Primary myelofibrosis is a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells. [1, 2, 3, 4] Older terms for this disorder include agnogenic myeloid metaplasia with myelofibrosis and chronic idiopathic myelofibrosis.  Primary myelofibrosis is categorized as a chronic myeloproliferative disorder, along with chronic myelogenous leukemia (CML), polycythemia vera, and essential thrombocytosis. (See Etiology.) 
The disorder is characterized by the following (see Workup):
Bone marrow fibrosis (myelofibrosis)
Leukoerythroblastosis and teardrop-shaped red blood cells (RBCs) in peripheral blood (see the image below)
Treatment for primary myelofibrosis is tailored to disease severity. Observation alone may be appropriate for low-risk, asymptomatic disease. Mild cases may require only supportive therapy. Higher-risk disease may respond to ruxolitinib. Splenomegaly may be an indication for splenectomy. Finally, allogeneic stem cell transplantation is a potentially curative. See Treatment and Medication.
Portal hypertension occurs in approximately 7% of patients with primary myelofibrosis and may be related to increased portal flow resulting from marked splenomegaly and to intrahepatic obstruction resulting from thrombotic obliteration of small portal veins. This may result in variceal bleeding or ascites. Hepatic or portal vein thrombosis may occur. Symptomatic portal hypertension is managed by splenectomy, with or without the creation of a portosystemic shunt. (See Presentation, Workup, and Treatment.)
Splenic infarction may occur and results in an acute or subacute onset of severe pain in the left upper quadrant that may be associated with nausea, fever, and referred left shoulder discomfort. The episode is usually self-limited and may last several days. Treat patients with hydration and opiate analgesics. Individuals with refractory cases of primary myelofibrosis may require splenectomy or splenic irradiation. (See Presentation and Treatment.)
Extramedullary hematopoiesis may involve any organ, and symptoms depend on the organ or site of involvement. It may result in gastrointestinal (GI) tract bleeding, spinal cord compression, seizures, hemoptysis, and/or effusions. These are easily controlled with low-dose radiation. (See Treatment.)
Patients with primary myelofibrosis are also prone to developing infectious complications because of defects in humoral immunity.
Osteosclerosis, hypertrophic osteoarthropathy, and periostitis may occur, resulting in significant pain and discomfort. This may require the administration of nonsteroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics. Gout or urate stones may develop as a result of uric acid overproduction. Allopurinol should be used to keep uric acid in the reference range.
In patients with primary myelofibrosis, the hematopoietic system is most affected. Other organ systems may be involved via extramedullary hematopoiesis. (See the image below.)
Clonality studies in patients with primary myelofibrosis demonstrate that myeloid cells arise from clonal stem cells; however, bone marrow fibroblasts and, sometimes, T cells are polyclonal. The cause of the excessive marrow fibrosis observed in primary myelofibrosis remains unclear.
Platelets, megakaryocytes, and monocytes are thought to secrete several cytokines, such as transforming growth factor beta (TGF-β), platelet-derived growth factor (PDGF), interleukin 1 (IL-1), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), which may result in fibroblast formation and extracellular matrix proliferation. In addition, endothelial proliferation and growth of capillary blood vessels in the bone marrow are observed and may be a result of TGF-β and bFGF production.
Neoangiogenesis is a hallmark feature of chronic myeloproliferative disorders. Approximately 70% of patients with primary myelofibrosis have substantial increases in bone marrow microvessel density. Neoangiogenesis in primary myelofibrosis is noted in medullary and extramedullary hematopoiesis. Increased serum vascular endothelial growth factor levels have been postulated as the underlying mechanism for increased angiogenesis.
Approximately 50-60% of patients with primary myelofibrosis have a gain-of-function mutation in the Janus kinase 2 (JAK2) gene, the JAK2 V617F mutation, which leads to increased cytokine responsiveness of myeloid cells. Another 5-10% of patients somatic mutations of JAK2 exon 12 or activating mutations of the thrombopoietin receptor gene MPL. In two separate studies, Klampfl et al and Nangalia et al found that mutations in the gene encoding calreticulin (CALR) were present in the majority of patients who lacked mutations in JAK2 or MPL. [7, 8] Mutations in NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 have been found in <5% of patients. 
No specific risk factors can be identified in most patients with primary myelofibrosis. However, exposure to radiation, Thorotrast contrast agents, and industrial solvents (eg, benzene, toluene) have been associated with an increased risk. [10, 11, 12, 13]
Primary myelofibrosis is an uncommon disease, with an annual incidence of approximately 0.5-1.5 cases per 100,000 individuals in the United States. The worldwide incidence of the disorder is unknown.
Primary myelofibrosis appears to be more common in white people than in individuals of other races. In addition, an increased prevalence rate of the disorder has been noted in Ashkenazi Jews.
