Myeloproliferative syndrome

Includes chronic myeloid leukemia, polycythemia rubra vera, essential thrombocythemia and agnogenic myeloid metaplasia (myelofibrosis).

Primary myelofibrosis and fibrotic stages of polycythemia vera and essential thrombocytosis are termed myelofibrosis.

Male and female preponderance in primary myelofibrosis and essential thrombocytosis, respectively.

Less common processes include systemic mastocytosis, chronic myelomonocytic leukemia, chronic eosinophilic leukemia and chronic neutrophilic leukemia.

Prevalence of essential thrombocytosis is 38-57 per 100,000, polycythemia vera 44-57 100,000 and myelofibrosis 4-6 per 100,000.

The prevalence of MF, ET, and PV in the US is estimated to be approximately 13,000, 134,000, and 148,000, respectively.

Myeloproliferative neoplasms are characterized by symptom profile that varies within and between each subtype but often includes: fatigue, pruritus, weight loss, and symptoms from splenomegaly.

Constitutional symptoms of fever, night sweats, and weight loss, and more frequently seen in patients with MF compared with those of PV or ET.

Laboratory variabilities depend on the type of myeloproliferative neoplasm including erythrocytosis, thrombocytosis, and leukocytosis, and sometimes myeloid immaturity, especially in progressive myelofibrosis.

Survival for patients with myelofibrosis is worse for patients with essential thrombocytosis or polycythemia vera.

Myeloproliferative proliferative neoplasms have a propensity for disease transformation into a blast phase akin to AML.

Patients with primary myelofibrosis compared with polycythemia rubra vera and essential thrombocytosis, displayed lower hemoglobin and platelet values and more frequent cytogenetic abnormalities, transfusion dependence, leukocyte count of at least 25,000mm3, and blast counts of at least 1%, supporting progress of a detrimental phenotype.

Life expectancy is reportedly shortened with respect to the general population.

Features of myeloproliferative syndrome include:

Overproduction of one or more blood elements, with dominance of a transformed clone

Hypercellular bone marrow and/or bone marrow fibrosis

Cytogenetic abnormalities

Susceptibility to thromboses and/or hemorrhage

Extra medullary hematopoiesis in the liver or spleen

Potential to transformed to acute leukemia

Combined annual incidence in the U.S. is 2.1 per 100,000 people.

Incidental rates in European countries of 0.4-2.8 per 100,000 persons annually for PV and 1.7 per 100,000 persons annually for ET.

Thought to arise from a transformation of a hematopoietic stem cell.

Myeloproliferative diseases associated with overproduction of mature, functional blood cells and a long clinical process.

Myeloproliferative neoplasms with clonal proliferation also had secondary changes in bone marrow stroma and plasma cytokines: Particularly in the setting of primary myelofibrosis or post polycythemia vera/essential thrombocytosis, myelofibrosis.

Bone marrow aspirate with iron staying in biopsy with reticulin stains and bone marrow cytogenetics are necessary to establish a diagnosis and distinguish morphological features visit between disease subtypes.

Primary myelofibrosis, polycythemia vera, and essential thrombocytosis originate from a common hematopoietic stem cell that dysregulates cell trafficking, division and response to growth factors, such that white blood cells, red blood cells and/or platelets are produced an abnormal numbers and proportion.

Bleeding and thrombosis are the primary causes of morbidity and mortality in chronic myeloproliferative disorders.

Myeloproliferative neoplasms associated with thrombosis are polycythemia Vera, essential thrombocytosis, myelofibrosis, and prefibrotic myelofibrosis.

The overall risk for thrombosis is approximately 20% in patients with any of the 4 above myeloproliferative neoplasms.

About 10-30% of patients report thrombotic events before the diagnosis of a myeloproliferative neoplasm, and the incidence of thrombosis after the diagnosis remains high at 10-20%.

Of myeloproliferative syndrome myelofibrosis has the shortness survival.

Essential thrombocytosis is primarily disorder of megakaryocytic/platelet lineage, whereas polycythemia rubra vera is primarily one of erythroid lineage.

Surgical interventions in essential thrombocytosis and polycythemia vera increased for thrombotic or hemorrhagic events.

Thrombotic events associated with advanced age and history of prior vascular events, with potential contributions from cardiovascular risk factors and the presence of extreme thrombocytosis, leukocytosis and high JAK2 levels.

Management of polycythemia and essential thrombocytosis risk for thrombosis directed at controlling the erythrocyte count, use of antiplatelet therapy and addition of myelosuppressive agents to normalize thrombocytosis.

Risk of vascular complications after splenectomy in such patients is 24% (Mesa).

Thrombosis occurs in one third of cases with 15-40% mortality.

Patients with polycythemia vera can present as isolated erythrocytosis, leucocytosis, or myelofibrosis.

Erythrocytosis is the laboratory change that distinguishes polycythemia vera from essential thrombocytosis and myelofibrosis.

Bone marrow histology in these disorders nonspecific.

Polycythemia rubra vera most common of the three chronic myeloproliferative disorders.

Eosinophilic leukemia associated with FIP1L1-PDGFRA fusion gene.

Early in the course of myelofibrosis CD34+ cells increased, greater than 15,000/µL, but this is not seen in polycythemia or essential thrombocytosis until later in time.

Tyrosine kinase mutation Val617Phe in the JH2 pseudokinase domain of Janus kinase-2 (JAK2) gene present in patients with sporadic myeloproliferative syndrome, most patients with polycythemia rubra vera, and half of the patients with essential thrombocytosis and myelofibrosis with myeloid metaplasia.

