Myelofibrosis

ALSO KNOWN AS: MF, primary myelofibrosis, agnogenic myeloid metaplasia, idiopathic myelofibrosis, myeloid metaplasia with 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 an aggressive blood cancer 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 mean age at diagnosis is about sixty-five. The principal risk factor for developing myelofibrosis is somatic mutations of the JAK2 gene, occurring in 60 to 65 percent of patients. These mutations cause the Janus-associated kinases (JAKs) protein to become continuously activated, leading to the overproduction of abnormal marrow cells responsible for blood platelet production. Exposure to radiation, benzene, or toluene also increases one’s risk. Up to 10 percent of cases are associated with myeloproliferative leukemia (MPL) gene mutation, and 20 to 25 percent involve a calreticulin (CALR) mutation. Other risk factors include having essential thrombocythemia or polycythemia vera and exposure to ionizing radiation or petrochemicals.

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 many 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 produced in 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 1.5 cases per 100,000 people in the United States. Among clonal hematologic disorders, myelofibrosis is the least prevalent. Between 10 and 20 percent of diagnoses are secondary myelofibrosis cases. Around 12 percent of primary myelofibrosis cases progress into acute myeloid leukemia.

Symptoms: In the early stages, myelofibrosis does not cause symptoms in one-third of patients. However, as normal blood cell production is increasingly affected, multiple symptoms arise, including fatigue, weakness, shortness of breath, an enlarged liver or spleen, dizziness and lightheadedness, bleeding, palpitations, bone pain, fever, pale skin, and bruising.

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. Physical exams and imaging tests—ultrasounds, magnetic resonance imaging, and computed tomography scans—may be performed to examine enlargement of the spleen or spinal cord compression.

A bone marrow biopsy, in which a medical provider uses a needle to withdraw bone marrow from the hip bone, can 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 and to complete further mutational testing.

Treatment and therapy: The goals of therapy for myelofibrosis include prolonging survival, symptom-oriented palliation, and improving the patient's quality of life. Allogenic hematopoietic stem cell transplant (allo-HSCT) is the only therapy that may cure primary myelofibrosis, but it is a risky procedure. Allo-HSCT is recommended for patients fit enough to undergo the 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. Androgens like Danocrine (danazol) or immunomodulatory agents like Thalomid (thalidomide) and Revlimid (lenalidomide) may increase red blood cell production. Hydroxyurea, a chemotherapeutic agent, can shrink enlarged spleens and reduce bone marrow scarring to treat splenomegaly. Radiation and interferon-alpha may reduce spleen size and alleviate bone pain. When other treatments are unsuccessful, the spleen may be surgically removed in a splenectomy.

Prognosis, prevention, and outcomes: The mean survival time from diagnosis ranges from three to less than ten years. Patients with severe anemia, weight loss, fatigue, night sweats, fever, and those older than sixty-five tend to have poorer survival rates. Around 12 percent of primary myelofibrosis cases progress into acute myelogenous leukemia.

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

Bibliography

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