Myelofibrosis

Myelofibrosis

Other names: Agnogenic myeloid metaplasia; Primary myelofibrosis; Myelofibrosis with myeloid metaplasia The myelofibrosis is a disease that affects the tissue spongy inside the bones (bone marrow), where are the mother cells that give rise to cells of the blood. In this disease, the bone marrow is replaced by fibrous tissue (scar) and cannot produce enough blood cells. This results in anemia, weakness, fatigue, and in many cases in the enlargement of the liver and spleen (hepatosplenomegaly). Because blood cell formation (hematopoiesis) in the bone marrow is disrupted, other organs such as the spleen or liver may begin to produce blood cells. This process, called extramedullary hematopoiesis, often leads to an enlarged spleen (splenomegaly) or an enlarged liver (hepatomegaly). People with splenomegaly may feel pain or fullness in the abdomen, especially below the ribs on the left side. Other common signs and symptoms of primary myelofibrosis include fever, night sweats, and bone pain. Primary myelofibrosis is most commonly diagnosed in people aged 50 to 80 but can occur at any age.

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Epidemiology

Primary myelofibrosis is a rare condition that affects approximately 1 in 500,000 people worldwide.

Cause

Mutations in the JAK2, MPL, CALR, and TET2 genes are associated with most cases of primary myelofibrosis. The JAK2 and MPL genes provide instructions for making proteins that promote the growth and division (proliferation) of blood cells. The CALR gene provides instructions for making a protein with multiple functions, including ensuring the proper folding of newly formed proteins and maintaining the correct levels of stored calcium in cells. The TET2 gene provides instructions for making a protein whose function is unknown. Mutations in either the JAK2 gene or the MPL gene that are associated with primary myelofibrosis lead to overactivation of the JAK/STAT pathway. The abnormal activation of JAK/STAT signaling leads to overproduction of abnormal megakaryocytes, and these megakaryocytes stimulate another type of cell to release collagen. Collagen is a protein that normally provides structural support for the cells in the bone marrow. However, in primary myelofibrosis, the excess collagen forms scar tissue in the bone marrow. Although mutations in the CALR gene and the TET2 gene are relatively common in primary myelofibrosis, it is unclear how these mutations are involved in the development of the condition.

Inheritance

This condition is generally not inherited but arises from gene mutations that occur in early blood-forming cells after conception. These alterations are called somatic mutations.

Signs and symptoms

The primary feature of primary myelofibrosis is bone marrow fibrosis, but it is often accompanied by:

• Abdominal fullness related to an enlarged spleen (splenomegaly).
• Bone pain
• Bruising and easy bleeding due to inadequate numbers of platelets
• Cachexia (loss of appetite, weight loss, and fatigue)
• Enlargement of both the liver and 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.

Primary Myelofibrosis blood stain

Diagnosis

Diagnosis of myelofibrosis is made on the basis of bone marrow biopsy. A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both. Blood tests: Most people with myelofibrosis have moderate to severe anemia. Eventually thrombocytopenia, a decrease of blood platelets develops. When viewed through a microscope, a blood smear will appear markedly abnormal, with presentation of pancytopenia, which is a reduction in the number of all blood cell types: red blood cells, white blood cells, and platelets. Red blood cells may show abnormalities including bizarre shapes, such as teardrop-shaped cells, and nucleated red blood cell precursors may appear in the blood smear (leukoerythroblastic reaction). Normally, mature red blood cells in adults do not have a cell nucleus, and the presence of nucleated red blood cells suggests that immature cells are being released into the bloodstream in response to a very high demand for the bone marrow to produce new red blood cells. Immature white cells and platelets (large megakaryocytes) are also seen in blood samples, and basophil counts are increased. A bone marrow biopsy will reveal collagen fibrosis, replacing the marrow that would normally occupy the space.

Treatment

In most cases, myelofibrosis worsens progressively. Treatment is aimed at relieving signs and symptoms and may include medications,blood transfusions, chemotherapy, radiotherapy and surgery. The bone marrow transplant or stem cell appears to improve symptoms and may cure the disease. options may include regular folic acid, allopurinol or blood transfusions. Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role. Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect. Splenectomy is sometimes considered as a treatment option for patients with myelofibrosis in whom massive splenomegaly is contributing to anaemia because of hypersplenism, particularly if they have a heavy requirement for blood transfusions.

FDA approved medicines The FDA approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis. the FDA approved fedratinib (INREBIC, Impact biomedicines, Inc.) as a treatment for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).

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