Primary MF- Agnogenic Myeloid Metaplasia(AMM); Idiopathic Myelofibrosis(IMF); MF Secondary to Essential Thrombocythemia (PTMMM) or Polycythemia Vera (PVMMM)
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What is myelofibrosis?
Myelofibrosis (MF) is one of the Philadelphia-chromosome-negative myeloproliferative neoplasms (MPNs), or chronic, progressive hematologic disorders in which there is abnormal production of blood cells by stem cells in the bone marrow. In MF, there is a build up of scar tissue (fibrosis) in the bone marrow, compromising its ability to form normal blood cells (hematopoiesis). The result is predominantly a reduction in red blood cells (RBCs; the cells that carry oxygen to the tissues), as well as platelets (cells that help the blood to clot) and sometimes white blood cells (WBCs; cells that help the body fight infection). In some cases, disruption of the bone marrow’s normal hematopoiesis may result in production of an excess of WBCs, but because these WBCs are produced by abnormal clones, they are not capable of functioning as normal WBCs do. Likewise, some individuals may have an excess of platelets during the course of MF.
Because the bone marrow cannot produce enough functioning blood cells, the body compensates by making them in other parts of the body, typically the liver and spleen. This is known extramedullary hematopoiesis, and it is characteristic of MF.
When MF occurs on its own, it is known as primary myelofibrosis (PMF). MF can also develop in individuals who have had other disorders of the bone marrow for many years (known as secondary MF), including the MPNs polycythemia vera (PV) and essential thrombocythemia (ET). The features of secondary MF are the same as those for PMF, so they are managed the same way.
MF is very rare. A recent study1 estimated the number of new cases of PMF (or the incidence) in the United States in 2010 was approximately 1 per 100,000. The number of people living with PMF (or the prevalence) was approximately 2 per 100,000. Progression to MF has been noted in approximately 10% of patients with PV2 and < 1% of patients with ET.3 MF typically is diagnosed later in life. In a recent study of 1054 patients, the median age at PMF diagnosis was 64 years (range 10-90 years), with 17% of subjects diagnosed under the age of 50 years.4 MF is somewhat more common in men than women.
MF develops over several years, and there may be no symptoms initially. Signs and symptoms that may develop as MF progresses include anemia, which contributes to feelings of fatigue and weakness; fullness or bloating in the left upper abdominal area, or feeling full after eating a small amount of food (early satiety) that may indicate an enlarged spleen; weight loss; bruising or bleeding easily; night sweats; fever; severe itching, often triggered by a bath or shower; bone and joint pain; and infections.
As MF progresses, blood cell production becomes more and more compromised, leading to complications due to inadequate RBCs, platelets, and WBCs. Anemia (abnormally low RBCs) may become more severe, sometimes requiring frequent blood transfusions to maintain adequate oxygen transport to tissues. Decreases in the number of platelets (the cells that help the blood to clot) may result in bleeding complications. Low numbers of functioning WBCs may result in increased susceptibility to infections. Enlargement of the spleen (splenomegaly) and liver (hepatomegaly) may cause severe abdominal pain. In addition, increased blood in the spleen may result in abnormally high pressure in the vein that carries blood from the spleen to the liver (portal hypertension). This can lead to increased blood flow in smaller veins in other abdominal organs that may rupture because of the high pressure, resulting in abdominal bleeding. In addition to the spleen and the liver, blood may form in other parts of the body, resulting in tumors made up of developing blood cells. Some patients with MF develop gout, a condition in which a build-up of uric acid results in inflammation and pain in the joints, especially the big toe. Approximately 20% of patients with MF develop acute myeloid leukemia (AML), a cancer of the blood.4
Both physical examination and a series of laboratory tests are used to determine if signs and symptoms are consistent with MF. Based on consensus, hematologists who are experts in the field of MPN have developed very specific criteria to confirm diagnosis of primary or secondary MF.
The World Health Organization (WHO) criteria for diagnosis of primary myelofibrosis5 are the current consensus criteria used for definitive diagnosis of PMF by hematologists. There are three major criteria and four minor criteria, determined by laboratory tests of samples of bone marrow (obtained via biopsy) and blood, as well as by physical examination. The major criteria are based on the presence of specific cell types and characteristics, as well as fibrosis in the bone marrow; ruling out the presence of another type of MPN or other blood disorder; and either the presence of a specific mutation on a gene called Janus kinase 2 (JAK2), the V617F mutation (present in approximately 65% of PMF patients),6 or other less common genetic mutations, or confirmation that the observations in the bone marrow are not due to an inflammatory disease or another type of malignancy. The minor criteria are based on the presence of immature blood cells and specific characteristics of blood cells on microscopic examination; anemia, indicated by low levels hemoglobin, the protein in RBCs that carries oxygen; elevated blood levels of a protein called lactate dehydrogenase, which may indicate tissue damage; and a physical examination indicating an enlarged spleen. A diagnosis of PMF requires the presence of all three major criteria and two of the four minor criteria.
The consensus criteria for the diagnosis of secondary MF that occurs in individuals with PV (called post-PV MF) and ET (called post-ET MF) were developed by the International Working Group for Myelofibrosis Research and Treatment.7 Major criteria for diagnosis of secondary MF are a confirmed previous diagnosis of PV or ET, and the presence of a certain degree of bone marrow fibrosis. In addition to the major criteria, at least two additional criteria, based on blood tests, physical examination showing enlargement of the spleen, and the presence of symptoms such as severe weight loss, night sweats, and fever (constitutional symptoms), must be present for diagnosis of secondary MF.
