K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760

International Journal of Current Trends in Pharmaceutical Research

Journal Home Page: www.pharmaresearchlibrary.com/ijctpr Review Article Open Access

A Review on Myeloproliferative disorder

K.B. Kotade*1, P.Kadbhane1, S.B Somwanshi2, K.B.Dhamak3

1Department of Pharmacology, P.R.E.S.’s, College of Pharmacy (For Women), Chincholi, Nashik-422 102. 2Department of Pharmaceutics, P.R.E.S.’s, College of Pharmacy (For Women), Chincholi, Nashik-422 102. 3Department of Pharmaceutical Chemistry, P.R.E.S.’s, College of Pharmacy (For Women), Chincholi, Nashik-422 102

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 where there is an overgrowth of cells in the bone marrow, often leading to increased number of cells in the . 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. (PV), Essential thrombocythemia (ET), Primary or idiopathic myelofibrosis (PMF), Chronic myelogenous (CML). Uncommon types of myeloproliferative disorder together make up about 5% of cases are chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia (CEL), . 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 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. Keywords: Bone marrow, Jenus kinase, Leukemia, Mutation, Myeloproliferative disorder (MPD).

A R T I C L E I N F O

CONTENTS 1. Introduction ...... 925 2. Causes of Myelopriliferative Disorder...... 925 3. Types of Chronic Myrloproliferative Disorder ...... 926 4. Conclusion ...... 931 5. References ...... 931

Article History: Received Accepted Available Online

27 February 2015, 29 March 2015, 15 May 2015 *Corresponding Author K.B. Kotade Department of Pharmacology, P.R.E.S.’s, College of Pharmacy (For Women), Chincholi, Nashik-422102. Manuscript ID: IJCTPR2525 PAPER-QR CODE

Citation: Int. J. Curnt. Tren. Pharm, Res.

K.B. Kotade, et al. A Review on Myeloproliferative disorder. , 2015, 3(3): 924-931.

International Journal of Current Trends in Pharmaceutical Research 924 K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760 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 1.properly Introduction cited. The term myeloproliferative disorder (MPD) was first The JAK2 V617F Mutation: introduced by Dr William in 1951 to emphasize the In 2005, several groups reported a single, acquired point clinicopathological similarities between chronic myeloid mutation in the Janus kinase 2 (JAK2) genes in the majority leukemia (CML), essential thrombocythemia (ET), of patients with Ph-negative myeloproliferative disorders. polycythemia vera (PV), and with myeloid metaplsia JAK2, a cytoplasmic tyrosine kinas, is critical for (MMM).Accordingly, these four disorders are currently instigating intracellular signaling by the receptors for referred as “classic MPD”. Myeloproliferative disorders are erythropoietin, thrombopoietin, interleukin-3, diseases in which too many of certain types of blood cells - colony-stimulating factor (G-CSF), and granulocyte– , , fibroblasts, red blood cells -are made colony-stimulating factor (GMCSF). Mice that in the bone marrow, the spongy tissue inside the large are deficient in Jak2 die at embryonic day 12.5, with a bones in the body where red and white blood cells and complete absence of definitive , a finding that platelets are made.The chronic myeloproliferative disorders underscores the vital role of JAK2 as a transducer of signals (MPD) are a group of related diseases that are characterized evoked by the binding of erythropoietin to its receptor. by neoplastic proliferation in one or more hematopoietic JAK2 binds to the erythropoietin receptor in the cell lines. Myeloproliferative disorder is the general name endoplasmic reticulum and is required for its cell-surface given to a group of conditions where there is an overgrowth expression. When erythropoietin binds to its receptor, it of cells in the bone marrow, often leading to increased