Myelofibrosis

Synonyms

8

Overview

Myelofibrosis is a disorder of the bone marrow, in which the marrow is replaced by fibrous (scar) tissue. When the bone marrow is scarred, it cannot make enough blood cells. This leads to anemia, weakness, fatigue, and often an enlarged spleen.  Myelofibrosis is an uncommon type of chronic leukemia — a cancer that affects the blood-forming tissues in the body. Myelofibrosis belongs to a group of diseases called myeloproliferative disorders. The condition occurs when blood stem cells develop somatic mutations in the JAK2, MPL, CALR, and TET2 genes. Other genes may also be involved. The condition is generally not inherited.  Although myelofibrosis can occur at any age, it typically develops after the age of 50. In most cases, myelofibrosis gets progressively worse. Treatment is aimed at relieving signs and symptoms and may include medications, blood transfusions, chemotherapy, radiation therapy and surgery.

Symptoms

Myelofibrosis usually develops slowly. In its very early stages, many people don't experience signs or symptoms. But as disruption of normal blood cell production increases, signs and symptoms may include:

  • Feeling tired, weak or short of breath, usually because of anemia
  • Pain or fullness below your ribs on the left side, due to an enlarged spleen
  • Pale skin
  • Excessive sweating during sleep (night sweats)
  • Fever
  • Frequent infections
  • Bone pain
  • Abdominal fullness related to an enlarged spleen (splenomegaly).
  • Bone pain
  • Bruising and easy bleeding due to inadequate numbers of platelets
  • Cachexia
  • Enlargement of spleen
  • Fatigue
  • Gout and high uric acid levels
  • Increased susceptibility to infection, such as pneumonia
  • Pallor and shortness of breath due to anemia
  • In rarer cases, a raised red blood cell volume
  • Cutaneous myelofibrosis is a rare skin condition characterized by dermal and subcutaneous nodules

Causes

Myelofibrosis occurs when blood stem cells develop a genetic mutation. Blood stem cells have the ability to replicate and divide into the multiple specialized cells that make up your blood — red blood cells, white blood cells and platelets.

It's not clear what causes the genetic mutation in blood stem cells. As the mutated blood stem cells replicate and divide, they pass along the mutation to the new cells. As more and more of these mutated cells are created, they begin to have serious effects on blood production. The end result is usually a lack of red blood cells — which causes the anemia characteristic of myelofibrosis — and an overabundance of white blood cells with varying levels of platelets. In people with myelofibrosis, the normally spongy bone marrow becomes scarred.

Several specific gene mutations have been identified in people with myelofibrosis. The most common is the Janus kinase 2 (JAK2) gene. Knowing whether the JAK2 gene or others are associated with your myelofibrosis helps determine prognosis and treatment.

Although the cause of myelofibrosis often isn't known, certain factors are known to increase risk:

  • Age. Myelofibrosis can affect anyone, but it's most often diagnosed in people older than 50.
  • Another blood cell disorder. A small portion of people with myelofibrosis develop the condition as a complication of essential thrombocythemia or polycythemia vera.
  • Exposure to certain chemicals. Myelofibrosis has been linked to exposure to industrial chemicals such as toluene and benzene.
  • Exposure to radiation. People exposed to high levels of radiation, such as survivors of atomic bomb attacks, have an increased risk of myelofibrosis. Some people who received a radioactive contrast material called Thorotrast, used until the 1950s, have developed myelofibrosis.

Prevention

There is no known prevention.

Diagnosis

Tests and procedures used to diagnose myelofibrosis include:

  • Physical exam. Your doctor will perform a physical exam. This includes a check of vital signs, such as pulse and blood pressure, as well as checks of your lymph nodes, spleen and abdomen.
  • Blood tests. In myelofibrosis, a complete blood count typically shows abnormally low levels of red blood cells, a sign of anemia common in people with myelofibrosis. White blood cell and platelet counts are usually abnormal, too. Often, white blood cell levels are higher than normal, although in some people they may be normal or even lower than normal. Platelet counts may be higher or lower than normal.
  • Imaging tests. Imaging tests, such as X-rays and magnetic resonance imaging (MRI), may be used to gather more information about your myelofibrosis.
  • Bone marrow examination. Bone marrow biopsy and aspiration can confirm a diagnosis of myelofibrosis. In a bone marrow biopsy, a needle is used to draw a sample of hardened bone marrow from your hipbone. During the same procedure, another type of needle may be used to withdraw a sample of the liquid portion of your bone marrow. The samples are studied in a laboratory to determine the numbers and types of cells found.
  • Gene tests. A sample of your blood or bone marrow may be analyzed in a laboratory to look for gene mutations in your blood cells that are associated with myelofibrosis.

