Primary myelofibrosis is a relatively rare bone marrow cancer.^[1] It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic stem cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with scar tissue.^[2][3]

The term myelofibrosis alone usually refers to primary myelofibrosis (PMF), also known as chronic idiopathic myelofibrosis (cIMF); the terms idiopathic and primary mean that in these cases the disease is of unknown or spontaneous origin. This is in contrast with myelofibrosis that develops secondary to polycythemia vera or essential thrombocythaemia. Myelofibrosis is a form of myeloid metaplasia, which refers to a change in cell type in the blood-forming tissue of the bone marrow, and often the two terms are used synonymously. The terms agnogenic myeloid metaplasia and myelofibrosis with myeloid metaplasia (MMM) were also used to refer to primary myelofibrosis.

Signs and symptoms[edit]

The primary feature of primary myelofibrosis is bone marrow fibrosis,^[3] 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.^[4]:746

Causes[edit]

There is an association between mutations to the JAK2, CALR, or MPL gene and myelofibrosis.^[5] Approximately 90% of those with myelofibrosis have one of these mutations and 10% carry none of these mutations. These mutations are not specific to myelofibrosis, and are linked to other myeloproliferative neoplasms, specifically polycythemia vera and essential thrombocythemia.^[3]

The V617F mutation to the JAK2 protein is found in approximately half of individuals with primary myelofibrosis.^[6] The V617F mutation is a change of valine to phenylalanine at the 617 position. Janus kinases (JAKs) are non-receptor tyrosine kinases essential for the activation of signaling that is mediated by cytokine receptors lacking catalytic activity. These include receptors for erythropoietin, thrombopoietin, most interleukins and interferon.^[6] JAK2 mutations are significant because JAK2 plays a role in controlling production of blood cells from hematopoietic stem cells. The V617F mutation appears to make hematopoietic cells more sensitive to growth factors that need JAK2 for signal transduction, which include erythropoietin and thrombopoietin.^[7]

The MPL gene codes for a protein that acts as a receptor for thrombopoietin. A mutation in that gene, known as a W515 mutation, leads to the production of an abnormal thrombopoietin receptor protein, which results in the overproduction of abnormal megakaryocytes. The abnormal megakaryocytes stimulate other cells, the fibroblasts, to produce collagen in the bone marrow,^[8] by secreting PDGF and TGF-β1.^[9]

Mechanism[edit]

Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, the formation of blood cellular components. It is one of the myeloproliferative disorders, diseases of the bone marrow in which excess cells are produced at some stage. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes)^[10] leads to replacement of the hematopoietic tissue of the bone marrow by connective tissue via collagen fibrosis. The decrease in hematopoietic tissue impairs the patient's ability to generate new blood cells, resulting in progressive pancytopenia, a shortage of all blood cell types. However, the proliferation of fibroblasts and deposition of collagen is a secondary phenomenon, and the fibroblasts themselves are not part of the abnormal cell clone.

In primary myelofibrosis, progressive scarring, or fibrosis, of the bone marrow occurs, for the reasons outlined above. The result is extramedullary hematopoiesis, i.e. blood cell formation occurring in sites other than the bone marrow, as the haemopoetic cells are forced to migrate to other areas, particularly the liver and spleen. This causes an enlargement of these organs. In the liver, the abnormal size is called hepatomegaly. Enlargement of the spleen is called splenomegaly, which also contributes to causing pancytopenia, particularly thrombocytopenia and anemia. Another complication of extramedullary hematopoiesis is poikilocytosis, or the presence of abnormally shaped red blood cells.

Myelofibrosis can be a late complication of other myeloproliferative disorders, such as polycythemia vera, and less commonly, essential thrombocythaemia. In these cases, myelofibrosis occurs as a result of somatic evolution of the abnormal hematopoietic stem cell clone that caused the original disorder. In some cases, the development of myelofibrosis following these disorders may be accelerated by the oral chemotherapy drug hydroxyurea.^[11]

The cause and risk factors for primary myelofibrosis are unknown.