provokes a conformational change in the receptor with number of cells in the blood. In myeloproliferative disorder consequent phosphorylation and activation of JAK2.63 the the cells in bone marrow multiply in an uncontrolled way. activated JAK2 then phosphorylates the receptor’s In contrast with leukemia, where there is an overgrowth of cytoplasmic domain, thereby promoting the docking of immature cells. In myeloproliferative disorders the cells downstream effector proteins and the initiation of mature with normal function, there are just too many of intracellular signaling cascades. them. It is important to remember, that myeloproliferative disorder are chronic disease that, in most cases, remain The JAK2 mutation in the myeloproliferative disorders is stable for many years and progress gradually overtime [1]. not in the germ line but, rather, is acquired. Sensitive methods demonstrate the mutation in more than 95% of The cause of myeloproliferative disorder remains unknown, patients with polycythemia Vera and in 50 to 60% of although there is now rapidly increasing knowledge of patients with essential thrombocythemia or idiopathic some of the changes that trigger the disease. myelofibrosis. A substantial proportion of patients with Myeloproliferative disorders are sometime described as polycythemia vera or idiopathic myelofibrosis are being clonal blood stem cell disorder. This means that result homozygous for the JAK2 mutation as a result of mitotic from a change, or mutation, in DNA of single blood stem recombination affecting chromosome 9p, 6-9 but this cells. This change (or changes) results in abnormal blood phenomenon is rarely detected in essential cell development, and in this case, the overproduction of thrombocythemia. The mutation is also found in a small blood cells.In myeloproliferative disorders the original minority of patients with the hypereosinophilic syndrome, mutation is preserved when the affected stem cells divided chronic myelomonocytic leukemia, chronic neutrophilic (proliferates) and produces a ‘clone’ a group of identical leukemia, myelodysplatic, or acute , but stem cells all with the same defect. Mutation in dividing not in patients with lymphoid or other cancers or in those cells occur all the time and cells have sophisticated without hematologic disorders. The presence of a mutant mechanisms within them to stop these abnormalities JAK2 in some patients with , persisting. A mutation of a gene known as jenus kinase especially older patients, raises the possibility that they may (JAK 2) is found in large proportion of people with have had a preceding, undiagnosed myeloproliferative myeloproliferative disorder. The discovery of mutation in disorder [3]. JAK2 gene is important because it has significant impact Screening Tests: on the way myeloproliferative disorder are diagnosed and Several laboratory methods of JAK2V617F mutation may be important for treatment in the future. Finally, detection are currently available, and one must interpret test myeloproliferative disorder are not contagious; we cannot results in the context of assay sensitivity. For example, in catch these disorders by being in contact with a one of the first reports on JAK2V617F, mutational myeloproliferative disorder have no family history of these frequency in PV increased from 73% to 97% by using an disease. The longer we live, more chance we have acquiring allele-specific PCR assay (~3% sensitivity) as compared to mutations that escape these safeguards. That’s why direct sequencing (~20% sensitivity). On the other hand, myeloproliferative disorder can become more common as false positive results could arise from the utilization of ultra we get older [2]. sensitive assay systems (~0.01% sensitivity) that could detect very low levels of JAK2V617F even in healthy 2. Causes of Myelopriliferative Disorder: individuals. In general, quantitative PCR methods are

