Myelofibrosis with myeloid metaplasia (MMM) is a CMPD characterized by bone marrow fibrosis, proliferation of megakaryocytic and granulocytic cells, and extramedullary hematopoiesis. MMM presents with an elevated WBC, teardrop RBCs, normocellular or hyper-cellular bone marrow, leukoerythroblastic anemia, splenomegaly, and the absence of the Philadelphia chromosome.28,29 MMM is a clonal hematopoietic stem cell expansion in the bone marrow with the production of reticulin and bone marrow fibrosis.30,31 Table 12.9 summarizes the key facts found in MMM.
There are many synonyms for this myeloprolif-erative disorder; they include agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis, idiopathic myelofibrosis, primary myelofibrosis, leukoerythroblas-tic anemia, and myelosclerosis with myeloid metaplasia.
The etiology of this disorder is unknown, and the mechanism of myelofibrosis is poorly understood. The clonal proliferation of hematopoietic stem cell is thought to produce growth factors and an abnormal cytokine release that mediates a bone marrow reaction that leads to fibrosis of the bone marrow.32,33 Platelets, megakaryocytes, and monocytes are thought to secrete cytokines, transforming growth factor beta (TGF beta), platelet-derived growth factor (PDGF), interleukin 1, and fibroblast growth factor, which may result in formation of the bone marrow matrix.32,33
Table 12.9 O Key Facts of Myelofibrosis
• Fibrosis of the bone marrow/reticulin silver stain
• Teardrop RBCs
• Absence of the Philadelphia chromosome
MMM has an evolution in the disease process. The initial phase is the prefibrotic stage, which is characterized by a hypercellular bone marrow with minimal reti-culin. The second phase is the fibrotic stage, which is characterized by the bone marrow having marked retic-ulin or collagen fibrosis. Normal hematopoiesis is blocked as the bone marrow becomes more fibrotic. This stage is characterized by a leukoerythroblastic blood smear: immature white cells and nRBCs combined with teardrop RBCs. Patients become pancy-topenic (decrease in all three cell lines). Extramedullary hematopoiesis contributes to the leukoerythroblastic blood picture, splenomegaly, and hepatomegaly. Myelofibrosis is a complicating reactive feature of the primary disease process.
In the early stages of the disease, the patient may be asymptomatic. Patients with myelofibrosis exhibit splenomegaly, an anemia, and marrow fibrosis. Many of the signs and symptoms are attributed to the pancy-topenia associated with the presence of a fibrotic bone marrow. Pancytopenia occurs as a result of decreased cell production because of the fibrosis marrow or ineffective hematopoiesis with increased spleen sequestration. Most patients exhibit symptoms of anemia. Patients who are thrombocytopenic and neutropenic tend to have bleeding tendencies and infection. Other symptoms include night sweats, low-grade fever, weight loss, and anorexia. Patients often complain of left upper quadrant discomfort due to the enlarged spleen and liver. Patients with myelofibrosis develop osteosclerosis, which can cause severe joint pain.
The peripheral blood and bone marrow biopsy provide information for diagnosis. The WBC and platelet counts may increase initially but will decrease as the disease progresses. The typical picture is a blood smear that shows leukoerythroblastosis and teardrop red cells (Fig. 12.4). Large platelets, megakaryocyte fragments, and immature blood cells may be found due to the crowding out of normal cell development by fibrosis in the bone marrow. A normocytic, normochromic anemia is present with hemoglobin of less than 10 g/dL.
The bone marrow is hypercellular with increased and abnormal megakaryocytes and megakaryocyte clusters. Bone marrow aspirates are sometimes dry taps in about 50% of the patients. This refers to the inability
of the physician to obtain a sample because the normal architecture of the bone marrow is disrupted by fibrotic tissue, reticulin.
Diagnosis is made on the basis of detecting splenomegaly and of the result of the CBC. Splenomegaly is the most common finding, followed by hepatomegaly.34 The PVSG has criteria for myelofibrosis as follows: splenomegaly, fibrosis of the bone marrow, a leukoery-throblastic blood picture, absence of increased RCM, absence of the Philadelphia chromosome, and exclusion of any other systemic disease. Table 12.10 summarizes the diagnostic criteria of MMM.35
There are no specific genetic defects. Cytogenetic abnormalities occur in about 60% of the patients.36 Cytogenetics rule out CML, myelodysplastic syndrome, and other chronic myeloid disorders. Various chromosomal abnormalities may occur, with the most common being del(13q), del(20q), and partial trisomy 1q.36
There are no available treatments to reverse the process of myelofibrosis. Asymptomatic patients are observed and require no treatment. Therapy for MMM is mainly supportive for the anemia and thrombocythemia. Hydroxyurea is used as a cytoreductive therapy to control leukocytosis, thrombocytosis, and organomegaly.28 Interferon-alfa is used in patients younger than 45 years. Splenectomy may be considered for treating patients with symptomatic splenomegaly that is refractory to hydroxyurea.37 Radiation may be used to treat
196 Part III • White Cell Disorders
Table 12.10 O Diagnostic Criteria for Myelofibrosis
A1 No preceding or allied subtype of CMPDs
A2 Early clinical stages
Slight or moderate splenomegaly
Thrombocythemia platelets >400 X 109/L
A3 Intermediate clinical stage
Definitive leukoerythroblastic blood picture/teardrop RBCs Splenomegaly No advance signs A4 Advanced clinical stage
One or more adverse signs Pathological Criteria
B1 Megakaryocytic and granulocytic proliferation Reduction RBC precursors Abnormal giant-sized megakaryocytes
Adapted from Spivak JL, Barosi G, Tognoni G, et al. Chronic myeloproliferative disorders. Hematology 1:200-224, 2003.
symptomatic extramedullar hematopoiesis. A more aggressive approach is an allogeneic peripheral stem cell or bone marrow transplant.38
MMM has the worst prognosis of all the myeloproliferative disorders. The median survival is approximately 3 to 5 years from diagnosis.29 The major causes of death are infection, cardiovascular disease, hemorrhage, thrombosis, progressive marrow failure, and transformation into an acute leukemia.29,31 Prognostic factors that affect survival include age, anemia, leukopenia, leukocytosis, circulating blasts, and karyotype abnormalities. There is a shorter survival with poor prognostic values.28,39
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