Myeloproliferative neoplasm

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Synonyms and keywords: MPN; Myeloproliferative disease; Myeloproliferative disorder; Myeloproliferation

Overview

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

Myeloproliferative neoplasm are a group of eight disease subtypes of the bone marrow in which excess cells are produced. Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes, including polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic myelogenous leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, myeloproliferative neoplasm not otherwise specified, and mastocytosis.They are related to, or may evolve into, myelodysplastic syndrome and acute myeloid leukemia, although the myeloproliferative diseases on the whole have a much better prognosis than these conditions. Clinical and pathologic features in the myeloproliferative neoplasms are due to dysregulated proliferation and expansion of myeloid progenitors in the bone marrow, resulting in altered populations of granulocytes, erythrocytes, or platelets in the peripheral blood. Myeloproliferative neoplasm is caused by a mutational events in the BCR–ABL, ”Janus kinase 2” (JAK2), ”calreticulin” (CALR), or myeloproliferative leukemia (MPL) genes. Patients may be asymptomatic at diagnosis. However, if symptoms present, symptoms of myeloproliferative neoplasm include fever, fatigue, and bleeding. The mainstay of therapy for myeloproliferative neoplasm is chemotherapy, cytoreduction, aspirin, and palliative care.

Historical Perspective

The first description of myeloproliferative neoplasm dates back to the late 19th century, when Sir Louis Vasquez studied a patient with excess red blood cells. Myeloproliferative neoplasm was first brought to attention as an important clinical entity by Dr. William Dameshek, an American hematologist, in 1951. In 2005, the link between the JAK2 mutation and polycythemia vera was discovered. The World Health Organization created diagnostic criteria for myeloproliferative neoplasms in 2008, and this was revised in 2016.

Classification

Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes: polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic myelogenous leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, myeloproliferative neoplasms unclassifiable, and mastocytosis. Each subtypes is based on a distinct malignant cell, and each subtype has different criteria for diagnosis.

Pathophysiology

The pathophysiology of myeloproliferative neoplasms is based on the specific subtype of myeloproliferative neoplasm. Each of the 8 different myeloproliferative neoplasms have a slightly different pathophysiologic basis. Primary cytogenetic abnormalities have not been identified in the majority of myeloproliferative neoplasms. Aberrant activation of tyrosine kinases and associated signaling pathways is frequently implicated as the disease-initiating event for many of the myeloproliferative neoplasms. Clinical and pathologic features in the myeloproliferative neoplasms are due to dysregulated proliferation and expansion of myeloid progenitors in the bone marrow, resulting in altered populations of granulocytes, erythrocytes, or platelets in the peripheral blood.

Causes

Myeloproliferative neoplasm is caused by mutations in various genes. Different gene mutations are responsible for each of the 8 subtypes of myeloproliferative neoplasms. Importantly, multiple different gene mutations can cause a single disease.

Differentiating Myeloproliferative Neoplasm from Other Diseases

Myeloproliferative neoplasm must be differentiated from myelodysplastic syndrome, acute myelogenous leukemia, [[acute lymphoblastic leukemia, Waldenstrom’s macroglobulinemia, and lymphoproliferative disorder. Each of these conditions has a unique set of causes, laboratory abnormalities, physical exam findings, and therapies.

Epidemiology and Demographics

The incidence of myeloproliferative neoplasm is approximately 7.8 per 100,000 individuals worldwide. The different subtypes of myeloproliferative neoplasm have different incidence and prevalence statistics. Males are more commonly affected than females, and older persons are more commonly affected than younger persons.

Risk Factors

There are four major categories of risk factors for myeloproliferative neoplasm. Genetic mutational events comprise the most common risk factor. Other risk factors include advanced age, prior cytotoxic chemotherapy, and autoimmune disease.

Screening

There are currently no guidelines for screening for myeloproliferative neoplasm. Monitoring of the complete blood count is done routinely.

Natural History, Complications and Prognosis

The natural history of myeloproliferative neoplasm begins with weight loss, fever, and night sweats. The natural history depends on the subtype of myeloproliferative neoplasm. Common complications of myeloproliferative neoplasm include splenomegaly, bleeding, thrombosis, bone marrow fibrosis, and acute leukemia. Prognosis depends on the subtype of myeloproliferative neoplasm. Each subtype has its own prognostic scoring system. In general, patients with polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia have better prognosis than patients with primary myelofibrosis. The prognosis is generally good with treatment.

Diagnosis

History and Symptoms

Patients may be asymptomatic at diagnosis. However, if symptoms present, symptoms of myeloproliferative neoplasm include fever, fatigue, and bleeding.

Physical Examination

Patients with myeloproliferative neoplasm are usually well-appearing. Physical examination of patients with chronic myelogenous leukemia is usually remarkable for skin bruising, fever, splenomegaly, and lymphadenopathy.

Laboratory Findings

Patients with myeloproliferative neoplasm are usually well-appearing. Physical examination of patients with chronic myelogenous leukemia is usually remarkable for skin bruising, fever, splenomegaly, and lymphadenopathy.

Chest X-Ray

The chest x-ray may be helpful in the diagnosis of myeloproliferative neoplasm and can reveal pleural effusions, pneumonia, and pulmonary edema.

CT

Abdominal and chest CT scan may be helpful in the diagnosis of myeloproliferative neoplasm. Findings on CT scan suggestive of myeloproliferative neoplasm include enlarged lymph nodes, hepatosplenomegaly, splanchnic venous thrombosis, and pulmonary embolism.

MRI

Brain MRI is helpful in the detection of thrombotic events, such as ischemic stroke, in patients with myeloproliferative neoplasm. Abdominal MRI is helpful in the detection of mesenteric thrombosis in patients with myeloproliferative neoplasm.

Ultrasound

Ultrasound may be helpful in the diagnosis of myeloproliferative neoplasm. Findings on abdominal ultrasound suggestive of myeloproliferative neoplasm include enlarged lymph nodes, hepatosplenomegaly, and ascites. Findings on extremity ultrasound include thrombosis.

Other Imaging Findings

Other imaging studies for myeloproliferative neoplasm include positron emission tomography (PET) scan, which helps to detect metastasis in bone marrow and to follow up medical treatment.

Other Diagnostic Studies

Other diagnostic studies for myeloproliferative neoplasm include bone marrow aspiration and trephine biopsy, erythropoietin level, lumbar puncture, and lymph node biopsy.

Treatment

Medical Therapy

Medical therapy for myeloproliferative neoplasm is based on the specific subtype of myeloproliferative neoplasm. The mainstay of therapy for myeloproliferative neoplasm is chemotherapy, cytoreduction, aspirin, and palliative care. Treatment is directed at reducing the excessive numbers of blood cells.

Surgery

Surgical intervention is usually not recommended for the management of chronic myelogenous leukemia unless there is splenomegaly.

Primary Prevention

There is no established method for primary prevention of myeloproliferative neoplasm.

Secondary Prevention

Secondary prevention measures include routine monitoring of laboratory values, including complete blood count (CBC) and metabolic panel.

Future of Investigational Therapies

Future or investigational therapies in myeloproliferative neoplasms include BLU-285, JQ1, and suberoylanilide hydroxamic acid. Each of these investigational agents carries a unique mechanism of action on myeloid cells. The agents are currently in clinical trials.

References

Historical Perspective

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2], Shyam Patel [3]

Overview

The first description of myeloproliferative neoplasm dates back to the late 19th century, when Sir Louis Vasquez studied a patient with excess red blood cells. Myeloproliferative neoplasm was first brought to attention as an important clinical entity by Dr. William Dameshek, an American hematologist, in 1951. In 2005, the link between the JAK2 mutation and polycythemia vera was discovered. The World Health Organization created diagnostic criteria for myeloproliferative neoplasms in 2008, and this was revised in 2016.

Historical Perspective

In 1892, Sir Louis Vasquez described the first form of myeloproliferative disease in a patient. He described a patient with excess red blood cell production (eventually found to be polycythemia vera, liver enlargement (hepatomegaly), and spleen enlargement (splenomegaly). It was thought that excess hematopoietic cell production resulted in organ enlargement. This was later termed extramedullary hematopoiesis.^[1]

In 1903, Sir William Osler later described a group of patients with elevated red blood cell counts.^[2]

In 1934, Alfred Goedel and Emil Epstein found that patients with thrombocytosis without erythrocytosis was a separate disease entity (later coined as essential thrombocythemia).^[1]

In 1940, Sir William Dameshek and Henthell described the clinical features of the myeloproliferative neoplasm now known as polycythemia vera. Patients were noted to have facial plethora, splenomegaly, elevated hemoglobin, and elevated platelet count.