International Journal of Current Trends in Pharmaceutical Research 925 K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760 preferred because of their potential value in measuring 2. Chronic eosinophilic leukemia (CEL). mutant allele burden and monitoring treatment response. 3. Mastocytosis[1]. Conventional DNA sequencing 4.1 Polycythemia Vere: A PCR amplified DNA sequence of interest (in this Introduction of PV: instance the mutated DNA region of JAK2) is processed Polycythemia Vera (PV) is a myeloproliferative disorder through an automated sequencer that is based on the Sanger characterized by overproduction of (RBC) DNA sequencing principle. The method is semi although white blood cells (WBC) and /or platelets can also quantitative, can distinguish a homozygous from a be increased in many patients. Normally the number of red heterozygous pattern of mutation in the absence of mixed cells in blood is controlled by the growth factor Clonality, and the reported sensitivity is above 5%. erythropoietin (EPO).When there is not enough red cells Pyrosequencing (sequencing-by-synthesis) erythropoietin is released from the kidney, where it is made. The technique of Pyrosequencing is based on the detection As the number of red cells increases, the erythropoietin of light signal (bioluminescence) from a luciferase reaction level falls and red cell production slows. In polycythemia using pyrophosphates that are released by the incorporation Vera the red cells grow even when EPO level are low. The of nucleotides by polymerase during in vitro DNA synthesis reason for this was discovered in 2005 when it was found as source of ATP. Specific nucleotides are added stepwise that most patients with polycythemia Vera had an abnormal to the reaction in order to determine the sequence of the or mutant JAK2 protein. JAK2 is part of the signal used by DNA strand of interest that is used as a template for DNA EPO to make the cells grow. The mutant JAK2 causes the synthesis. The method is suitable for quantitative red cells to grow whether EPO is present or not. measurements and can distinguish homozygous from Polycythemia vera (PV), a myeloproliferative disorder with heterozygous mutation pattern, and assay sensitivity is a poorly understood pathogenesis,1 predominantly affects estimated at 5%. people in the 6th decade of life, but nearly a fifth of the Melting curve assay patients are diagnosed with PV before the age of 50[6]. A fluorescence-tagged primer that is complementary to Pathophysiology: either wild-type (WT) or mutated sequence is incorporated The primary defect involves a pluripotent stem cell capable in a standard PCR reaction and differences in the of differentiating into red blood cells, , and dissociation temperature of the primer from either the WT platelets. Clonality has been demonstrated through glucose- or mutant sequence is used to differentiate between the two. 6-phosphate dehydrogenase (G6PD) studies as well as In other words, mismatched binding dissociates at a lower restriction fragment length polymorphism of the active X temperature. The method is semi quantitative with a 1% to chromosome. Erythroid precursors in PV are exquisitely 10% reported assay sensitivity. sensitive to erythropoietin, which leads to increased red Allele-specific PCR blood cell production. Precursors in PV are also more There are several different methodologies that utilize allele- responsive to cytokines such as interleukin-3 (IL-3), specific (AS) primers, in the context of both qualitative and granulocyte-macrophage colony-stimulating factor, and quantitative platforms. One such assay is very sensitive steel factor. Myeloid and megakaryocytic elements are (0.01%-0.1%) and involves the use of a mutation specific often increased in the bone marrow (Fig 2). More than 60% forward primer that results in the amplification of only the of patients have endogenous colony unit mutated sequence that is detected by capillary formation. electrophoresis.23 Another AS-PCR method, referred to as amplification refractory mutation system (ARMS; reported Increased red blood cell production in PV leads to an sensitivity of 1%-2%), uses two primer pairs to specifically increased red cell mass and increased blood viscosity. This amplify both WT and mutant DNA sequence in a single in turn can lead to arterial or venous thrombosis, bleeding, reaction. In general, AS-PCR methods are suitable for or both. The haematocrit is directly proportional to the quantitative measurements on a real-time PCR platform, number of thrombotic events. Investigators have using either genomic DNA or cDNA [4,5]. demonstrated a reduction in cerebral blood flow in patients with haematocrit between 53% and 62%. An increased 3. Types of Chronic Myrloproliferative count can also contribute to bleeding and Disorder: thrombosis. Although platelet aggregation abnormalities Myeloproliferative disorders are described according to the exist in most patients, these abnormalities do not appear to blood cell which is most affected. There are four types of correlate with the risk of bleeding or thrombosis. Increased myeloproliferative disorder that together represent around production and breakdown of blood cells can lead to 95% of all cases. hyperuricemia and hyper metabolism[7]. 1. Polycythemia Vera (PV). 2. Essential thrombocythemia (ET). Signs and Symptoms of polycythemia Vera: 3. Primary or idiopathic myelofibrosis (PMF).  Fatigue, general malaise. 4. Chronic myelomonocyte leukemia (CML).  Trouble breathing. Uncommon types of myeloproliferative disorder together  Intense itching after bathing in warm water. make up about 5% of cases. These include:  Stomachaches. 1. Chronic neutrophilic leukemia (CNL).  Purple spots or patches on skin.

