Human blood is fundamental to health. It supplies oxygen and nutrients to tissues, removes waste, transports hormones and other signals throughout the body, regulates body pH and body temperature, and circulates cells with important role in immune system, defence and protection from haemorrhage.¹

Blood is composed of plasma (liquid) and 3 main types of blood cells:

• red blood cells (erythrocytes)
• white blood cells (leucocytes)
• platelets (thrombocytes).

There are 3 types of leucocytes: lymphocytes, monocytes and granulocytes, the granulocytes being divided into neutrophils, eosinophils, and basophils.¹

Blood cell production is known as haematopoiesis.

Bone marrow is the only source of new blood cells during childhood and adult life.²

Blood cells are derived from a pluripotent stem cell (immature cell) that can repopulate the entire haematopoietic system.³

Myeloproliferative neoplasms (MPNs) are a subset of bone marrow cancers. They are a group of diseases characterized by the production of too many of one or more types of myeloid blood cells in the bone marrow.

Haematopoiesis involves 3 processes:

• proliferation (rapid increase in the number)
• differentiation
• apoptosis (programmed cell death).

It is controlled by molecules circulating in blood, including growth factors and cytokines.
A growth factor is a substance which sends signals to the stem cells, so they can produce the right number of mature cells.^1,4

Janus kinase 2 (JAK2) is a gene that provides instructions for making a protein that promotes the growth and division (proliferation) of cells. This protein is part of a signalling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell‘s nucleus. The JAK2 protein is especially important for controlling the production of blood cells from haematopoietic stem cells.⁴

Mutations in a particular gene, especially genes that affect the JAK/STAT pathway, may lead to the occurrence of MPNs.

MPNs are a group of diseases in which bone marrow stem cells produce excess numbers of one or more types of blood cells (red cells, white cells and/or platelets).

Most common types of MPNs include:
• polycythaemia vera (PV)
• essential thrombocythaemia (ET)
• myelofibrosis (MF).¹

Mutation of the JAK2 gene is detected in almost all patients with PV and in approximately 50% of those with ET and MF.^2,5

The 3 “driver mutations“ detected in some patients are: JAK2 gene, CALR (calreticulin) and MPL (myeloproliferative leukaemia proto‑oncogene thrombopoietin receptor). They also activate JAK-STAT pathways.

Polycythaemia vera (PV) is a type of cancer in which the bone morrow overproduces red blood cells, white blood cells and thrombocytes and carries a significant risk of thrombotic complications.⁶

PV is the most common MPN with an incidence of up to 3 per 100,000 per annum.⁶

PV can occur at any age, but it is generally diagnosed from late middle age onwards.¹

Almost all PV patients have JAK2 V617F mutation, and some have exon 12 JAK2 mutation.

These mutations usually happen because of copying mistake when a cell was dividing.

The red blood cells accumulate in the bone marrow and in the blood stream where they increase the blood volume and cause the blood to become thicker, or more viscous than normal.¹ This increase in red cells is measured by the haemoglobin or haematocrit (also known as packed cell volume).

As the blood is thicker than normal in people with PV, it cannot flow as easily, especially through the smaller blood vessels.

If left untreated, this increases the risk of thrombosis, the formation of a blood clot within a blood vessel. Blood clots can form in various parts of the body including the veins of the legs causing deep vein thrombosis (DVT), in the lungs (causing a pulmonary embolism) or can develop in arteries leading to the heart (causing myocardial infarction or heart attack)or the brain (causing a stroke).⁶

PV may progress to myelofibrosis (MF). Life expectancy for PV in general is somewhat shorter than normal, but still very good. About 5-10% of people with PV will develop MF overtime (for each 5 years) and 5% will develop acute myeloid leukaemia (AML).

