Myelofibrosis with Myeloid Metaplasia: New Developments in Pathogenesis and Treatment

Abstract

Myeloid metaplasia with myelofibrosis (MMM) is a chronic myeloproliferative disorder (CMPD) characterized by progressive anemia, massive splenomegaly, both hepatosplenic and non-hepatosplenic extramedullary hematopoiesis (EMH), a leukoerythroblastic blood smear, circulating progenitor cells, and marked bone marrow stromal reaction including collagen fibrosis, osteosclerosis and angiogenesis. The overall median survival is 5 years although it might range from 2 to 15 years depending on the presence or absence of clinically defined prognostic factors. Death is often due to leukemic transformation, portal hypertension or infection. In addition to shortened survival, quality of life is often affected by frequent red blood cell transfusions, profound constitutional symptoms, and cachexia. Drug therapy and autologous hematopoietic stem cell transplantation (HSCT) are of only palliative value and have not been shown to improve survival. The role of allogeneic HSCT, both myeloablative and non-myeloablative, is actively being investigated. Both splenectomy and radiation therapy have defined therapeutic roles to control EMH-associated symptoms. Analysis of the molecular biology of the disease is underway with the aid of animal models leading to the identification of novel therapeutic targets. Among the novel agents tested, thalidomide seems the most promising although newer agents are on the horizon.

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…Additionally, scrutinized evaluations of follow-up studies including BM examinations were in keeping with a stepwise evolution of the disease process starting with a prefibrotic precursor stage and progressing over many years into overt MMM [103,106,107,109,110,[112][113][114]. Concerning the dynamics of disease process in PMF, the former gold standard for the diagnosis of MMM [6,22,23,89,115,116] or agnogenic myeloid metaplasia (AMM) should be avoided, because these criteria include only the advanced or overt stages of a wide spectrum of clinical and morphological disease manifestations [102]. Particularly, to underscore the fact that overt myelofibrosis is not a necessary diagnostic feature of this MPN category, the term PMF was recommended to the WHO by the International Working Group on Myelofibrosis [117].…”

“…The presence of the JAK2V617F mutation in precursor stages of PMF does not exert a specific diagnostic impact, because it may be found in about 50% of patients [11,91]. A remarkable point is that progression of prodromal PMF into MMM/AMM [6,22,115,116] is not triggered by the JAK2V617F mutation status, but by a number of relevant target genes that are involved in matrix modeling and regulation of fibrillogenesis [119]. Clinical data in these prodromal stages of PMF are usually characterized by only minimal abnormalities as borderline to slight anemia, minimal splenomegaly, a very low or missing peripheral blast count but often a conspicuous thrombocytosis [93,98,102,103,106,107,[109][110][111]120] as shown in Table III.…”

A Rare Presentation of Extramedullary Hematopoiesis in Post-polycythemic Myelofibrosis

“…Since the incidence of MF in first 10 years is low and it is usually manifested in patients with a long duration of disease, the occurrence of MF is rather early in our patient and may suggest an aggressive subgroup [4]. Among chronic myeloproliferative disorders, EMH is most commonly seen in idiopathic MF since it is associated with the highest rate of bone marrow fibrosis (up to 80 % at presentation) and circulating progenitor cells [5,6]. Foci of EMH are most commonly found in the spleen, liver and lymph nodes, but may also infrequently occur at other sites as kidney, adrenal glands, pleura and peritoneum [7][8][9][10][11].…”

Advances in the Therapy of Chronic Idiopathic Myelofibrosis

“…This causes a decrease in ploidy and cell size and an increase in the number of promegakaryoblasts [79]. Its use in CIMF has been advocated on the basis of the important role that megakaryocytes play in the pathogenesis of CIMF by secreting cytokines that promote fibrosis and osteosclerosis [80]. Improvement in platelet counts was observed in 13 of 20 patients with advanced CIMF treated with anagrelide in a trial conducted by Yoon et al [81].…”