Myeloproliferative disorders

Overview

Myeloproliferative diseases are severe situations in which an abnormally large number of blood cells are generated. This can interfere with regular blood processes. Overactive signaling in blood-producing cells causes myeloproliferative diseases.

 

What is a Myeloproliferative Disorder (MPD)?

Myeloproliferative diseases are a type of slow-growing blood cancer in which the bone marrow produces an abnormally large number of red blood cells, white blood cells, or platelets, which accumulate in the blood. The kind of myeloproliferative disease is determined by whether an abnormally large number of red blood cells, white blood cells, or platelets are produced. When the body produces too many of one kind of blood cell, it typically affects one type of blood cell more than the others.

Chronic myeloproliferative diseases are classified into six types:

• Chronic myelogenous leukemia (CML),
• Polycythemia vera, 
• Primary myelofibrosis (also known as chronic idiopathic myelofibrosis), 
• Essential thrombocythemia, 
• Chronic neutrophilic leukemia, and 
• Chronic eosinophilic leukemia.

Bone consists of compact bone, spongy bone, and bone marrow. The outer layer of the bone is composed of compact bone. Spongy bone, which is mainly found at the extremities of bones, contains crimson marrow. Bone marrow is located in the middle of most bones and contains many blood veins. Bone marrow comes in two varieties: red and yellow. Blood stem cells found in red marrow can develop into red blood cells, white blood cells, or platelets. Yellow marrow is primarily composed of fat.

A blood stem cell can develop into a myeloid or lymphoid stem cell. A lymphoid stem cell develops into a white blood cell. Myeloid stem cells differentiate into one of three kinds of adult blood cells:

• Red blood cells that carry oxygen and other substances to all tissues of the body.
• Granulocytes, which are white blood cells that help fight infection and disease.
• Platelets that form blood clots to stop bleeding.

In myeloproliferative neoplasms, an abnormally large number of blood stem cells differentiate into one or more kinds of blood cells. Neoplasms often worsen gradually as the number of additional blood cells grows.

 

Causes of Myeloproliferative disorders

Overproduction of one or more kinds of cells causes all myeloproliferative diseases. Nobody knows what causes cell overproduction, but hypotheses include:

• Genetics. Some people with CML have an abnormally shortened chromosome known as the Philadelphia chromosome.
• Environment.  myeloproliferative diseases may be caused by excessive exposure to radiation, electrical wiring, or toxins.

 

Risk Factors

These factors may increase your risk for developing a myeloproliferative disorder:

Polycythemia vera

• Gender. Men are 2 times more likely than women to develop the condition.
• Age. People older than 60 are most likely to develop the condition, though it may happen at any age.
• Environment. Exposure to intense radiation may increase the risk for the condition.
  

Essential thrombocytosis

• Gender. Women are 1.5 times more likely than men to develop the condition.
• Age. People older than 60 are most likely to develop the condition, though 20% of those with this condition are under 40.
• Environment. Some researchers suggest that exposure to chemicals or to electrical wiring may increase a person's risk for the condition.
  

Primary myelofibrosis

• Gender. Men are slightly more likely than women to develop the condition.
• Age. People ages 60 to 70 are most likely to develop the condition.
• Environment. Exposure to petrochemicals, such as benzene and toluene, and intense radiation may increase the risk of developing the condition.
  

Chronic myelogenous leukemia (CML)

• Gender. Men are more likely than women to develop the condition.
• Age. People ages 45 to 50 are the most likely to develop the condition.
• Environment. Exposure to intense radiation may increase the risk of developing the condition.

 

Symptoms of Myeloproliferative disorders 

Many patients who have myeloproliferative neoplasms have no symptoms. A regular blood test might lead to your diagnosis. If you do experience symptoms, they may include:

• Frequent headaches
• Tiredness (fatigue) 
• Bruising or unusual bleeding
• Problems with your eyes - such as blurred vision
• Ringing in your ears
• Getting more infections than usual

Inform your doctor if you see anything out of the ordinary. Most of the time, it isn't cancer, but if it is, catching it early can make all the difference.

 

Primary myelofibrosis

Primary myelofibrosis is a condition in which normal bone marrow tissue is eventually replaced by a fibrous scar-like substance. This causes gradual bone marrow loss over time.

Under normal circumstances, the bone marrow supplies a fine network of fibers for stem cells to divide and proliferate on. These fibers are produced by fibroblasts, which are specialized cells in the bone marrow.

Chemicals generated by a large number of platelets and aberrant megakaryocytes (platelet-forming cells) overstimulate fibroblasts in primary myelofibrosis. This causes the bone marrow to overgrow thick coarse fibers, which progressively replace normal bone marrow tissue. This gradually disrupts the natural bone marrow environment, preventing necessary amounts of red cells, white cells, and platelets from being produced. This causes anemia, low platelet counts, and the creation of blood cells in regions other than the bone marrow, such as the spleen and liver, which increase as a consequence.

