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A rare myeloproliferative neoplasm characterized by stem-cell derived clonal over proliferation of mature myeloid lineages, such as erythrocytes, leukocytes, and megakaryocytes, with variable degrees of megakaryocyte atypia, associated with reticulin and/or collagen bone marrow fibrosis, osteosclerosis, ineffective erythropoiesis, angiogenesis, extramedullary hematopoiesis, and abnormal cytokine expression.
ORPHA:824Classification level: Disorder
The annual incidence of primary myelofibrosis (PMF) is approximately 1 case per 100,000 individuals, although an increased prevalence is noted in Ashkenazi Jews.
Age at diagnosis is usually in adulthood, around the sixth decade of life. Clinical manifestations depend on the type of blood cell(s) affected and may include severe anemia, pallor, petechiae, ecchymosis, bleeding, thrombosis, pancytopenia, pruritus, hypermetabolic state, marked hepato/splenomegaly, and/or constitutional symptoms, such as fatigue, fever, and night sweats. Symtomatic portal hypertension and non hepatoslenic extramedullary hematopoiesis may lead to variceal bleeding, ascites, pleural effusion and/or pulmonary hypertension. Leukemic transformation is observed in approximately 20% of patients.
Evidence strongly suggests that PMF is attributed to the dysregulation of the JAK2-STAT5 signaling pathway. The mutation JAK2V617F on the JAK2 gene is the most prevalent mutation reported. Additionally, mutations in the MPL gene, which encodes the thrombopoietin receptor, and CALR. Furthermore, the megakaryocyte lineage contributes to the pathogenesis as these cells produce various profibrotic, angiogenic and pro-inflammatory cytokines, which are believed to play a role in bone marrow fibrosis, osteosclerosis and angiogenesis.
The diagnosis is based on the presence of major and minor criteria. It requires meeting all three major criteria, and at least one minor criterion. Major criteria include megakaryocytic proliferation and presence of reticulin and/or collagen fibrosis grades 2 or 3. The absence of other sign of blood and bone marrow cells proliferation and tumour (WHO classification). The mutations test for JAK2, CALR or MPL. Minor criteria include blood test for anemia, Leukocytosis, LDH level and Leukoerythroblastosis.
Differential diagnosis of PMF includes other closely related myeloid neoplasms, such as chronic myeloid leukemia, essential thrombocythemia, polycythemia vera, myelodysplastic syndromes, chronic myelomonocytic leukemia, acute panmyelosis with myelofibrosis and acute megakaryoblastic leukemia.
The pathology is not inherited although it is linked with important gene mutations which occur at any time in life. Although most cases appear to be sporadic, familial predisposition has been recognized for many years in a subset of cases and epidemiological studies have indicated the presence of common susceptibility alleles.
Management and treatment
Historically, splenectomy and hematopoietic stem cell transplantation (HSCT) have been the treatment for PMF, with the latter being the only treatment modality which prolongs survival or potentially cures PMF. HSCT, however, is associated with important morbidity and high transplant-related death therefore, individual patient risk-benefit assessment is necessary. Drug therapy with JAK inhibitors improves symptoms and splenomegaly but has not been shown to favorably modify disease natural history or prolong survival and therefore risk-benefit should also be carefully evaluated.
Severity and prognosis are variable depending on the affected genes and symptoms. Risk assessment using the International Prognostic Scoring System (IPSS) and the Dynamic IPSS (DIPSS) has proven useful in classifying patients into risk categories at diagnosis and later time points. A more recent score (MIPPS70) is particularly useful for risk stratification for transplantation-age patients.
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