Idiopathic Myelofibrosis

Chronic IMF (other designations include agnogenic myeloid metaplasia or myelofibrosis with myeloid metaplasia) is a clonal disorder of a multipotent hematopoietic progenitor cell of unknown etiology characterized by marrow fibrosis, extramedullaryhematopoiesis, and splenomegaly. Chronic IMF is the least common chronic myeloproliferative disorder, and establishing this diagnosis in the absence of a specific clonal marker is difficult because myelofibrosis and splenomegaly are also features of both PV and CML. Furthermore, myelofibrosis and splenomegaly also occur in a variety of benign and malignant disorders, many of which are amenable to specific therapies not effective in chronic IMF. In contrast to the other chronic myeloproliferative disorders and so-called acute or malignant myelofibrosis, which can occur at any age, chronic IMF primarily afflicts individuals in their sixth decade or later.

Etiology

The etiology of chronic IMF is unknown. Nonrandom chromosome abnormalities such as 9p, 20q-, 13q-, trisomy 8 or 9, or partial trisomy 1q are common, but no cytogenetic abnormality specific to the disease has been identified. The degree of myelofibrosis and the extent of extramedullaryhematopoiesis are also not related. Fibrosis in this disorder is associated with overproduction of transforming growth factor β and tissue inhibitors of metalloproteinases, while osteosclerosis is associated with overproduction of osteoprotegerin, an osteoclast inhibitor. Marrow angiogenesis occurs due to increased production of vascular endothelial growth factor (VEGF). Importantly, fibroblasts in chronic IMF are polyclonal and not part of the neoplastic clone.

Clinical Features

No signs or symptoms are specific for chronic IMF. Many patients are asymptomatic at presentation, and the disease is usually detected by the discovery of splenic enlargement and/or abnormal blood counts during a routine examination. However, in contrast to its companion myeloproliferative disorders, night sweats, fatigue, and weight loss may be presenting complaints. A blood smear shows the characteristic features of extramedullaryhematopoiesis: teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes; myeloblasts may also be present. Anemia, usually mild initially, is the rule, while the leukocyte and platelet counts are either normal or increased, but either can be depressed. Mild hepatomegaly may accompany the splenomegaly but is unusual in the absence of splenic enlargement; isolated lymphadenopathy should suggest another diagnosis. Both serum lactate dehydrogenase and alkaline phosphatase levels can be elevated. The LAP score can be low, normal, or high. Marrow is usually inaspirable due to the myelofibrosis, and bone x-rays may reveal osteosclerosis. Exuberant extramedullaryhematopoiesis can cause ascites, portal, pulmonary or intracranial hypertension, intestinal or ureteral obstruction, pericardial tamponade, spinal cord compression, or skin nodules. Splenic enlargement can be sufficiently rapid to cause splenic infarction with fever and pleuritic chest pain. Hyperuricemia and secondary gout may ensue.

Diagnosis

While the clinical picture described above is characteristic of chronic IMF, all of the clinical features described can also be observed in PV or CML. Massive splenomegaly commonly masks erythrocytosis in PV, and reports of intraabdominal thromboses in chronic IMF most likely represent instances of unrecognized PV. In some patients with chronic IMF, erythrocytosis has developed during the course of the disease. Furthermore, since many other disorders have features that overlap with chronic IMF but respond to distinctly different therapies, the diagnosis of chronic IMF is one of exclusion, which requires that the disorders listed in Table 103-3 be ruled out. A diagnostic algorithm has been proposed but does not distinguish one disease causing myeloid metaplasia from another.

The presence of teardrop-shaped red cells, nucleated red cells, myelocytes, and promyelocytes establishes the presence of extramedullaryhematopoiesis, while the presence of leukocytosis, thrombocytosis with large and bizarre platelets, and circulating myelocytes suggests the presence of a myeloproliferative disorder as opposed to a secondary form of myelofibrosis. Marrow is usually not aspirable due to increased marrow reticulin, but marrow biopsy will reveal a hypercellular marrow with trilineage hyperplasia and, in particular, increased numbers of megakaryocytes in clusters and with large, dysplastic nuclei However, there are no characteristic morphologic abnormalities that distinguish IMF from the other chronic myeloproliferative disorders. Splenomegaly due to extramedullaryhematopoiesis may be sufficiently massive to cause portal hypertension and variceal formation. In some patients, exuberant extramedullaryhematopoiesis can dominate the clinical picture. An intriguing feature of chronic IMF is the occurrence of autoimmune abnormalities such as immune complexes, antinuclear antibodies, rheumatoid factor, or a positive Coombs' test. Whether these represent a host reaction to the disorder or are involved in its pathogenesis is unknown. Cytogenetic analysis of blood is useful both to exclude CML and for prognostic purposes, because complex karyotype abnormalities portend a poor prognosis in chronic IMF. For unknown reasons, the number of circulating CD34+ cells is markedly increased in chronic IMF (>15,000/ µL) compared to the other chronic myeloproliferative disorders, unless they too develop myeloid metaplasia. Importantly, approximately 45% of chronic IMF patients, like patients with its companion myeloproliferative disorders PV and ET, express the JAK2 V617F mutation, often as homozygotes. Such patients had a poorer survival in one retrospective study but not in another, where they were found to be older and to have higher hematocrits than those patients who were JAK2 V617F-negative.

Complications

Survival in chronic IMF varies according to specific clinical features but is shorter than in patients with PV or ET. The natural history of chronic IMF is one of increasing marrow failure with transfusion-dependent anemia and increasing organomegaly due to extramedullaryhematopoiesis. As with CML, chronic IMF can evolve from a chronic phase to an accelerated phase with constitutional symptoms and increasing marrow failure. About 10% of patients develop an aggressive form of acute leukemia for which therapy is usually ineffective. Important prognostic factors for disease acceleration include anemia, leukocytosis, thrombocytopenia, the presence of circulating myeloblasts, older age, the presence of complex cytogenetic abnormalities, and constitutional symptoms such as unexplained fever, night sweats, or weight loss.

Chronic Idiopathic Myelofibrosis: Treatment

No specific therapy exists for chronic IMF. Anemia may be due to gastrointestinal blood loss and exacerbated by folic acid deficiency, and in rare instances, pyridoxine therapy has been effective. However, anemia is more often due to ineffective erythropoiesis uncompensated by extramedullaryhematopoiesis in the spleen and liver. Neither recombinant erythropoietin nor androgens, such as Danazol, have proved consistently effective as therapy for anemia. Erythropoietin may worsen splenomegaly and will be ineffective if the serum erythropoietin level is >125 mU/L. A red cell splenic sequestration study can establish the presence of hypersplenism, for which splenectomy is indicated. Splenectomy may also be necessary if splenomegaly impairs alimentation and should be performed before cachexia sets in. In this situation, splenectomy should not be avoided because of concern over rebound thrombocytosis, loss of hematopoietic capacity, or compensatory hepatomegaly. However, for unexplained reasons, splenectomy increases the risk of blastic transformation. Splenic irradiation is, at best, temporarily palliative and associated with a significant risk of neutropenia and infection. Allopurinol can control significant hyperuricemia, and hydroxyurea has proved useful for controlling organomegaly in some patients. The role of IFN- α is still undefined and its side effects are more pronounced in the older individuals who are usually afflicted with this disorder. Glucocorticoids have been used to control constitutional symptoms and autoimmune complications and may ameliorate anemia alone or in combination with low dose thalidomide (50-100 mg/d). Allogeneic bone marrow transplantation is the only curative treatment and should be considered in younger patients; reduced-intensity conditioning regimens may permit hematopoietic cell transplantation to be extended to older individuals.

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