J. Taylor Whaley, MD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: October 25, 2012
Myelofibrosis is a rare cancer of the bone marrow in which the marrow is replaced by scar tissue and is not able to make healthy blood cells. It is classified as a type of chronic leukemia and belongs to a group of blood disorders called myeloproliferative diseases. It may also be called primary myelofibrosis, chronic idiopathic myelofibrosis or myelosclerosis with myeloid metaplasia.
A myeloproliferative disorder is a disease in which the bone marrow produces either too many or too few of certain blood cells, most of which do not function properly (each disorder's name comes from the cells that are affected). This group of diseases also includes chronic myelogenous leukemia, polycythemia vera (PV), essential thrombocythemia (ET), chronic neutrophillic leukemia and chronic eosinophillic leukemia. PV and ET can progress to myelofibrosis and account for 10-15% of myelofibrosis cases. Myelofibrosis can progress to other, more aggressive, types of leukemia. The disease can have a variable prognosis with some patients living decades while others progress to more aggressive forms with survival times less than 2 years.
In order to understand myelofibrosis, it is helpful to understand how normal bone marrow functions. The bone marrow is a spongy area in the center of our bones. Its role is to produce blood cells.
Larger bones have more bone marrow, and therefore produce more blood cells. The larger bones include the femur (top part of the leg or thigh), the hip bones, and parts of the rib cage. The bone marrow contains hematopoietic stem cells (or blood stem cells), which are cells that can produce one type of blood cell over and over again. It also contains a small percentage of cells that are in development and are not yet mature. These immature cells are called blasts. Once the cell has matured, it moves out of the bone marrow and into the circulating blood. The body has mechanisms to know when more cells are needed and has the ability to produce them in an orderly fashion.
In the case of myelofibrosis, one blood stem cell acquires the ability to reproduce without regulation, producing large numbers of immature blood cells. When looked at under a microscope, these abnormally produced cells look different then the healthy cells and do not function properly. The body continues to produce these abnormal, non-functional cells, leaving little space for healthy cells. At the same time, these cells release chemicals that cause the bone marrow to become "fibrous" or fill with scar tissue, further interfering with the ability to produce healthy blood cells. In addition, these abnormal cells may be produced in other areas of the body, most often the spleen or liver, which results in an enlarged spleen or liver that can be felt by the physician.
Myelofibrosis is a rare diagnosis, though the exact incidence is not known. It is likely underestimated as less severe and/or asymptomatic disease may go undetected. However, estimates suggest the annual incidence in the United States population to range from 0.3 to 1.5 cases per 100,000 persons.
Aging is the major risk factor for developing myelofibrosis, as the disorder usually develops in people over age 50, with the average age at the time of diagnosis being about 60 years old. About 15% of all patients diagnosed with myelofibrosis are under the age of 50 and about 6% under 40. There are no other known risk factors.
Myelofibrosis primarily develops without a known cause (called primary myelofibrosis);however, other myeloproliferative diseases can progress into myelofibrosis. Ten to fifteen percent of myelofibrosis cases have developed from a diagnosis of polycythemia vera or essential thrombocythemia (called secondary myelofibrosis). Though some families have a predisposition for the disease, it is not passed on or inherited. The disease appears to be caused by a change in a gene that occurs during a person's lifetime. Perhaps this change is due to exposure to something in our environment (which family members may have in common).
Currently, there is no known intervention to prevent myelofibrosis. Additionally, there is no screening test for the disease. There is not a specific test for myelofibrosis, however, routine blood work can be used as a screen to check the red and white blood cell counts as well as the platelet count. These tests can prompt further, more invasive testing, such as a bone marrow biopsy.
About one third of individuals with myelofibrosis have no symptoms, which can make the disease difficult to detect. As the number of abnormal cells increase and healthy cells decrease, symptoms tend to develop, most often related to a low red blood cell count (anemia) or enlarged spleen. Anemia commonly presents as paleness, generalized fatigue, and shortness of breath during activity. Approximately 50-70% of patients report fatigue at the time of diagnosis. People may also develop chest pain or dizziness as the heart has to work harder to get adequate oxygen to the brain and other organs when the red blood cell count is low. A minority of patients report "constitutional symptoms", which include weight loss, low-grade fever, and night sweats. Many patients will also experience intense itching, known as pruritis, secondary to generalized inflammation.
