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Myelofibrosis, also known as myeloid metaplasia, chronic idiopathic myelofibrosis, osteomyelofibrosis and primary myelofibrosis is a disorder of the bone marrow. It is currently classified as a myeloproliferative disease in which the proliferation of an abnormal type of bone marrow stem cell results in fibrosis, or the replacement of the marrow with collagenous connective tissue fibers.
History and terminology
Myelofibrosis was first described in 1879 by Gustav Heuck.
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.
Signs and symptoms
- Abdominal fullness related to an enlarged spleen (splenomegaly).
- Bone pain
- Bruising and easy bleeding due to inadequate numbers of platelets
- Increased susceptibility to infection, such as pneumonia or diarrhea
- Pallor and shortness of breath while doing physical work due to anemia
- Because of a high rate of cell turnover, hyperuricemia and gout may also complicate the picture
- In rarer cases, a raised Mean corpuscular volume above normal ranges (I.e. 100fl+)
- Primary myelofibrosis can begin with a blood picture suggestive of Polycythemia Vera or CML
- Most patients have moderate to severe anemia
- Eventually the patient develops thrombocytopenia
- The peripheral smear appears markedly abnormal
- Red cell abnormality includes bizarre shapes, (tear drop- shaped RBCs).
- Nucleated erythroid precursors are seen in the peripheral blood
- Immature white cells are also seen and basophils are increased
- Teardrop shaped red blood cells on a peripheral smear
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 normoblast, granulocyte precursor and megakaryocytes, which are often prominent in terms of their numbers and bizarre morphology. Sometimes disproportional activity of any one of the three major cell lines 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.
The bone marrow in a typical case is hypocellular and diffusely fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually dysplastic.
The bone marrow is replaced by collagen fibrosis, impairing the patient's ability to generate new blood cells resulting in a progressive pancytopenia. It is usually reactive following other myeloproliferative disorders, such as polycythemia vera, chronic myeloid leukemia or essential thrombocytosis. Extramedullary haematopoeisis occurs as the haemopoetic cells migrate away from the bone marrow, to the liver and spleen. Patients often have hepatosplenomegaly and poikilocytosis.
In primary myelofibrosis, a progressive scarring (fibrosis) of the bone marrow occurs. As a result, blood forms in sites other than the bone marrow, such as the liver and spleen. This causes an enlargement of these organs. The cause and risk factors are unknown. It commonly occurs in the spent phase of Polycythemia rubra vera, possibly in response to the medication hydroxyurea poisoning the marrow and blood.
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The one known 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. These options may include regular folic acid, allopurinol or blood transfusions. Dexamethasone, alpha-interferon and hydroxycarbamide may play a role.
Lenalidomide and thalidomide may be used in its treatment, though they can cause gout and leave the patient susceptible to diseases such as pneumonia.
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.
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.
The disorder usually develops slowly and is mainly observed in people over the age of 50. It may also develop as a side-effect of treatment with some drugs that target hematological disorders.
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