Myeloproliferative Neoplasms (MPN)
Myeloproliferative neoplasms are a group of conditions where a clonal malignancy develops as a result of a somatic mutation in a single haematopoietic myeloid stem cell. As a result, there are increased numbers of mature Red blood cells, granulocytes, and platelets. There are 3 main diseases which fit under the umbrella of "myeloproliferative neoplasms":
1) Polycythemia vera
2) Essential thrombocythaemia
3) Primary myelofibrosis.
In each of these diseases, while there is increased number of all types of myeloid cells, there is a dominant type of cell which is present in higher numbers than the others. These disease entities are closely related because genetic mutations in the JAK2, Calreticulin (CALR) and MPL genes are found in varying proportions in each.
Polycythemia Vera (PV)
Polycythemia means an increase in the haemoglobin concentration. Polycythemia vera is a primary form of polycythemia as it is due to an acquired mutation. This is differentiated from secondary causes of polycythemia, where there is an increase in red blood cell/haemoglobin production in response to something else. Examples of causes of secondary polycythaemia include chronic lung disease, smoking, and sleep apnea, where the body produces more Hb/RBCs to provide more oxygen in the body as a response to hypoxia. (Polycythemia is described in more detail in the FBC page).
>90% of patients with polycythaemia vera have a JAK2 mutation. This mutation causes increased downstream signalling which then results in increased RBC and platelet production by stimulating erythropoietin and thrombopoietin receptors. There is also some increase in granulocyte production.
Clinical Features
As a result of the increased Hb, the blood becomes more viscous. Therefore symptoms of polycythemia vera are largely due to hyperviscosity. These include headaches, blurred vision, and breathlessness. Aquagenic pruritus is also a reported symptom, where there is itchiness classically after a warm bath.
Thrombosis and haemorrhage are also clinical features of PV. This is because PV affects the quality of platelet production. Gout may occur as a result of increased turnover of cells. Splenomegaly occurs as there are more red blood cells to destroy. 1,2
Investigations
Management
Aspirin is used to reduce the risk of thrombotic complications.
Venesection (removing blood) reduces the haematocrit.
Hydroxycarbamide is a chemotherapy drug, which reduces the production of cells (cytoreduction) by inhibiting DNA synthesis. This is used in high risk patients.
Interferon alpha is also a form of cytoreductive therapy, and is preferred in younger patients.
JAK Inhibitors such as Ruxolitinib are used in some cases where other treatment options have not adequately controlled the disease. 1,2
Complications
Polycythemia vera increases the risk of thrombosis and haemorrhage. Thrombosis occurs due to high viscosity of the blood, and increased platelet production. Haemorrhage occurs due to defective platelet function. There is also risk of transformation to acute leukaemia and myelofibrosis.1,2
Essential Thrombocythemia (ET)
Essential thrombocythemia is an idiopathic persistent raised platelet count. Other causes of thombocythemia (reactive thrombocythaemia) such as iron deficiency, malignancy and inflammatory disorders need to be excluded prior to making a diagnosis of ET. 1,2
Clinical Features
Patients may be asymptomatic and picked up after a routine blood test. Due to the high levels of platelets in the blood, there is a risk of thrombosis. These platelets are functionally abnormal, which increases the risk of haemorrhage. Additionally, thrombosis in the blood vessels supplying the hands and feet can cause erythromelalgia, a burning sensation in the hands and feet. Headaches and visual disturbances may occur as a consequence of increased blood viscosity. 1,2
Investigations
The Calreticulin (CALR) gene is involved in transducing signals and in transcribing genes. When this is mutated, the CALR protein interacts with the thrombopoietin receptor. This eventually leads to increased platelet production.
The MPL gene encodes for the thrombopoietin receptor. When constitutive signalling of these gene occurs, it causes increased platelet production.
Management
Similar to polycythemia vera, the main aim of management is to reduce the risk of thrombosis and haemorrhage. All patients have to have their cardiovascular risk factors reviewed and addressed. Low risk patients (those younger than 60, who have not had a thrombotic event) can be managed with low dose aspirin. Those at high risk (age>60, very high platelet count, and previous thrombotic event) need cytoreductive therapy which may include hydroxycarbamide. Other therapies include interferon and angrelide (platelet-reducing drug).
Complications
The risk of leukaemic transformation is low. There is a risk of transforming to myelofibrosis. 1,2
Primary Myelofibrosis
Primary myelofibrosis is progressive fibrosis that occurs because of abnormal megakarocytes in the bone marrow. These megakaryotcytes and platelets secrete growth factors and cytokines such as Platelet-derived Growth Factor (PDGF), which stimulates fibroblasts. Fibroblasts then cause collagen fibrosis of the bone marrow. As a result, the spleen and liver become sites for haematopoiesis. While polycythemia vera and essential thrombocythemia can progress to myelofibrosis, they are called "post-polycythemia" or "post-thrombocythemia" myelofibrosis (not primary myelofibrosis). 1,2
Clinical Features
Failure of the bone marrow to produce adequate amount of haematopoietic cells results in this process occurring in other sides of the body. This is called extramedullary haematopoiesis, and occurs in the liver and spleen. Because of the extramedullary haematopoiesis occurring in the spleen, most patients present with massive splenomegaly, which can cause symptoms such as abdominal discomfort. Other features include weight loss, decreased appetite, fever and night sweats due to the high catabolic state of the body. When fibrosis in the marrow causes a decrease in red blood cell, white blood cell and platelet function/quantity, patients present with features of marrow failure including lethargy, infections and bleeding.1,2
Investigations
Peripheral Blood Film in Myelofibrosis showing a leucoerythroblastic picture with immature white blood cells and a nucleated (immature) red blood cell.
Image courtesy: Dr Pip Nicolson
Management
Supportive therapy includes Red blood cell transfusions when patients are severely/symptomatically anaemic. Folic acid also helps in managing severe anaemia. Allopurinol to prevent/manage gout is used due to rapid cell turnover in this disease.
Ruxolitinib is a JAK2 inhibitor. It can help improve symptoms and increase survival. Hydroxycarbamide can reduce symptoms. If splenomegaly causes significant discomfort, treatment with splenectomy may be required.
Allogenic stem cell transplantation is a potential curative management option.1-3
Complications
10-20% of cases undergo leukaemic transformation.2
References
1. Provan D, Dokal I, Vos J, Baglin T. Oxford Handbook of Clinical Haematology. 4th ed. Oxford: Oxford University Press; 2015.
2. Hoffbrand V, Moss P. Hoffbrand's Essential Haematology. Oxford: John Wiley & Sons, Ltd; 2016.
3. Tidy C. Myelofibrosis. Bone marrow cancers, what is myelofibrosis. [Internet]. Patient.info. 2016 [cited 26 May 2020]. Available from: https://patient.info/doctor/myelofibrosis