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Journal of Clinical Oncology : Official... Nov 2005The primary disease process in myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is... (Review)
Review
The primary disease process in myelofibrosis with myeloid metaplasia (MMM) is clonal myeloproliferation with varying degrees of phenotypic differentiation. This is characteristically accompanied by secondary intramedullary collagen fibrosis, osteosclerosis, angiogenesis, and extramedullary hematopoiesis. Modern clonality studies have confirmed the multipotent stem-cell origin of the neoplastic process in MMM. The nature of the specific oncogenic mutation(s) is currently being unraveled with the recent discovery of an association between a somatic point mutation of JAK2 tyrosine kinase (V617F) and bcr/abl-negative myeloproliferative disorders, including MMM. The pathogenetic mechanisms that underlie the secondary bone marrow stromal changes in MMM are also incompletely understood. Mouse models of this latter disease aspect have been constructed by either in vivo overexpression of thrombopoietin (TPOhigh mice) or megakaryocyte lineage restricted underexpression of the transcription factor GATA-1 (GATA-1low mice). Gene knockout experiments using such animal models have suggested the essential role of hematopoietic cell-derived transforming growth factor beta1 in inducing bone marrow fibrosis and stromal cell-derived osteoprotegerin in promoting osteosclerosis. However, experimental myelofibrosis in mice does not recapitulate clonal myeloproliferation that is fundamental to human MMM. Other cytokines that are implicated in mediating myelofibrosis and angiogenesis in MMM include basic fibroblast, platelet-derived, and vascular endothelial growth factors. It is currently assumed that such cytokines are abnormally released from clonal megakaryocytes as a result of a pathologic interaction with neutrophils (eg, emperipolesis). This latter phenomenon, through neutrophil-derived elastase, could also underlie the abnormal peripheral-blood egress of myeloid progenitors in MMM.
Topics: Animals; Bone Marrow; Cytokines; Disease Models, Animal; Gene Expression Regulation, Neoplastic; Humans; Mice; Mutation; Primary Myelofibrosis
PubMed: 16293880
DOI: 10.1200/JCO.2004.00.9316 -
Blood Oct 2019
Topics: Adult; Bone Marrow; Erythropoiesis; Female; Humans; Lupus Erythematosus, Systemic; Primary Myelofibrosis
PubMed: 31698419
DOI: 10.1182/blood.2019002479 -
Current Hematologic Malignancy Reports Oct 2020Myelofibrosis is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly. Currently approved medical therapies do not improve splenomegaly in all... (Review)
Review
PURPOSE OF REVIEW
Myelofibrosis is a chronic myeloproliferative neoplasm which can lead to massive splenomegaly. Currently approved medical therapies do not improve splenomegaly in all patients and effects are not sustained. Thus, spleen-directed therapies (i.e., splenectomy and splenic irradiation) have been used in some cases to palliate the signs and symptoms of the disease. Here, we critically review the literature regarding palliative splenectomy and splenic irradiation in myelofibrosis, and discuss their position in the current treatment landscape.
RECENT FINDINGS
Retrospective studies have demonstrated that splenectomy improves symptoms of splenomegaly, decreases complications of portal hypertension, and decreases transfusion dependence. However, it carries a significant peri-operative and long-term morbidity and mortality rate. Splenic irradiation reduces splenic size but is limited by duration of response and myelosuppression. Spleen-directed therapies in myelofibrosis may be considered for refractory symptoms and complications of massive splenomegaly after carefully weighing the associated risks, though overall survival may not be impacted. Development of medical therapies that target and reverse the underlying disease pathophysiology is required in order to have a significant impact on the natural history of the disease process.
Topics: Humans; Palliative Care; Primary Myelofibrosis; Radiotherapy; Splenectomy; Splenomegaly; Treatment Outcome
PubMed: 32827272
DOI: 10.1007/s11899-020-00598-x -
American Journal of Hematology Dec 2011Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow... (Review)
Review
DISEASE OVERVIEW
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.
DIAGNOSIS
Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation or +9/13q- cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.
RISK STRATIFICATION
The Dynamic International Prognostic Scoring System-plus (DIPSS-plus) prognostic model for PMF can be applied at any point during the disease course and uses eight independent predictors of inferior survival: age >65 years, hemoglobin <10 g/dL, leukocytes >25 × 10(9) /L, circulating blasts ≥1%, constitutional symptoms, red cell transfusion dependency, platelet count <100 × 10(9) /L, and unfavorable karyotype (i.e., complex karyotype or sole or two abnormalities that include +8, -7/7q-, i(17q), inv(3), -5/5q-, 12p- or 11q23 rearrangement). The presence of 0, 1, "2 or 3," and ≥4 adverse factors defines low, intermediate-1, intermediate-2, and high-risk disease with median survivals of ~15.4, 6.5, 2.9, and 1.3 years, respectively. A >80% two-year mortality is predicted by monosomal karyotype, inv(3)/i(17q) abnormalities, or any two of circulating blasts >9%, leukocytes ≥40 × 10(9) /L or other unfavorable karyotype.