Primary myelofibrosis is an uncommon chronic illness that affects around one in every 100,000 people. It can develop at any age, but is most commonly diagnosed between the ages of 60 and 70. The exact etiology of primary myelofibrosis is uncertain. It can be classed as JAK2 mutation positive (carrying the JAK2 mutation) or negative (not having the JAK2 mutation) (not having the JAK2 mutation).

In a tiny percentage of individuals, long-term exposure to high amounts of benzene or very high doses of ionising radiation may raise the risk of primary myelofibrosis. Around one-third of myelofibrosis patients have a history of polycythemia (post-polycythaemic myelofibrosis) or essential thrombocythemia (post-ET myelofibrosis).

 

Symptoms and complications of primary myelofibrosis

Around 20% of persons with primary myelofibrosis have no symptoms when they are first diagnosed, and the illness is discovered by chance as a result of a routine blood test. Others have symptoms gradually over time. Anemia symptoms include inexplicable weariness, weakness, shortness of breath, and palpitations. Fever, unintentional weight loss, pruritus (generalized itching), and excessive perspiration, particularly at night, are some nonspecific symptoms.

When individuals with primary myelofibrosis are first diagnosed, they almost always have an enlarged spleen (splenomegaly). In almost one-third of cases, the spleen is greatly enlarged. Feelings of discomfort, pain, or fullness in the upper left side of the abdomen are common symptoms. An enlarged spleen can also put pressure on your stomach, producing bloating, discomfort, and a loss of appetite. An enlarged liver (hepatomegaly), which occurs in around two-thirds of cases, can also cause abdominal pain.

Other less common symptoms include bone and joint pain, and bleeding problems.

 

How is myelofibrosis diagnosed?

A physical examination that reveals an enlarged spleen, blood tests, and a bone marrow examination are used to identify primary myelofibrosis. Primary myelofibrosis is identified only when all other causes of marrow fibrosis have been ruled out 

• Full blood count

Primary myelofibrosis patients can appear with variable degrees of anemia. When inspected under a microscope, red cells are sometimes characterized as 'teardrop-shaped.' White cell and platelet counts may be higher than normal in the early stages of this sickness, but low white cell and platelet counts are typical in more advanced disease.

• Bone marrow examination

Due to marrow fibrosis, it is usually hard to extract any samples of bone marrow fluid using a needle and syringe (bone marrow aspiration). This is referred to as a 'dry tap.' Typically, a bone marrow trephine biopsy reveals abnormal fibrosis in the marrow cavity.

Cytogenetic and molecular examination of blood and bone marrow cells is also performed to aid in diagnosis and may aid in prognosis. JAK2 mutations are identified in around 50% of persons with primary myelofibrosis. It is yet unknown why some individuals with JAK2 mutations develop myelofibrosis while others do not.

 

How is myelofibrosis treated?

Some people have no symptoms when they are first diagnosed with primary myelofibrosis and do not require therapy right away, aside from frequent medical check-ups to closely monitor their illness.

Others' therapy is mostly supportive, with the goal of preventing problems caused by low blood counts and an enlarged spleen (splenomegaly). This entails making every attempt to enhance your quality of life by alleviating any symptoms of anemia or an enlarged spleen, as well as avoiding and treating any consequences that may emerge as a result of your condition or its treatment. This may entail blood transfusions on a regular basis, as well as biotherapy or chemotherapy. Antibiotics may be required to both prevent and treat infections.

To treat an enlarged spleen, biotherapy may be employed. Splenectomy (surgical removal of the spleen) may be recommended in some situations, especially if your spleen has expanded to the point that it is causing significant symptoms. If you have an increasing requirement for blood transfusions, a splenectomy may be considered. This occurs occasionally because the spleen destroys blood cells, particularly platelets, at a rapid pace. Small doses of radiation can also be used to shrink the spleen. This generally offers 3 to 6 months of temporary relief.

Some younger patients with a match may be offered an allogeneic (donor) stem cell transplant. This is a medical technique that provides the sole possibility of cure for myelofibrosis sufferers. It entails the use of extremely high doses of chemotherapy, with or without radiation, followed by the infusion of blood stem cells supplied by a suitable match donor. Stem cell transplants are risky and only acceptable for a small number of younger individuals (usually under 60 years of age).

 

• JAK2 inhibitors

JAK2 inhibitors function by inhibiting the action of the JAK2 protein, which may result in less splenomegaly and fewer symptoms. They are also effective in individuals with myelofibrosis who do not have the JAK2 mutation. A deteriorating anemia or a decreased platelet count are possible side effects. Several JAK2 inhibitors are now in clinical development or may be accessible in the near future.