In 1951, Sir William Dameshek, an American hematologist, discovered myeloproliferative neoplasms. Dr. Dameshek was a pioneer in the field and paved the way for future investigations into the details of this condition. He grouped a variety of conditions together and classified these individual conditions are myeloproliferative neoplasms.^[3]

In 1967, Fialkow and colleagues showed evidence for clonally-derived myelopoiesis, based on studies showing the presence of the same G6PD polymorphism in erythrocytes and granulocytes. These studies suggested that one clone gave rise to multiple cell types.^[1]

In 1976, Adamson and colleagues showed evidence for panmyeloid clonal expansion, meaning that a single clone could give rise to multiple lineages including erythrocytes, granulocytes, and megakaryocytes.^[1]

In 2005, Ross Levine and colleagues found that the JAK2 V617F mutation was the molecular basis for polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis.^[4] High-throughput sequencing of DNA was performed in patients who were diagnosed with these myeloproliferative neoplasms. Healthy persons were found to not harbor this mutation, suggesting high specificity of the mutation for myeloproliferative neoplasm. It was noted that the JAK2 mutation resulted in a constitutively active tyrosine kinase.^[5]^[6]^[7]^[8]^[9] It was eventually noted that more than 95% of patients with polycythemia vera harbored the JAK2 V617F mutation, and 55-60% of patients with myelofibrosis had the mutation. The mutation was also found to be in 50% of patients with primary myelofibrosis.

In 2006, Pikman and colleagues found that the MPL W515L mutation was associated with myeloproliferative neoplasms.^[10] It was noted that, in patients without the JAK2 V617F mutation, the MPL mutation served as the pathogenic stimulus for myeloproliferation via activation of JAK-STAT signaling.^[10]

In 2007, Scott and colleagues discovered that JAK2 exon 12 mutations (which are distinct from the V617F mutation in exon 14) could result in polycythemia vera.^[11]

In 2008, the World Health Organization developed original criteria for the diagnosis of myeloproliferative neoplasm.^[2]

In 2009, Langemeijer and colleagues noted that TET2 and ASXL1 mutations and somatic copy-number loss were found to be associated with myeloproliferative neoplasms. These mutations were first found to be associated with myelodysplastic syndrome. These studies were conducted via single nucleotide polymorphism arrays and comparative genomic hybridization.

In 2016, the World Health Organization developed a revision for the diagnostic criteria for myeloproliferative neoplasm.

References

↑ ^1.0 ^1.1 ^1.2 ^1.3 Levine RL, Gilliland DG (2008). “Myeloproliferative disorders”. Blood. 112 (6): 2190–8. doi:10.1182/blood-2008-03-077966. PMC 2962533. PMID 18779404.
↑ ^2.0 ^2.1 Vannucchi AM (2017). “From leeches to personalized medicine: evolving concepts in the management of polycythemia vera”. Haematologica. 102 (1): 18–29. doi:10.3324/haematol.2015.129155. PMC 5210229. PMID 27884974.
↑ Dameshek W (1951). “Some speculations on the myeloproliferative syndromes”. Blood. 6 (4): 372–5. PMID 14820991.
↑ Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ; et al. (2005). “Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis”. Cancer Cell. 7 (4): 387–97. doi:10.1016/j.ccr.2005.03.023. PMID 15837627.
↑ Baxter EJ, Scott LM, Campbell PJ; et al. (2005). “Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders”. Lancet. 365: 1054–1061. PMID 15781101.
↑ James C, Ugo V, Le Couedic JP; et al. (2005). “A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera”. Nature. 434 (7037): 1144–1148. PMID 15793561.
↑ Levine RL, Wadleigh M, Cools J; et al. (2005). “Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis”. Cancer Cell. 7 (4): 387–397. PMID 15837627.
↑ Kralovics R, Passamonti F, Buser AS; et al. (2005). “A gain-of-function mutation of JAK2 in myeloproliferative disorders”. N Engl J Med. 352 (17): 1779–1790. PMID 15858187.
↑ Campbell PJ, Scott LM, Buck G; et al. (2005). “Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study”. Lancet. 366 (9501): 1945–1953. PMID 16325696.
↑ ^10.0 ^10.1 Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M; et al. (2006). “MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia”. PLoS Med. 3 (7): e270. doi:10.1371/journal.pmed.0030270. PMC 1502153. PMID 16834459.
↑ Scott LM, Tong W, Levine RL, Scott MA, Beer PA, Stratton MR; et al. (2007). “JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis”. N Engl J Med. 356 (5): 459–68. doi:10.1056/NEJMoa065202. PMC 2873834. PMID 17267906.

Classification

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2], Shyam Patel [3]

Overview

Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes: polycythemia vera, essential thrombocythemia, primary myelofibrosis, chronic myelogenous leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, myeloproliferative neoplasms unclassifiable, and mastocytosis. Each subtypes is based on a distinct malignant cell, and each subtype has different criteria for diagnosis.

Classification

Myeloproliferative neoplasm may be classified according to the World Health Organization into eight subtypes as follows:^[1]^[2]^[3]

Disease	Cell of origin	W.H.O. Diagnostic criteria
Polycythemia vera	Erythroid precursor	Major criteria: Hemoglobin > 16.5 g/dl in men or hemoglobin > 16 g/dl in women Bone marrow biopsy showing hypercellularity for age and trilineage growth (panmyelosis) Presence of JAK2 V617F or exon 12 mutation Minor criterion: Subnormal erythropoietin level Diagnosis requires meeting all 3 major criterion or the top 2 major plus the 1 minor criterion
Essential thrombocythemia	Megakaryocyte	Major criteria: Platelet count > 450,000 per microliter Bone marrow biopsy showing mainly the proliferation of megakaryocytes with an increased number of enlarged and mature megakaryocytes Not meeting criteria for other myeloproliferative neoplasms Presence of JAK2, CALR, or MPL mutation Minor criterion: Presence of a clonal marker or absence of reactive thrombocytosis Diagnosis requires meeting all 4 major criteria or the first 3 major plus the 1 minor criterion
Primary myelofibrosis	Megakaryocyte	Major criteria: Presence of megakaryocyte proliferation and atypia with reticulin fibrosis Not meeting criteria for other myeloproliferative neoplasms Presence of JAK2, CALR, or MPL mutation Minor criteria: Anemia White blood cell count >11,000 per microliter Palpable splenomegaly Elevated LDH Leukoerythroblastic smear Diagnosis requires meeting all major criteria and at least 1 minor criterion
Chronic myeloid leukemia	Common myeloid progenitor	Presence of BCR-ABL translocation (chromosomes 9 and 22)
Chronic neutrophilic leukemia	Neutrophil	Peripheral blood white blood cell count > 25,000 per microliter with rare myeloblasts and no dysgranulopoiesis Bone marrow hypercellularity with increased granulocytes and normal maturation and <5% myeloblasts Not meeting criteria for other myeloproliferative neoplasms Absence of genetic rearrangements of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 Presence of CSF3R T618I or other characteristic mutation
Chronic eosinophilic leukemia	Eosinophil	No formal W.H.O. criteria Typically associated with >1,500 eosinophils per microliter in peripheral blood Typically associated with rearrangements of PDGFRA, PDGFRB, FGFR1, JAK2
Myeloproliferative neoplasm, unclassifiable	Variable	Not meeting criteria for other subcategories
Mastocytosis	Mast cell	Major criteria: Dense multifocal aggregates of >15 mast cells in bone marrow or other organs Minor criteria: Presence of C-kit D816V mutation Expression of CD2, CD25, or both on mast cells Serum tryptase level >20ng/ml when a patient is at baseline health Atypical morphology or spindles in >25% of mast cells in bone marrow or other organs Diagnosis requires meeting the one major plus one minor criterion, or 3 minor criteria

References

↑ Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM; et al. (2016). “The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia”. Blood. 127 (20): 2391–405. doi:10.1182/blood-2016-03-643544. PMID 27069254.
↑ Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A; et al. (2009). “The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes”. Blood. 114 (5): 937–51. doi:10.1182/blood-2009-03-209262. PMID 19357394.
↑ Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O; et al. (2017). “Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future”. Cancer Res. 77 (6): 1261–1270. doi:10.1158/0008-5472.CAN-16-2234. PMC 5354959. PMID 28254862.

Pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

The pathophysiology of myeloproliferative neoplasms is based on the specific subtype of myeloproliferative neoplasm. Each of the 8 different myeloproliferative neoplasms have a slightly different pathophysiologic basis. Primary cytogenetic abnormalities have not been identified in the majority of myeloproliferative neoplasms. Aberrant activation of tyrosine kinases and associated signaling pathways is frequently implicated as the disease-initiating event for many of the myeloproliferative neoplasms. Clinical and pathologic features in the myeloproliferative neoplasms are due to dysregulated proliferation and expansion of myeloid progenitors in the bone marrow, resulting in altered populations of granulocytes, erythrocytes, or platelets in the peripheral blood.