RISK-ADAPTED THERAPY
Observation alone is adequate for asymptomatic low/intermediate-1 risk disease. Allogeneic stem cell transplantation or experimental drug therapy is considered for intermediate-2/ high risk disease. Conventional or experimental drug therapy is reasonable for symptomatic intermediate-1 risk disease. Splenectomy and low-dose radiotherapy are used for drug-refractory splenomegaly. Radiotherapy is also used for the treatment of non-hepatosplenic EMH, PMF-associated pulmonary hypertension, and extremity bone pain.
Topics: Abnormal Karyotype; Bone Marrow; Decision Trees; Diagnosis, Differential; Humans; Practice Guidelines as Topic; Primary Myelofibrosis; Prognosis; Risk Assessment; Severity of Illness Index
PubMed: 22086865
DOI: 10.1002/ajh.22210 -
Journal of Thrombosis and Haemostasis :... Apr 2020The risk of thromboembolism in myelofibrosis remains incompletely understood.
BACKGROUND
The risk of thromboembolism in myelofibrosis remains incompletely understood.
OBJECTIVES
To examine the association between myelofibrosis and each of venous and arterial thromboembolism.
METHODS
A cohort of 1 469 790 adults without a diagnosis of myelofibrosis was identified on 1 January 2007, from the electronic medical records of the largest health-care provider in Israel. Participants were followed until 31 December 2016 for the occurrence of myelofibrosis. Four randomly selected controls (without myelofibrosis) were matched to each case of myelofibrosis on age, sex, religious identification, and index date. The two groups were followed from the index date until 31 December 2017 for the occurrence of venous and arterial thromboembolism.
RESULTS
The study included 642 patients with myelofibrosis and 2568 matched controls. Myelofibrosis was independently associated with increased risk of venous thromboembolism but not with arterial thromboembolism. The propensity score adjusted hazard ratios (HRs) were 6.88 (95% confidence interval [CI], 2.02-23.45) for venous thromboembolism, and 0.94 (0.49-1.77) for arterial thromboembolism. Atypical sites of venous thromboembolism occurred almost exclusively in patients with myelofibrosis (four events of Budd Chiari versus none, and two mesenteric vein thrombosis events versus one) and were more likely to occur around the time of myelofibrosis diagnosis. No significant association was found between JAK2 inhibitor treatment (ruxolitinib) and the risk of venous HR 0.97 (0.30-3.12) or arterial thromboembolism 1.68 (0.78-3.62).
CONCLUSIONS
Myelofibrosis is associated with increased risk of venous thromboembolism but not of arterial thromboembolism. Atypical sites of venous thromboembolism are more frequent in myelofibrosis and are more likely to occur shortly after diagnosis.
Topics: Adult; Cohort Studies; Humans; Israel; Primary Myelofibrosis; Retrospective Studies; Risk Factors; Venous Thromboembolism
PubMed: 32017387
DOI: 10.1111/jth.14754 -
International Journal of Clinical... Feb 1979A case of myelofibrosis successfully treated by the use of splenectomy has been reported. The feeling of the authors is that splenectomy should be considered at a much... (Review)
Review
A case of myelofibrosis successfully treated by the use of splenectomy has been reported. The feeling of the authors is that splenectomy should be considered at a much earlier stage of the disease, when the patient is a better risk with a longer survival. We see no valid physiological reasoning for leaving a spleen in, which is valueless to the patient in addition to causing multiple side effects, directly and indirectly from its size and overactivity. This is especially true when attempts to reduce the size have potential hazards, none are completely effective and when the physiological necessity for this reticulo endothelial site seems to be unnecessary. Perhaps it would be of greatest value if all cases of myelofibrosis should be seen at the inception and throughout by the hematological and surgical service together.