International Journal of Current Trends in Pharmaceutical Research 926 K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760  Nosebleed, gum or stomach bleeding, or blood in urine. normal blood count. The treatment or combination of  Throbbing and problems with vision. treatment chosen will depend on several factor including  High blood pressure. the duration and severity of disorder, whether or not you  Blockage of blood vessels. This may cause heart have a history of blood clots, age and general health. disease, stroke or gangrene(tissue death) of arms and Venesection: legs[7]. Venesection is a procedure in which a controlled amount of blood is removed from bloodstream. This procedure is Diagnostic criteria: commonly used when people are first diagnosed with Full blood count: People with polycythemia Vera have a polycythemia Vera because it can help to rapidly reduce high red cell count with a correspondingly high hemoglobin high red cell count. In process similar to a blood level and haematocrit, due to the excessive production of donation,450-500mls of blood is removed, usually from a red cells. A raised platelet count and raised white blood large vein in front of elbow. The procedure may need to be count is common finding. In most patients the diagnosis is repeated frequently at first, usually every few days, until confirmed by JAK2 mutation. The JAK2 testing is done on haematocrit is reduced to the desired level. After this need a regular blood test and is positive in nearly all cases. to have the procedure repeated periodically, for example at Another finding that helps to confirm the diagnosis of monthly intervals, to help maintain a normal blood count. polycythemia vera is an enlarged Spleen. Many people with polycythemia Vera also need other Red cell mass: treatments in addition to (or instead of) venecection to help Measurement of the total red cell mass was previously control their blood count. necessary for making a diagnosis of polycythemia Vera. Chemotherapy: However, with the availability of the test for JAK2 Myelosupressive (bone marrow suppressing) drugs are mutation in most cases it is no longer needed. Polycythemia commonly used to reduce blood cell production in the bone Vera is diagnosed when the red cell mass is 25% greater marrow. These drugs are commonly used for people with a than the average normal expected value. This test is now high platelet count, complication due to blood cloting or mainly used when the hemoglobin is high and the JAK2 bleeding, or symptoms of an enlarged spleen. They are also mutation is negative. used for some people who are unable to tolerate Bone marrow examination: Venesection or whose disease is no longer responding to A bone marrow biopsy is not always necessary in patient Venesection. The most commonly used Myelosupressive with polycythemia Vera. However, when performed, the agent is a chemotherapy drug called hydroxyurea. It is bone marrow is abnormal with increased number of normal particularly useful in controlling a high platelet count in cells. Fibrosis or scarring of bone marrow may be older patient and therefore reducing the risk of thrombosis. prominent, especially if the disease has been present for Hydroxyurea is taken in capsule form every day. As number of year. Iron stores measured in bone marrow may hydroxyurea is a chemotherapy drug, it can affect fertility. be depleted since iron is being used to make more and more Most people who take hydroxyurea have very few side red cells, and iron absorption is reduced. effects but a small number of people do not tolerate it well. Bone marrow aspirate and biopsy: Hydroxyurea can increase the number of minor skin cancer A procedure that involves removing some marrow for in people with sun damaged skin. Rarely, people taking examination in the laboratory. The biopsy is small core of hydroxyurea can develop ulcer around their ankles. Another bone is taken under local or occasionally general less commonly used chemotherapy drug is busulphan. This anaesthetic, from the back of the hip. A sample of bone drug is taken in tablet form. marrow and soft inner bone is withdrawn or aspirated for Interferon: testing under a microscope. Interferon’s is a substance produced naturally by the body’s Other tests that may be performed: immune systems. It plays an important role in fighting Blood tests: disease. In polycythemia Vera, synthetic interferon is a. Serum vitamin B-12 level-which can be high sometime prescribed for patient to help control the b. Uric acid level-high production of blood cells. Interferon’s is usually given three c. Erythropoitin levels-low times a week as an injection under the skin using a very d. Coagulation studies –to see if your blood is small needle. A weekly injection is also now available and clotting normally is becoming more widely used. Side effect of interferon’s e. Blood oxygen level-usually normal but if the can be unpleasant but they can minimized by starting with oxygen is low it points to a cause other than PV small dose, and building up to the full dose over several for the high haemoglobin. weeks. The main side effects are flu-like symptoms such as Other examinations: chill, fever, aches, pains and weakness. a. Chest X-ray –to rule out lung disease. Aspirin: b. Abdominal ultrasound or CT scan – to rule out Aspirin has been shown to significantly reduce the risk of kidney disease and measure the kidney and liver thrombosis in people with polycythemia Vera. It is usually size [4,7]. given to all patients with polycythemia Vera unless there is Treatment for polycythemia Vera: a reason not to give it. Aspirin works by preventing your The goal of treatment for polycythemia Vera is to reduce platelets from clumping together to form harmful blood the number of cells in the blood and help to maintain a clots in different parts of your body. Aspirin can irritate the