Prognosis

Complications that may result from myelofibrosis include:

  • Increased pressure on blood flowing into your liver. Normally, blood flow from the spleen enters your liver through a large blood vessel called the portal vein. Increased blood flow from an enlarged spleen can lead to high blood pressure in the portal vein (portal hypertension). This in turn can force excess blood into smaller veins in your stomach and esophagus, potentially causing these veins to rupture and bleed.
  • Pain. A severely enlarged spleen can cause abdominal pain and back pain.
  • Growths in other areas of your body. Formation of blood cells outside the bone marrow (extramedullary hematopoiesis) may create clumps (tumors) of developing blood cells in other areas of your body. These tumors may cause problems such as bleeding in your gastrointestinal system, coughing or spitting up of blood, compression of your spinal cord, or seizures.
  • Bleeding complications. As the disease progresses, your platelet count tends to drop below normal (thrombocytopenia) and platelet function becomes impaired. An insufficient number of platelets can lead to easy bleeding — an issue that you and your doctor will want to discuss if you're contemplating any type of surgical procedure.
  • Painful bones and joints. Myelofibrosis can lead to hardening of your bone marrow and inflammation of the connective tissue that is found around the bones. This may cause bone and joint pain.
  • Acute leukemia. Some people with myelofibrosis eventually develop acute myelogenous leukemia, a type of blood and bone marrow cancer that progresses rapidly.

Treatment

Immediate treatment may not be necessary:

If you aren't experiencing symptoms and don't show signs of anemia, an enlarged spleen or other complications, treatment usually isn't necessary. Instead, your doctor is likely to monitor your health closely through regular checkups and exams, watching for any signs of disease progression. Some people remain symptom-free for years.

Approved therapy:

Ruxolitinib Phosphate (Jakafi) - FDA-approved indication: Treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Treatment of patients with polycythemia vera who have had an inadequate response to or are intolerant of hydroxyurea.
Treatments for anemia:

If myelofibrosis is causing severe anemia, you may consider treatment, such as:

  • Blood transfusions. If you have severe anemia, periodic blood transfusions can increase your red blood cell count and ease anemia symptoms, such as fatigue and weakness. Sometimes, medications can help improve anemia.
  • Androgen therapy. Taking a synthetic version of the male hormone androgen may promote red blood cell production and may improve severe anemia in some people. Androgen therapy does have risks, including liver damage and masculinizing effects in women.
  • Thalidomide and related medications. Thalidomide (Thalomid) and the related drugs lenalidomide (Revlimid) and pomalidomide (Pomalyst) may help improve blood cell counts and may also relieve an enlarged spleen. These drugs may be combined with steroid medications. Thalidomide and related drugs carry a risk of serious birth defects and require special precautions. This type of treatment is being studied in clinical trials.

Treatments for enlarged spleen:

If an enlarged spleen is causing complications, your doctor may recommend treatment. Your options may include:

  • Surgical removal of the spleen (splenectomy). If the size of your spleen becomes so large that it causes you pain and begins to cause harmful complications — and if you don't respond to other forms of therapy — you may benefit from having your spleen surgically removed. Risks include infection, excessive bleeding and blood clot formation leading to stroke or pulmonary embolism. After the procedure, some people experience liver enlargement and an abnormal increase in platelet count.
  • Chemotherapy. Chemotherapy drugs may reduce the size of an enlarged spleen and relieve related symptoms, such as pain.
  • Radiation therapy. Radiation uses high-powered beams, such as X-rays, to kill cells. Radiation therapy can help reduce the size of the spleen, when surgical removal isn't an option.

Stem cell transplant:

Allogeneic stem cell transplantation — stem cell transplantation from a suitable donor — is the only treatment that has the potential to cure myelofibrosis. But it also has a high risk of life-threatening side effects.

Most people with myelofibrosis, because of age, stability of the disease or other health problems, don't qualify for this treatment.

Prior to a stem cell transplant, also called a bone marrow transplant, you receive very high doses of chemotherapy or radiation therapy to destroy your diseased bone marrow. Then you receive infusions of stem cells from a compatible donor.

After the procedure, there's a risk that the new stem cells will react against your body's healthy tissues, causing potentially fatal damage (graft-versus-host disease). Other risks include organ or blood vessel damage, cataracts, and the development of a different cancer later on.

Doctors are studying a reduced-intensity transplant, also called a nonmyeloablative transplant or minitransplant. Reduced-intensity transplants use lower doses of pre-transplant chemotherapy and radiation. Although reduced-intensity transplantation has side effects, doctors hope that it will one day be a safer option for older adults.