Essential Thrombocythaemia (ET) is a type of myeloproliferative neoplasm characterized by an overproduction of the platelets. Platelets are normally needed in the body to control bleeding, but an increased number of platelets can lead to abnormal blood clotting which can block the blood flow in the vessels.¹

ET is a rare disease, but it is usually associated with longer overall survival, compared with other MPNs.^6,7

The chance of getting ET increases with age. The median age at presentation is 68 years.⁸

ET is characterised by genetic fault or mutations in several genes like Janus Kinase 2 ( JAK2), Calreticulin (CALR) and MPL (myeloproliferative leukaemia proto-oncogene thrombopoietin receptor) gene.

Patients with ET have a high risk of thrombosis (blood clots) and bleeding. These blood clots block the oxygen supply to various organs and tissues.

Blockages can occur in smaller blood vessels (toes and fingers) causing redness of the skin, burning and pain. Blockages in the arteries supplying the heart (causing a myocardial infarction or heart attack), kidneys or brain (causing a stroke) can lead to significant tissue damage, or ischemia (tissue death).⁶

Clots in veins (deep vein thrombosis) and lung (pulmonary embolism) are also common.

Rarely ET can evolve into PV and MF, as well as AML.

Myelofibrosis (MF) is a type of bone marrow disorder characterized by the formation of abnormal fibrous and scarred tissue that affects the body’s normal production of blood cells.^8,9

Depending on the grade of the bone marrow fibrosis, it can be divided into early stage MF (called prefibrotic MF) and late stage MF (also called overt MF). PV and ET can both progress to MF (termed post ET/PV MF) which is clinically indistinguishable from primary MF.

In its early phase there are hardly any collagen fibres and many people don’t experience signs or symptoms. Early myelofibrosis is characterized by benign manifestations.

Early MF can also appear similar to PV and ET because blood counts can be high, and it is important to exclude this finding at time of diagnosis. The anaemia or enlarged spleen are usually the main reason for initial presentation.

Atypia of megakaryocytes (cells that maturate into platelets) are very common in MF. Additional features include abnormal new bone formation.⁵

In overt MF the bone marrow is being invaded by reticulin deposits and collagen fibres.

Fibrous tissue eventually fills the bone marrow, reducing the production of all blood cells. The red blood cells that do enter the bloodstream can be malformed, looking like teardrops instead of circles. There may be too few normal, mature red blood cells to carry oxygen, causing anaemia.

In overt MF, heavily scarred tissue (known as fibrosis) is building up in the bone marrow. The bone marrow is, as a result, less able to produce blood cells and blood cells are not able to develop properly. Consequently, the spleen and sometimes also the liver will enlarge. Patients often have a lot of symptoms due to the large spleen and falling blood counts.

The accelerated MF is a transition phase into AML, characterized by an increased percent of blasts (10-19%).

All Philadelphia-negative classical MPNs have overlapping features, making the diagnosis challenging for clinicians.^8,11

Bone marrow examination and search for somatic mutations in the three driver genes represent major diagnosis criteria in combination with clinical, haematologic and morphologic criteria.^8,11

The bone marrow examination is eventually repeated also during follow-up in the presence of signs of progressive disease.¹¹

The four major diagnosis criteria for ET are: thrombocytosis (platelet count value ≥ 450 X 109/L), bone marrow biopsy showing megakaryocytic proliferation and very rarely minor reticulin fibres, not meeting WHO criteria for other myeloid neoplasm and the presence of one of the 3 driver gene mutation). The JAK2 is present in 60-65% of patients, CALR mutation in 20-25% and MPL mutation in 10%. About 10% do not carry any of these somatic mutations (also called triple‑negative cases).^5,8,11

The minor criterion for ET requires the presence of a clonal marker and the absence of reactive thrombocytosis.

A complete diagnosis of ET requires meeting all 4 major criteria or the first 3 major criteria plus the minor criterion.

The three major diagnosis criteria for PV include erythrocytosis (haemoglobin value > 16.5 g/dL in men or 16.0 g/dL in women or haematocrit > 49% in men or > 48% in women or increased red cell mass), bone marrow hypercellularity (also called panmyelosis) and JAK2 mutation.^5,8,11

The JAK2 V617F mutation is present in about 96% of patients while JAK2 exon 12 mutation is found in about 4% of patients.⁸

The minor criterion for PV consists of decreased serum erythropoietin production.

