Overview

What is myelofibrosis?

Myelofibrosis is a rare type of blood cancer in which the bone marrow (the soft, spongy tissue inside most bones) is replaced by fibrous scar tissue. It is considered a form of chronic leukemia. When myelofibrosis occurs on its own, it is called primary myelofibrosis. If it occurs as the result of a separate disease, it is known as secondary myelofibrosis (e.g. scar tissue in the bone marrow as a complication of an autoimmune disease).

The bone marrow contains immature blood-forming cells that may develop into three types of specialized blood cells: red blood cells, white blood cells, or platelets. When a change (mutation) occurs in the DNA of a single cell, the mutation will be passed on to new cells when the defective cell divides.

As time goes by, more and more abnormal cells are produced. They can also gain additional mutations making the cancer cells more aggressive over time. They can eventually replace the normal cells in the bone marrow. The bone marrow begins to lose its ability to produce normal blood cells. Abnormal blood-forming cells can also grow outside the bone marrow in the liver, lungs, lymph nodes, and other organs.

What are the characteristics of myelofibrosis?

One characteristic of myelofibrosis is the overproduction of giant cells called megakaryocytes. Megakaryocytes normally release tiny fragments called platelets. Platelets play an important role in the formation of blood clots at the site of an injury.

When myelofibrosis occurs, the bone marrow produces too many megakaryocytes, accompanied by the release of proteins called cytokines. Cytokines are the same substances that make you feel ill when you have the flu. The cytokines in myelofibrosis cause inflammation and buildup of more fibrous tissue in the bone marrow.

Anemia may occur when there is a deficiency in red blood cell production. Thrombocytopenia may occur when there is a deficiency in platelet production. Patients with low platelet counts can be more susceptible to bleeding.

In about 12% of all cases, primary myelofibrosis will progress to acute myeloid leukemia, a very aggressive form of blood cancer.

How common is myelofibrosis?

Myelofibrosis is a rare condition, with about 1.5 cases reported per 100,000 people each year in the United States. It occurs in both men and women. People of any age can have myelofibrosis, although it is more likely to be diagnosed in people over age 50. For children diagnosed with myelofibrosis, the onset is usually before age 3.

Symptoms and Causes

What causes myelofibrosis?

The underlying cause of primary myelofibrosis has not yet been determined. Although myelofibrosis is not inherited, it is associated with DNA changes in certain genes. Proteins called janus-associated kinases (JAKs) play a role in myelofibrosis. JAKs regulate the production of blood cells in bone marrow by signaling the cells to divide and grow. If the JAKs become overactive, too many or too few blood cells will be produced.

About 50% of patients have a mutation in the JAK2 gene. Another 5-10% of patients have a mutation in the myeloproliferative leukemia (MPL) gene. A mutation called calreticulin (CALR) accounts for approximately 35% of myelofibrosis cases.

Risk factors for myelofibrosis include exposure to ionizing radiation or to petrochemicals, such as benzene or toluene.

When myelofibrosis occurs on its own, it is called primary myelofibrosis. Sometimes myelofibrosis can develop in patients with other bone marrow cancers, such as essential thrombocythemia (production of excess platelets) or polycythemia vera (production of excess red blood cells). This is known as post-essential thrombocythemia or post-polycythemia vera myelofibrosis.

What are the symptoms of myelofibrosis?

A person with myelofibrosis might not have any symptoms for many years. About one-third of patients do not show symptoms during the early stages of the disorder. However, during the course of the disease, they may experience the following symptoms or conditions:

Anemia: A deficiency of red blood cells often accompanied by fatigue, weakness, and shortness of breath
Pale skin
Enlarged spleen (splenomegaly): This may result in a sensation of fullness or discomfort in the upper left section of the abdomen.
Portal hypertension: An increase in blood pressure in the vein that carries blood from the spleen to the liver
Dilated veins in the stomach and esophagus: These veins may rupture and cause bleeding.
Night sweats
Unexplained blood clots
Frequent infections
Fever
Itching
Abnormal bleeding or bruising
Enlarged liver
Bone or joint pain
Weight loss
Extramedullary hematopoiesis: Abnormal growth of blood-forming cells outside the bone marrow. These cells may enter other parts of the body, such as the lungs, gastrointestinal tract, spinal cord, brain or lymph nodes. The cells can form masses (tumors) that compress organs or impair their function.

Diagnosis and Tests

How is myelofibrosis diagnosed?

Your doctor will perform a physical examination and ask about your medical history, including any symptoms you are experiencing. The doctor will check for signs of an enlarged spleen or anemia.

Diagnostic tests that may be performed include:

Complete blood count (CBC): An elevated number of white blood cells and platelets and a lower than normal number of red blood cells may suggest myelofibrosis.
Blood tests: Elevated levels of uric acid, bilirubin, and lactic dehydrogenase may mark the presence of myelofibrosis.

Additional tests may be needed to confirm the diagnosis, including

Gene mutation analysis: Blood cells may be examined for certain mutations associated with myelofibrosis.
Bone marrow biopsy: A sample of bone marrow may be removed for examination under a microscope.
Imaging tests: An ultrasound test may be performed to check for enlargement of the spleen.

Management and Treatment

How is myelofibrosis treated?

Various methods are available for treating myelofibrosis, depending on the patient’s symptoms and individual circumstances. Some people may not exhibit symptoms for years. Even if they do not require immediate treatment, they should be monitored for any changes that indicate worsening of their condition.

For most patients, the goal is to manage conditions associated with myelofibrosis. Jakafi® (ruxolitinib) is the first drug approved by the Food and Drug Administration for the treatment of intermediate or high-risk myelofibrosis. It is a multikinase inhibitor that works to suppress overactive janus-associated kinase (JAK) signaling.

The medication is taken orally. It helps to relieve some of the symptoms associated with the disease, including enlargement of the spleen, night sweats, itching, weight loss, and fever.

Medications used to treat anemia include:

Glucocorticoids
Androgens (synthetic male hormones)
Immunomodulators: Interferon is given via intramuscular or subcutaneous (under the skin) injections. Thalidomide and lenalidomide are taken orally. Pomalidomide is being investigated in clinical trials for treatment of anemia associated with myelofibrosis.
Chemotherapy drugs: Hydroxyurea is taken orally and cladribine is administered intravenously.
Blood transfusions may be performed to increase the number of red blood cells in patients with severe anemia.

Medications used to treat enlargement of the spleen (splenomegaly) include

Jakafi
Hydroxyurea
Interferon

In severe cases, removal of the spleen (splenectomy) or radiation therapy may be needed. Radiation therapy may also be used to treat extramedullary hematopoiesis (abnormal growth of blood-forming cells outside the bone marrow).

Prevention

How can myelofibrosis be prevented?

Myelofibrosis cannot be prevented, but allogeneic hematopoietic cell transplantation (HCT) may be a potential cure. The procedure involves replacing a patient’s immune system with that of a suitable donor. This new immune system seeks out and kills the cancerous cells in the bone marrow of the myelofibrosis patient as well as provides healthy blood-making bone marrow cells. Immediately before the transplant, the patient must undergo chemotherapy and/or radiation therapy to suppress his or her own immune system, so the cells from the donor will take.

HCT carries a high risk of complications and is only suitable for certain patients. The risk of a complication is higher for people with other medical conditions. Various factors must be taken into account for patients who may be candidates for the procedure, including their age, the severity of their symptoms, other risk factors, and the likelihood of success.

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Myelofibrosis