An Overview of Myelofibrosis

A Rare Disease Affecting the Bone Marrow

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Myelofibrosis, also known as agnogenic myeloid metaplasia, is a rare disease that causes the scarring of bone marrow. The scarring (fibrosis) impairs the marrow’s ability to produce the type and number of blood cells the body needs to function normally. This can lead to abnormal blood cell counts and other serious complications, some of which can be fatal.

Myelofibrosis is classified as a myeloproliferative neoplasm, a group of disorders characterized by the overproduction of at least one type of blood cell. Neoplasm refers to the abnormal, excessive growth of tissues characteristic of both cancerous and benign tumors. As such, myelofibrosis is not technically "cancer" but one that can lead to certain blood cancers. It can also be caused by certain cancers.

Some people with myelofibrosis may not have symptoms or require immediate treatment. Others will experience aggressive disease and develop symptoms such as severe anemia, liver impairment, and an enlarged spleen. Myelofibrosis can be diagnosed with blood tests and a bone marrow biopsy. The one known curative treatment is a stem cell transplant

Symptoms

Myelofibrosis causes the progressive failure of the bone marrow, impairing its ability to produce red blood cells (responsible for transporting oxygen to and removing waste from the body), white blood cells (responsible for immune defense), and platelets (responsible for clotting).

When this occurs, blood-forming cells in other organs of the body are forced to take over, placing excessive strain on the organs and causing them to swell.

As many as 20% of people with myelofibrosis will have no symptoms. Those who do may experience anemia (low red blood cells), leukopenia (low white blood cells), thrombocytopenia (low platelets), splenomegaly (enlarged spleen), and hepatomegaly (enlarged liver).

Symptoms of myelofibrosis may include:

  • Fatigue and weakness
  • Shortness of breath
  • An unhealthy pale appearance
  • Abdominal swelling and tenderness
  • Bone pain
  • Easy bruising and bleeding
  • Loss of appetite and weight
  • Increased risk of infection, including pneumonia
  • Skin nodules (cutaneous myelofibrosis)
  • Gout

Complications

As the disease progresses and begins to affect multiple organs, it can lead to serious complications, including:

Causes

Myelofibrosis is a complex disease that can either be classified as a primary or secondary neoplasm.

Primary myelofibrosis is a form of the disease that develops spontaneously in the bone marrow. It is often referred to as primary idiopathic myelofibrosis since the cause is idiopathic (meaning of unknown origin).

Secondary myelofibrosis is the type in which changes in the bone marrow are triggered by another disease or condition. As such, myelofibrosis is considered secondary to a primary cause.

Genetics

Irrespective of the classification, myelofibrosis is largely associated with genetic mutations of hemopoietic (blood-forming) cells in the bone marrow. These mutations impair the bone marrow's ability to function normally.

The mutations most closely linked myelofibrosis involve the JAK2, CALR, or MPL gene. Around 90% of cases involve at least one of these mutations, while 10% carry none of these mutations.

The JAK2 V617F mutation is the most common gene mutation and can, on its own, trigger the development of myelofibrosis.

Risk Factors

With myelofibrosis, it is unknown why the specific genes start to mutate. However, there are known risk factors associated with both primary and secondary myelofibrosis, including:

  • A family history of myeloproliferative disease
  • Jewish descent
  • Older age
  • Certain autoimmune conditions, specifically Crohn's disease

Secondary myelofibrosis is further linked to other diseases or conditions that directly or indirectly affect the bone marrow, including:

Diagnosis

If myelofibrosis is suspected, the diagnosis will typically start with a review of your medical history (including risk factors) and various blood and imaging tests. A physical exam will also be performed to check for liver or spleen enlargement of the liver or abnormal skin nodules.

The blood test panel would typically include:

Imaging tests, such as X-ray, computed tomography (CT), or magnetic resonance imaging (MRI), can help detect organ enlargement, vascular distension, or the abnormal hardening of the bone (osteosclerosis) common with myelofibrosis.

A bone marrow biopsy is routinely used to identify characteristic changes in the bone marrow and help stage the disease. It involves the insertion of a long needle into the center of the bone to extract a sample of bone marrow. A bone marrow biopsy is a moderately invasive procedure that can be performed on an outpatient basis under local anesthesia.

Differential Diagnoses

In order to ensure the correct diagnosis, the doctor would exclude all other possible causes for your symptoms (referred to as a differential diagnosis). Chief among these are other classical chronic myeloproliferative neoplasms, including:

Being diagnosed with these diseases doesn't necessarily mean that myelofibrosis in uninvolved. In some cases, myelofibrosis may be secondary to the related disease, most especially with polycythemia vera and essential thrombocythemia.