A slight male preponderance appears to exist for primary myelofibrosis; however, in younger children, girls are affected twice as frequently as boys.
Primary myelofibrosis characteristically occurs in individuals over age 50 years, with the median age at diagnosis being approximately 65 years. However, the disease has been reported in persons in all phases of life, from neonates to octogenarians.
Approximately 22% of affected patients are younger than 56 years. Primary myelofibrosis in children usually occurs in the first 3 years of life.
The median length of survival for patients with primary myelofibrosis is 3.5-5.5 years. The 5-year survival rate is about half of that expected for age- and sex-matched controls. Fewer than 20% of patients are expected to be alive at 10 years.  The common causes of death in patients with primary myelofibrosis are infections, hemorrhage, cardiac failure, postsplenectomy mortality, and transformation into acute leukemia. Leukemic transformation occurs in approximately 20% of patients with primary myelofibrosis within the first 10 years.
Advanced age and anemia are associated with shorter survival. Renal failure, hepatic failure, and thrombosis have also been reported as causes of death.
Other poor prognostic factors include the following:
Leukocytosis (leukocyte count of 10,000-30,000/μL)
Increased numbers of granulocyte precursors
Thrombocytopenia (platelet count of <100,000/μL)
Bone marrow vascularity is significantly increased in patients with primary myelofibrosis. Increased bone marrow microvascular density has also been reported in approximately 70% of patients with primary myelofibrosis, and it is an independent poor prognostic factor for survival.
A study of 570 patients with primary myelofibrosis found that prognostic significance exists for carriage of mutations in CALR (favorable) and ASXL1 (unfavorable). Patients who were CALR + ASXL1 – had the longest survival (median 10.4 years), whereas those who were CALR –ASXL1 + the shortest survival (median 2.3 years). Patients who were either CALR + ASXL1 + or CALR –ASXL1 – had similar rates of survival (median 5.8 years). The prognostic model was independent of the dynamic international prognostic scoring system (DIPSS; see below). 
Rozovski and colleagues developed a prognostic model for primary myelofibrosis consisting of four elements: age and mutations in the Janus kinase 2 (JAK2), CALR, and myeloproliferative leukemia virus (MPL) genes. By itself, the JAK2V617F allele burden proved to have prognostic significance: median overall survival (OS) was 80 months in patients with a JAK2V617F allele burden of 50% or over, versus 50 months in those with a JAK2V617F allele burden of less than 50% (P=0.01). 
The best prognosis, with a median survival of 126 months, was seen in patients aged 65 years or under who had a low JAK2V617F allele burden and CALR and MPL mutations. The worst was in patients older than 65 years with a low JAK2V617F allele burden or no JAK2, CALR, or MPL mutations (“triple negative”) who had a median survival of only 35 months. Intermediate survival duration occurred in patients with one risk factor. 
A simple scoring system to determine the prognosis in primary myelofibrosis has been proposed.  This system uses two adverse prognostic factors: a hemoglobin value of less than 10 g/dL and a total white blood cell (WBC) count of less than 4000/μL or greater than 30,000/μL. Patients with no risk factors are at low risk, those with both the risk factors are at high risk, and those with a single risk factor are at intermediate risk. Median survival times for low-risk groups are 93 months; intermediate-risk groups, 26 months; and high-risk groups, 13 months.
Low-risk patients with an abnormal karyotype have a worse outcome than do those with a normal karyotype (median survival, 50 mo vs 112 mo). Leukocytosis (>30,000/μL) and abnormal karyotype have reportedly been associated with increased risk of transformation to acute myelogenous leukemia (AML).
The Dynamic International Prognostic Scoring System–plus (DIPSS-plus) for primary myelofibrosis uses the following eight adverse factors to predict survival  :
Age older than 65 years
Hemoglobin level lower than 10 g/dL
Leukocyte count higher than 25 × 109/L
Platelet count lower than 100 × 109 /L
Circulating blasts of 1% or more
Red cell transfusion dependency
Unfavorable karyotype (ie, complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), 5/5q-, 12p-, or 11q23 rearrangement)
DIPSS plus classifications and median survival times are as follows:
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Asheesh Lal, MBBS, MD Physician, Department of Internal Medicine, Lexington Medical Center
Disclosure: Nothing to disclose.
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences
Disclosure: Nothing to disclose.
Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College
Disclosure: Received honoraria from Novartis for speaking and teaching; Received consulting fee from Novartis for speaking and teaching; Received honoraria from Celgene for speaking and teaching.
Author: Asheesh Lal, MBBS, MD, Physician, Department of Internal Medicine, Lexington Medical Center.
Editors: Karen Seiter, MD, Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College; Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference; Emmanuel C Besa, MD, Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University.
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