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Myelofibrosis in agnogenic myeloid metaplasia (AMM) is a secondary reaction to the clonal hemopathy. Several biologic and clinical studies indicate that fibroblasts do not share a common origin with hematopoietic tissue agnogenic myeloid metaplasia. In patients with AMM, analysis of G6PD isoenzymes demonstrates that marrow fibroblasts contain both isoenzymes whereas blood cells contain only one, and karyotypic analyses show that marrow fibroblasts.
AMM occurs mainly in middle-age and elderly patients (median age at diagnosis is 60), and men and women are affected with equal frequency. AMM does occur in other age groups and has rarely been reported in children, with boys affected approximately twice as often as girls. A familial occurrence has been reported.
AMM may be asymptomatic in as many as 25% of patients, and the diagnosis is made after investigation of abnormal blood findings or the discovery of splenomegaly. Half or more of patients report fatigue. Weight loss is often noted (7 to 39%), and other evidence of a hypermetabolic state such as fever and night sweats occur in 5 to 20% of patients. Bleeding and ecchymoses occur in a similar proportion of patients. The patient may note a mass (spleen) in the abdomen, but other symptoms attributable to splenomegaly are uncommon, unless splenic infarction has occurred. Gout may be present and renal colic also may be an initial complaint.
Splenomegaly is the only abnormal physical finding in most patients at presentation. The spleen may be so large that its lower border is below the pelvic brim and its right border protrudes across the midline of the abdomen. Even when barely palpable, the spleen usually is firm. Absence of a palpable spleen is rare but does not exclude the diagnosis of AMM. Hepatomegaly is found in about 50% of patients; petechiae, ecchymoses, and lymphadenopathy are detected in a few. Portal hypertension may be present.
Natural History and Survival
AMM is incurable and has a median survival of 3 to 7 years. Less than 20% of patients survive more than 10 years. This prognosis approximates the median time to development of blast crisis in CML, and it is considerably worse than survival in the other CMPDs, essential thrombocythemia, and polycythemia vera. There may be an asymptomatic period that precedes the diagnosis.
Over time the severity of symptoms and cytopenias in AMM progress despite occasional spontaneous improvements. Even if it is not present at diagnosis, weight loss often becomes troublesome, particularly in the advanced stages of the disease. It usually appears to be out of proportion to the degree of anorexia. Edema of the lower extremities becomes more common with disease progression and may be produced by the enlarged spleen and liver with compression of the inferior vena cava. Infection, especially pneumonia, may supervene and may be related to subtle immune deficiency even in the absence of neutropenia, although both may be present. Coexisting serious illnesses, such as congestive heart failure or chronic lung disease, usually are present when death is
The causes of death in patients with AMM are variable. Infection, hemorrhage, cardiac failure, and cerebrovascular accidents are common, and death attributable to renal failure, hepatic failure, or thrombosis is reported in most series. In one series of 53 cases, death was due to cardiac causes in 18 cases, to hemorrhage in 13 cases, to leukemic conversion in 12 cases, and to infection in 7 cases. Leukemic conversion has been reported in 5 to 20% of patients with AMM, but in many instances the diagnosis of AML
Because many proposed treatments carry a significant risk of morbidity or even mortality, there must be a clear indication for the intervention. Standard care is supportive and directed toward specific complications. Because of variability in disease progression, many patients require no therapy for prolonged periods. Generally, asymptomatic patients require only observation. Allopurinol should be used to keep serum levels of uric acid within normal limits to avoid urate nephropathy and renal calculi and to reduce the
Androgens may be given to treat severe anemia, especially when the anemia results primarily from decreased red cell production . In a series of 23 patients, 57% responded to weekly injections of nandrolone with an increase in hematocrit to 30% or greater and
Some authors recommend aggressive treatment with chemotherapy early in the course of disease because AMM is a disorder of clonal stem cell proliferation. Because chemotherapy rarely induces a hematologic remission and has not yet been shown to alter the overall course of disease, most investigators have restricted its use to relief of symptoms. Cytoreductive therapy can often reduce the size of the liver and spleen and alleviate weight loss, fever and night sweats. It may also be useful in reducing leukocyte and
Several situations warrant use of radiation therapy. Symptoms of splenic enlargement, splenic infarction, or cytopenias related to hypersplenism may respond to irradiation when there is a contraindication to splenectomy. In one small series, 71% of patients treated for pain experienced relief and 16 of 26 patients treated for splenomegaly experienced a greater than 50% reduction in spleen size. Small x-ray fractions (15 to 100 rad) given 3 days per week and a low total dose (15 to 650 rad) gave satisfactory
Splenectomy should be considered for portal hypertension and for symptoms of painful splenomegaly. Although the spleen is a site of extramedullary hematopoiesis, the bone marrow remains the major producer of blood cells, so an aplastic crisis does not occur postoperatively despite concerns of some early investigators. Splenectomy is thus also useful for treatment of refractory hemolytic anemia, severe thrombocytopenia, or excessive transfusion requirement. However, the procedure is hazardous in AMM patients
Several treatment schemes have been attempted based on increased understanding of the pathogenesis of AMM. Interferons have been tried in small numbers of patients based on their in vitro activity in suppressing actions of TGF-beta and their efficacy in treating CML. Interferon-alpha has been reported to diminish bone pain, thrombocytopenia, and splenic enlargement, but its efficacy is limited by severe flu-like symptoms and, on occasion, worsened anemia. Vitamin D analogs have antiproliferative effects on