Treatment

Right now, there are no drugs that can cure myelofibrosis. Treatments are primarily intended to relieve symptoms, improve blood cell counts, and prevent complications. The only curative option is a bone marrow/stem cell transplant.

Treatment decisions are ultimately guided by:

  • Whether or not you have symptoms
  • Your age and overall health
  • The risks involved with your specific case

If you don't have symptoms and are at low risk of complications, you may only need to be regularly monitored to see if the disease is progressing. No other treatment may be needed.

If you are symptomatic, the focus would be placed on treating severe anemia and splenomegaly. If your symptoms are severe, a bone marrow transplant may be advised.

Anemia

Anemia is a condition in which you lack enough healthy red blood cells to carry adequate oxygen to the body's tissues. It is one of the most common features of myelofibrosis and one that can be treated or prevented with the following interventions:

  • Blood transfusions are used to treat severe anemia and are often given periodically to people with severe myelofibrosis. Anti-anemia drugs like Epogen (epoetin alfa) may be prescribed if the kidney is involved. An iron-rich diet along with iron, folate, and vitamin B12 supplements may also help.
  • Androgen therapy involves the injection of synthetic male hormones like Danocrine (danazol) to stimulate red blood cell production. Androgen therapy may cause masculinizing effects in women and increase the risk of liver damage with long-term use.
  • Glucocorticoids are types of steroid drugs that reduce systemic inflammation and may improve red blood cells counts. Prednisone is the most commonly prescribed steroid, the long-term use of which may cause cataracts and an increased risk of infection.
  • Immune-modulating drugs like Thalomid (thalidomide), Revlimid (lenalidomide), and Pomalyst (pomalidomide) can help increase red blood cell counts while reducing spleen enlargement. Thalidomide is avoided in women of reproductive age due to the high risk of birth defects.

Splenomegaly

With myelofibrosis, the spleen is the organ most affected by bone marrow failure since it has a high concentration of hemopoietic cells. There are several options used to treat myelofibrosis-associated splenomegaly:

  • Chemotherapy drugs, such as hydroxyurea and cladribine, are often used in the first-line treatment of splenomegaly to reduce swelling and pain.
  • Jakafi (ruxolitinib) is a chemotherapy drug that targets the JAKS mutations most commonly associated with myelofibrosis. Jakafi may cause nausea, diarrhea, liver inflammation, reduced platelets, and increased cholesterol in some.
  • Splenectomy, the surgical removal of the spleen, may be recommended if the size of the spleen is so large as to cause pain and increase the risk of complications. While there are risks associated with any surgery, a splenectomy usually does not affect your life span or quality of life.
  • Radiation therapy may be considered in a splenectomy is not an option. Side effects may include nausea, diarrhea, fatigue, loss of appetite, skin rash, and hair loss (usually temporary).

Bone Marrow Transplant

A bone marrow transplant, also known as a stem cell transplant, is a procedure used to replace diseased bone marrow with stem cells from the healthy bone. For myelofibrosis, the procedure is called allogeneic stem cell transplant (meaning that a donor is required).

A bone marrow transplant has the potential to cure myelofibrosis but also carries a high risk of life-threatening side effects. This includes graft-versus-host disease in which the transplant cells attack healthy tissues.

Prior to the transplant, you will undergo conditioning treatment (involving either chemotherapy or radiation therapy) to destroy all diseased bone marrow. You will then receive an intravenous (IV) infusion of stem cells from a compatible donor. The conditioning helps reduce the risk of rejection by suppressing your immune system but also places you at a high risk of infection.

Because of these risks, an extensive evaluation is needed to determine whether you are a good candidate for a stem cell transplant.

Prognosis

Based on the current body of evidence, the median survival time for people with myelofibrosis is 3.5 to 5.5 years from the time of diagnosis. This doesn't mean, however, that you can only have only three to five years to live if diagnosed with myelofibrosis.

Many factors play into the estimated survival times in people with myelofibrosis. Being diagnosed before 55, for example, increases your median survival to 11 years. Some people live even longer than that.

Among the other factors that can increase survival times are:

  • Being under 65 at the time of diagnosis
  • Hemoglobin counts greater than 10 grams per deciliter (g/dL)
  • White blood cell count of less than 30,000 per microliter (mL)

The severity of symptoms (including spleen enlargement, fever, night sweats, and weight loss) also plays a role in survival times.

A Word From Verywell

So far, the survival time of people with primary myelofibrosis appears more closely related to their symptoms and blood abnormalities than any one treatment or treatment approach.

As such, the disease needs to be treated on an individualized basis, weighing the potential benefits and risks through every stage of the disease. If you are uncertain about a recommended treatment or don't think you're being treated aggressively enough, do not hesitate to seek a second opinion from a qualified hematologist or oncologist specializing in myeloproliferative neoplasms.

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