Treatments for MF are aimed primarily at managing symptoms and reducing the risks of complications of the condition. Treatments for MF that may be used depend on an individual’s age and the signs and symptoms they are experiencing. These factors help hematologists classify patients with MF into various risk categories, ranging from low to high, for the purpose of determining the best individual treatment option.
Hematologists who are experts in the field of MPN have developed consensus recommendations for the management and treatment of MF, based on both clinical practice and the body of evidence available from multiple research studies.8
Treatment for anemia may be initiated depending on hemoglobin level. Medications that stimulate the production of RBCs, such as darbepoetin and epoetin alfa may be used in individuals with anemia who have no or mild splenomegaly.9 These agents may not be effective if transfusions are required to maintain hemoglobin levels or if levels of the body’s endogenous protein for stimulating RBC production (erythropoietin) are low.9 Other medications that may be used to treat anemia include corticosteroids, androgen therapies (testosterone, fluoxymesterone, or danazol), and drugs known as immunomodulatory agents (thalidomide or lenalidomide).
Splenomegaly may be treated with medications known as cytoreductive agents, or agents that reduce the excess number of cells. The cytoreductive drug of choice is hydroxyurea. In some cases, cladribine, busulfan, or melphalan may be used. In severe cases where splenomegaly does not respond to drug therapy and is associated with discomfort and other uncontrolled signs and symptoms of MF, splenectomy (surgical removal of the spleen) may be an option. Radiation may be used in cases where splenectomy is not an option; however, its effects are transient, lasting a median of 3 of 6 months.
Since the consensus recommendations were published, a new drug, ruxolitinib (a drug that inhibits JAK2), was approved for treatment of symptoms of MF, including splenomegaly,10 providing an additional pharmaceutical option for treatment of this complication. The safety and effectiveness of other new drugs for the treatment of MF, including other JAK2 inhibitors, are currently being evaluated in clinical trials. In addition, support for the use of pegylated interferon-alpha in some patients with MF has recently been demonstrated.11
Treatments for splenomegaly also often help alleviate some of the constitutional symptoms associated with MF (e.g., early satiety, weight loss, night sweats, itching, and fever).
Allogeneic stem cell transplantation (alloSCT) is the only treatment that has the potential to cure MF.8 AlloSCT involves administration of high- or reduced-intensity regimens of chemotherapy or radiation to impair the bone marrow’s ability to make new stem cells, followed by transplantation of stem cells from a healthy donor. This treatment is associated with relatively high rates of side effects, including death, and its long-term effectiveness may be limited. AlloSCT may be a treatment option in younger patients classified with higher risk MF, where the risks and benefits of the procedure must be carefully weighed.
As with any treatment, there may be side effects associated with treatments for MF. Hematologists use the consensus recommendations as guidelines while considering what is the right treatment for an individual. Decisions regarding whether to treat and the right treatment for MF should be made considering the benefits and risks of the treatment, and these considerations may change over time.
- Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leukemia & Lymphoma. 2013;Early online: 1-6.
- Passamonti F, Rumi E, Caramella M, Elena C, Arcaini L, Boveri E, Del Curto C, Pietra D, Vanelli L, Bernasconi P, Pascutto C, Cazzola M, Morra E, Lazzarino M. A dynamic prognostic model to predict survival in post-polychythemia vera myelofibrosis. Blood. 2008;111:3383-3387.
- Barbui T, Theile J, Passamonti F, Rumi E, Boveri E, Ruggeri M, Rodeghiero F, D’Amore ESG, Randi ML, Bertozzi I, Marino F, Vannucchi AM, Antonioli E, Carrai V, Gisslinger H, Buxhofer-Ausch V, Mullauer L, Carobbio A, Gianatti A, Gangat N, Hanson CA, Tefferi A. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: An international study. J Clin Oncol. 2011;29:3179-3184.
- Cervantes F, Dupriez B, Pereira A, Passamonti F, Reilly JT, Morra E, Vannucchi AM, Mesa RA, Demory J-L, Barosi G, Rumi E, Tefferi A. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113:2895-2901.
- Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellstrom-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes. Blood. 2009;114:937-951.
- Tefferi A, Vainchenker W. Myeloproliferative neoplasms: Molecular pathophysiology, essential clinical understanding, and treatment strategies. J Clin Oncol. 2011;29(5):573-582.
- Barosi G, Mesa R, Thiele J, Cervantes F, Campbell PJ, Verstovek S, Durpiez B, Levine RL, Passamonti F, Gotlib J, Reilly JT, Vannucchi AM, Hanson CA, Solberg LA, Orazi A, Tefferi A, On behalf of the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: A consensus statement from the international working group for myelofibrosis research and treatment. Leukemia. 2008;22:437-438.
- Barbui T, Barosi G, Birgegard G, et al. Philadelphia-negative classical myeloproliferative neoplasms: critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol. Feb 20 2011;29(6):761-770.
- Tefferi A. How I treat myelofibrosis. Blood. 2011;117:3494-3504.
- Incyte Corporation. Prescribing information: JAKAFI®(ruxolitinib) tablets, for oral use. 2013.
- Ianotto JC, Boyer-Perrard F, Gyan E, Laribi K, Cony-Makhoul P, Demory J-L, De Renzis B, Dosquet C, Rey J, Roy L, Dupriez B, Knoops L, Legros L, Malou M, Hutin P, Ranta D, Schoenwald M, Andreoli A, Abgrall J-F, Kiladjian J-J. Efficacy and safety of pegylated-interferon -2a in myelofibrosis: A study by the FIM and GEM French cooperative groups. Br J Haematol. 2013;162:783-791.