Severe anemia, easy bruising or bleeding and multiple infections can result because of the lack of healthy blood cells. An enlarged spleen (splenomegaly) and/or liver (hepatomegaly) may also occur. When the bone marrow scars, the liver and spleen try to make blood cells to compensate (called extramedullary hematopoiesis), causing these organs to swell. Approximately 25-50% of patients will have symptoms from an enlarged spleen at diagnosis, including pain with deep breaths, loss of appetite and feeling full after eating a small amount (early satiety). Extramedullary hematopoiesis can also occur in other parts of the body (lymph nodes, spinal cord, lungs), causing swelling in these areas, leading to symptoms.
The World Health Organization (WHO) has developed the following criteria for the diagnosis of myelofibrosis. A patient must meet all 3 major criteria as well as 2 minor criteria for a diagnosis of primary myelofibrosis.
CBC is the most common blood test. It uses a machine to evaluate the number of red blood cells, platelets, and white blood cells circulating in the blood. The amount of hemoglobin, the substance which carries oxygen in red blood cells, is also assessed on a CBC. A low red blood cell count is known as anemia, which is common in this disease. Additionally, the platelet counts and white blood cells counts can either be elevated or low.
A small sample of blood can be smeared on a slide and examined under a microscope to count cells by hand as well as examine them for defects.
The body's normal response to anemia is to form new blood cells. Because this occurs poorly in myelofibrosis, immature blood cells are seen in the circulating blood. This is known as leukoerythroblastosis. Red blood cells frequently appear abnormal in myelofibrosis on a peripheral smear with unusual shapes and sizes, reflecting defective production of the red blood cells.
Defects in the appearance of the platelets and white blood cells can also be seen on a peripheral smear. Similar to red blood cells, immature platelets and white blood cells may be seen on a blood smear.
A bone marrow biopsy is required for the diagnosis of myelofibrosis. Generally, this involves local anesthetic being injected into the buttock region and a small core of bone marrow taken out using a needle. A bone marrow aspiration, which is less invasive, is frequently unsuccessful because of the scarring. The scarring will cause the aspiration to be "dry."
In myelofibrosis, the bone marrow typically finds fibrosis, or scarring, of the marrow. Hyperplasia, which is an increase in the precursor cells (the cells that develop into mature red & white blood cells and platelets), is nearly always seen. This increase in precursor cells can be in one or multiple cell lines. For example an increase in the number of megakaryocytes, which will go on to form platelets in the blood, is known as megakaryocyte hyperplasia. These megakaryocytes may also appear abnormal under the microscope. Increased (thrombocytosis) or decreased (thrombocytopenia) platelets can be seen in the peripheral blood of individuals as well.
In 2005, it was discovered that many patients with myelofibrosis have a gene mutation that can be detected with testing. The most common mutation, occurring in 50-60% of cases, is found in the JAK2 (Janus Kinase 2) gene. This gene is important to the system our body uses to signal the need for more blood cells. When the "JAK2V617F" mutation is present, the gene can no longer say "stop making cells", causing the overgrowth of immature, non-functional cells.
For another 5-10% of patients, the abnormality is found in the MPL gene, which is also involved in the pathway that signals for more blood cells to be produced.
The median survival of all patients with myelofibrosis is slightly higher than 5 years. Because survival times range from decades to less than 2 years, it was necessary to create a scoring system to assist physicians in making informed decisions regarding prognosis and treatment options. The most widely used classification system is the International Prognosis Score System (IPSS). The IPSS assigns a point value based on various abnormalities. These points are added up to calculate a score specific to each person. This score can be used as a measure of the aggressiveness of the disease. Each of the following indicators of aggressive disease are given 1 point in the IPSS:
These are tallied to achieve a score, which corresponds to a risk group – low risk (score 0), intermediate 1 (score 1), intermediate 2 (score 2), high risk (score ≥3). Other scoring systems include the Dynamic IPSS and the Dynamic IPSS Plus, which incorporate the need for transfusion of red blood cells as well as unfavorable genetic changes. Additionally, the age at diagnosis and how generally healthy the person is at the time of diagnosis are critical when selecting a therapy. Median survival is up to 15 years for low risk disease (less than 1 risk factor) versus 2-3 years for patients with high risk disease (3 or more adverse features).
