Agnogenic Myeloid Metaplasia With Myelofibrosis 

Agnogenic myeloid metaplasia with myelofibrosis is a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells.^{[1, 2, 3, 4]} Agnogenic myeloid metaplasia is categorized as a chronic myeloproliferative disorder, along with chronic myelogenous leukemia (CML), polycythemia vera, and essential thrombocytosis. (See Etiology.)^[5]

The disorder is characterized by anemia, bone marrow fibrosis (myelofibrosis), extramedullary hematopoiesis, leukoerythroblastosis, teardrop-shaped red blood cells (RBCs) in peripheral blood, and hepatosplenomegaly (see the image below). (See Workup.)

Complications

Portal hypertension occurs in approximately 7% of patients with agnogenic myeloid metaplasia 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 Clinical, 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 agnogenic myeloid metaplasia may require splenectomy or splenic irradiation. (See Clinical 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 agnogenic myeloid metaplasia 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.

For patient education information, see the Cancer Center, as well as Anemia.

In patients with agnogenic myeloid metaplasia, the hematopoietic system is most affected. Other organ systems may be involved via extramedullary hematopoiesis. (See the image below.)

Clonality studies in patients with agnogenic myeloid metaplasia 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 agnogenic myeloid metaplasia 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 agnogenic myeloid metaplasia have substantial increases in bone marrow microvessel density. Neoangiogenesis in agnogenic myeloid metaplasia is noted in medullary and extramedullary hematopoiesis. Increased serum vascular endothelial growth factor levels have been postulated as the underlying mechanism for increased angiogenesis.

Risk factors

No specific risk factors can be identified in most patients with agnogenic myeloid metaplasia, although exposure to radiation, Thorotrast contrast agents, and industrial solvents (eg, benzene, toluene) have been associated with an increased risk.^{[6, 7, 8, 9]}

A study by Fredericksen et al found that patients with chronic myeloproliferative neoplasms have an increased incidence of secondary hematologic and nonhematologic cancers. Patients with essential thrombocytopenia had a standardized incidence ratio for developing nonhematologic cancer of 1.2; patients with polycythemia vera had a ratio of 1.6; and patients with CML had a ratio of 1.6.^[10]

Agnogenic myeloid metaplasia 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.

Race-, sex-, and age-related demographics

Agnogenic myeloid metaplasia 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 agnogenic myeloid metaplasia; however, in younger children, girls are affected twice as frequently as boys.

Agnogenic myeloid metaplasia 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. Agnogenic myeloid metaplasia in children usually occurs in the first 3 years of life.

The median length of survival for patients with agnogenic myeloid metaplasia is 3.5-5.5 years. The 5-year survival rate is about half of that expected for age- and sex-matched controls. Less than 20% of patients are expected to be alive at 10 years.^[11] The common causes of death in patients with agnogenic myeloid metaplasia are infections, hemorrhage, cardiac failure, postsplenectomy mortality, and leukemic transformation. Leukemic transformation occurs in approximately 20% of patients with agnogenic myeloid metaplasia within the first 10 years.

Advanced age and anemia are associated with shorter survival, and renal failure, hepatic failure, and thrombosis have also been reported as causes of death.

Other poor prognostic factors of agnogenic myeloid metaplasia include the presence of hypercatabolic symptoms, leukocytosis (leukocyte count of 10,000-30,000/μL), leukopenia, circulating blasts, increased numbers of granulocyte precursors, thrombocytopenia (platelet count of < 100,000/μL), and karyotype abnormalities.

Bone marrow vascularity is significantly increased in patients with agnogenic myeloid metaplasia. Increased bone marrow microvascular density has also been reported in approximately 70% of patients with agnogenic myeloid metaplasia, and it is an independent poor prognostic factor for survival.

Scoring systems

A simple scoring system to determine the prognosis in agnogenic myeloid metaplasia has been proposed.^[12] This system uses 2 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 (DIPSS) for primary myelofibrosis uses the following 5 risk factors to predict survival:

• Age older than 65 years
• Hemoglobin level lower than 10 g/dL
• Leukocyte count higher than 25 10⁹/L
• Circulating blasts of 1% or more
• Constitutional symptoms

A 2011 study was carried out to refine the DIPSS by incorporating prognostic information from karyotype, platelet count, and transfusion status. The study also found that the presence of either unfavorable karyotype or thrombocytopenia predicted inferior leukemia-free survival.^[13]