PMF is most likely to be diagnosed in individuals over the age of 50. 50% of affected individuals are over the age of 65 at diagnosis. If children are affected, it is often before the age of three. In the adult population, males and females are affected equally while in younger children, girls are more likely to be affected than boys. It is estimated that 1.5 new cases of PMF are diagnosed each year per 100,000 individuals in the United States.

PMF occurs as a result of genetic changes in hematopoietic stem cells. This genetic change or mutation leads to the uncontrolled proliferation of abnormal and immature blood cells. These immature cells are called blasts and are unable to mature into RBC’s, WBC’s, and platelets and are also unable to carry out the functions of healthy blood cells.

About half of the affected individuals have a mutation in the JAK2 gene. The protein encoded by JAK2 is involved in the regulation of blood cell production in the bone marrow. Other genes that are less commonly mutated in PMF are CALR, and MPL. CARL encodes a protein that is involved in various physiological and disease-causing processes including regulating the function of other genes and facilitating the communication between cells. MPL  is involved in the production of a molecule that responds to thrombopoietin, a hormone that induces platelet production in the bone marrow.

One of the main features of MPL is an increase in the production of megakaryocytes. These are immature cells that develop into platelets. The overproduction of megakaryocytes contributes to the formation of scar tissue in the bone marrow by releasing molecules called cytokines. Cytokines are small proteins that facilitate cellular communication, especially during an immune response. Cytokine release causes inflammation in the bone marrow that damages that eventually leads to fibrosis or scarring. Over time, the scar tissue hinders the production of healthy blood cells. As scar tissue takes up more space in the bone marrow, hematopoietic stem cells migrate to other tissues outside of the bone marrow such as the liver, spleen, and lymph nodes to produce blood cells, a process known as extramedullary hematopoiesis which can cause swelling and the enlargement of the liver, spleen, etc. The spleen is an organ that is responsible for the removal and recycling of old or abnormal red blood cells. As a result of an increased production of abnormal blood cells, the spleen also grows larger to meet the increased demand. 

Symptoms of PMF vary among individuals. Many of those affected may not experience any symptoms for years. The most common symptom is anemia or a reduction in the number of RBC’s which leads to fatigue, shortness of breath, lightheadedness, headaches, and pale skin color. If the number of WBC’s is reduced, individuals may experience recurrent or prolonged infections as the immune system struggles to clear infections. The reduced number of platelets can cause easy bruising and bleeding especially from the gums and the nose. 

An enlarged spleen due to increased demand and extramedullary hematopoiesis is commonly found in PMF. An enlarged spleen, also known as splenomegaly, can cause a feeling of fullness as it presses on the stomach. It can also cause pain in the upper left portion of the abdomen. The liver may also be enlarged in PMF as a result of extramedullary hematopoiesis.

Extramedullary hematopoiesis can also lead to the formation of nodules called fibrohematopoietic tumors in the digestive tract, lungs, liver, spleen, etc. These masses can grow in size and exert pressure on surrounding structures which can have varying effects depending on the organ. For example, fibrohematopoietic tumors in the digestive tract can cause bleeding.

As the disease progresses, individuals may experience bone and joint pain. Another possible complication is portal hypertension. This occurs as a result of an increased blood flow to the liver from the spleen which causes blood pressure in the vessel that delivers blood to the liver to rise. Digestive tract veins may not be able to bear this extra pressure and rupture, causing bleeding on digestive organs such as the stomach and the esophagus. 

Other symptoms may include fever, night sweats, and itching. PMF can develop into acute myeloid leukemia, a form of blood cancer.

PMF is diagnosed based on a set of major and minor criteria. Major criteria are finding an increased number of megakaryocytes and fibrosis in the bone marrow, as well as finding a mutation in one of the JAK2, CARL, and MPL genes. Minor criteria include anemia that cannot be explained by another condition, an increased number of WBC’s, an enlarged spleen that is palpable, and leukoerythroblastosis. Leukoerythroblastosis describes the presence of immature RBC’s and WBC’s which are normally only found in the bone marrow, in the circulating blood. 

