What is Myelofibrosis?

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) characterized by scarring (fibrosis) of the bone marrow. This fibrosis replaces the blood-producing cells and leads to diminished blood production and an enlarged spleen. Primary means it develops spontaneously—not preceded by another MPN or other medical condition. Primary MF is related to the MPNs polycythemia vera and essential thrombocythemia, and often has the same genetic mutations. Secondary MF is often preceded by the other MPNs, and is referred to as post-polycythemia vera MF or post-essential thrombocythemia MF. Though they develop differently, primary and secondary MF have similar symptoms and are treated basically the same way.

There are usually many constitutional (whole body or systemic) symptoms that go along with MF, in contrast to the less severe MPNs. An MF patient may present with elevated or decreased platelets and white blood cells. By the time it is diagnosed, the red counts can be low to normal. As fibrosis increases in the bone marrow, the marrow becomes unable to make blood cells effectively. The cells that are formed are usually irregular and not functioning properly. Eventually this leads to extreme anemia, infections, or uncontrolled bleeding. The only cure for MF is a stem cell transplant, but there are many treatments to stabilize counts and help symptoms.

Causes of MF

As with other MPNs, the underlying cause of MF is not well understood. The large majority of those diagnosed have either the JAK2 (janus kinase 2), CALR (calreticulin), or MPL mutation, and a small percentage have no known mutation. These mutations are acquired, meaning you aren’t born with them. They aren’t passed on to children, but there is likely a genetic predisposition to acquiring a mutation, and there are family clusters of MPNs.

In MF, mutated stem cells in the bone marrow stimulate the fibroblast cells to produce an excess of collagen, leading to the fibrosis (scarring) in the bone marrow, characteristic of MF. As the healthy bone marrow gets crowded out by the fibrosis, blood producing cells migrate to other parts of the body and make blood cells (extramedullary hematopoiesis). This is commonly in the spleen and liver, causing enlargement, but can also occur in other areas of the body. The fibrosis also alters the production of all blood cell types in number and shape.

Risk Factors for MF

• Over the age of 50, though it can occur at any age
• More common in men
• Having another blood cancer
• Environmental factors, such as benzene or toluene, or radiation
• A genetic predisposition

Common Symptoms of MF

Some MF patients have no symptoms early in their disease. As MF develops so do the signs and symptoms. The main ones are:

• Weakness, fatigue, and shortness of breath, increasing as anemia worsens
• Pain and fullness in the upper abdomen, especially after eating, from an enlarged spleen and liver
• Diminished appetite
• Muscle wasting and weight loss
• Bone pain
• Night sweats or fever
• Easy bruising or bleeding from lowered or irregular platelets
• Itching
• Distention of the abdomen from portal vein hypertension (increased pressure in the vein leading to the liver)
• Susceptibility to infection if the white blood cell count is lowered

Diagnosis of MF

• A physical examination, including palpation of the spleen and lymph glands
• A complete blood count (CBC)
• Genetic testing of the blood for JAK2, CALR, or MPL
• A bone marrow biopsy to determine the extent of fibrosis and look for chromosomal abnormalities
• Possibly next generation sequencing to detect gene mutations that might indicate the likelihood of transformation to acute leukemia
• Imaging tests, such as ultrasound

Complications of MF

• Excessive bleeding resulting from decreased platelets
• Infection because of low white blood cell counts
• Splenic infarction or rupture (rarely) from a severely enlarged spleen
• Progression to acute leukemia

Treatment of MF

Treatment of MF depends largely on the progress of the disease, the symptoms being experienced, and the prognosis. Valuable tools, called the Revised International Prognosis Scoring System (IPSS-R) and the Dynamic International Prognosis Scoring System (DIPSS), as well as DIPSS-Plus which incorporates cytogenic data and molecular markers, have been developed in recent years for scoring an individual’s disease progression and help make decisions on medication and when to initiate stem cell transplant.

A major goal of treatment for MF is to stabilize blood counts and prevent or reverse fibrosis. Other treatments involve reducing many of the constitutional (whole body) symptoms of the disease. Early in the disease, treatment might be minimal, but in Intermediate-2 or High-Risk MF, multiple treatments may be used.

Here are some of the available treatments for MF:

• Stem cell transplant is the only potential cure for MF, but there are many risks involved with transplant. Additionally, many people do not qualify because of age, other health conditions, or advanced MF.

Treatment to help with constitutional symptoms and reduce spleen size:

• Ruxolitinib (Jakafi) or fedratinib (Inrebic)— targeted immunosuppressants that work by inhibiting the JAK enzyme. This can stabilize blood counts, reduce spleen size, and help itching, night sweats, fatigue, and bone pain
• Vonjo (Pacritinib) – is indicated for the treatment of adults with intermediate or high-risk myelofibrosis with cytopenia
• Interferon— can reduce spleen size, help with itching, bone pain, and night sweats, and possibly reduce fibrosis
• Hydroxyurea— can reduce spleen size and help prevent blood clots
• Radiation of the spleen to reduce extramedullary hematopoiesis and enlargement
• Surgical removal of the spleen (splenectomy)—only used in extreme cases and comes along with many side effects
• Palliative care

Treatment for anemia

• Androgens (synthetic versions of male hormones), such as danazol
• Thalidomide or lenalidomide, combined with steroids
• Blood transfusions

Investigational medications that are in various trials:

• JAK inhibitors, such as momelotinib and pacritinib
• Epigenetic drugs/HDACs (histone deacetylase inhibitors), such as givinostat and panobinostat
• Telomerase inhibitors, such as imetelstat
• Immunomodulators, such as pomalidomide
• mTOR inhibitors, such as everolimus

Prognosis

Patients with low-risk MF can have a life expectancy of over 10 years. This would include those without anemia, constitutional symptoms, high white counts, with no circulating blasts, and under the age of 65. Those who meet the conditions for intermediate or high-risk disease can have a considerably shorter life expectancy. They can ask their doctor to walk them through the IPSS or DIPSS risk stratification tools to help them make treatment decisions. MF can progress to acute myelogenous leukemia.