Pathophysiology

Polycythemia Vera

Physiology

In order to understand the pathophysiology of polycythemia vera, one must understand normal physiology of erythroid cell production. Under normal conditions, the hormone erythropoietin will bind to the erythropoietin receptor on erythroid cell, resulting in activation of the JAK-STAT signaling pathway. Specifically, the erythropoietin receptor is associated with the JAK2 protein, and binding of the erythropoietin receptor by its endogenous ligand (erythropoietin) will stimulate a basal level of erythroid cell production.

Pathophysiology

In patients with polycythemia vera, this normal signaling process is excessively activated and dysregulated. The pathophysiology of polycythemia vera is well-defined and is specific to this subcategory of myeloproliferative neoplasm.

The disease-initiating event is the development of the Janus kinase (JAK2) V617F point mutation or JAK2 exon 12 mutation. This results in aberrant activation of JAK2 signaling, resulting in excess signal transduction via intracellular STAT5 signaling. The JAK2 mutation results in autonomous erythroid cell production. This leads to proliferation of erythroid precursors, with resultant increase in red blood cell production and increase in hemoglobin content. Greater than 95% of cases of polycythemia vera are due to the JAK2 mutation.
Mutations in phosphoinositide-3-kinase (PI3K) and AKT have also been implicated in the pathophysiology of polycythemia vera but are less common.

For more information, go to Polycythemia vera pathophysiology.

Essential Thrombocythemia

The pathophysiology of essential thrombocythemia is most commonly due to either a mutation in one of 3 genes: JAK2, CALR, or MPL.^[1]

The pathophysiology of JAK2-mutant essential thrombocythemia is similar to JAK2-mutant polycythemia vera, except that the abnormal cell is the megakaryocyte in essential thrombocythemia. The JAK2 mutation accounts for 63% of essential thrombocythemia cases.
The CALR mutation is second most common mutation in essential thrombocythemia and accounts for 23% of cases. The pathophysiology of CALR-mutant essential thrombocythemia involves a mutation in calreticulin, which is a chaperone protein in the endoplasmic reticulum. This mutation results in aberrant activation of the thrombopoietin receptor.
The least common, yet well-defined, mutation in essential thrombocythemia is the MPL mutation. This accounts for 4% of essential thrombocythemia. The MPL gene encodes the thrombopoietin receptor, and a point mutation involving a tryptophan codon in the MPL gene causes excess activation of this receptor, resulting in excess platelet production.

For more information, go to Essential thrombocytosis pathophysiology.

Chronic Myeloid Leukemia

The pathophysiology of chronic myeloid leukemia involves the Philadelphia chromosome translocation, in which parts of two chromosomes (the 9^th and 22^nd by conventional karyotypic numbering) switch places. As a result, part of the BCR (“breakpoint cluster region”) gene from chromosome 22 is fused with the ABL gene on chromosome 9. This abnormal “fusion” gene generates a protein of p210 or sometimes p185. Because ABL carries a domain that can add phosphate groups to tyrosine residues (a tyrosine kinase), the BCR–ABL fusion gene product is also a tyrosine kinase. The fused BCR–ABL protein interacts with the interleukin 3beta receptor, which results in excess myeloid cell production. The BCR–ABL transcript is continuously active and does not require activation by other cellular messaging proteins. In turn BCR–ABL activates a cascade of proteins which control the cell cycle, speeding up cell division. Moreover the BCR-ABL protein inhibits DNA repair, causing genomic instability and making the cell more susceptible to developing further genetic abnormalities. The action of the BCR–ABL protein is the pathophysiologic cause of chronic myelogenous leukemia.^[2]

Primary Myelofibrosis

The pathophysiology of primary myelofibrosis is most commonly due to either a mutation in one of 3 genes: JAK2, CALR, MPL.^[1] The pathophysiology of JAK2-mutation primary myelofibrosis is similar to JAK2-mutant polycythemia vera, except that the abnormal cell is the megakaryocyte, which produces excess PDGF and TGF-beta and stimulates excess collagen production. The JAK2 mutation accounts for 59% of primary myelofibrosis cases. The CALR mutation is second most common mutation in primary myelofibrosis and accounts for 27% of cases. The pathophysiology of CALR-mutant primary myelofibrosis involves a mutation in calreticulin, which is a chaperone protein in the endoplasmic reticulum. This mutation results in aberrant activation of the thrombopoietin receptor. The least common, yet well-defined, mutation in essential thrombocythemia is the MPL mutation. This accounts for 7% of primary myelofibrosis cases. The MPL gene encodes the thrombopoietin receptor, and a point mutation involving a tryptophan codon in the MPL gene causes excess activation of this receptor, resulting in excess megakaryocyte-mediated PDGF and TGF-beta production, which creates bone marrow fibrosis.

Chronic Neutrophilic Leukemia

The pathophysiology of chronic neutrophilic leukemia involves a point mutation in the colony-stimulating factor 3 receptor (CSF3R) gene. The point mutation replaces isoleucine for threonine at the 618th position (T618I). This point mutation is pathognomonic for chronic neutrophilic leukemia, though it is a rare mutation overall and accounts for only a few hundred cases in the United States. It is found in 83% of patients with chronic neutrophilic leukemia.^[3] This mutation results in aberrant activation of the receptor, which stimulating neutrophil production. Although this mutation is the most frequent driver mutation for chronic neutrophilic leukemia, other mutations that have been described in chronic neutrophilic leukemia include SET binding protein 1 (SETBP1) mutations, which are also found in atypical chronic myeloid leukemia. This mutation contributes to the pathophysiology of chronic neutrophilic leukemia by altering DNA replication.

Chronic Eosinophilic Leukemia

The pathophysiology of chronic eosinophilic leukemia most commonly involves rearrangements affecting the platelet-derived growth factor receptors (PDGFRA and PDGFRB).^[4] Upon deletion of the intervening CHIC2 locus on chromosome 4, the FIP1L1 locus (located upstream of PDGFRA) is juxtaposed to the PDGFRA locus, and FIP1L1 drives the expression of PDGFRA. This is the most frequent clonal event in hypereosinophilic syndrome.^[4] Excess PDGFR expression results in stimulation of eosinophil production. Other genes that are known to be involved in chronic eosinophilic leukemia include fibroblast growth factor receptor 1 (FGFR1) and PCM1-JAK2. Eosinophils can deposit in various organs, including the liver and heart, and this can create end-organ damage in chronic eosinophilic leukemia.

Myeloproliferative Neoplasm, Unclassifiable

There is no specific pathophysiologic basis for myeloproliferative neoplasm, unclassifiable. However, the final pathophysiologic event is the stimulation of cells of the myeloid lineage, similar to other subtypes of myeloproliferative neoplasm.

Mastocytosis

The pathophysiology of mastocytosis, or mast cell neoplasm, has been largely unknown for decades. It was later discovered the mast cell arises from the common myeloid progenitor. The most common molecular mutation in mastocytosis is the c-kit D816V mutation. The D816V mutation is found in more than 80% of patients with mastocytosis.^[5] Under normal conditions, the c-kit protein (also known as CD117) allows for expansion of hematopoietic cells, which is highly regulated. In mastocytosis, aberrant c-kit activation results in excess and uncontrolled production of myeloid-derived cells, such as mast cells. c-kit is a tyrosine kinase that signals via PI3K and mTOR, and this leads to cell proliferation. Mast cells accumulate in the bone marrow, skin, and other organs. End-organ damage commonly occurs in systemic mastocytosis.^[5]

Gallery

	Philadelphia chromosome. A piece of chromosome 9 and a piece of chromosome 22 break off and trade places. The BCR/ABL gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called the Philadelphia chromosome.^[6]
	Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.^[6]

References

↑ ^1.0 ^1.1 Schmoldt A, Benthe HF, Haberland G (1975). “Digitoxin metabolism by rat liver microsomes”. Biochem Pharmacol. 24 (17): 1639–41. PMID http://dx.doi.org/10.1182/blood-2013-11-538983 Check |pmid= value (help).
↑ Hehlmann R, Hochhaus A, Baccarani M; European LeukemiaNet (2007). “Chronic myeloid leukaemia”. Lancet. 370 (9584): 342–50. PMID 17662883.
↑ Menezes J, Cigudosa JC (2015). “Chronic neutrophilic leukemia: a clinical perspective”. Onco Targets Ther. 8: 2383–90. doi:10.2147/OTT.S49688. PMC 4562747. PMID 26366092.
↑ ^4.0 ^4.1 Legrand F, Renneville A, MacIntyre E, Mastrilli S, Ackermann F, Cayuela JM; et al. (2013). “The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases”. Medicine (Baltimore). 92 (5): e1–e9. doi:10.1097/MD.0b013e3182a71eba. PMC 4553979. PMID 23982058.
↑ ^5.0 ^5.1 Gallogly MM, Lazarus HM, Cooper BW (2017). “Midostaurin: a novel therapeutic agent for patients with FLT3-mutated acute myeloid leukemia and systemic mastocytosis”. Ther Adv Hematol. 8 (9): 245–261. doi:10.1177/2040620717721459. PMC 5639976. PMID 29051803.
↑ ^6.0 ^6.1 National Cancer Institute. Physician Data Query Database 2015.http://www.cancer.gov/types/leukemia/patient/cml-treatment-pdq

