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Myelofibrosis

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. In patients with AMM, analysis of G6PD isoenzymes demonstrates that marrow fibroblasts contain both isoenzymes whereas blood cells contain only one.

Features of Disease at Diagnosis

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.

Symptoms

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

Signs

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 at

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, leading to some variability in survival statistics. On the basis of the average observed rate of splenic enlargement, Ward and Block estimated that the disease may already have been present for 1 year for each centimeter that the spleen extends below the

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

Therapy

No form of therapy has as yet been shown to prolong survival or to have a consistent beneficial effect on the progression of myelofibrosis. 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

Androgens and Corticosteroids

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

 

TABLE 92-3 -- Therapy for Patients with AMM
Indication Therapeutic Option
Asymptomatic Observation
Hyperuricemia or gout Allopurinol
Anemia Trial of androgens and corticosteroids

Transfusion

  Splenectomy for refractory

  Hemolysis or

  Excessive transfusion requirement
Severe thrombocytopenia Splenectomy
Splenic pain Splenectomy or irradiation
Portal hypertension Splenectomy
Symptomatic extramedullary focus Irradiation
Severe hypermetabolic symptoms Chemotherapy
Hepatomegaly after splenectomy Chemotherapy
Symptomatic thrombocytosis Chemotherapy

Chemotherapy

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

Irradiation

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

Splenectomy

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

Experimental Therapies

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 megakaryocytes, which appear to be a major source of cytokines promoting myelofibrosis , and it has been observed that treatment of rickets with vitamin D may reverse myelofibrosis associated with that condition. Based on these considerations, vitamin D

Surgical removal of fibrous tissue from the marrow cavities has been used to shift hematopoiesis into the medullary space again in patients with several types of myelofibrosis. Mechanical curettage of small amounts (150 g) of fibrotic marrow from the iliac bones of one patient with AMM was associated with an increase in hemoglobin values despite the observation that fibrosis recurred in the