Diagnosis of PV requires meeting all 3 major criteria or the first 2 major criteria and the minor criterion.

The diagnosis criteria in early stage (prefibrotic) MF and late stage (overt) MF are similar. Differences are defined by the grade of the reticulin and/ or collagen fibrosis and by the presence of leukoerythroblastosis in overt unlike early MF.

While prefibrotic MF is characterized by lack of collagen or reticulin fibres, overt MF is distinguished by the presence of either reticulin and/or collagen fibrosis grade 2 or 3 with abnormal stem cell trafficking and extramedullary haematopoiesis in the liver and/ or the spleen.^5,8,11

Most patients with prefibrotic MF have thrombocytosis and therefore the diagnostic approach implies a differential diagnosis with ET, done through bone marrow biopsy.⁸

Other major criteria include atypical megakaryocytic proliferation in the bone marrow with fibrosis 0 and 1 in prefibrotic MF, grade 2 or 3 in overt MF, not meeting WHO criteria for other myeloid neoplasms, presence of one of the 3 driver gene mutations or another clonal marker or absence of reactive reticulin fibrosis, secondary to infection, autoimmune disorder or other chronic inflammatory conditions.^5,8,11

The JAK2 V617F mutation is present in 60‑65% of patients, CALR mutation in 25‑30% of patients and MPL in about 4-5% of patients.8 About 5-10% do not carry any of these somatic mutations (triple-negative cases).⁸

Other possible clonal mutations, for example, are ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1.

The minor criterion currently used for the diagnosis of MF include:

• Anaemia not attributed to other condition;
• An increase in the white blood count level above 11×109/l;
• Palpable splenomegaly;
• Increased lactate dehydrogenase level above the upper limit of normal;
• Leukoerythroblastosis (presence of immature forms of red and white cells in the peripheral blood), only for overt MF.

The MF diagnosis include meeting all 3 major criteria and at least one minor criterion, confirmed in two consecutive determinations.

The clinical overlap between PV and ET is substantial.

Clinical features of ET include headache, dizziness, syncope, atypical chest pain, visual upset, paraesthesia and discoloration of the skin caused by swelling of the venules owing to obstruction of capillaries (called livedo reticularis).⁶

Small arteries of the legs and hands are causing burning pains, erythema and redness due to local congestion.

ET is also characterized by blood clots and bleeding.^6,14

Bleeding symptoms occur in ~25% of patients while blood clots occur in ~20% of patients with ET, with a prevalence of arterial blood clots.

Splenomegaly is less common and less marked in ET, compared to other MPNs.⁶

In PV patients may present with blood clots (up to ~40% patients), bleeding (up to ~20% patients), or vague symptoms (~40% patients) of headache, dizziness, weakness, excessive sweating, ringing in the ears or gout.⁶

Physical examination may identify facial redness of the skin (called plethora) or abnormalities associated with erythrocytosis such as gross obesity, hypertension, evidence of obstructive airways disease or cyanotic cardiac conditions.

Splenomegaly and hepatomegaly may occur.⁶

A history of itching (especially after bathing, called aquagenic pruritus) suggests PV (occurs in ~50% patients). A burning sensation in fingers and toes with erythema, pallor, or cyanosis (erythromelalgia) is typical of PV.⁶

A multitude of symptoms are present in MF.

The diverse symptomatology is caused mainly by splenomegaly, anaemia and inflammatory processes.

Splenomegaly is almost universal (> 80%) with moderate-to-massive enlargement. Abdominal pain, abdominal discomfort (heavy sensation in left upper quadrant), dyspepsia and nausea are caused by the enlarged spleen irritating the surrounding tissues. Compression of the stomach is causing early satiety. Variable hepatomegaly (liver enlargement) is present (up to 70%).⁶

Bone marrow failure is causing anaemia and infections, while extramedullary haematopoiesis is causing progressive splenomegaly and hepatomegaly.^6,9

Inflammation is causing constitutional symptoms that include fever, night sweats and pruritus.⁹

Micro and macrovascular pathologic processes lead to concentration issues, vertigo, headaches, dizziness, numbness, tingling, insomnia.

