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Myelofibrosis with Myeloid Metaplasia

Myelofibrosis with myeloid metaplasia represents both agnogenic myeloid metaplasia and the fibrotic stages of polycythemia vera and essential thrombocythemia. The latter two conditions are also referred to as post polycythemic myelofibrosis and post thrombocythemic myelofibrosis. Myelofibrosis with myeloid metaplasia is currently classified under the broad category of chronic myeloid disorders. Classification of the chronic myeloid disorders is based on certain molecular, cytogenetic, morphologic, and clinical characteristics. In the context of a chronic myeloid disorder, the demonstration of the bcr/ab1 genetic translocation between chromosomes 9 and 22 mandates a diagnosis of chronic myelocytic leukemia. The bcr/abl-negative group may be divided into two major subgroups; the myelodysplastic syndrome and the chronic myeloproliferative disorders.

The peripheral blood smear provides the first clue to the diagnosis of myelofibrosis with myeloid metaplasia. The characteristic feature of myelophthisis includes the presence of teardrop-shaped red blood cells, nucleated erythrocytes and granulocytes.

However, a myelophthisic blood picture may also result from bone marrow infiltration by metastatic cancer or infectious granulomata. The bone marrow biopsy is required for establishing the diagnosis. However, there are several other causes of bone marrow fibrosis than need to be considered before the diagnosis of myelofibrosis with myeloid metaplasia.

Clinical aspects

Myelofibrosis with myeloid metaplasia is the least frequent among the chronic myeloproliferative disordersand its incidence is estimated to be 1.3/100,000/year in Olmstead County, Minnesota. The median age at presentation is 60 years with a male to female ratio of 1.2:1. Approximately 5 and 17 percent of the patients are diagnosed before the age of 40 and 50 years, respectively. Most patients present with anemia and marked splenomegaly.

The major cause of hepatosplenomegaly in myelofibrosis with myeloid metaplasia is extramedullary hematopoiesis. Hepatomegaly is often associated with markedly elevated levels of alkaline phosphatase, a fraction of which comes from the bone as a result of associated osteosclerosis. Extramedullary hematopoiesis may involve many other organs including lymph nodes 0ymphadenopathy), the peritoneum (ascites), pleura (pleural effusion), paraspinal and epidural spaces (cord compression), urinary bladder (dysuria), intestinal tract (polyps), the pulmonary parenchyma (respiratory distress), the pericardium (tamponade).

Portal hypertension in agnogenic myeloid metaplasia may develop as a result of either massive splenomegaly (increased splanchnic blood flow) or intrahepatie obstruction (presinusoidal EMH, portal fibrosis, thrombotic obliteration of small portal veins).


Reported median survival times in myelofibrosis with myeloid metaplasia vary substantially with average figures between 3 to 5 years. According to a recent study, risk factors for decreased survival were advanced age (>60 years), hepatomegaly, weight loss, anemia (hemoglobin <10 gm/dL), leukocytosis (white count >30,000/:L), leukopenia (white count <4,000/:L), circulating blasts >2 percent, male sex, thrombocytopenia (platelet count < 150,000/:L).


At present, only allogeneic hematopoietic stem cell transplantation has a "curative" potential in myelofibrosis with myeloid metaplasia. Earlier studies had raised some concern regarding successful engraftment of stem cells in a fibrotic marrow. However, more recent studies have demonstrated the lack of an adverse effect, on stem cell engraftment, of bone marrow fibrosis and the curative potential of allogeneic hematopoietic stem cell transplantationin both agnogenic myeloid metaplasia and PPMM/PTMM.

The combination of an androgen preparation (fluoxymesterone, Halotestin, 10 mg orally twice a day) and a corticosteroid (prednisone 30 mg orally) improves anemia in approximately 25%.

Hydroxyurea (starting dose 500 mg PO BID) may result in reduction of spleen size and control of thrombocytosis and leukocytosis in some patients. Unfortunately, anemia may get worse on HU therapy and thrombocytopenia may develop. When HU fails to control splenomegaly associated complications (mechanical discomfort, hypercatabolic symptoms.

After splenectomy, almost all patients experience improvement in hypercatabolic symptoms and portal hypertension. In addition, approximately a third of the patients with refractory anemia may benefit from splenectomy.

Current investigational therapeutic approaches in myelofibrosis with myeloid metaplasia include allogeneic hematopoietic stem cell transplantation, autologous hematopoietic stem cell transplantation, and the use of a variety of anti-fibroid and anti-angiogenic drugs. Preliminary results from some of these treatment trials will be available.