 

Polycythemia Vera

polycythemia vera (PV) is classified as a myeloproliferative neoplasm. It mostly causes the body to overproduce red blood cells. Sometimes the body produces an excess of white blood cells or platelets. It is referred to be a chronic condition since it progresses slowly over time.

Doctors are unsure why the body produces an abnormally large number of blood cells, but most patients with polycythemia vera have an alteration, or mutation, in the JAK2 (Janus kinase 2) gene. It is unknown what causes this gene mutation.

Polycythemia vera patients are often between the ages of 60 and 65. It is extremely rare among persons under the age of 40. Men are more likely than women to develop polycythemia vera. The majority of persons who have polycythemia vera do not have a family history of the condition. Polycythemia vera has the potential to progress to acute myelogenous leukemia (AML) or idiopathic myelofibrosis.

 

Polycythemia Vera Symptoms

In its early stages, polycythemia vera may not manifest any symptoms. When the blood has an excess of red blood cells and platelets, symptoms might arise. As the condition progresses, these symptoms may pose issues or difficulties. An increase in the number of white blood cells does not normally create apparent symptoms, but it can indicate a higher risk of clot development.

Other medical diseases can mimic the symptoms of polycythemia vera. Consult your doctor if you experience any of the following symptoms:

• Headache
• Dizziness
• Fatigue
• Ringing in the ears
• Vision changes such as blurred vision or blind spots
• Shortness of breath or trouble breathing when lying down
• Itchy skin, mainly after a warm bath
• Reddish or purplish skin, especially on the palms, ear lobes and face
• Gout, which causes painful swelling of the joints
• Burning feeling in the feet
• Abdominal discomfort or feeling of fullness if the spleen is enlarged
• Blood clots
• Bleeding that is heavier than normal

 

Diagnosis

Polycythemia vera is generally diagnosed after a visit to your family doctor or when a regular blood test reveals a problem with the blood. Your doctor will question you about any symptoms you are experiencing and will perform a physical exam to see if your spleen or liver is enlarged. Your doctor will arrange tests to check for polycythemia vera or other health issues based on this information.

Polycythemia Vera is diagnosed using some of the same techniques that are used to rule out or confirm leukemia. Among these tests are:

• Complete blood count (CBC) to measure the number and quality of white blood cells, red blood cells and platelets
• Blood chemistry tests to check how well certain organs are working
• Reverse transcriptase polymerase chain reaction (RT-PCR) to see if cells in a sample of blood or bone marrow have the JAK2 gene mutation
• Bone marrow aspiration and biopsy to confirm whether or not you have polycythemia Vera

 

Treatments

Your healthcare team will design a treatment plan just for you. Treatment is determined on your symptoms, the rate at which your polycythemia vera advances, your age, and your general health. The purpose of polycythemia vera therapy is to regulate symptoms and reduce the risk of consequences. Treatments are available for:

• Thin the blood when there are too many red blood cells
• Prevent bleeding when you don’t have enough platelets
• Help blood clot when you have too many platelets
  
  

1. Phlebotomy

For those with polycythemia vera, phlebotomy is typically the first line of therapy. For many years, it may be the only therapy required.

When there are too many red blood cells in the body, phlebotomy is done to help thin the blood. It is carried out in the same manner as blood donation. To withdraw blood, a needle is placed into a vein. Blood is drawn every 1-2 weeks, or more frequently, until the amount of red blood cells decreases. To avoid a decline in blood pressure, saline solution is sometimes injected back into the body.

Phlebotomy may produce dizziness, headaches, and ringing in the ears. These adverse effects normally subside shortly after phlebotomy and can be prevented by arriving at the session fully hydrated.

2. Drug therapy

When phlebotomy alone cannot control the overproduction of these cells, drugs may be employed to reduce red blood cell or platelet levels. When repeated phlebotomy generates an overproduction of platelets, drugs may be utilized. Drugs are also used to address issues caused by blood clots or bleeding. They can assist those who are suffering from severe symptoms that aren't alleviated by acetylsalicylic acid (ASA, aspirin, salicylate) or phlebotomy.

The following drugs may be used to treat polycythemia vera:

• Hydroxyurea (Hydrea) – most commonly given drug
• Interferon alfa (Intron A, Wellferon)
• Anagrelide (Agrylin)
• Ruxolitinib (Jakavi) – offered if there is a JAK2 gene mutation

 

Essential thrombocythemia

Another myeloproliferative condition is essential thrombocythemia, in which the bone marrow creates an abnormally large number of megakaryocytes, which eventually mature into platelets. Platelets are the blood-clotting cells, and changes in their quantity or function can increase the likelihood of clotting and bleeding.