Sites of hematopoiesis[edit]

The principal site of extramedullary hematopoiesis in myelofibrosis is the spleen, which is usually markedly enlarged, sometimes weighing as much as 4000 g. As a result of massive enlargement of the spleen, multiple subcapsular infarcts often occur in the spleen, meaning that due to interrupted oxygen supply to the spleen partial or complete tissue death happens. On the cellular level, the spleen contains red blood cell precursors, granulocyte precursors and megakaryocytes, with the megakaryocytes prominent in their number and in their bizarre shapes. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition, as discussed under "Mechanism" above. Sometimes unusual activity of the red blood cells, white blood cells, or platelets is seen.

The liver is often moderately enlarged, with foci of extramedullary hematopoiesis. Microscopically, lymph nodes also contain foci of hematopoiesis, but these are insufficient to cause enlargement.

There are also reports of hematopoiesis taking place in the lungs. These cases are associated with hypertension in the pulmonary arteries.^[12]

The bone marrow in a typical case is hypercellular and diffusely fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually dysplastic.

Diagnosis[edit]

Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50.^[13] It may also develop as a side-effect of treatment with some drugs that target hematological disorders, such as polycythemia vera or chronic myeloid leukemia.
Diagnosis of myelofibrosis is made on the basis of bone marrow biopsy.^[3] A physical exam of the abdomen may reveal enlargement of the spleen, the liver, or both.^[3]

Blood tests are also used in diagnosis. Primary myelofibrosis can begin with a blood picture similar to that found in polycythemia vera or chronic myeloid leukemia. 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.

When late in the disease progression an attempt is made to take a sample of bone marrow by aspiration, it may result in a dry tap, meaning that where the needle can normally suck out a sample of semi-liquid bone marrow, it produces no sample because the marrow has been replaced with collagen fibers. A bone marrow biopsy will reveal collagen fibrosis, replacing the marrow that would normally occupy the space.

Treatment[edit]

The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks.^[14]
Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below).^[15] These options may include regular folic acid,^[16]allopurinol^[17] or blood transfusions.^[18]Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.^[19][20][21]

Lenalidomide and thalidomide may be used in its treatment, though peripheral neuropathy is a common troublesome side-effect.^[21]

Frequent blood transfusions may also be required.^[18] If the patient is diabetic and is taking a sulfonylurea, this should be stopped periodically to rule out drug-induced thrombocytopenia.^{[citation needed]}

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. However, splenectomy in the presence of massive splenomegaly is a high-risk procedure, with a mortality risk as high as 3% in some studies.^[22]

In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis.^[23][24] Ruxolitinib serves as an inhibitor of JAK 1 and 2.
The New England Journal of Medicine (NEJM) published results from two Phase III studies of ruxolitinib. These data showed that the treatment significantly reduced spleen volume, improved symptoms of myelofibrosis, and was associated with much improved overall survival rates compared to placebo.^[25][26] However, the beneficial effect of ruxolitinib on survival has been recently questioned^[27].

Chiropractic is also considered as an alternative pain control option for patients with myelofibrosis.^[28]

History[edit]

Myelofibrosis was first described in 1879 by Gustav Heuck.^[29][30]

Older terms include "myelofibrosis with myeloid metaplasia" and "agnogenic myeloid metaplasia". The World Health Organization utilized the name "chronic idiopathic myelofibrosis", while the International Working Group on Myelofibrosis Research and Treatment calls the disease "primary myelofibrosis". In 2008 WHO has adopted the name of "primary myelofibrosis." Eponyms for the disease are Heuck-Assmann disease or Assmann's Disease, for Herbert Assmann,^[31] who published a description under the term "osteosclerosis" in 1907.^[32]

It was characterised as a myeloproliferative condition in 1951 by William Dameshek.^[33][34] The Leukemia and Lymphoma Society describes myelofibrosis as a rare type of blood cancer, manifesting as a type of chronic leukemia.^[35]

References[edit]

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