Because there are very few curative options for myelofibrosis, most therapies are aimed at minimizing symptoms. Many patients do not meet criteria for aggressive therapies, and treatment is focused on palliation with primary goals of limiting the symptoms associated with the decreased blood counts, improving quality of life, and decreasing the risk of progression to acute leukemia. Generally speaking, patients that are not candidates for stem cell transplant (see below) and do not have symptoms are not treated until symptoms develop. Selecting the appropriate treatment for a patient is very important and a number of studies have demonstrated ways to determine which treatment is appropriate for a given person.
The discovery of JAK2 mutations in 2005 opened the door to development of a targeted therapy for people with myelofibrosis. Following this discovery, several clinical trials began, hoping to take advantage of the mutation and develop a new treatment. Although these agents have proven useful in alleviating symptoms associated with myelofibrosis, none have proven effective as a cure. Collectively, these therapies are known as JAK2 inhibitors.
Ruloxitinib (Brand name- Jakafi) is a JAK2 inhibitor and became the first FDA-approved drug for treating MF patients in 2011. This approval was based on a trial published in the New England Journal of Medicine in 2010, which demonstrated that the drug is well tolerated and led to reductions in symptoms including spleen size, abdominal discomfort, early satiety, bone pain, night sweats and itching. Although Jakafi did not decrease the burden of myelofibrosis in the bone marrow, it did reduce the level of pro-inflammatory cytokines in the blood. It is currently only used in patients with symptomatic intermediate and high risk disease.
Pomalidomide, a new immunomodulator, has also shown some promise. In a study from the Mayo Clinic, it demonstrated improvement in anemia related to myelofibrosis in patients with the JAK2 mutation.
Many medications are the subject of clinical trials for the treatment of myelofibrosis. JAK2 inhibitors continue to be explored in clinical trials. Additionally, immunomodulators, including lenalidomide and thalidomide, appear to have some activity in symptomatic myelofibrosis. mTOR inhibitors, including everolimus, are also currently of interest as well. A trial with everolimus demonstrated improved symptoms in patients with symptomatic high-risk disease. Etanercept, a Tumor Necrosis Factor (TNF) receptor, appears to improve constitutional symptoms in myelofibrosis as well. All of these medications remain under investigation.
Interferon is an immune therapy that works by reducing the overabundance of unhealthy blood cells and reduces the cytokines that lead to fibrosis in the marrow. It appears to work best in those with early myelofibrosis secondary to PV or ET. Interferon has significant side effects that can be difficult to tolerate.
Currently, the only curative treatment is allogeneic stem cell transplant (where the bone marrow comes from a donor). Stem cell transplants have risks related to complications. For this reason, they are generally reserved for people in good health, who are younger than 60 and have a "matched" donor. Current guidelines recommend stem cell transplant only in young patients with high risk disease.
Given that most people present with MF at an older age and that MF is a chronic disease, supportive care is extremely important to limit symptoms and maintain a high quality of life. Supportive care treatments include the following:
A combination of androgen preparation (fluoxymestrone, Halotestin) and corticosteroids (prednisone) can be used to improve anemia. Exogenous Erythropoietin administration has also been shown to improve anemia in 30-50% of patients.
Hydroxyurea: is a drug that is thought to interfere with the synthesis of DNA and is used in the treatment of other blood disorders. It has been shown to decrease the size of the spleen and help control platelet and WBC counts.
Because the enlarged spleen can be a source of discomfort, its removal can alleviate symptoms. Surgical removal is associated with risks as the spleen has an important role in infection fighting. Indications for splenectomy in patients who continue to have splenomegaly despite drug therapy include thrombocytopenia, frequent red cell transfusions and symptomatic portal hypertension. One study of splenectomy in 314 patients with myelofibrosis found that 75% benefitted from the procedure with resolution of severe thrombocytopenia and becoming transfusion-independent. In this study, the benefit lasted for a median of 1 year. If surgical removal of the spleen is not possible, a short course of radiation therapy to the spleen can be given to transiently improve symptoms.