Causes

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

Myeloproliferative neoplasm is caused by mutations in various genes. Different gene mutations are responsible for each of the 8 subtypes of myeloproliferative neoplasms.^[1]

Causes


Myeloproliferative neoplasm subtype	Causative gene mutation

Polycythemia vera	JAK2 V617F in 95% of cases^[2] CALR MPL
Essential thrombocythemia	JAK2 V617F in 50-60% of cases^[3] CALR MPL
Primary myelofibrosis	JAK2 V617F in 50-60% of cases^[4] CALR MPL
Chronic myeloid leukemia	BCR-ABL SETBP1 in atypical CML^[5]
Chronic neutrophilic leukemia	CSF3R^[6] SETBP1 in rare cases
Chronic eosinophilic leukemia	FIP1L1-PDGFRA^[7] PDGFRB^[7] FGFR1^[7] PCM1-JAK2
Myeloproliferative neoplasm, unclassifiable	Variable
Mastocytosis	c-kit D816V^[8]

References

↑ Ganfyd. Polycythaemia vera 2015.http://www.ganfyd.org/index.php?title=Polycythemia_vera
↑ Griesshammer M, Gisslinger H, Mesa R (2015). “Current and future treatment options for polycythemia vera”. Ann Hematol. 94 (6): 901–10. doi:10.1007/s00277-015-2357-4. PMC 4420843. PMID 25832853.
↑ Antonioli E, Carobbio A, Pieri L, Pancrazzi A, Guglielmelli P, Delaini F; et al. (2010). “Hydroxyurea does not appreciably reduce JAK2 V617F allele burden in patients with polycythemia vera or essential thrombocythemia”. Haematologica. 95 (8): 1435–8. doi:10.3324/haematol.2009.021444. PMC 2913097. PMID 20418246.
↑ Rumi E, Pietra D, Pascutto C, Guglielmelli P, Martínez-Trillos A, Casetti I; et al. (2014). “Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis”. Blood. 124 (7): 1062–9. doi:10.1182/blood-2014-05-578435. PMC 4133481. PMID 24986690.
↑ Piazza R, Valletta S, Winkelmann N, Redaelli S, Spinelli R, Pirola A; et al. (2013). “Recurrent SETBP1 mutations in atypical chronic myeloid leukemia”. Nat Genet. 45 (1): 18–24. doi:10.1038/ng.2495. PMC 3588142. PMID 23222956.
↑ Szuber N, Tefferi A (2018). “Chronic neutrophilic leukemia: new science and new diagnostic criteria”. Blood Cancer J. 8 (2): 19. doi:10.1038/s41408-018-0049-8. PMC 5811432. PMID 29440636.
↑ ^7.0 ^7.1 ^7.2 Falchi L, Verstovsek S (2015). “Eosinophilia in Hematologic Disorders”. Immunol Allergy Clin North Am. 35 (3): 439–52. doi:10.1016/j.iac.2015.04.004. PMC 4515577. PMID 26209894.
↑ Valent P, Akin C, Hartmann K, Nilsson G, Reiter A, Hermine O; et al. (2017). “Advances in the Classification and Treatment of Mastocytosis: Current Status and Outlook toward the Future”. Cancer Res. 77 (6): 1261–1270. doi:10.1158/0008-5472.CAN-16-2234. PMC 5354959. PMID 28254862.

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Differentiating myeloproliferative neoplasm from other Diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2] Zahir Ali Shaikh, MD [3] Mohamad Alkateb, MBBCh [4] Shyam Patel [5]

Overview

Myeloproliferative neoplasm must be differentiated from myelodysplastic syndrome, acute myelogenous leukemia, acute lymphoblastic leukemia, Waldenstrom’s macroglobulinemia, and lymphoproliferative disorder. Each of these conditions has a unique set of causes, laboratory abnormalities, physical exam findings, and investigations.

Differentiating Myeloproliferative Neoplasm from other Diseases

ABBREVIATIONS

EPO: Erythropoietin, FISH: Fluorescence in situ hybridization, Hb: Hemoglobin, LAD: Leukocyte alkaline dehydrgenase, LAP: Leukocyte alkaline phosphatase, LDH: Lactate dehydrogenase, LFTs: Liver function tests, NL: Normal, PCR: Polymerase chain reaction, Plt: Platelet, PUD: Peptic ulcer disease, RFTs: Renal function tests, WBCs: White blood cells.

