Primary Myelofibrosis (PMF)
What is MF?
Myelofibrosis (MF) is a chronic bone marrow disorder in which excessive scar tissue forms in the bone marrow and impairs its ability to produce normal blood cells. MF is thought to be caused by abnormal blood stem cells in the bone marrow. The abnormal stem cells produce more mature cells that grow quickly and take over the bone marrow, causing both fibrosis (scar tissue formation) and chronic inflammation. As a result, the bone marrow becomes less able to create normal blood cells and blood cell production may move to the spleen, causing enlargement, or to other areas of the body. Classified as a myeloproliferative neoplasm (MPN), MF can arise on its own (primary myelofibrosis, PMF), or as a progression of polycythemia vera (post-PV-MF) or essential thrombocythemia (post-ET-MF). The manifestations of PMF, post-PV-MF and post-ET-MF are virtually identical and treatment is generally the same for all three.
Many symptoms of MF are caused by insufficient numbers of normal blood cells or chronic inflammation. Symptoms may include the following:
• Tiredness, weakness, or shortness of breath with mild exertion. These symptoms usually result from anemia (low red blood cell count) or chronic inflammation.
• Fullness, discomfort or pain in the left upper area of the abdomen and early satiety, as a result of an enlarged spleen pressing on the stomach and other organs
• Fever, caused by inflammation or infection
• Night sweats, caused by inflammation
• Weight loss or malnutrition, caused by inflammation and an enlarged spleen pressing on the stomach and bowels
• Bone pain
• Itching (pruritus), caused by a chronic state of inflammation
• Easy bleeding or bruising, as a result of low platelet counts or otherwise compromised blood coagulation
• Susceptibility to infection, as a result of low white blood cell count or diminished production of antibodies
• Joint pain, caused by gout. Gout may develop as a result of excessive uric acid production.
• Portal hypertension (increased blood pressure within the portal vein, which carries blood from the spleen to the liver) caused by a progressively enlarging spleen. Portal hypertension can lead to varices (dilated veins) within the stomach and esophagus, which may rupture and bleed. Liver function may be compromised as well.
• Abnormal growth of blood forming cells outside of the bone marrow (called extramedullary hematopoiesis, or EMH) can occur in different parts of the body, including lymph nodes, lungs, and spinal cord, causing symptoms in these areas. EMH occurs when blood-forming cells leave the bone marrow and settle in other organs.
• Some patients with myelofibrosis may have no symptoms, particularly early in the course of the disease.
A doctor reviews many factors before making a diagnosis. Every case of MF is different, so a medical history, a physical examination and laboratory tests are needed.
Even if people living with myelofibrosis do not have symptoms, they may have signs. Symptoms are what you feel; a “sign” is something a doctor notices during a physical examination.
Common signs on physical examination include:
• An enlarged spleen (splenomegaly)
• Pale mucous membranes (pallor), caused by anemia
Laboratory tests include:
• Blood tests, including a complete blood count (CBC), which often shows abnormal blood cell counts. Red blood cells (erythrocytes), white blood cells (leukocytes), platelets (thrombocytes) or other blood cell types are commonly affected in MF and counts may be either too high or too low.
• Bone marrow biopsy, which allows examination of the bone marrow under a microscope. A biopsy may reveal changes in the bone marrow that might suggest MF, including scar tissue formation and atypical appearance of bone marrow precursors
• Gene mutation analysis of blood cells, which can identify specific mutations associated with some cases of MF. Mutations in JAK2 and MPL can be identified through gene mutation analysis.
• Imaging tests, such as ultrasound of the spleen, may be done to help assess whether the spleen may be enlarged.
The prognosis of MF is different for every patient. People in a good prognostic group can live for many years without having major symptoms; those with a poor prognosis may progress more quickly.
In general, the most important factors that determine prognosis are age, white blood cell counts, number of “blasts” (immature blood cells) in the blood, “constitutional symptoms”(night sweats, weight loss, fever, pruritus), anemia (low red blood cells), transfusion dependence, low platelets and abnormal chromosome analysis.
For most patients, the most important symptoms to be managed in cooperation with a doctor are anemia (not enough red blood cells to carry oxygen), splenomegaly (enlarged spleen), extramedullary hematopoiesis (production of blood cells in organs outside the bone marrow), thrombosis and thrombohemorrhagic complications (blood clotting or bleeding complications), leukocytosis (too many white blood cells), thrombocytosis (too many platelets), “constitutional symptoms”(fatigue, night sweats, weight loss, pruritus, fever, bone and joint pain) and gout.
For a small number of patients, MF can transform to acute myeloid leukemia (AML), a serious blood and bone marrow cancer which progresses quickly. When AML does arise from MF, it is often difficult to treat and can be rapidly fatal.
Each patient with MF may have a different set of symptoms and different treatment requirements. Your doctor can describe available treatments that may be appropriate for you, your symptoms and your specific circumstances. Some people with myelofibrosis may remain symptom free for many years and may not require immediate treatment, but they do need to be monitored over time for any signs or symptoms that may suggest worsening of the disease.
