Primary myelofibrosis (PMF) is a rare
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
blood cancer. It is classified by the
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
(WHO) as a type of
myeloproliferative neoplasm, a group of cancers in which there is growth of abnormal cells in the
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
. This is most often associated with a
somatic mutation in the
JAK2,
CALR, or
MPL gene markers. In PMF, the healthy marrow is replaced by scar tissue (
fibrosis), resulting in a lack of production of normal blood cells. Symptoms include anemia, increased infection and an enlarged spleen (
splenomegaly).
In 2016,
prefibrotic primary myelofibrosis
Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate o ...
was formally classified as a distinct condition that progresses to overt PMF in many patients, the primary diagnostic difference being the grade of fibrosis.
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 is an enlargement of the spleen. The spleen usually lies in the left upper quadrant (LUQ) of the human abdomen. Splenomegaly is one of the four cardinal signs of ''hypersplenism'' which include: some reduction in number of circulatin ...
(splenomegaly).
* Bone pain
* Bruising and easy bleeding due to inadequate numbers of
platelets
*
Cachexia
Cachexia () is a complex syndrome associated with an underlying illness, causing ongoing muscle loss that is not entirely reversed with nutritional supplementation. A range of diseases can cause cachexia, most commonly cancer, congestive heart fa ...
(loss of appetite, weight loss, and fatigue)
*
Enlargement of both the liver and spleen
* Fatigue
* Fevers
* Chills
* Weight loss
*
Gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of a red, tender, hot and swollen joint, caused by deposition of monosodium urate monohydrate crystals. Pain typically comes on rapidly, reaching maximal intens ...
and
high uric acid levels
* Increased susceptibility to infection, such as
pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severit ...
* Pallor and shortness of breath due to
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
* In rarer cases, a raised
red blood cell volume
* Cutaneous myelofibrosis is a rare skin condition characterized by
dermal and subcutaneous
nodules.
Causes
The underlying cause of PMF is unknown (
idiopathic disease
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...
). There is an association between
mutations
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, m ...
to the
JAK2,
CALR, or
MPL gene and myelofibrosis.
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.
The V617F mutation to the JAK2 protein is found in approximately half of individuals with primary myelofibrosis.
The V617F mutation is a change of
valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
to
phenylalanine
Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amin ...
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
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...
,
thrombopoietin, most
interleukins and
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten th ...
.
JAK2 mutations are significant because JAK2 plays a role in controlling production of blood cells from
hematopoietic stem cells
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within ...
. The V617F mutation appears to make
hematopoietic cells more sensitive to growth factors that need JAK2 for
signal transduction
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events, most commonly protein phosphorylation catalyzed by protein kinases, which ultimately results in a cellula ...
, which include
erythropoietin
Erythropoietin (; EPO), also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production ( erythropoiesis) in th ...
and
thrombopoietin.
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
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...
in the bone marrow,
by secreting
PDGF and
TGF-β1.
Mechanism
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
cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in au ...
s 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
connective tissue
Connective tissue is one of the four primary types of animal tissue, along with epithelial tissue, muscle tissue, and nervous tissue. It develops from the mesenchyme derived from the mesoderm the middle embryonic germ layer. Connective tiss ...
via collagen
fibrosis. The decrease in hematopoietic tissue impairs the patient's ability to generate new blood cells, resulting in progressive
pancytopenia
Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells ( red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.).
If only two parameters from the complete blood ...
, a shortage of all blood cell types. However, the proliferation of
fibroblast
A fibroblast is a type of biological cell that synthesizes the extracellular matrix and collagen, produces the structural framework ( stroma) for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells ...
s and deposition of
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...
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 hemopoietic cells are forced to migrate to other areas, particularly the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
and
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . . 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
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...
and
anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
. Another complication of extramedullary hematopoiesis is
poikilocytosis, or the presence of abnormally shaped
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s.
Myelofibrosis can be a late complication of other myeloproliferative disorders, such as
polycythemia vera, and less commonly,
essential thrombocythemia. In these cases, myelofibrosis occurs as a result of
somatic evolution Somatic evolution is the accumulation of mutations and epimutations in somatic cells (the cells of a body, as opposed to germ plasm and stem cells) during a lifetime, and the effects of those mutations and epimutations on the fitness of those ce ...
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
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
drug
hydroxyurea.
Sites of hematopoiesis
The principal site of
extramedullary hematopoiesis in myelofibrosis is the
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , 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
Granulocytes are
cells in the innate immune system characterized by the presence of specific granules in their cytoplasm. Such granules distinguish them from the various agranulocytes. All myeloblastic granulocytes are polymorphonuclear. They ha ...