Some patients experience fatigue, weight loss and night sweats.⁶

Inefficient haematopoiesis leads to cytopenia (reduction in the number of mature blood cells).9 Around 20–30% of patients with MF are diagnosed in prefibrotic stage which may clinically mimic ET.

Approximately 70–80% of patients are diagnosed in the fibrotic stage.⁶

Risk-adapted therapy in PV and ET is based on the estimation of risk factors, such as age, forming of blood clots, cardiovascular risk factors, extreme platelets count and leucocytosis. Both PV and ET could happen in young patients.^6,8

ET: Some patients require oral chemotherapy or cytoreductive therapy and immunotherapy (hydroxycarbamide, interferon-α or anagrelide). Aspirin (or similar antiplatelets) are used to prevent forming of blood clots.17 Hydroxycarbamide is the treatment of choice in combination with aspirin (when not contraindicated) for patients > 60 years.^5,10

PV: For patients with low risk of blood clots, regular venesection is carried out. Efficacy of 75-100 mg aspirin administered daily to patients (without history of major bleeding or gastric intolerance) was demonstrated.^5,10

High-risk patients are given also a cytoreductive treatment.⁸ Interferon-α may be preferred to hydroxycarbamide in younger patients < 40 years.^5,10

Hydroxycarbamide is the medication of choice in older high-risk patients. Hydroxycarbamide can be useful to reduce splenomegaly and proliferative blood counts. Anagrelide is useful for control of thrombocytosis in PV patients who do not tolerate or fail to respond to hydroxycarbamide or interferon-α.

Ropeginterferon α-2b was approved in February 2019 in EU as first-line monotherapy in adults for the treatment of polycythaemia vera without symptomatic splenomegaly.

Ruxolitinib effectively controls blood count, spleen size and symptoms and is indicated for the treatment of adult patients with PV who are resistant to or intolerant of hydroxyurea.^5,10

In pregnancy, close monitoring is recommended and treatment in some cases.

Allo-SCT is the only curative option for MF patients and is typically reserved for patients whose life expectancy is below 5 years.¹⁸

The treatment strategy should be carefully considered according to the individual needs of patients.5,10,20 In some cases, with no symptoms at diagnosis, the “wait and watch“ approach is the best. In other cases, JAK inhibitors or clinical trials are viable treatment options.

1. Treatment for anaemia
• Periodic blood transfusions can increase the red blood cell count and ease anaemia symptoms like fatigue and weakness. Danazol, corticosteroids (prednisone) and erythropoietin are treatments that can ameliorate anaemia in MF patients. ^5,10,12,20

• The immunomodulator thalidomide is now rarely used because of toxicity and modest efficacy. Lenalidomide is recommended only in the presence of 5q abnormality.^5,10

2. Treatment for splenomegaly
• Ruxolitinib (JAK2 inhibitor) is currently the only oral agent approved for the spleen volume reduction and improvement in symptoms and quality of life for patients with MF. ^5,10,20

• Emerging data supports the addition of azacitidine to ruxolitinib in patients with elevated blasts (accelerated MF, 10-19% blasts) in transition to AML Other strategies have focused on improving cytopenias, through amelioration of bone marrow fibrosis or other mechanisms. This is important, because cytopenias are the commonest reason for ruxolitinib interruption. ^5,10,19

• Splenectomy (surgical removal of the spleen) or radiation therapy (for spleen size reduction) when surgical removal isn’t an option.

3. Bone marrow transplant
• The risk of transplantation is determined by taking into account the overall risk of comorbidity, age of the patient, previous transfusions (with more than 20 units) and significant splenomegaly.^5,10,20
SCT is massively influenced by genetic (mutation tests) and presence of donor and how well the matching is.