A physical exam can reveal an enlargement in the liver or the spleen, features of anemia such as paleness, and features of low platelet count such as bruisings. However, further testing is required to confirm the diagnosis. 

The initial test done to diagnose PMF is a blood test that can reveal any abnormalities in the number of blood cells. In addition, the blood sample is examined microscopically to look for teardrop cells which are red blood cells shaped like teardrops due to the effect of being pushed out of the bone marrow. The microscopic examination can also reveal a leukoerythroblastic picture where immature red and white blood cells are found in the circulating blood.

Next, a bone marrow biopsy may be performed to assess the architecture of the bone marrow microscopically. A bone marrow biopsy is a procedure in which a needle is used to take a sample of the bone marrow, typically the hip bone. A bone marrow biopsy can reveal whether there is any scarring in the bone marrow and whether there is an increased number of megakaryocytes. 

Imaging studies such as ultrasound may be done to check for an enlarged liver or spleen. Lastly, genetic tests can detect mutations in the associated genes. 

Drugs that suppress the production of blood cells in the bone marrow such as hydroxyurea are used to control increased numbers of WBC’s and platelets as well as spleen enlargement. Corticosteroids that reduce the immune system’s ability to cause inflammation may also improve symptoms. If anemia is present, erythropoietin can be administered. Erythropoietin is a hormone that induces the production of red blood cells. If erythropoietin is not sufficient to control anemia, blood transfusions may be needed. Ruxolitinib is a drug that inhibits JAK1 and JAK2 enzymes, proteins that are involved in PMF and are responsible for regulating blood cell production. It is effective in individuals with a JAK2 mutation but also in those with mutations in CARL and MPL. It is effective in reducing the size of the spleen and symptom control and may improve survival and slow bone marrow scarring. 

If the enlargement of the spleen is causing severe pain, portal hypertension, or other significant symptoms, a surgical procedure may be recommended to remove the spleen. 

The only treatment option that may cure PMF is stem cell transplantation. It is an invasive, surgical procedure in which the blood cell producing cells in the bone marrow of a healthy donor is collected to replace the abnormal cells in the bone marrow of the affected individual. Although potentially curative, a stem cell transplant is an invasive, high-risk procedure associated with a risk of death or significant complications. Thus, individuals are selected for a stem cell transplant based on strict criteria. Usually, only younger, healthy individuals with high-risk PMF qualify for this procedure. 

PMF is classified as low-risk, intermediate-risk, and high-risk based on the presence or absence of a number of factors such as severe anemia, advanced age, weight loss, profound fatigue, night sweats, fever, an increased or decreased number of WBC’s, immature WBC’s in circulating blood, and high-risk genetic findings. About half of the individuals with high-risk PMF live for longer than 2 years, while half of the individuals with low-risk PMF live for longer than 10 years.

Stem cell transplantation is the only treatment option that may cure PMF while other treatment options can improve quality of life and slow down progression.

About one-fifth of individuals affected by PMF may develop acute myeloid leukemia, which is one of the main causes of death among those affected.

Barosi G. Myelofibrosis with myeloid metaplasia: diagnostic definition and prognostic classification for clinical studies and treatment guidelines. J Clin Oncol. 1999 Sep;17(9):2954-70. doi: 10.1200/JCO.1999.17.9.2954. PMID: 10561375.

Tefferi A, Pathogenesis of Myelofibrosis With Myeloid Metaplasia,. Journal of Clinical Oncology. 2005;23(33):8520-8530. DOI: 10.1200/JCO.2004.00.9316

Tefferi, A. (2003), The Forgotten Myeloproliferative Disorder: Myeloid Metaplasia. The Oncologist, 8: 225-231. https://doi.org/10.1634/theoncologist.8-3-225

Tefferi A. Myelofibrosis with Myeloid Metaplasia. New England Journal Medicine. 2000; 342:1255-1265. DOI: 10.1056/NEJM200004273421706