Disease		Clinical manifestations		Diagnosis										Other features
		Symptoms	Signs	CBC & Peripheral smear								Bone marrow biopsy	Other investigations
				WBCs						Hb	Plt
				WBC	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Hb	Plt
Chronic myeloid leukemia (CML)^[1]^[2]		Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<2%	+	↑	↑	↑	↓	NL	Hypercellurarity with ↑ granuloscytosis and ↓ erythrocytosis Fibrosis	FISH for t(9;22)(q34;q11.2) Reverse transcriptase quantitative PCR (RQ-PCR) for BCR-ABL	Granulocytic dysplasia is minimal/absent May present with blast crisis Absolute leukocytosis (median of 100,000/µL) Classic myelocyte bulge thrombocytopenia indicates advanced stage
Polycythemia vera (PV)^[3]^[4]^[5]^[6]		Constitutional Thromboembolism and bleeding Pruritus after a warm bath PUD related	Facial ruddiness Related to underlying cause Splenomegaly Renal bruit	NL or ↑	None	–	↑ or ↓	NL or ↑	NL	↑↑	NL	Hypercellularity for age with tri-lineage growth Myelofibrosis (in up to 20% of patients)	Radioisotope studies Serum EPO levels LFTs RFTs Imaging studies ↓ Serum ferritin ↓ Folate levels ↑↑ B12 levels	May transform into myelofibrosis or leukemia
Primary myelofibrosis (PMF)^[7]^[8]^[9]^[10]		Constitutional Anemia related Bleeding Infection Abdominal Pain	Hepatosplenomegaly Petechiae & ecchymoses Abdominal distension Lymphadenopathy	↓	Erythroblasts	–	Absent	NL	NL	↓	↓	Variable with fibrosis or hypercellularity	JAK2 mutation CALR mutation MPL mutation ↑ LAP ↑ LAD ↑ Uric acid ↑ B12 levels	Bone marrow aspiration shows a dry tap Variable with leukocytosis or leukopenia
Essential thrombocythemia (ET)^[11]^[12]^[13]		Headache Dizziness Visual disturbances Priapism Acute chest pain	Splenomegaly Skin bruises	NL or ↑	None	–	↓ or absent	NL	NL	↓	↑↑	Normal/Hypercellular	JAK2 mutation CALR mutation MPL mutation	Thrombosis Hemorrhage Pregnancy loss
Disease		Symptoms	Sign	WBC	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Hb	Plt	Bone marrow biopsy	Other investigations	Other features
Myelodysplastic /myeloproliferative neoplasms (MDS/MPN)	Chronic myelomonocytic leukemia (CMML)^[14] ^[15]^[16]	Constitutional Anemia related Bleeding Infections Bone pain Leukemia Cutis	Organomegaly Bruising	↑	< 20%		NL	↑	↑↑	↓	↓	Myelodysplastic and myeloproliferative feature	Cytogenetic analysis Flow cytometry ↑ LDH	Overlapping of both, MDS and MPN Absolute monocytosis > 1 × 10⁹/L (defining feature) MD-CMML:WBC ≤ 13 × 10⁹/L (FAB) MP-CMML:WBC > 13 × 10⁹/L (FAB)
	Atypical chronic myeloid leukemia (aCML), BCR-ABL1-^[17]^[18]	Asymptomatic Constitutional Hyperviscosity and/or anemia related Bleeding Infection	Splenomegaly (46–76%) Purpura Anemia related Priapism	↑	<20%	+	<2% of WBCs	N/A	N/A	↓	↓	Granulocytic hyperplasia with prominent dysplasia	Cytogenetic analysis Flow cytometry	Granulocytic dysplasia is prominent Absence of BCR-ABL or PDGFRA, PDGFRB, or FGFR1 rearrangements WBC > 13 × 10⁹/L
	Juvenile myelomonocytic leukemia (JMML)^[19]^[20]	Infections Anemia related	Hepatosplenomegaly Lymphadenopathy Rash	↑	↑	N/A	N/A	N/A	↑	↓	↓	Hypercelluar with ↑ myeloid cells in stages of maturation	Cytogenetic analysis Flow cytometry ↓ Serum Iron ↑ B12 levels	Polyclonal hypergammaglobulinemia
	MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T)^[21]^[22]^[23]	Constitutional Anemia related Thrombosis	Variable	NL or ↑	NL	–	NL	N/A	N/A	↓	↑	Hypercellularity with dyserythropoiesis and increased megakaryocytes	Cytogenetic analysis Flow cytometry ↑ Serum Iron	Large atypical megakaryocytes Ringed sideroblasts SF3B1 mutation
Disease		Symptoms	Sign	WBC	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Hb	Plt	Bone marrow biopsy	Other investigations	Other features
Chronic neutrophilic leukemia (CNL)^[24]^[25]^[26]		Asymptomatic Constitutional symptoms Bleeding Infection	Splenomegaly Heptomegaly Purpura Anemia related	↑	Minimal	+	NL	NL	NL	↓	↓	Uniforme and intense hypercellularity with minimal to none fibrosis Neutrophil toxic granulations and Dohle bodies	FISH Imaging for hepatosplenomegaly ↑ LDH ↑ B12 levels	Associationed with polycythemia vera and plasma cell disorders Leukocytosis with chronic neutrophilia
Chronic eosinophilic leukemia, not otherwise specified (NOS)^[27]^[28]^[29]^[30]		Constitutional Rash Rhinitis Gastritis Thromboembolism related	Hypertension Eczema, mucosal ulcers, erythema Angioedema Ataxia Anemia Lymphadenopathy Hepatosplenomegaly	↑	Present	+	↑	↑↑	↑	↓	↓	Hypercelluar with ↑ eosinophilic precursors, ↑ eosinophils, and atypical mononuclear cells	FISH Cytogenetic analysis of purified eosinophils and X-chromosome inactivation analysis ↑ B12 levels ↑ LDH	Heart failure Lung fibrosis Encephalopathy Erythema annulare centrifugam
MPN, unclassifiable		Similar to other myeloproliferative neoplasms	Similar to other myeloproliferative neoplasms	↑	Variable	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↑	↑ megakaryocyte proliferation with variable hypercellularity in granulocytic or erythrocytic cell lines	May resemble other myeloproliferative neoplasms	Similar to other myeloprolifeartive neoplasms but do not fulfil the criteria to be classified to a specific type
Mastocytosis^[31]^[32]^[33]^[34]		Constitutional Pruritus & Flushing Urticaria & Blisters Hypotension & PUD Bleeding Bronchoconstriction	Mastocytosis exanthema Blistering Swelling Lymphadenopathy Bleeding Fibrosis	↑	None	–	NL	↑	NL	↓	↓ or ↑	Multifocal dense infiltrates of mast cells with atypical morphology in >25 %	Cytogenetic analysis for c-KIT receptor mutations Serum tryptase levels 24-hour urine test for N-methyl histamine and 11-beta-prostaglandine ↑ Alkaline phosphatase ↑ LDH	Skin most commonly involved Susceptibility to anaphylaxix Osteoporosis
Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1–JAK2^[35]^[36]^[37]^[38]		Asymptomatic Constitutional Rash Cough & breathlessness Peripheral neuropathy/ encephalopathy	Fever Lymphadenopathy	↑	NL	–	NL	↑	↑	NL	↓	Myeloid expansion with eosinophilia	FISH shows t(8;13) and t(8;22)	May present or evolve into acute myeloid or lymphoblastic leukemia Leukocytosis (30 – 59 × 10⁹/L
Disease		Symptoms	Sign	WBC	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Hb	Plt	Bone marrow biopsy	Other investigations	Other features
B-lymphoblastic leukemia/lymphoma^[39]^[40]		Constitutional Anemia related Bleeding Infection Bone pain	Pallor Petechiae Organomegaly Lymphadenopathy	NL or ↑	>25%	N/A	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Hypercellular with blast infilterationwith or without myelodysplasia	Cytogenetic analysis Flow cytometry FISH Auer bodies	May present as extramedullary disease (Myeloid sarcoma)
Myelodysplastic syndromes (MDS)^[41]^[42]		Constitutional Anemia related Bleeding Infection	Pallor Petechiae Organomegaly	↓	Variable	–	↓	↓	↓	↓	↓	Hypercellular/ normocellular bone marrow with dysplastic changes	Cytogenetic analysis Flow cytometry Macro-ovalocytes Basophilic stippling Howell-Jolly body	Leukemia transformation Acquired pseudo-Pelger-Huët anomaly
Acute myeloid leukemia (AML) and related neoplasms^[43]^[44]		Constitutional Anemia related Bleeding Bone pain Joint pain Infections	Infection related Pallor Leukemia cutis Bruising & petechiae Lymphadenopathy Hepatosplenomegaly	NL or ↑	↑	N/A	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Increased immaturemyeloid cells with dysplasia	Cytogenetic analysis Flow cytometry FISH ↑ Potassium ↑ Uric acid ↑ Phosphorus ↓ Calcium ↑ LDH	Common in Down syndrome
Blastic plasmacytoid dendritic cell neoplasm^[45]^[46]^[47]^[48]		Cutaneous symptoms (brown/purple nodular lesions) on face, scalp, lower limb & trunk	Brown/violaceous bruise like lesions Lymphadenopathy Splenomegaly	NL	↑		NL	NL	NL	↓	↓	Malignant cells	Immunohistochemistry or flow cytometry for CD4 & CD56 Neutropenia	TdT expression positive May develop chronic myelomonocytic leukemia (CMML)
Disease		Symptoms	Sign	WBC	Blasts	Left shift	Baso- phils	Eosino- phils	Mono- cytes	Hb	Plt	Bone marrow biopsy	Other investigations	Other features
T-lymphoblastic leukemia/ lymphoma	T-lymphoblastic leukemia/ lymphoma^[49]^[50]^[51]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	>25% blasts (Leukemia) <25% blasts (Lymphoma)	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysis Flow cytometry FISH ↑ LDH Positive for TdT	May involve brain, skin, and testes.
	Provisional entity: Natural killer (NK) cell lymphoblastic leukemia/lymph^[52]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	N/A	Cytogenetic analysis FISH Flow cytometry ↑ LDH	Similar to T-cell lymphoblastic leukemia but may have more aggressive clinical course. Diagnosis is usually based on presence of CD56 expression, and T-cell-associated markers such as CD2 and CD7. B-cell markers are absent.
	Provisional entity: Early T-cell precursor lymphoblastic leukemia^[53]^[54]	Constitutional Anemia Related Bleeding Superior vena cava syndrome	Lymphadenopathy Mediastinal mass Pleural effusions Tracheal obstruction Pericardial effusions	↑	↑	±	↑ or ↓	↑ or ↓	↑ or ↓	↓	↓	Hypercelluarity with increased T cells precursors	Cytogenetic analysis FISH Flow cytometry ↑ LDH	Similar to T-cell lymphoblastic leukemia but is more aggressive clinically and cell are characterized by cytometry as CD1a⁻, CD8⁻, CD5⁻ (dim), and positivity for 1 or more stem cell or myeloid antigens. Gene expression indicates more immature cells as compared to other subtypes of T-cell neoplasms.

