Myelofibrosis
Encyclopedia
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 collagen
ous connective tissue fibers.
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 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.
. It is usually reactive following other myeloproliferative disorders, such as polycythemia rubra vera 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.
Other treatment options are largely supportive, and do not alter the course. These options may include regular folic acid
, allopurinol
or blood transfusion
s. 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 as a treatment for Myelofibrosis. Ruxolitinib is a twice daily drug which serves as an inhibitor of JAK 1 and 2.
.
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
. It is currently classified as a myeloproliferative disease
Myeloproliferative disease
The myeloproliferative diseases are a group of diseases of the bone marrow in which excess cells are produced. They are related to, and may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than...
in which the proliferation of an abnormal type of bone marrow
Bone marrow
Bone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
stem cell results in fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
, or the replacement of the marrow with collagen
Collagen
Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...
ous 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
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
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.
Signs and symptoms
- Abdominal fullness related to an enlarged spleenSplenomegalySplenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
(splenomegaly). - Bone pain
- Bruising and easy bleeding due to inadequate numbers of platelets
- Fatigue
- Increased susceptibility to infection, such as pneumoniaPneumoniaPneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
or diarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and... - Pallor and shortness of breath while doing physical work due to anemiaAnemiaAnemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...
- Because of a high rate of cell turnover, hyperuricemia and gout may also complicate the picture
Clinical Course
- Primary myelofibrosis can begin with a blood picture suggestive of Polycythemia VeraPolycythemia veraPolycythemia vera is a blood disorder in which the bone marrow makes too many red blood cells. It may also result in the overproduction of white blood cells and platelets. Most of the health concerns associated with polycythemia vera are caused by the blood being thicker as a result of the...
or CMLChronic myelogenous leukemiaChronic myelogenous leukemia , also known as chronic granulocytic leukemia , is a cancer of the white blood cells. It is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood... - Most patients have moderate to severe anemia
- Eventually patient develops thrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
- The peripheral smear appears markedly abnormal
- Red cell abnormality includes bizarre shapes
- Nucleated erythroid precursors are seen in the peripheral blood
- Immature white cells are also seen and basophils are increased
Morphology
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.
Pathophysiology
The bone marrow is replaced by collagen fibrosis, impairing the patient's ability to generate new blood cells resulting in a progressive pancytopeniaPancytopenia
Pancytopenia is a medical condition in which there is a reduction in the number of red and white blood cells, as well as platelets.If only two parameters from the full blood count are low, the term bicytopenia can be used...
. It is usually reactive following other myeloproliferative disorders, such as polycythemia rubra vera or essential thrombocytosis
Essential thrombocytosis
Essential thrombocythemia is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause. In some cases this disorder may be progressive, and rarely may evolve into acute myeloid leukemia or myelofibrosis...
. Extramedullary haematopoeisis occurs as the haemopoetic cells migrate away from the bone marrow, to the liver and spleen. Patients often have hepatosplenomegaly
Hepatosplenomegaly
Hepatosplenomegaly is the simultaneous enlargement of both the liver and the spleen . Hepatosplenomegaly can occur as the result of acute viral hepatitis or infectious mononucleosis, or it can be the sign of a serious and life threatening lysosomal storage disease...
and poikilocytosis
Poikilocytosis
Poikilocytosis refers to the presence of poikilocytes in the blood. Poikilocytes are abnormally shaped red blood cells as seen on a blood film in humans and many wild and domestic species of animals, though they are common in some clinically normal small ruminants, particularly goats.Normal red...
.
In primary myelofibrosis, a progressive scarring (fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
) of the bone marrow occurs. As a result, blood forms in sites other than the bone marrow, such as the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
. 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
Hydroxyurea
Hydroxycarbamide or hydroxyurea is an antineoplastic drug, first synthesized in 1869, used in myeloproliferative disorders, specifically polycythemia vera and essential thrombocythemia...
poisoning the marrow and blood.
Treatment
The only known cure is allogeneic stem cell transplantation, but this approach involves significant risks.Other treatment options are largely supportive, and do not alter the course. These options may include regular folic acid
Folic acid
Folic acid and folate , as well as pteroyl-L-glutamic acid, pteroyl-L-glutamate, and pteroylmonoglutamic acid are forms of the water-soluble vitamin B9...
, allopurinol
Allopurinol
Allopurinol is a drug used primarily to treat hyperuricemia and its complications, including chronic gout.- Mechanism of action :...
or blood transfusion
Blood transfusion
Blood transfusion is the process of receiving blood products into one's circulation intravenously. Transfusions are used in a variety of medical conditions to replace lost components of the blood...
s. Dexamethasone
Dexamethasone
Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant...
, alpha-interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...
and hydroxycarbamide may play a role.
Lenalidomide
Lenalidomide
Lenalidomide , initially known as CC-5013 and marketed as Revlimid by Celgene, is a derivative of thalidomide introduced in 2004....
and thalidomide
Thalidomide
Thalidomide was introduced as a sedative drug in the late 1950s that was typically used to cure morning sickness. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used...
may be used in its treatment, though they can cause gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...
and leave the patient susceptible to diseases such as pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
.
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
Thrombocytopenia
Thrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
.
In November 2011, the FDA approved Ruxolitinib as a treatment for Myelofibrosis. Ruxolitinib is a twice daily drug which serves as an inhibitor of JAK 1 and 2.
Epidemiology
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 disordersHematology
Hematology, also spelled haematology , is the branch of biology physiology, internal medicine, pathology, clinical laboratory work, and pediatrics that is concerned with the study of blood, the blood-forming organs, and blood diseases...
.