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 cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s,
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s, 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
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either si ...
. These cases are associated with
hypertension in the pulmonary arteries.
The
bone marrow
Bone marrow is a semi-solid biological tissue, tissue found within the Spongy bone, spongy (also known as cancellous) portions of bones. In birds and mammals, bone marrow is the primary site of new blood cell production (or haematopoiesis). It i ...
in a typical case is hypercellular and diffusely
fibrotic. Both early and late in disease, megakaryocytes are often prominent and are usually
dysplastic.
Diagnosis
Epidemiologically, the disorder usually develops slowly and is mainly observed in people over the age of 50.
Diagnosis is made on the basis of
bone marrow biopsy.
Fibrosis grade 2 or 3 defines overt PMF whereas grade 0 or 1 defines
prefibrotic primary myelofibrosis
Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate o ...
.
A physical exam of the abdomen may reveal enlargement of the
spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it i ...
,
or both.
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
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...
, a decrease of
blood platelets develops. When viewed through a microscope, a
blood smear
A blood smear, peripheral blood smear or blood film is a thin layer of blood smeared on a glass microscope slide and then stained in such a way as to allow the various blood cells to be examined microscopically. Blood smears are examined in th ...
will appear markedly abnormal, with presentation of
pancytopenia
Pancytopenia is a medical condition in which there is significant reduction in the number of almost all blood cells ( red blood cells, white blood cells, platelets, monocytes, lymphocytes, etc.).
If only two parameters from the complete blood ...
, which is a reduction in the number of all blood cell types:
red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s,
white blood cell
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s, 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
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...
fibrosis, replacing the marrow that would normally occupy the space.
Treatment
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
Folate, also known as vitamin B9 and folacin, is one of the B vitamins. Manufactured folic acid, which is converted into folate by the body, is used as a dietary supplement and in food fortification as it is more stable during processing a ...
,
allopurinol or
blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s.
Dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena ...
, alpha-
interferon
Interferons (IFNs, ) are a group of signaling proteins made and released by host cells in response to the presence of several viruses. In a typical scenario, a virus-infected cell will release interferons causing nearby cells to heighten th ...
and
hydroxyurea (also known as hydroxycarbamide) may play a role.
Lenalidomide
Lenalidomide, sold under the trade name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is used after at least one other treatment and gen ...
and
thalidomide may be used in its treatment, though
peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
is a common troublesome side-effect.
Frequent
blood transfusions may also be required.
If the patient is
diabetic
Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level (hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
and is taking a
sulfonylurea, this should be stopped periodically to rule out drug-induced
thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients a ...
.
Splenectomy is sometimes considered as a treatment option for patients with myelofibrosis in whom massive
splenomegaly is contributing to
anaemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
because of
hypersplenism, particularly if they have a heavy requirement for
blood transfusion
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mo ...
s. 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 U.S.
Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
(FDA) approved
ruxolitinib (Jakafi) as a treatment for intermediate or high-risk myelofibrosis. Ruxolitinib serves as an inhibitor of JAK 1 and 2.
''
The New England Journal of Medicine
''The New England Journal of Medicine'' (''NEJM'') is a weekly medical journal published by the Massachusetts Medical Society. It is among the most prestigious peer-reviewed medical journals as well as the oldest continuously published one.
H ...
'' (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. However, the beneficial effect of ruxolitinib on survival has been recently questioned.
In August 2019, the FDA approved
fedratinib (Inrebic) as a treatment for adults with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis (MF).
In March 2022, the FDA approved
pacritinib (Vonjo) with an
indication to treat adults who have intermediate or high-risk primary or secondary myelofibrosis and who have platelet (blood clotting cells) levels below 50,000/µL.
[ ]
History
Myelofibrosis was first described in 1879 by
Gustav Heuck.
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
Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. ''Myelo'' refers to the bone marrow, ''proliferative'' describes the rapid gro ...
condition in 1951 by
William Dameshek.
The disease was also known as ''myelofibrosis with myeloid metaplasia'' and ''agnogenic myeloid metaplasia''
The
World Health Organization
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level o ...
utilized the name ''chronic idiopathic myelofibrosis'' until 2008, when it adopted the name of ''primary myelofibrosis''.
In 2016, the WHO revised their classification of
myeloproliferative neoplasms to define
Prefibrotic primary myelofibrosis
Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate o ...
as a distinct clinical entity from overt PMF.
References
External links
{{Myeloid malignancy, us=y, state=collapsed
Myeloid neoplasia
Rare cancers
Idiopathic diseases