International Journal of Current Trends in Pharmaceutical Research 927 K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760 lining of the stomach which can result in pain or discomfort  Burning or thrombing pain, redness, and swelling in the stomach, causing nausea, heartburn or loss of of the hands and feet. appetite. Taking aspirin with food or milk may help prevent  Gastrointestinal bleeding or blood in urine [6]. this. In addition, many people are prescribed enteric-coated Diagnosis and treatment: aspirin that allows the drug to pass through the stomach and The diagnosis of essential thrombocythaemia is made only into the intestine before dissolving. This helps to reduce the when other causes of a raised platelet count have been risk of stomach upset. excluded Anagrelide hydrochloride: Diagnosis: Anagrelide hydrochloride (anagrelide or Agrylin®) is a Full blood count: drug used to reduce high platelet counts in people with A persistently raised platelet count is the most common polycythaemia Vera and essential thrombocythaemia. sign of essential thrombocythaemia. Under the microscope However, studies have shown that hydroxyurea is more the platelets may be abnormally large. Fragments of effective in most patients in reducing the risk of Megakaryocytes, the cells from which platelets are complications - thus anagrelide is used only in people who released, may also be seen in the blood film. Around a third do not tolerate hydroxyurea [8]. of people with essential thrombocythaemia will also have a Essential Thrombocythemia: mildly raised red cell and/or white cell count. Introduction: Essential thrombocythemia (also called Jak2 and other mutation: primary thrombo- cythemia), a disease that results in the A mutant form of JAK2 can be found in about 50% of overproduction of platelets by the bone marrow, generally patients with essential thrombocythaemia. This is the same affects people over 50. (Elevated numbers of platelets can mutation found in most people with polycythaemia Vera. also occur as a result of infection, iron deficiency, and other About 5% of patients with ET have a mutation in a different secondary causes.) Platelets, also known as thrombocytes, gene, the MPL receptor - which is the receptor or prevent bleeding or cause it to stop. High numbers of thromboparetin (TPP) the growth factor for platelets. The platelets can result in increased blood clotting or sometimes result of these changes is that platelet production continues increased bleeding. Essential thrombocythemia (ET), is a even when the body has too many platelets. chronic myeloproliferative disorder characterized by a high Bone marrow examination: platelet count. It originates from a pluripotent stem cell. ET In essential thrombocythaemia the bone marrow is usually generally shows a slight female preponderance (1.5-2.1). found to be overactive, similar to polycythaemia Vera. An The median age at diagnosis is 60 years although there is excess number of abnormal Megakaryocytes is a common very wide range of ages in which the disease can appear finding. Cytogenetic and molecular analysis of blood and (18-90 years).approximately half of the people are bone marrow cells may be carried out in the laboratory to asymptomatic while the other half have vasomotor, help confirm the diagnosis. Other blood tests may be done thrombotic or hemorrhagic disturbance [1]. to check general health and how well kidneys, liver and Pathophysiology: other vital organs are functioning[9]. The proliferative of megakaryocytic is primarily caused by Treatment: clonal stem cells, as confirmed by enzyme and genetic People at high-risk of thrombosis, a chemotherapy drug analysis. Megakaryocytes progenitor cells in ET are called hydroxyurea in combination with low-dose aspirin is hypersensitive to the action of several cytokines, including often used as first-line treatment. Hydroxyurea works by IL-3 and IL-6, and possibly thrombopiotin. This lead to suppressing the function of bone marrow and therefore increase platelet production. There is controversy regarding controlling platelet production, while aspirin prevents spontaneous Megakaryocytes formation in ET. platelets from clumping together and forming harmful clots Thrombopoietin and its associated receptor pathways do not in body. Anagrelide hydrochloride (anagrelide or Agrylin®) appear to be involved in the development of ET. Increased and interferon may also be used. Studies have shown that platelet count in ET are associated with increased hydroxyurea is better at reducing complications than thrombotic and hemorrhagic complication .decreasing anagrelide and is usually preferred. Those people at low- platelet count in EET can decrease thrombotic risk may be treated using low dose aspirin, or an equivalent complication .high platelet count are associated with drug alone. They usually have a very good outlook with no acquired von Willebrand disease resulting from the difference compared with the general population. adsorption of von Willebrand multimers onto platelet Plateletpheresis mambranes .A reduction in the platelet count is associated Very rarely, if platelet count is very high and have with correction of the defect and cessation of bleeding. symptoms of clotting or bleeding, platelet count will need Qualitative abnormalities in platelets themselves are also to be reduced quickly to prevent further complications. In likely to contribute to the increased risk of thrombotic and these emergency situations, excess platelets can be removed hemorrhage complication in ET, because reactive from your bloodstream using a procedure known as thrombocytosis is not associated with an increased risk of Plateletpheresis. During this procedure a portion of blood is thrombosis or bleeding, even with high platelet count. passed through a special machine called a cell separator. Platelet aggregation studies in ET are often abnormal. The blood is drawn from a cannula (plastic needle) placed Signs and Symptoms of essential thrombocythemia:- in a vein in one arm. The machine spins the blood very  Heart attacks or stoke. quickly and removes the excess platelets. This is a  Headache. continuous process. While platelets are being removed the