The JAK2 gene mutation causes the substitution of phenylalanine for valine at position 617 and is found in majority of patients with polycythemia rubra vera and many patients with essential thrombocytopenia or idiopathic myelofibrosis.

Myeloproliferative syndrome-JAK2 gene encodes a cytoplasmic tyrosine kinase.

Majority of patients with Ph negative myeloproliferative disorders have acquired point mutation in the Janus kinase 2 (JAK2) gene.

Syndrome associated with 1of 3 exclusive mutations:JAK2, CALR, or MPL.

Commonly associated with signal transducers and activators of transcription (JAK-STAT) and phosphatidylinositol 3-kinase (PI3K) pathways in red and myeloid cells.

Activation of these pathways cause aberrant synthesis of inflammatory cytokines that are the driving force of myeloproliferative neoplasm clone expansion and disease progression.

These cytokines also result in a higher blood, viscosity, blood cell activation, formation of leukocyte platelet complexes, increased synthesis of neutrophil extracellular traps and different pro coagulation factors, endothelial dysfunction, overproduction of micro particles and reactive oxygen species, all associated with increased risk of atherosclerosis and thrombosis in myeloproliferative neoplasms.

Janus kinase 2 gene is found in about three fourths of patients with myeloproliferative syndromes.

The valine-to-phenylalanine (V617 F) alteration constitutively activities JAK2, resulting in increased phosphorylation of it substrates causing an increased cytokine responsiveness of myeloid cells.

P Vera has the JAK2 V617F mutation in 95% of patients and in 50 to 60% of those with essential thrombocythemia or primary myelofibrosis.

Some patients (2-3%) with P Vera have somatic mutations of JAK2 exon 12.

Essential thrombocythemia or primary myelofibrosis have activating mutations of the thrombopoietin receptor gene MPL in 5 to 10% of patients with non-mutated JAK2.

MPL mutations are reported in approximately 5 to 8% of all patients with MF and 1 to 4% of patients with ET.

Frameshift mutation in axon 9 of the calreticulin gene (CALR) reported in approximately 20 to 35% of all patients with ET and MF accounts for approximately 60 to 80% of patients with JAK 2/MPL-negative ET and MF.

Approximately one third of patients with essential thrombocythemia or primary myelofibrosis do not carry any mutation in JAK2 or MPL.

Erythroid precursors with JAK2 mutation change are hypersensitive to erythropoietin.

Most CML patients carry the BCR/ABL1 mutation, but the patients with polycythemia vera, primary myelofibrosis, and essential thrombocytosis are all BCR/ABL1 negative.

Polycythemia rubra vera and essential thrombocytosis are both capable progressing to a fibrotic state resembling primary myelofibrosis.

Evaluation includes: History and physical examination for signs of palpable spleen and or liver, complete blood count, chemistry panel, review of peripheral blood smear, a bone marrow examination biopsy for reticulin and collagen staining, testing for mutations in the JAK2, CALR, and MPL, testing for BCR/ABL, testing for bone marrow histology showing hypocellularity and dysplastic megakaryocytes, EPO level, serum iron studies and HLA typing for patients with MF for consideration of allogeneic bone marrow transplant.

Once a diagnosis of a myeloproliferative syndrome is confirmed, next generation sequencing is recommended for mutational prognostication.

The International Prognostic Scoring System (IPSS) utilizes age greater than 65 years, the presence of constitutional symptoms, hemoglobin of less than 10 g/dL, leukocyte count of 25,000 or greater, and circulating blasts of 1% or greater at diagnosis to be independent predictors of inferior survival.

IPPS stratifies patients at diagnosis center for risk groups based on the presence of zero, one, two, and three or more adverse factors: low risk, intermediate-1 risk, intermediate-2 risk and high risk with a median survival of 135 months, 95 months, 48 months, and 27 months, respectively.

A risk modified stratification system DIPSS has been developed using the same prognostic variables as in IPSS: age greater than 65 years, presence of constitutional symptoms, hemoglobin level less than 10 g/dL, leukocyte count greater than 25,000, and circulating blessed cells one percent or greater: for different risk groups: low risk zero adverse points, intermediate-1 risk one or two  points, intermediate-2 risk three or four points, and high risk five or six points, with a median survival rate of not reached, 14 years, four years, and 1.5 years, respectively.

Treatment of patients with PV and ET is based on risk stratification for thrombosis.

Patients who are at high risk for thrombosis are older, have a prior history of arterial or venous thrombosis.

The most important prognostic factors for future thrombotic events and patients with myeloproliferative neoplasms or age older than 60 years and prior thrombotic events.

In patients with ET, the JAK2+mutation confers additional thrombotic risk.

Cardiovascular risk factors are considered as well in a patient’s overall risk for thrombosis.

In addition to aspirin, the maintenance of hematocrit of less than 45% in PV.

Cytoreduction with hydroxyurea improves thrombosis free survival in high-risk patients with ET.

Recumbent interferon has demonstrated high rates of complete hematological response in essential thrombocytopenia, 95%, and polycythemia vera 68% and 74% of patients who demonstrate a decline in JAK2 allele burden.

In a study of myeloproliferative neoplasms Hydrea revealed complete hematological response in 64.4% of those treated while interferon had a complete hematological remission in 78.9% of those treated with interferon: Hydrea associated with a greater risk of secondary malignancies including AML, myelodysplastic syndrome and skin cancer compared with interferon(25 versus 8%).

Use of pegylated interferon in patients with PV and ET revealed comparable results when compared to hydroxyurea.

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