Myelofibrosis with Myeloid Metaplasia (MMM)/Idiopathic myelofibrosis/Agnogenic myeloid metaplasia

Disease Chronic myeloproliferative disorder Phenotype / cell stem origin The disease is a chronic myeloproliferative disorder originating from a mutated pluripotent stem cell capable of producing red blood cells, granulocytes, megakaryocytes and lymphoid cells. Fibrosis of the marrow is the hallmark of the disease, however fibroblasts are not part of the malignant process and fibrosis represents a reaction of marrow stromal cells. Epidemiology MMM has an incidence of 0.3 to 1.5 new cases per year in 100.000 persons. Male predominance was observed in some studies and not confirmed in others. The average age at diagnosis is 60 years. Exposure to radiation and to organic solvents increases the risk of developing MMM. Clinics MMM usually presents with fatigue, weight loss, splenomegaly with or without symptoms. Anemia and various alterations of the white blood cell and/or platelet count are frequently seen at diagnosis. Thrombocytopenia-related bleeding may occur. MMM must be distinguished from myelodysplasia with fibrosis, from acute megakayoblastic leukemia and . CLINICS As the disease progresses, increased marrow fibrosis with severe symptomatic peripheral cytopenias and extramedullary hemopoiesis predominate, with consequent massive splenomegaly, hepatomegaly with portal hypertension, pulmonary hypertension. Leukemic transformation may represent the terminal event in 5-20% of the cases. Cytology Teardrop poikilocytosis and leukoerythroblastosis are present in the peripheral blood (PB) smear. Platelet are increased in size. The bone marrow is usually hypercellular at presentation with remarkably increased megakaryocytes and, to a lesser degree, granulocytes. Reticulin fibrosis is always present. Hemopoietic cellularity is patchy, with some areas showing hypercellularity and other being depleted of hemopoietic cells. The spleen histology shows extramedullary hemopoiesis involving predominantly the sinusoids. Treatment The treatment depends on the patient¹s general condition and symptoms. Supportive treatment is required for anemia and profound thrombocytopenia. Cytoreductive treatment with busulphan, hydroxyurea, thioguanine, low-dose melphalan or chlorambucil, interferon-a may be useful to control progressive splenomegaly. Irradiation of the spleen may be also employed. Danazol or low-dose dexamethasone can be used to ameliorate anemia. Allogeneic bone marrow transplantation should be considered for patients aged 60 years or less. Prognosis The median survival is approximately 5 years. Causes of death include infection, leukemic transformation, bleeding, hepatic failure with portal hypertension due to myeloid metaplasia, heart failure. Cytogenetics Cytogenetics Morphological a) Chromosome lesions: The absence of the t(9;22)/BCR-ABL fusion is an absolute diagnostic requirement. Approximately 40-50% of the patients analyzed at diagnosis show a clonal defect. The proportion of cytogenetically abnormal cases increases at disease transformation into acute leukemia, were up to 90% of the cases carry a clonal defect. Non-random chromosome aberrations are del(13q), del(20q) and gain of 1q. These abnormalities represented 65% of abnormal cases in a study. Other recurrent chromosome aberrations include trisomy 8 and del(12p) , monosomy 7/del(7q) , der(6)t(1;6)(q21-23;p21.3). The latter abnormality leads to trisomy 1q21-23 to 1qter and to loss of 6p21 to 6pter. FISH on deparaffinized bone biopsies showed a 56% incidence of cytogenetic lesions in a study using probes for 7q31, 12p, 13q14, 17p13, 20q13, 21q22, cen7, cen8, cen11 and cen17. b) Prognostic significance: The presence of abnormal karyotype does not appear to be an independent prognostic factor, whereas +8, 12p deletion and -7/7q- were associated with an inferior outcome at multivariate analysis.