For those with MF that require treatment, Jakafi (ruloxitinib) has recently become the first drug approved by the FDA for treating MF patients. Additionally some medicines approved for other diseases can be used to treat the signs and symptoms of MF. These medicines may not be effective for everyone, and some have potentially serious side effects.
Therapies currently used include the following:
• Jakafi (developed by Incyte; also called ruxolitinib)
The discovery of JAK2 mutations in MF, PV and ET in 2005 has provided a long-sought opportunity to develop more effective, targeted therapies for MPNs. A targeted therapy is one that is designed to be more specific for abnormal cells. In 2011, after years of development and clinical trials, Jakafi (also known as ruloxitinib) became the first FDA-approved drug for treating MF patients. Jakafi is taken orally and inhibits the activity of JAK2 and the related protein JAK1. In clinical trials, Jakafi reduced spleen size, abdominal discomfort, early satiety, bone pain, night sweats and itching in MF patients. Jakafi also reduced the level of “pro-inflammatory cytokines” in the blood, which cause the symptoms of chronic inflammation. The allelic burden of JAK2 V617F (a measure of the number of abnormal cells present) was not significantly reduced and Jakafi does not appear to be a cure for MF. So far, the impact of Jakafi on survival has not been fully established.
Importantly, Jakafi is effective in treating MF patients regardless of whether they harbor a JAK2 mutation, apparently because the JAK1 and JAK2 pathways are important in MF even when there is no JAK2 mutation present. Jakafi inhibits both normal JAK1 and JAK2 and JAK2V617F.
Because Jakafi targets normal JAK1 and JAK2, as well as abnormal JAK2, it may interfere with normal blood cell production and common side effects include thrombocytopenia (reduced platelets) and anemia (reduced red blood cells).
• Allogenic stem cell transplantation (ASCT)
ASCT is the only known potential cure for MF, but is not suitable for many patients due to high risk of complications. In this procedure, if a suitable donor can be found, hematopoietic (blood-forming) stem cells are transferred from the healthy donor to the recipient who has MF, to replace their defective stem cells. Prior to the stem cell infusion, high doses of chemotherapy and or radiation therapy are administered to eradicate the diseased bone marrow.
Importantly, ASCT is appropriate for a relatively small number of people with MF. In general, the risk associated with this treatment rises with age and the presence of other disease conditions which may impair organ function; therefore, in older people who may also have other coexisting health problems, there is a higher risk of death from the procedure. Graft versus host disease (GVHD) is another potentially life-threatening complication of ASCT, where the donor’s stem cells react against the recipient’s healthy tissues.
In the hope of improving the outcome of ASCT in older people, reduced-intensity conditioning regimens are now being administered. These strategies, also known as non-myeloablative or minitranplants, use lower doses of chemotherapy or radiation prior to transplant and are particularly promising for those older individuals who, despite their MF, remain fit, and have good organ function.
In general, the decision to pursue ASCT should involve consideration of the patient’s age, the severity of symptoms, response to other therapies, risk tolerance and the patient’s transplant-related prognostic score (a rough measure of likely success, based on factors specific to the patient and the transplant, including, extent of splenomegaly, number of transfusions and whether the transplant is from a related donor).
A number of other drugs that inhibit JAK2 (“JAK inhibitors”) are currently in clinical trials, including CEP-701 (lestuartinib), TG10138, CYT387 and SB1518. Conclusion of these studies will determine whether these drugs may also be promising for treating MF patients.
For many patients with MF, available treatment approaches may not be effective, and experimental treatments (which involve receiving a novel drug or treatment on a clinical trial), may be an appropriate option. Examples of ongoing clinical trials include experimental therapies with JAK2 inhibitors. As of the current date, only Jakafi (ruxolitinib) has been FDA approved for MF therapy.
Other therapies are generally used to treat specific symptoms of MF. Below is a list of specific symptoms of MF and available therapeutics used to treat these symptoms:
• Anemia may be treated with corticosteroids, androgens (including danazol and halotestin), thalidomide, lenalidomide, blood transfusions, or erythropoiesis stimulating agents (ESAs).
• Splenomegaly may be treated with Jakafi, hydroxyurea (HU), cladibrine, interferon, or, in severe cases, radiation or splenectomy.
• Risk of thrombosis may be managed with low-dose aspirin therapy or hydroxyurea.
• Extramedullary hematopoiesis may be treated with radiation therapy.
• Constitution symptoms, such as night sweats, pruritus, weight loss and fever may be treated with Jakafi.
Novel therapies/Clinical trials:
• Pomalidomide is a chemical relative of thalidomide and lenalidomide and has been shown to effectively treat anemia in early studies. These “immunomodulating” drugs work in many ways, including targeting the patient’s immune system to attack abnormal cells in order to make room for the normal cells that make red blood cells. With enhanced anti-cancer activity and lower toxicity compared to the other drugs in its class, pomalidomide has shown promise in initial studies and is now in phase 3 clinical trials for its use as first line therapeutic for treating anemia in MF patients. Importantly, Pomalidomide does not appear to be effective in treating MF patients who do not have the V617F mutation. Pomalidomide appears to be well tolerated and side effects, while infrequent, can include myelosuppression (decreased blood counts) and neuropathy (nerve problems).