Following any signs of disease progression, treatment must be adapted accordingly.¹²

A stem cell transplant (SCT) is what used to be called a bone marrow transplant. It aims to bring back healthy stem cells, which then produce normal blood cells.

There are two main types of SCT:
• Autologous or autograft – this uses the patient‘s own stem cells, commonly collected from adipose (fat) tissue, peripheral blood or bone marrow – these are never used for patients with MF as the patient’s bone marrow is unhealthy;

• Allogeneic or allograft – this uses donor stem cells, either from a relative or an accredited donor registry;
Allogeneic SWCT is the only valuable option in MF.

The two types of stem cell therapy have different advantages and disadvantages.

Stem cell transplantation is a very complex process that may span several months.^19,20

Supportive therapy is an important part of treatment for MPN. It is given to relieve symptoms and lessen the problems caused by abnormal blood cell counts or treatment for MPN.

Some patients have no symptoms when they are first diagnosed with MPN and are put on what is called a ‘watch and wait’ approach, especially if there is no anaemia, enlarged spleen or other complications.

Blood transfusions, antibiotics and intravenous fluids can all be important elements of medical supportive care.^5,10,15

Antibiotics are given to prevent or treat infections.

Danazol, prednisone and erythropoietin are treatments that can ameliorate anaemia.¹⁵

Growth factors are substances that regulate the growth, division and survival of cells. They help return blood cell counts to normal.²¹

In PV adequate fluid intake must be maintained in order to avoid dehydration. Allopurinol (300 mg daily) can be prescribed to minimize risks of hyperuricaemia.

Acute gout is managed by standard therapies. ^5,10

A) BLOOD TRANSFUSIONS
B) ANTIBIOTICS TO PREVENT OR TREAT INFECTIONS
C) PROPER HYDRATION
D) MEDICATION FOR ANAEMIA

Family doctors play a key role in managing patients with MPN, starting with the observation of enlarged spleen at the physical exam, and abnormalities in blood count, namely anaemia or leukocyte count above the normal range in the peripheral blood.

Supportive care involves making every effort to improve the quality of life, by relieving any symptoms and by preventing and treating any complications that arise from disease or treatment. ^5,10

Many aspects of supportive care are things that the patient can do him(her)-self.

The patient should be informed about the disease course and vascular risk factors (such as smoking) should be carefully managed.⁵

Various reactions like numbness, denial, anger, guilt, depression may subsequently emerge during the time the patient comes to accept the diagnosis, what it means, and what is to be done clinically. ^5,10

Within the haematological team support and practical information about the disease and its management are offered to the patient.

Age and estimation on the likelihood to develop thrombotic complications is the main driver for the risk-adapted therapy in PV and ET.^6,22

For each MPN, there is a slight chance that the disease will develop into a different MPN, e.g. ET or PV into MF or ET into PV or for all of them into an acute leukaemia.

ET is generally associated with a more favourable prognosis compared with other MPNs.^8,23

ET involves increased risk of thrombosis and bleeding and may progress to AML.⁵

JAK2 V617F – mutant ET involves a high‑risk of thrombosis and may progress to PV or MF.⁸

CALR – mutant ET involves lower risk of thrombosis and higher risk of progression to myelofibrosis.⁸

Triple-negative ET is an indolent disease with low incidence of vascular events.⁸

PV patients have increased risk of developing thrombosis and may progress to secondary MF and less commonly to a blast phase similar to AML.

JAK2 V617F allele burden > 50% was found to represent a risk factor for progression to secondary MF.^6,8

Untreated PV carries a significant risk of early thrombotic complications.

There is also a risk of bleeding notably from peptic ulcers.⁶

MF can change over time, progressing from early chronic phase to accelerated phase.

MF is associated with a lower relative survival rate compared with PV and ET and a very significant negative impact on patient’s quality of life.

