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Myelofibrosis, also known as osteomyelofibrosis, is a disorder of the bone marrow. It is currently classified as a myeloproliferative neoplasm, in which the proliferation of an abnormal clone of hematopoietic progenitor cells in the bone marrow and other sites results in fibrosis, or the replacement of the marrow with collagenous connective tissue fibers. The term myelofibrosis alone usually refers to primary myelofibrosis (PMF) (chronic idiopathic myelofibrosis [cIMF]), the idiopathic form of the disease, in contrast with myelofibrosis secondary to polycythemia vera or essential thrombocythaemia. Myelofibrosis is a form of myeloid metaplasia, and often the two terms are used synonymously. Agnogenic myeloid metaplasia and myelofibrosis with myeloid metaplasia (MMM) also overlap on the same spectrum.
Myelofibrosis is a clonal neoplastic disorder of hematopoiesis, and is one of the myeloproliferative disorders. Production of cytokines such as fibroblast growth factor by the abnormal hematopoietic cell clone (particularly by megakaryocytes) leads to replacement of the hematopoietic tissue of the bone marrow by collagen fibrosis, impairing the patient's ability to generate new blood cells and resulting in a progressive pancytopenia. However, the proliferation of fibroblasts and deposition of collagen is a secondary phenomenon, and the fibroblasts are not themselves part of the abnormal cell clone. Enlargement of the spleen commonly results in hypersplenism, which also contributes to causing pancytopenia, particularly thrombocytopenia and anemia. Myelofibrosis can result as a late complication of other myeloproliferative disorders, such as polycythemia vera or essential thrombocytosis. Extramedullary haematopoeisis occurs as the haemopoetic cells migrate away from the bone marrow, to the liver and spleen, and patients often have hepatomegaly, massive splenomegaly and poikilocytosis.
In primary myelofibrosis, progressive scarring (fibrosis) of the bone marrow occurs, for the reasons discussed above. As a result, extramedullary hematopoeisis (blood cell formation occurring in sites other than the bone marrow) ensues, particularly in the liver and spleen. This causes an enlargement of these organs. The cause and risk factors for primary myelofibrosis are unknown. Myelofibrosis also commonly occurs as a late complication of Polycythemia rubra vera, and less commonly as a late complication of essential thrombocytosis, by means of somatic evolution (clonal evolution) of the underlying abnormal hematopoietic progenitor cell clone, and possibly accelerated by the oral chemotherapy drug hydroxyurea in some cases.
The principal site of extramedullary hematopoiesis in myeloid metaplasia with primary myelofibrosis is the spleen which is usually markedly enlarged, sometimes weighing as much as 4000 g. As is always true when splenomegaly is massive, multiple subcapsular infarcts are often present. Histologically the spleen contains red blood cell precursors, granulocyte precursors and megakaryocytes, with the latter usually being prominent in terms of their numbers and bizarre morphology. Sometimes disproportional activity of any one of the three major cell lines is seen. Megakaryocytes are believed to be involved in causing the secondary fibrosis seen in this condition, as discussed under "Pathophysiology" above.
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 extramedullary hematopoiesis taking place in the lungs. These cases are associated with pulmonary arterial hypertension.
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.
Dry tap on bone marrow aspiration +Reticulin or collagen fibrosis in bone marrow biopsy.
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The one known curative treatment is allogeneic stem cell transplantation, but this approach involves significant risks. Other treatment options are largely supportive, and do not alter the course of the disorder (with the possible exception of ruxolitinib, as discussed below). These options may include regular folic acid, allopurinol or blood transfusions. Dexamethasone, alpha-interferon and hydroxyurea (also known as hydroxycarbamide) may play a role.
Frequent blood transfusions may also be required. If the patient is diabetic and is taking sulfonylureas medication this should be stopped periodically to rule out drug-induced thrombocytopenia.
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.
In November 2011, the FDA approved ruxolitinib (Jakafi) as a treatment for myelofibrosis. Ruxolitinib is a twice daily drug which serves as an inhibitor of JAK 1 and 2. The New England Journal of Medicine (NEJM) published results from two Phase III studies of Jakafi™ (ruxolitinib), a JAK1 and JAK2 inhibitor recently approved by the Food and Drug Administration (FDA) for the treatment of intermediate or high-risk myelofibrosis (MF). These data, which were included in the New Drug Application for Jakafi, showed that the treatment significantly reduced spleen volume and improved symptoms of MF. Additionally, in an updated analysis, treatment with Jakafi was associated with improved overall survival compared to placebo.
Older terms include "myelofibrosis with myeloid metaplasia" and "agnogenic myeloid metaplasia". The World Health Organization utilizes the name "chronic idiopathic myelofibrosis", while the International Working Group on Myelofibrosis Research and Treatment calls the disease "primary myelofibrosis". Eponyms for the disease are Heuck-Assmann disease or Assmann's Disease, for Herbert Assmann, who published a description under the term "osteosclerosis" in 1907.
It was characterised as a myeloproliferative condition in 1951 by Dameshek. The Leukemia and Lymphoma Society describes myelofibrosis as a rare type of blood cancer, manifesting as a type of chronic leukemia.