Differentiating Myeloproliferative neoplasm from other Diseases

Characteristic	Causes	Physical examination	Laboratory abnormalities	Therapy	Other associations
Myeloproliferative neoplasm	JAK2 mutation CALR mutation MPL mutation BCR-ABL translocation CSF3R mutation SETBP1 mutation PDGFRA or PDGFRB rearrangement	Splenomegaly Hepatomegaly Evidence of infection Pallor	Elevated hemoglobin Elevated white blood cell count Elevated platelet count Elevated eosinophil and/or neutrophil count Bone marrow fibrosis	Ruxolitinib Hydroxyurea Anagrelide Imatinib Midostaurin Stem cell transplant	Variable features based on the subtype of myeloproliferative neoplasm
Myelodysplastic syndrome	Prior exposure to alkylating agents Prior exposure to topoisomerase II inhibitors Age-related changes in hematopoietic stem cells Deletion of chromosome 5q or 7 Gain of chromosome 8	Mucosal bleeding Petechiae Ecchymoses Evidence of infection Pallor	Dysplasia in at least 10% of cells of at least 1 cell line Low white blood cell count Anemia Neutropenia Thrombocytopenia	Lenalidomide Decitabine Azacitidine Erythropoiesis-stimulating agents (ESAs) Granulocyte colony-stimulating factor (G-CSF) Transfusion support Stem cell transplant for high-risk myelodysplastic syndrome	Age-related changes in the bone marrow contribute to myelodysplastic syndrome
Acute myeloid leukemia	Chromosomal instability Sporadic mutations Prior exposure to benzene Prior exposure to alkylating agents Prior exposure to topoisomerase II inhibitors Germline RUNX1 mutation	Pyrexia Evidence of infection Pallor Mucosal bleeding Bruising	Anemia Thrombocytopenia Neutropenia Elevated LDH Elevated uric acid Elevated phosphorus Elevated potassium Low calcium Greater than 20% myeloblasts on bone marrow aspirate^[55]	Cytarabine Anthracycline Enasidenib Liposomal daunorubicin plus cytarabine Gemtuzumab ozogamycin Midostaurin Stem cell transplant	Variable prognosis based on cytogenetic and molecular profile Four new FDA-approved therapies became available in 2017
Acute lymphoblastic leukemia	Chromosomal instability Sporadic mutations	Neurologic deficits Pallor Lymphadenopathy	Anemia Thrombocytopenia Neutropenia Elevated LDH Elevated uric acid Elevated phosphorus Elevated potassium Low calcium Greater than 20% lymphoblasts on bone marrow aspirate	HyperCVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)^[56] R-HyperCVAD (inclusion of rituximab) Peg-asparaginase Intrathecal methotrexate Intrathecal cytarabine Blinatumomab (bispecific T cell engager) Inotuzumab ozogamycin (anti-CD22 antibody) Tisagenlecleucel (chimeric antigen receptor T (CAR-T) cell therapy) Stem cell transplant	Sanctuary sites include the central nervous system (CNS) and testes^[57]
Waldenstrom’s macroglobulinemia	MYD88 mutation Lymphoplasmacytic cell proliferation	Hepatomegaly Splenomegaly Retinal vascular dilation and thrombosis Decreased visual acuity Headache	Elevated immunoglobulin M (IgM) paraprotein Presence of M-spike on protein electrophoresis Elevated serum free light chains (kappa and lambda) Increased serum viscosity	Rituximab Ibrutinib Plasmapheresis	MYD88 mutation testing is standard-of-care Plasmapheresis should be initiated if symptoms of hyperviscosity are present Typically does not require stem cell transplant
Lymphoproliferative disorder^[58]	Epstein-Barr virus (EBV) Human immunodeficiency virus (HIV) Human T cell lymphotrophic virus-1 (HTLV-1) Post-transplant status (post-transplant lymphoproliferative disorder (PTLD)) Chromosomal instability Sporadic mutations Rheumatologic disease	Lymph node enlargement Splenomegaly Hepatomegaly	Elevated lymphocyte count with presence of clonality Anemia Thrombocytopenia Neutropenia	Variable based on the etiology Cytotoxic chemotherapy Antiviral agents Biologic therapy with anti-CD20 monoclonal antibodies Tapering immunosuppressive medications (for post-transplant lymphoproliferative disorder)	Can be due to a variety of causes Variable prognosis

References

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↑ Paola Villafuerte-Gutierrez, Montserrat Lopez Rubio, Pilar Herrera & Eva Arranz (2018). “A Case of Myeloproliferative Neoplasm with BCR-FGFR1 Rearrangement: Favorable Outcome after Haploidentical Allogeneic Transplantation”. Case reports in hematology. 2018: 5724960. doi:10.1155/2018/5724960. PMID 30647980.
↑ Kamiya-Matsuoka C, Garciarena P, Amin HM, Tremont-Lukats IW, de Groot JF (December 2013). “B lymphoblastic leukemia/lymphoma presenting as seventh cranial nerve palsy”. Neurol Clin Pract. 3 (6): 532–534. doi:10.1212/CPJ.0b013e3182a78ef0. PMC 6082360. PMID 30107017.
↑ Zhang X, Rastogi P, Shah B, Zhang L (September 2017). “B lymphoblastic leukemia/lymphoma: new insights into genetics, molecular aberrations, subclassification and targeted therapy”. Oncotarget. 8 (39): 66728–66741. doi:10.18632/oncotarget.19271. PMC 5630450. PMID 29029550.
↑ Germing U, Kobbe G, Haas R, Gattermann N (November 2013). “Myelodysplastic syndromes: diagnosis, prognosis, and treatment”. Dtsch Arztebl Int. 110 (46): 783–90. doi:10.3238/arztebl.2013.0783. PMC 3855821. PMID 24300826.
↑ Gangat N, Patnaik MM, Tefferi A (January 2016). “Myelodysplastic syndromes: Contemporary review and how we treat”. Am. J. Hematol. 91 (1): 76–89. doi:10.1002/ajh.24253. PMID 26769228.
↑ Islam A, Catovsky D, Goldman JM, Galton DA (September 1985). “Bone marrow biopsy changes in acute myeloid leukaemia. I: Observations before chemotherapy”. Histopathology. 9 (9): 939–57. PMID 3864727.
↑ Orazi A (2007). “Histopathology in the diagnosis and classification of acute myeloid leukemia, myelodysplastic syndromes, and myelodysplastic/myeloproliferative diseases”. Pathobiology. 74 (2): 97–114. doi:10.1159/000101709. PMID 17587881.
↑ F. Julia, T. Petrella, M. Beylot-Barry, M. Bagot, D. Lipsker, L. Machet, P. Joly, O. Dereure, M. Wetterwald, M. d’Incan, F. Grange, J. Cornillon, G. Tertian, E. Maubec, P. Saiag, S. Barete, I. Templier, F. Aubin & S. Dalle (2013). “Blastic plasmacytoid dendritic cell neoplasm: clinical features in 90 patients”. The British journal of dermatology. 169 (3): 579–586. doi:10.1111/bjd.12412. PMID 23646868. Unknown parameter |month= ignored (help)
↑ Livio Pagano, Caterina Giovanna Valentini, Alessandro Pulsoni, Simona Fisogni, Paola Carluccio, Francesco Mannelli, Monia Lunghi, Gianmatteo Pica, Francesco Onida, Chiara Cattaneo, Pier Paolo Piccaluga, Eros Di Bona, Elisabetta Todisco, Pellegrino Musto, Antonio Spadea, Alfonso D’Arco, Stefano Pileri, Giuseppe Leone, Sergio Amadori & Fabio Facchetti (2013). “Blastic plasmacytoid dendritic cell neoplasm with leukemic presentation: an Italian multicenter study”. Haematologica. 98 (2): 239–246. doi:10.3324/haematol.2012.072645. PMID 23065521. Unknown parameter |month= ignored (help)
↑ Joseph D. Khoury (2018). “Blastic Plasmacytoid Dendritic Cell Neoplasm”. Current hematologic malignancy reports. 13 (6): 477–483. doi:10.1007/s11899-018-0489-z. PMID 30350260. Unknown parameter |month= ignored (help)
↑ Shinichiro Sukegawa, Mamiko Sakata-Yanagimoto, Ryota Matsuoka, Haruka Momose, Yusuke Kiyoki, Masayuki Noguchi, Naoya Nakamura, Rei Watanabe, Manabu Fujimoto, Yasuhisa Yokoyama, Hidekazu Nishikii, Takayasu Kato, Manabu Kusakabe, Naoki Kurita, Naoshi Obara, Yuichi Hasegawa & Shigeru Chiba (2018). “[Blastic plasmacytoid dendritic cell neoplasm accompanied by chronic myelomonocytic leukemia successfully treated with azacitidine]”. [[[Rinsho ketsueki] The Japanese journal of clinical hematology]]. 59 (12): 2567–2573. doi:10.11406/rinketsu.59.2567. PMID 30626790.
↑ You MJ, Medeiros LJ, Hsi ED (September 2015). “T-lymphoblastic leukemia/lymphoma”. Am. J. Clin. Pathol. 144 (3): 411–22. doi:10.1309/AJCPMF03LVSBLHPJ. PMID 26276771.
↑ Patel KJ, Latif SU, de Calaca WM (March 2009). “An unusual presentation of precursor T cell lymphoblastic leukemia/lymphoma with cholestatic jaundice: case report”. J Hematol Oncol. 2: 12. doi:10.1186/1756-8722-2-12. PMC 2663564. PMID 19284608.
↑ Elreda L, Sandhu M, Sun X, Bekele W, Cohen AJ, Shah M (2014). “T-cell lymphoblastic leukemia/lymphoma: relapse 16 years after first remission”. Case Rep Hematol. 2014: 359158. doi:10.1155/2014/359158. PMC 4005062. PMID 24822133.
↑ Sedick Q, Alotaibi S, Alshieban S, Naheet KB, Elyamany G (2017). “Natural Killer Cell Lymphoblastic Leukaemia/Lymphoma: Case Report and Review of the Recent Literature”. Case Rep Oncol. 10 (2): 588–595. doi:10.1159/000477843. PMID 28868017.
↑ Jain N, Lamb AV, O’Brien S, Ravandi F, Konopleva M, Jabbour E, Zuo Z, Jorgensen J, Lin P, Pierce S, Thomas D, Rytting M, Borthakur G, Kadia T, Cortes J, Kantarjian HM, Khoury JD (April 2016). “Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: a high-risk subtype”. Blood. 127 (15): 1863–9. doi:10.1182/blood-2015-08-661702. PMC 4915808. PMID 26747249.
↑ Haydu JE, Ferrando AA (July 2013). “Early T-cell precursor acute lymphoblastic leukaemia”. Curr. Opin. Hematol. 20 (4): 369–73. doi:10.1097/MOH.0b013e3283623c61. PMC 3886681. PMID 23695450.
↑ Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T; et al. (2017). “Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel”. Blood. 129 (4): 424–447. doi:10.1182/blood-2016-08-733196. PMC 5291965. PMID 27895058.
↑ Terwilliger T, Abdul-Hay M (2017). “Acute lymphoblastic leukemia: a comprehensive review and 2017 update”. Blood Cancer J. 7 (6): e577. doi:10.1038/bcj.2017.53. PMC 5520400. PMID 28665419.
↑ Inaba H, Greaves M, Mullighan CG (2013). “Acute lymphoblastic leukaemia”. Lancet. 381 (9881): 1943–55. doi:10.1016/S0140-6736(12)62187-4. PMC 3816716. PMID 23523389.
↑ Kipps TJ, Stevenson FK, Wu CJ, Croce CM, Packham G, Wierda WG; et al. (2017). “Chronic lymphocytic leukaemia”. Nat Rev Dis Primers. 3: 16096. doi:10.1038/nrdp.2016.96. PMC 5336551. PMID 28102226.

