What is myelofibrosis?

Related conditions:
Myeloproliferative disorders, including polycythemia
vera (increased numbers of red blood cells) and essential
thrombocytosis (overproduction of platelets in the bone marrow)

Definition:
Myelofibrosis is a disorder that disrupts the normal production of blood
cells, leading to scarring (fibrosis) of the bone marrow, anemia, and
splenomegaly (enlargement of the spleen).

Risk factors: Myelofibrosis is most common in patients over fifty
years old; the median age at diagnosis is about sixty-five years old. The
principal risk factor for developing myelofibrosis is somatic mutations of the
JAK2 gene. These mutations cause a JAK2 protein to become
continuously activated, leading to the overproduction of abnormal marrow cells
that are responsible for the production of blood platelets. Exposure to radiation,
benzene, or toluene also increases one’s risk. There may also be an association
between myelofibrosis and other blood cell disorders such as essential
thrombocythemia or polycythemia vera.

Etiology and the disease process: Hematopoiesis is the process of
making blood cells. It begins in the bone marrow with a hematopoietic stem cell
that can develop into specialized blood cells, including red blood cells (which
transport oxygen), white blood cells (which are involved in the immune system),
and platelets (which form clots).

Myelofibrosis develops when the genetic material in a hematopoietic stem cell
changes or acquires a mutation and then begins to replicate and affect normal
blood cell production. Approximately 50 percent of patients with myelofibrosis
have somatic mutations in the JAK2 gene; mutations in the
CALR, MPL, and TET2 genes
are less common than JAK2 mutations but still account for a
significant portion of cases of primary myelofibrosis. JAK2 and
MPL promote cellular growth and proliferation, and mutations
in those genes stimulate an overactivation of the JAK/STAT pathway, leading to the
overproduction of bone marrow cells. These abnormal bone marrow cells stimulate
another type of cell to release collagen, and the excess collagen causes fibrosis
(scar tissue) in the bone marrow.

The accumulation of scar tissue may displace normal blood cells being produced
within the marrow. Therefore, blood cell production may begin to occur in other
parts of the body, most often the spleen and liver. However, blood cell production
in those tissues is not as efficient and increases organ size. Severe
anemia (a lack of red blood cells) can also occur, leading
to weakness and fatigue. The abnormal hematopoietic stem cells can also spread to
other organs in the body and form tumors (primarily in the adrenals, kidneys,
lymph nodes, breasts, and lungs).

Incidence: Myelofibrosis is rare, with an age-adjusted incidence rate
of 0.25 cases per 100,000 people in the United States. Among clonal hematologic
disorders, myelofibrosis is the least prevalent.

Symptoms: In the early stages, myelofibrosis does not cause any
symptoms. However, as normal blood cell production becomes more affected, multiple
symptoms may arise, including fatigue, weakness, shortness of breath, an enlarged
liver or spleen, dizziness and lightheadedness, bleeding, palpitations, and bone
pain.

Screening and diagnosis: Screening for myelofibrosis includes blood
tests, which can involve testing for the presence of JAK2 or
MPL mutations, peripheral blood smear findings to indicate the
presence of teardrop-shaped red blood cells, and blood count findings to assess
anemia and levels of platelets and white blood cells. To examine enlargement of
the spleen or spinal cord compression, physical exams, as well as imaging tests
(ultrasounds, magnetic resonance imaging, and computed tomography scans) may be
performed.

A bone marrow biopsy, in which a needle is used to withdraw the bone
marrow from the hip bone, may be done to confirm a diagnosis. The harvested bone
marrow cells can be viewed under a microscope to examine signs of scarring and the
types and number of cells within the marrow as well as to complete further
mutational testing.

Treatment and therapy: The goals of therapy for myelofibrosis include
prolongation of survival, symptom-oriented palliation, and improvement of the
patient's quality of life. Allogenic hematopoietic stem cell transplant
(allo-HSCT) is the only therapy that may cure primary myelofibrosis. Allo-HSCT is
recommended for patients who are fit enough to undergo with procedure with
manageable comorbidities and who have a human leukocyte antigen–matched sibling or
unrelated donor. For symptom management, red cell transfusions can improve anemia.
Androgen (a hormone) or thalidomide (an immunomodulatory agent) may increase red
blood cell production. For the treatment of splenomegaly, hydroxyurea, a
chemotherapeutic agent, can shrink enlarged spleens and may reduce bone marrow
scarring. Radiation and interferon-alpha may reduce spleen size and alleviate bone
pain. When other treatments do not work, the spleen may be surgically removed in a
process known as a splenectomy.

Prognosis, prevention, and outcomes: The mean survival time from
diagnosis ranges from 3.5 years to less than 10 years. Patients with severe
anemia, certain symptoms (weight loss, fatigue, night sweats, and fever), and
those older than the age of sixty-five tend to have poorer mean survival rates. In
some patients, myelofibrosis can progress to acute myelogenous
leukemia or lymphoma, which can be fatal.

There are no known ways to prevent myelofibrosis. To alleviate or prevent symptoms
of anemia, the diet should include nutrients that promote blood formation, such as
iron, folic acid, and vitamin B12.

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