Also, it is associated with a substantial long-term risk of developing potentially life-threatening complications such as liver failure, portal hypertension (high blood pressure affecting the venous portal system, causing veins rupture and bleeding), cardiac failure, pulmonary hypertension, „acute abdomen”, splenic infarcts and cachexia (loss of weight, muscle atrophy, fatigue, weakness and significant loss of appetite).^9,15

CALR- mutant MF is associated with longer survival compared with other genotypes, while triple-negative MF is an aggressive myeloid neoplasm with a high-risk of leukemic evolution.⁸

Acute leukaemia
Around 20% of the patients with MF present a variable risk to eventually develop acute myelogenous leukaemia, a type of blood and bone marrow cancer that progresses rapidly.¹⁵

The accelerated phase of MF is characterised by the presence of 10-19% blasts (immature abnormal white blood cells).

The course of the disease will be accelerated, the symptoms will intensify, and more aggressive treatment will be required.

PV, ET and MF affect each person differently.

As they are all long-term diseases, learning to deal with the disease and staying positive are best strategies besides the recommended therapies. Benefits have been noted with yoga, mindfulness etc.

Lifestyle must be adapted with focus on the management of the constitutional symptoms and the prevention of long-term, life‑threatening complications.

All efforts should be done to reduce stress associated to the initial diagnosis and mitigate negative feelings that may appear when facing an uncertain prognostic.

Reducing some of the daily tasks are recommended (as fatigue will appear during the disease).²⁵

Cigarette smoking leads to a chronic inflammatory state driving clonal evolution and disease progression.²⁶

Diabetes, as an important risk factor for hypercoagulability (thrombophilia) and the development of atherothrombosis and venous thromboembolism must be carefully managed.

Support community and open discussions are recommended. There are many different places to find a wide range of information on MPNs.

www.mpnvoice.org.uk
www.mpninfo.org
www.mpnresearchfoundation.org
www.patientpower.info

Always consult a haematologist and oncologist specialized in MPNs for they are the best source for any medical advice or treatment-related question.

The MPN diagnosis is extremely challenging but a lot of things can be done to improve the quality of life.

Education through healthcare providers can improve the current status of the disease and can create for patients a clearer insight into MPN and as well as an important extension of survival.

Smoking must be ceased, and cardiovascular disease risk factors must be carefully monitored.

A full blood count, including a white blood cell count differential, must be performed before initiating some therapies. Also, lipid monitoring in some cases are indicated.

Daily physical activity is indicated as well as a healthy diet, maintaining a normal weight and muscle mass to help keep the cholesterol and blood sugar within normal limits.²⁵

Patients with PV and high haematocrit value should have long-term haematological followup with measurements at least 3-monthly. For patients on cytotoxic therapy with hydroxycarbamide the full blood count should be checked every 8–12 weeks.^5,10

Patients with ET should be advised to make lifestyle changes (smoking, exercise, obesity) to reduce their risk of thrombosis and atherosclerosis. Reversible cardiovascular risk factors should be treated (hypertension, hypercholesterolaemia, diabetes mellitus). Antiinflammatory drugs should be avoided due to risk of bleeding.^5,10

A) HEALTHY DIET TO KEEP NORMAL CHOLESTEROL AND BLOOD SUGAR LEVELS
B) QUIT SMOKING
C) PERFORM DAILY PHYSICAL ACTVITIES

The goals in the management of MPN are normalizing the life span, reduction of cardiovascular complications (mainly in PV and ET), prevention of haematological progression and improved quality of life.²⁷

Early after being diagnosed, patients must be encouraged to have frank discussions with their health professionals as to how the treatment will affect them in their personal and professional lives.

Some patients benefit from psychological counselling in order to overcome the difficulties associated with the unpredictable course and duration of this disease.

Anaemia, occurring in more than one third of the patients worsens the prognosis.

There are different needs for the various types of MPN at different stages or risk levels.

New treatments for patients with MPN are currently undergoing different phases of clinical development, aiming to become a cure for these disorders.

A) FRANK DISCUSSIONS WITH HEALTH PROFESSIONALS
B) PSYCHOLOGICAL COUNSELLING
C) MULTIDISCIPLINARY HEALTH ASSISTANCE

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