Epidemiology and Demographics

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

The incidence of myeloproliferative neoplasm is approximately 7.8 per 100,000 individuals worldwide. The different subtypes of myeloproliferative neoplasm have different incidence and prevalence statistics. Males are more commonly affected than females, and older persons are more commonly affected than younger persons.

Epidemiology and Demographics

Incidence

The incidence of myeloproliferative neoplasm is approximately 7.8 per 100,000 individuals worldwide.^[1] This statistic includes all eight subtypes of myeloproliferative neoplasm. There are varying incidences for the different subtypes of myeloproliferative neoplasm.
The incidence of polycythemia vera is 0.4-2.8 per 100,000 persons per year.^[2]
The incidence of essential thrombocythemia is 0.38-1.7 per 100,000 persons per year.^[2]
The incidence of primary myelofibrosis is 0.1-1 per 100,000 persons per year.^[2]

Prevalence

The prevalence of myeloproliferative neoplasm depends on the particular subtype.
The prevalence of polycythemia vera is 44-57 per 100,000 persons.^[2]
The prevalence of essential thrombocythemia is 38-57 per 100,000 persons.^[2]
The prevalence of primary myelofibrosis is 4-6 per 100,000 persons.^[2]

Age

The prevalence of myeloproliferative neoplasm increases with age.^[3]
The average age of diagnosis is 60-70.^[3]

Gender

Males are more commonly affected with myeloproliferative neoplasm than females.^[3]
Females are more likely to be affected by the abdominal symptoms of myeloproliferative neoplasm.^[4]
Females are also more likely to develop thrombocytopenia than males.^[4].
Females have a shorter disease duration.

Race

The prevalence of myeloproliferative neoplasm does not vary by race.^[3]

References

↑ Centers for Disease Control and Prevention. WTC Health Program.Myeloid Malignancieshttp://www.cdc.gov/wtc/pdfs/WTCHP_PP_MyeloidMalignancies_02012014.pdf
↑ ^2.0 ^2.1 ^2.2 ^2.3 ^2.4 ^2.5 Agarwal MB, Malhotra H, Chakrabarti P, Varma N, Mathews V, Bhattacharyya J; et al. (2015). “Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia”. Indian J Med Paediatr Oncol. 36 (1): 3–16. doi:10.4103/0971-5851.151770. PMC 4363847. PMID 25810569.
↑ ^3.0 ^3.1 ^3.2 ^3.3 Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA; et al. (2008). “Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs”. Blood. 112 (1): 45–52. doi:10.1182/blood-2008-01-134858. PMID 18443215.
↑ ^4.0 ^4.1 Geyer HL, Kosiorek H, Dueck AC, Scherber R, Slot S, Zweegman S; et al. (2017). “Associations between gender, disease features and symptom burden in patients with myeloproliferative neoplasms: an analysis by the MPN QOL International Working Group”. Haematologica. 102 (1): 85–93. doi:10.3324/haematol.2016.149559. PMC 5210236. PMID 27540137.

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Risk Factors

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

There are four major categories of risk factors for myeloproliferative neoplasm. Genetic mutational events comprise the most common risk factor. Other risk factors include advanced age, prior cytotoxic chemotherapy, and autoimmune disease.

Risk factors

Mutations: Genetic mutations are the most important risk factors for development of myeloproliferative neoplasm. Mutations in JAK2, CALR, and MPL are the most common risk factors for myeloproliferative neoplasms and are causative mutations in the disease. There are multiple other genetic mutations associated with myeloproliferative neoplasms (please see Causes section).

Advanced age: Age is a major risk factor for the development of myeloproliferative neoplasm. Aging is associated with the acquisition of mutations in cells, and these mutations can lead to the development of hematologic malignancies.

Prior cytotoxic therapy: Treatment-related myeloproliferative neoplasms is emerging as an important clinical entity to recognize ^[1] Patients who receive chemotherapy for other conditions are at risk for developing myeloproliferative neoplasms after many years. The reason for treatment related myeloproliferation is that cytotoxic agents induce DNA damage, which results in increased oncogenic potential within cells. Alkylating agents and topoisomerase II inhibitors are the most commonly implicated agents. Hydroxyurea is also implicated in the development of myeloproliferative neoplasms.

Autoimmunity: A prior history of autoimmune disease is associated with a risk for developing myeloproliferative neoplasms.^[2] The etiology for the link between autoimmunity and myeloproliferative neoplasm is thought to be antigenic stimulation which results in immune cell activation and aberrant proliferation. There is specifically an increased risk of myeloproliferative neoplasm is patients with:
- Crohn’s disease: This carries a 2.9-fold increased risk.
- Immune thrombocytopenia purpura: This carries a 1.8-fold increased risk.
- Polymyalgia rheumatica: This carries a 1.7-fold increased risk.
- Giant cell arteritis: This carries a 5.9-fold increased risk.
- Reiter’s reactive arthritis: This carries a 15.9-fold increased risk.
- Aplastic anemia: This carries a 7.8-fold increased risk.

References

↑ Björkholm M, Derolf AR, Hultcrantz M, Kristinsson SY, Ekstrand C, Goldin LR; et al. (2011). “Treatment-related risk factors for transformation to acute myeloid leukemia and myelodysplastic syndromes in myeloproliferative neoplasms”. J Clin Oncol. 29 (17): 2410–5. doi:10.1200/JCO.2011.34.7542. PMC 3107755. PMID 21537037.
↑ Kristinsson SY, Landgren O, Samuelsson J, Björkholm M, Goldin LR (2010). “Autoimmunity and the risk of myeloproliferative neoplasms”. Haematologica. 95 (7): 1216–20. doi:10.3324/haematol.2009.020412. PMC 2895049. PMID 20053870.

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Screening

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

There are currently no guidelines for screening for myeloproliferative neoplasm. Monitoring of the complete blood count is done routinely.

Screening

There are currently no guidelines for screening for myeloproliferative neoplasm. Routine monitoring of complete blood count (CBC) once yearly is sufficient for screening for hematologic diseases in general.^[1]

References

↑ Rumi E, Cazzola M (2017). “Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms”. Blood. 129 (6): 680–692. doi:10.1182/blood-2016-10-695957. PMC 5335805. PMID 28028026.

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Natural History, Complications, and Prognosis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Mohamad Alkateb, MBBCh [2] Shyam Patel [3]

Overview

The natural history of myeloproliferative neoplasm begins with weight loss, fever, and night sweats. The natural history depends on the subtype of myeloproliferative neoplasm. Common complications of myeloproliferative neoplasm include splenomegaly, bleeding, thrombosis, bone marrow fibrosis, and acute leukemia. Prognosis depends on the subtype of myeloproliferative neoplasm. Each subtype has its own prognostic scoring system. In general, patients with polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia have better prognosis than patients with primary myelofibrosis. The prognosis is generally good with treatment.