• Everolimus (also known as RAD001) is an inhibitor of the mTOR/AKT pathway, which is highly active in MF blood producing cells and appears to contribute to abnormal cell growth. In phase 1/2 clinical trials, Everolimus was well tolerated and able to reduce both spleen size and systemic symptoms.
• Epigenetic drugs change the way genes are organized to make them more or less accessible for use by the cell. Recent studies with epigenetic drugs have found that the HDAC inhibitor, Givinostat, and two hypomethylating agents, azacitidine and decitabine, were minimally effective in treating MF in early studies (in contrast to their effectiveness in treating PV). Another HDAC inhibitor, panobinostat, is under study. “HDAC inhibitors” protect specific organizational marks on DNA, while “hypomethylating agents” remove other organizational marks.
Risk factors associated with MF include
• Age – Most often diagnosed in people ages 60 - 70
• Environment -- Exposure to petrochemicals (such as benzene and toluene) and ionizing radiation may increase the risk of developing the condition.
No one knows exactly what triggers the start of myelofibrosis or other myeloproliferative neoplasms. In the majority of cases, myelofibrosis is not inherited—you can’t pass it on to your children and you didn’t get it from your parents (although some families do demonstrate a clear predisposition). Recently, researchers have discovered that these diseases may be caused by gene mutations (changes in DNA) that are acquired (that is, they are not heritable). Some of these mutations affect proteins that work in signaling pathways in your cells. Think of a pathway as a chain of signals that your cells use to communicate messages and know what to do.
About 50% to 60% of people with myelofibrosis have a mutation called "JAK2V617F" (found in the JAK2 gene) within their blood-forming cells. JAK2 (short for Janus kinase 2) is a kind of messenger inside blood cells and participates in a relay system that receives signals from the body. When the body needs more blood cells, it sends signals to JAK2, which then signals to the cell to start growing and dividing. The V617F mutation causes JAK2 to become “constitutively active”, which means that JAK2 can no longer stop signaling. Mutant JAK2 tells blood cells to grow and divide even when the body is not asking for more blood cells. The V617F mutation is one way that JAK pathway signaling can become deregulated and cause disease. Between 5 and 10% of patients will have a mutation in another gene named MPL, which also affects the JAK signaling pathway.
Researchers now know that myelofibrosis is complex and is not caused by JAK2 mutations alone. There may be many contributing factors, including mutations of other genes in other pathways.
The frequency of MPN has been estimated in different ways, but, until recently, no reliable large scale studies of prevalence and incidence had been conducted in the United States. Prevalence refers to the total number of patients living with MPNs at any given time. Incidence of MPNs refers to the number of patients newly diagnosed each year.
In order to determine the true prevalence and incidence of MPNs, the MPN Research Foundation and the Leukemia and Lymphoma Society co-sponsored a study by Dr. Xiaomei Ma of Yale University School of Medicine designed to answer this question. Dr. Ma’s study examined the prevalence of PV and ET in the United States and was published in the American Journal of Hematology (1) in 2008.
According to Dr. Ma’s study, there were 22 cases of PV and 24 cases of ET diagnosed per 100,000 individuals in the United States in 2003. The study findings indicate a total of 65,243 patients with PV and 71,078 with ET, for a combined total of approximately 136,000 PV and ET patients living in the United States in 2003.
The prevalence of myelofibrosis was not included in the Yale study; however, a study by the Mayo Clinic reported an incidence of 1.46 per 100,000 individuals and a median survival of 7 years (2). This rate of incidence translates to an estimated prevalence of 30,000 myelofibrosis patients in the United States. Another study has evaluated national databases and estimates the number of new cases per year to be 0.41 cases per 100,000 individuals (3).
While PV, ET and MF are more common with advancing age, an important finding of the above studies is that as many as 16% of newly diagnosed cases affect individuals under the age of 50, with 6-7% occurring in those under 40 years of age. The most recent study, by the Mayo Clinic in 2009, finds improved survival in patients under 60 years old in recent years, due to advances in MF treatment (4).
1. Ma X, Vanasse G, Cartmel B, Wang Y, Selinger HA. Prevalence of polycythemia vera and essential thrombocythemia. Am J Hematol, 2008, 83:359-62
2. Mesa R, Silverstein M, Jacobson, Wollan P, Tefferi A. Population-based incidence and survival figures in essential thrombocythemia and agnogenic myeloid metaplasia: an Olmsted county study, 1976-1995.Am J Hematol, 1999; 61:10-5
3.Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, Edwards BK, List AF. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood,2008 Jul 1;112(1):45-52. Epub 2008 Apr 28.
4. Vaidya R, Siragusa S, Huang J, Schwager SM, Hanson CA, Hussein K, Pardanani A, Tefferi A. Mature survival data for 176 patients younger than 60 years with primary myelofibrosis diagnosed between 1976 and 2005: evidence for survival gains in recent years. Mayo Clin Proc. 2009 Dec;84(12):1114-9.