Topics: Bone Marrow; Diagnosis, Differential; Humans; Liver; Male; Middle Aged; Primary Myelofibrosis; Prognosis; Spleen
PubMed: 370037
DOI: No ID Found -
Cancer Mar 2016Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by... (Review)
Review
Primary myelofibrosis, the most aggressive of the classic Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), is a clonal disorder characterized by often debilitating constitutional symptoms and splenomegaly, bone marrow fibrosis and resultant cytopenias, extramedullary hematopoiesis, risk of leukemic transformation, and shortened survival. Post-polycythemia vera and post-essential thrombocythemia myelofibrosis represent similar entities, although some differences are being recognized. Attempts to classify patients with myelofibrosis into prognostic categories have been made since the late 1980s, and these scoring systems continue to evolve as new information becomes available. Over the last decade, the molecular pathogenesis of MPNs has been elucidated considerably, and the Janus kinase (JAK) 1/2 inhibitor ruxolitinib is the first drug specifically approved by the US Food and Drug Administration to treat patients with intermediate-risk and high-risk myelofibrosis. This article reviews the evolution of prognostic criteria in myelofibrosis, emphasizing the major systems widely in use today, as well as recently described, novel systems that incorporate emerging data regarding somatic mutations. Risk factors for thrombosis and conversion to MPN blast phase also are discussed. Finally, the practical usefulness of the current prognostic classification systems in terms of clinical decision making is discussed, particularly within the context of some of their inherent weaknesses. Cancer 2016;122:681-692. © 2015 American Cancer Society.
Topics: Age Factors; Blast Crisis; Clinical Decision-Making; Hemoglobins; Humans; Leukocyte Count; Primary Myelofibrosis; Prognosis; Risk Factors; Thrombosis
PubMed: 26717494
DOI: 10.1002/cncr.29842 -
Leukemia & Lymphoma Mar 2004Autoimmune myelofibrosis is a distinct clinicopathological entity, recognizing immunopathogenetic mechanisms and occurring isolately or in association with systemic... (Review)
Review
Autoimmune myelofibrosis is a distinct clinicopathological entity, recognizing immunopathogenetic mechanisms and occurring isolately or in association with systemic and/or organ-specific autoimmune diseases. It results in chronic cytopenias, and is defined by a pattern including bone marrow, peripheral blood, serological and clinical features. It has to be distinguished from other disorders having myelofibrosis. Among these, the most relevant differential diagnosis is with chronic idiopathic myelofibrosis, particularly when disclosing autoimmune clinical and/or laboratory features as epiphenomenon related to a secondary immune-dysregulation. Here we report on 3 patients admitted because of chronic cytopenias. In all of them, the clinicopathological evaluation essentially demonstrated myelofibrosis, not clustered megakaryocytes, reactive lymphoid infiltration in marrow biopsies, absence of significant tear-drop poikilocytosis and leukoerythroblastosis on peripheral blood smears, normal-sized spleen, positive autoimmune serology. The resulting patterns met the diagnosis of autoimmune myelofibrosis occurring isolately in a patient and associated with Sjögren's syndrome or concomitant Sjögren's syndrome and Hashimoto's thyroiditis in the other two, respectively. Transient improvements in cytopenias and unmodified myelofibrosis were observed following corticosteroid treatment. It is noteworthy the lack of a specific therapy, being the underlying pathophisiology of myelofibrosis still unclear. In conclusion, increased awareness of the clinicopathological pattern identifying autoimmune myelofibrosis is recommended in order to improve basic and clinical knowledge of this emerging entity.
Topics: Adult; Aged; Autoimmune Diseases; Blood Cells; Bone Marrow Cells; Bone Marrow Examination; Female; Humans; Middle Aged; Pancytopenia; Primary Myelofibrosis
PubMed: 15160919
DOI: 10.1080/10428190310001597982 -
Archives of Disease in Childhood Nov 1980Two siblings developed a fulminant fatal myeloproliferative disease at 7 and 8 weeks of age. The illness presented with pallor, haemorrhagic symptoms, and...
Two siblings developed a fulminant fatal myeloproliferative disease at 7 and 8 weeks of age. The illness presented with pallor, haemorrhagic symptoms, and hepatosplenomegaly, and the blood picture was that of pancytopenia and leucoerythroblastosis. Bone marrow histology showed reduced haemopoiesis with generalised fibrosis. Histiocytes were present, but haemophagocytosis was not prominent. There was evidence of extramedullary haemopoiesis in the spleen, with a chronic inflammatory infiltrate of other organs. The condition closely resembles acute idiopathic myelofibrosis of infancy, but the early onset with severe pancytopenia and the histological appearances may arouse suspicion of the possible familial nature of the condition. Although clinically resembling familial haemophagocytic reticulosis, the uncharacteristic bone marrow, liver, and spleen histology serve to exclude this diagnosis.
Topics: Bone Marrow; Female; Humans; Infant; Male; Primary Myelofibrosis
PubMed: 7436463
DOI: 10.1136/adc.55.11.888 -
European Journal of Haematology Aug 1990
Review
Topics: Humans; Primary Myelofibrosis; Prognosis
PubMed: 2209820
DOI: 10.1111/j.1600-0609.1990.tb00419.x