International Journal of Current Trends in Pharmaceutical Research 928 K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760 rest of blood is being returned to via another cannula, People with often have varying placed in other arm. Plateletpheresis is usually carried out degrees of anemia when diagnosed. When examined under in hospital. It usually takes about two hours to complete the microscope the red cells are often described as being [10]. ‘teardrop-shaped’. Higher than normal numbers of white Primary and Ideopathic Fibrosis: cells and platelets may be found in the early stages of this Introduction: disorder, but low white cell and platelet counts are common Myelofibrosis was first described in 1879 By Gustav heuck. in more advanced disease. Older terms include "myelofibrosis with myeloid Bone marrow examination: metaplsia" and "agnogenic myeloid metaplsia". The world It is not always possible to obtain any samples of bone health organization utilizes the name "chronic idiopathic marrow fluid using a needle and syringe (bone marrow myelofibrosis", while the International Working Group on aspiration) due to the marrow fibrosis. This is known as a Myelofibrosis Research and Treatment calls the disease ‘dry tap’. The bone marrow trephine biopsy typically shows "primary myelofibrosis". Eponyms for the disease are abnormal fibrosis of the marrow cavity. Cytogenetic and Heuck-Assmann disease or Ashman’s Disease, for Herbert molecular analysis of blood and bone marrow cells is also Assmann who published a description under the term carried out under the microscope to help confirm the "osteosclerosis" in 1907. It was characterized as a diagnosis [12]. myeloproliferative condition in 1951 by Dameshek. The Treatment: Leukemia and Lymphoma Society describes myelofibrosis A chemotherapy drug such as hydroxyurea may be used to as a rare type of blood cancer, manifesting as a type of reduce an enlarged spleen. In some cases, the surgical chronic leukemia. removal of the spleen (called a splenectomy) may be considered, especially if your spleen has enlarged so much Primary myelofibrosis (also called idiopathic myelofibrosis that it is causing severe symptoms. A splenectomy may also or agnogenic myeloid metaplasia) is a disorder in which be considered if have an increased need for blood normal bone marrow tissue is gradually replaced with a transfusions. It is less helpful for those who have low fibrosis scar-like material. Overtime, this leads to platelet counts. Small doses of radiotherapy to the spleen progressive bone marrow failure. Primary fibrosis is a rare can also be given to reduce its size. chronic disorder diagnosed in an estimated 1 person per 1oo’ooo each year. It can occur at any age but is usually This usually provides temporary relief for about 3 to 6 diagnosed in between age of 60-70 years .In about 50% months. Bone marrow or stem cell transplants using a cases there is mutation in jak2 gene [11]. sibling or unrelated donor can be successful at curing Pathophysiology: patients with myelofibrosis. They can be a good option for Clonal studies have demonstrated as a stem cells origin. younger patients with advanced disease. However, The clonal proliferation of hematopoietic stem is believed transplant is not commonly recommended and the decision to produce growth factor that lead to the fibrosis of the bone to proceed to transplant needs to be considered very marrow. Initially, the bone marrow is hypercellular, but carefully. There are considerable side effects from the normal hematopoiesis is diminished as the bone marrow treatment and in some cases there can be complications that become fibrotic and patient becomes pancytopenic. may be fatal [12, 13]. Because of this, the extramedullary hematopoiesis Chronic Myelomoncyte Leukemia: occurring in the liver and spleen causes these organs to Introduction: enlarge [11]. In patients with chronic myelomonocytic leukemia Signs and symptoms: (CMML), the body increases its production of monocytes (a Many symptoms are attributable to the pancythopenia type of ) and has difficulty producing associated with myelofibrosis. Pancythopenia occurs as a normal numbers of other types of blood cells. CMML is result of decrease hematopoiesis and splenic sequestration. classified either as a myeloproliferative disease or a Most patients are anemic and feel short of breath and myelodysplatic syndrome and its treatment depends in part fatigued. Thrombocytopenia and can lead to on how it manifests itself, but often entails blood hemorrhage and infective. Other Conventional system transfusions and sometimes oral or intravenous include symptoms include anorexia, weight loss and night chemotherapy to control the disease [14]. sweats. The WBC and platelet are counts might increase initially but typically decrease as the progresses. The blood Pathophysiology: film display a characteristic leucoerethroblastic picture CMML was initially characterized as a myelodysplatic caused by crowding out of normal hematopoietic element syndrome because of the associated dysplasia and cytopenia by fibrosis in bone marrow. Patient might complain of in some patient’s myeloproliferative features (increased abdominal discomfort and decrease appetite because of ). High peripheral count s are often splenic and hepatic enlargement resulting from associated with pericardial, pleural, synovial , and ascetic extramedullary hematopoiesis portal hypertension and effusions, as well as hepatomegaly and splenomegaly jaundice can occur as a result of increased hepatic blood secondary to tissue infiltration by monocytes[14]. flow [12] Sign and symptoms: Diagnosis: Full blood count:

International Journal of Current Trends in Pharmaceutical Research 929 K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760 People with this disease often have symptoms of anemia polyclonal γ globulin is associated with a relatively benign, headache, pallor and may develop abdominal pain due to corticosteroid-responsive disease (Gleich syndrome). enlargement of the spleen. Some have a low white blood count or a low platelet count, and therefore are susceptible Diagnosis and treatment: to infections. Common symptoms and signs of the disease This is often a difficult diagnosis to make. While a simple include fatigue, weight loss, fever and night sweats, blood test will demonstrate that high numbers of splenomegaly, and hepatomagely. Serositis is another are present, it is often difficult to find out what CMML characteristic, but relatively infrequent, disease the cause of this is. Eosinophils are increased in the blood feature and might involve the joints (arthritis), pericardial in allergic reactions, in response to some infections (such as (pericarditis and pericardial effusion), peritoneum (ascites). intestinal worms), related to abnormal lymphocytes, or due The bone marrow is often hypercellular with granulocytic to a myeloproliferative disorder. In some people mutations proliferation, as predominant feature. Dysplasia is usual and that affect the growth of eosinophils can be detected by a may involve 1, 2 or all myeloid lineages[15]. blood test. Treatment: Chronic Neutrophilic Leukemia: The natural course of chronic eosinophilic leukemia can Introduction: vary considerably between individuals. The disease may Chronic neutrophilic leukemia (CNL) is characterized by remain stable for many years, even decades, or it may mature neutrophilic leukemia leukocytosis with few or on quickly progress and transform to an acute leukemia. circulating immature granulocytes, monocytes, or Because of this, the most appropriate treatment for each basoplilia. Affected patient usually have splenomegaly, and patient is decided upon on an individual basis. Treatment bone marrow histology reveals granulocytic hyperplasia may include corticosteroids, chemotherapy drugs such as without evidence of dysplasia or substantial reticulin hydroxyurea, and interferon therapy. Some patients may fibrosis. By definition, patient with CNL features “Right respond to a newer drug called imatinib mesylate, most shifted” neutrophilia with less than 5% immature often used in the treatment of chronic myeloid leukemia. A granulocytes. stem cell transplant may be considered in selected cases Signs and symptoms: [17]. Fatigue is the most common presenting symptoms. Other Mastocytosis: reported symptoms include weight loss, easy bruising, bone Introduction: pain, and night sweats. Most patients have palpable In patients with systemic mastocytosis, the mast cells (cells splenomegaly. involved in allergic reactions) are present in excess Diagnosis and treatment: numbers. Mastocytosis can be present only in the skin Treatment options may include the use of chemotherapy (cutaneous mastocytosis or chronic urticaria), but in drugs such as busulphan or hydroxyurea, which are given in systemic mastocytosis increased numbers of mast cells are tablet or capsule form. These drugs are used to control the present throughout the body, including the gastrointestinal high white cell count[4,16]. tract and the bone marrow. Mastocytosis is a disorder that Chronic Eosinophilic Leukemia: results from the overproduction of mast cells, in bone Patients with eosinophilia have an abnormally high number marrow. These cells accumulate in the blood, spleen, skin of eosinophils, a type of white blood cell, in their blood. and other body tissue. Excess number of mast cells release Eosinophilia is not a type of cancer but it often occurs in large amount of histamine and other substance collect reaction to something else in the body. High levels of which can cause allergy-type reaction in affected tissue. eosinophils indicate that the body may be reacting to an There are two main types of Mastocytosis: allergen or parasite, or to substances produced by the cells 1. Cutaneous Mastocytosis: Only affecting the skin, of cancers such as Hodgkin’s disease and chronic myeloid this is most commonly seen in children, and has a leukemia. Thus, eosinophilia is most commonly a reaction good prognosis, often resolving at puberty. to a disease process rather than a specific disease itself. 2. Systemic Mastocytosis: More common in adult, Blood eosinophilic that is neither secondary nor clonal is this affects bone marrow and other tissue, operationally labeled as “idiopathic.” Hypereosinophilic including the skin [1]. syndrome is a subcategory of idiopathic eosinophilia that Signs and symptoms: requires documentation of both a target organ damage and Constitutional symptoms: fatigue, weight loss, Sweating an absolute eosinophile count of 1.5 × 10⁹/L or higher for at and fevers. Skin symptoms: Itch, Urticaria and dermatographism. least 6 month [1]. Systemic symptoms: a. Release of granules, Signs and symptoms: b. Abdominal Pain, The presence of eosinophilia-associated tissue damage, c. Flushing, including cardiomyopathy, gastroenteritis, cutaneous, d. Fainting, hepatoslenomegaly, and either cytopenia and cytosis. An e. Headache, HES phenotype with episodic angiodema, urticaria, fever, f. Rapid Pulse, weight gain, and elevated levels of serum IgE, IgM, and g. Cough and shortness of breath. Musculoskeletal problems:

International Journal of Current Trends in Pharmaceutical Research 930 K.B. Kotade et al, IJCTPR, 2015, 3(3): 924–931 ISSN: 2321-3760 Including bone pain, Osteoporosis, Fractures, joint and include chemotherapy in tablet form and/or interferon muscle aches. therapy to help control the overproduction of mast cells in the bone marrow. Many cases of Mastocytosis in adults Diagnosis and treatment: have been shown to have a mutation of a protein called The diagnosis of Mastocytosis can be made on skin or bone KIT, which is a growth factor for the cells that causes them marrow biopsies, and by measuring the blood level of to keep growing. New drugs that block this mutant protein tryptase, an enzyme released by the mast cells. Treatment are being developed and may prove useful for treating decisions tend to be made on an individual basis and may Mastocytosis [1, 18].

4. Conclusion Myeloproliferative diseases are a heterogenous group of therapeutics. Patients are at risk for thrombotic and disorders characterized by cellular proliferation of 1 or hemorrhagic events. They are also at risk of developing more hematologic cell lines in the peripheral blood, distinct secondary acute leukemia from their underlying disorder, as from acute leukemia. In this regard the most exciting well as from their treatment. Though myeloproliferative development concerns a novel jak2 somatic point mutation. disorders are serious, and may pose certain health risks, The discovery has provided guidance for to focus for people with these conditions often live for many years after additional pathogenetic studies and development of diagnosis. in reduced side effects.

5. References 1. Myeloproliferative Disorders - a guide for patients, 9. G Finazzi, T Barbui . Evidence and expertise in families and whanau, http://www.leukaemia.org. the management of polycythemia vera and nz/page/213v essential thrombocythemia. Leukemia, 2008, 2. A Tefferi. Classification, Diagnosis and 22(8): 1494-502. Management of Myeloproliferative Disorders in 10. AM Florena. Value of bone marrow biopsy in the the JAK2V 617F Era, American Society of diagnosis of essential thrombocythemia. Hematology, 2006, 81(4): 553-563. Haematologica, 2004, 89:911-919 . 3. C James , V Ugo , JP Couedic . A unique clonal 11. J Kutti, B Ridell. Epidemiology of the JAK2 mutation leading to constitutive signalling myeloproliferative disorders: essential causes polycythaemia vera. Nature, 2005, 434 thrombocythaemia, polycythaemia vera and (7037): 1144-8. idiopathic myelofibrosis. Pathol Biol., 2001, 4. Pascal mossu. Diagnostic value of serum 49(2): 164-6. erythropoietin level in patient with absolute 12. P Frencesco. Polycythemia Vera in young patient : erythrocytosis, Haematologica, 2004, 89: 1194- a study on long term risk of thrombosis, 1198. myelofibrosis and leukemia. Haematologica, 5. JV Jovanovic, A Ivey , AM Vannucchi, E Lippert, 2003, 88: 13-18. EL Oppliger, B Cassinat. Establishing optimal 13. A Tefferi. Myelofibrosis with myeloid metaplasia. quantitative-polymerase chain reaction assays for Med Prog. 2000, 34(17): 1255-1265. routine diagnosis and tracking of minimal residual 14. S O'Brien, A Tefferi, P Valent. Chronic disease in JAK2-V617F-associated myelogenous leukemia and myeloproliferative myeloproliferative neoplasms: a joint European disease. Hematology, 2004, 146-62. Leukemia. Jul 17, 2013. 15. NJ Donato, M Talpaz. Clinical use of tyrosine 6. RL Levin, M Wadleigh, J Cools. Activating kinase inhibitors: therapy for chronic myelogenous mutation in the tyrosine kinase JAK2 in leukemia and other cancers. Clin Cancer polycythemia vera, essential thrombocythemia, Res.,2000,6(8):2965-6. and myeloid metaplasia with myelofibrosis. 16. S Faderl, HM Kantarjian, M Talpaz. New Cancer Cell, 2005, 7(4): 387-97. treatment approaches for chronic myelogenous 7. A Tefferi, LA Solberg, MN Silverstein. A clinical leukemia. Semin Oncol., 2000, 27(5): 578-86. update in polycythemia vera and essential 17. Williams Hematology, McGraw-Hill, 7th ed, thrombocythemia. Am J Med, 2000, 109(2): 141-9. 2005. 8. B Gunnar. Adverse effects and benefits of two 18. HP Horny, K Sotlar,P Valent. Mastocytosis: state years of anagrelide treatment for thrombocythemia of the art. Pathobiology, 2007, 74 (2): 121–32. in chronic myeloproliferative disorders. Haematologica, 2004, 89:520-527.

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