica, 2004, 89: J Kutti, B Ridell. Epidemiology of the myeloproliferative disorders: essential thrombocythaemia, polycythaemia vera and idiopathic myelofibrosis. Pathol Biol., 2001, 49(2): P Frencesco. Polycythemia Vera in young patient : a study on long term risk of thrombosis, myelofibrosis and leukemia. Haematologica, 2003, 88: A Tefferi. Myelofibrosis with myeloid metaplasia. Med Prog. 2000, 34(17): S O'Brien, A Tefferi, P Valent. Chronic myelogenous leukemia and myeloproliferative disease. Hematology, 2004, NJ Donato, M Talpaz. Clinical use of tyrosine kinase inhibitors: therapy for chronic myelogenous leukemia and other cancers. Clin Cancer Res.,2000,6(8): S Faderl, HM Kantarjian, M Talpaz. New treatment approaches for chronic myelogenous leukemia. Semin Oncol., 2000, 27(5): Williams Hematology, McGraw-Hill, 7th ed, HP Horny, K Sotlar,P Valent. Mastocytosis: state of the art. Pathobiology, 2007, 74 (2): International Journal of Current Trends in Pharmaceutical Research 931