Fatigue, fevers, weight loss, and night sweats are all symptoms of essential thrombocythemia. Clotting complications such as deep vein thrombosis, pulmonary embolism, heart attack, or stroke might occur. High platelet counts can occasionally cause bruising or bleeding. The illness can also create an enlarged spleen due to aberrant blood cell synthesis, resulting in splenomegaly symptoms.

In rare cases, essential thrombocythemia can proceed to secondary myelofibrosis, a disorder in which scar tissue grows in the bone marrow. This causes reduced blood production in the marrow and spleen enlargement as it tries to compensate by producing blood cells.

Gene mutations in the Janus kinase 2 (JAK2), calreticulin (CALR), or MPL proto-oncogene are frequently the cause of essential thrombocythemia. These genetic mutations cause uncontrolled megakaryocyte formation, resulting in elevated platelet levels. Essential thrombocythemia is more common in women than in men and in people older than age 60.

 

Treatment of Essential Thrombocytopenia

Watchful waiting is commonly used to treat essential thrombocythemia in patients younger than 60 years old who have no signs or symptoms and an appropriate platelet level. Other patients' treatment may include the following:

• Chemotherapy.
• Anagrelide therapy.
• Immunotherapy (interferon alfa or pegylated interferon alpha).
• Platelet apheresis.
• A clinical trial of a new treatment.

 

Surgery and Other Procedures

Blood cells are formed in locations other than the bone marrow in primary myelofibrosis, CML, and late stage polycythemia vera. This causes these organs to grow in size. When spleen enlargement becomes uncomfortable, the patient may have surgery to remove it.

In severe cases of primary myelofibrosis, the patient may require a stem cell transplant. In this operation, aberrant bone marrow stem cells (cells that produce blood cells) are replaced with healthy stem cells. A stem cell transplant, on the other hand, has life-threatening complications. In one study, 5-year survival was 62 percent in persons under 45 years old and 14 percent in those over 45.

A bone marrow transplant may be a possibility for persons with CML. Healthy bone marrow cells begin to proliferate and make healthy blood cells after a stem cell or bone marrow transplant.

In those with polycythemia vera, eliminating some blood from the body may reduce the risk of stroke. It is the major treatment for polycythemia vera and the only one that has improved survival. Anemia patients may require blood transfusions. Low-dose aspirin may reduce the incidence of blood clots in persons with polycythemia vera.

 

Nutrition and Dietary Supplements

A myeloproliferative disease treatment plan may involve a variety of complementary and alternative therapy. Inquire with your medical team about the best methods to combine these therapies into your entire treatment plan. Always inform your doctor about any herbs or supplements you use or intend to use, as certain supplements may conflict with standard cancer therapies.

Conventional medical therapy is required for myeloproliferative diseases. There are no supplements that can help with these diseases particularly. Following a nutritious diet and doing regular exercise, on the other hand, may assist to keep your body robust while dealing with a myeloproliferative condition. Consider the following suggestions:

• Consume antioxidant-rich foods such as fruits (such as blueberries, cherries, and tomatoes) and vegetables (such as squash and bell peppers).
• Avoid refined meals such as white breads, pastas, and sugar in particular.
• For protein, consume fewer red meats and more lean meats, cold-water fish, tofu (soy, if no allergy), or beans.
• Use healthy oils like olive or vegetable oil.
• Trans-fatty acids are present in commercially baked items such as cookies, crackers, cakes, French fries, onion rings, doughnuts, processed meals, and margarine.
• Avoid caffeine, alcohol, and tobacco.
• Drink 6 to 8 glasses of filtered water daily.
• Exercise at least 30 minutes daily, 5 days a week.

 

Prognosis and Complications

Myeloproliferative diseases have a gradual onset and do not necessarily result in life-threatening symptoms. However, the ramifications of these illnesses might be severe. Among the complications are:

• Enlargement of the spleen and liver
• Gout
• Anemia
• Bleeding
• Kidney or liver failure
• Heart attacks or stroke
• Infection
• CML can transform into acute leukemia, a more dangerous condition.

The survival rate for myeloproliferative disorders varies, depending on both the type of disorder and the kind of symptoms each person experiences.

 

Conclusion 

Myeloproliferative disorders are a group of blood diseases thought to be caused by mutations in bone marrow stem cells. These stem cells ordinarily give rise to mature blood cells such as red blood cells that carry oxygen, white blood cells that fight infection, and platelets that aid in blood clotting. Many persons with these disorders have little, if any, symptoms; nonetheless, problems such as stroke can arise in patients with poorly managed illness. There are several successful therapy options for myeloproliferative diseases. The type of condition you have, your symptoms, and other considerations will all influence your specific care strategy.