Natural History

The symptoms of myeloproliferative neoplasm usually develop in the sixth decade of life and start with symptoms such as anorexia, weight loss, and fatigue. The onset of symptoms is usually insidious, and the symptoms do not frequently cause many problems initially. The disease progresses quite slowly, typically over a period of months to years. However, without treatment, patients will develop severe symptoms, such as abdominal pain, bruising, bleeding, thrombosis, fever, and infection which may eventually lead to death.^[1]^[2] The natural history of myeloproliferative neoplasm is dependent upon the subtype of myeloproliferative neoplasm and by the prognostic group. The natural history of myelodysplastic syndrome / myeloproliferative neoplasm overlap syndrome (MDS/MPN) is poor.^[3] In general, the natural history of patients above the age of 60, the presence of a JAK2 mutation, and a history of thrombosis is worse than the natural history of patients under age 60, the absence of JAK2 mutation, and no history of thrombosis.^[4] Thrombosis is an inevitable part of the natural history of many subtypes of myeloproliferative neoplasms, especially polycythemia vera and essential thrombocythemia. Approximately 41% of patients with polycythemia vera, for example, will experience thrombosis.^[5]

Complications

Myeloproliferative neoplasm may lead to the following complications:^[6]^[7]^[8]^[9]^[10]^[11]

Thrombosis: Clot formation occurs in 15% of patients with myeloproliferative neoplasm.

Deep venous thrombosis: Clots can develop in the deep veins of the lower extremities, such as the popliteal vein or femoral vein.
Pulmonary embolism: Clots can develop in the segmental or subsegmental arteries of the pulmonary vasculature.
Myocardial infarction: Clots can develop within the coronary arteries, and this is usually exacerbated by underlying cardiac risk factors.
Stroke: Clots can develop in the anterior or posterior circulation in the brain.
Budd-Chiari syndrome: Clots can develop in the hepatic vein.
Splanchnic vein thrombosis: Clots can develop in mesenteric vasculature like the splenic vein, superior mesenteric vein, inferior mesenteric vein, or portal vein.

Bleeding: Bleeding is especially common in patients with essential thrombocythemia with very high platelet counts, as this leads to a paradoxical effect known as acquired von Willebrand disease. In this condition, platelets interfere with the function of von Willebrand factor.

Epistaxis: Bleeding can occur in the anterior or posterior circulation of the nasal cavity.
Gingival bleeding: Bleeding gums is typically seen after brushing teeth.
Menorrhagia: Pelvis bleeding commonly occurs in pre-menopausal females.
Metrorrhagia: Irregular pelvic bleeding can occur in pre-menopausal females.
Petechiae: Pinpoint hemorrhages can occur in the skin.

Splenomegaly: Extramedullary hematopoiesis occurs when the bone marrow is unable to sustain normal cell production.
Gout: Gout occurs most often in patients with polycythemia vera.
Peptic ulcer

Clonal proliferation^[4]

Myelofibrosis: This is a condition in which the bone marrow becomes replaced by collagen and reticulin fibers. When myelofibrosis occurs in the setting of polycythemia vera, it is referred to as post-polycythemia vera (post-PV) myelofibrosis. When myelofibrosis occurs in the setting of essential thrombocythemia, it is referred to as post-essential thrombocythemia (post-ET) myelofibrosis. Myelofibrosis carries an overall poor prognosis given that collagen fibers preclude normal hematopoiesis, resulting in infections, bleeding, and fatigue.

Acute myeloid leukemia: This is a malignancy of the hematopoietic stem cell (specifically myeloid precursors). It is characterized by clonal proliferation and resultant cytopenias and ineffective hematopoiesis. Patients typically die as a result of infections and/or bleeding.

End-organ damage: Deposition of myeloid cells in organs can result in permanent organ damage. This is especially true to chronic eosinophilic leukemia, in which eosinophils can deposit in the lungs, heart, or other tissues and impair the function of these organs.

Microvascular symptoms^[4]

Prognosis

The prognosis of myeloproliferative neoplasm depends upon the subtype. Each subtype of myeloproliferative neoplasm has a different prognostication system. Overall, the prognosis for patients with polycythemia vera, essential thrombocythemia, and chronic myeloid leukemia is good, and prognosis of primary myelofibrosis is worse. For example, the median survival of patients with polycythemia vera is 33 years.^[12] The median survival of patients with essential thrombocythemia is 24 years.

Polycythemia vera

In polycythemia vera, patients are prognosticated based on two risk groups as follows:


Prognostic Group	Defining Features

Low risk	No history of thrombosis, and Age < 60
High risk	History of thrombosis, or Age > 60

Essential thrombocythemia

In essential thrombocythemia, patients are prognosticated based on four risk groups as follows:^[12]


Prognostic Group	Defining Features

Very low risk	No history of thrombosis Age < 60 JAK2 or MPL wild-type
Low risk	No history of thrombosis Age < 60 JAK2 or MPL mutation present
Intermediate risk	No history of thrombosis Age > 60 JAK2 or MPL wild-type
High risk	History of thrombosis, or Age > 60 with JAK2 or MPL mutation present

Primary myelofibrosis

In primary myelofibrosis, patients are prognosticated into four risk groups, based on the Dynamic International Prognostic Scoring System (DIPSS). The adverse prognostic features are age > 65 years, white blood cell count > 25,000/microliter, hemoglobin < 10 g/dl, peripheral blood blast count > 1%, and presence of constitutional symptoms. Each adverse prognostic feature is assigned 1 point (except 2 points for hemoglobin < 10g/dl).^[12]


Prognostic Group	Points

Low risk	0
Intermediate-1 (INT-1) risk	1 or 2
Intermediate-2 (INT-2) risk	3 or 4
High risk	5 or 6

Recently, the DIPSS scoring system was revised to 3 additional adverse features. These adverse features include platelet count < 100,000 per microliter, transfusion dependence, and unfavorable karyotype (monosomy 5, monosomy 7, trisomy 8, isochromosome 17, chromosome 11q23 rearrangement (MLL gene rearrangement). This new system is known as DIPSS-Plus and is used when karyotype information is available.^[12]


Prognostic Group	Points

Low risk	0
Intermediate-1 (INT-1) risk	1
Intermediate-2 (INT-2) risk	2 or 3
High risk	4 to 6

Chronic myeloid leukemia

In chronic myeloid leukemia, the prognostication is based on the Sokal score, which includes age, spleen size, platelet count, and blast count.


Prognostic Group	Sokal Score	Median Survival

Low risk	< 0.8	5 years
Intermediate risk	0.8-1.2	2-2.5 years
High risk	>1.2	2.5 years

Without treatment, Myeloproliferative neoplasm may result in death. The 5- and 10-year survival rates for myeloproliferative neoplasm are 74% to 93% and 61% to 84%, respectively. Gene expression profiling may eventually have an important role in the prognostication of myeloproliferative neoplasm.^[13]

References

↑ Ma X, Does M, Raza A, Mayne ST (2007). “Myelodysplastic syndromes: incidence and survival in the United States”. Cancer. 109 (8): 1536–42. doi:10.1002/cncr.22570. PMID 17345612.
↑ Agarwal MB, Malhotra H, Chakrabarti P, Varma N, Mathews V, Bhattacharyya J; et al. (2015). “Myeloproliferative neoplasms working group consensus recommendations for diagnosis and management of primary myelofibrosis, polycythemia vera, and essential thrombocythemia”. Indian J Med Paediatr Oncol. 36 (1): 3–16. doi:10.4103/0971-5851.151770. PMC 4363847. PMID 25810569.
↑ DiNardo CD, Daver N, Jain N, Pemmaraju N, Bueso-Ramos C, Yin CC; et al. (2014). “Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy”. Leukemia. 28 (4): 958–61. doi:10.1038/leu.2014.8. PMC 3981947. PMID 24492324.
↑ ^4.0 ^4.1 ^4.2 Vannucchi AM (2017). “From leeches to personalized medicine: evolving concepts in the management of polycythemia vera”. Haematologica. 102 (1): 18–29. doi:10.3324/haematol.2015.129155. PMC 5210229. PMID 27884974.
↑ Stein BL, Oh ST, Berenzon D, Hobbs GS, Kremyanskaya M, Rampal RK; et al. (2015). “Polycythemia Vera: An Appraisal of the Biology and Management 10 Years After the Discovery of JAK2 V617F”. J Clin Oncol. 33 (33): 3953–60. doi:10.1200/JCO.2015.61.6474. PMC 4979103. PMID 26324368.
↑ Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia/leukemia/polycythemia-vera/?region=ab
↑ Zoraster RM, Rison RA (2013). “Acute embolic cerebral ischemia as an initial presentation of polycythemia vera: a case report”. J Med Case Rep. 7: 131. doi:10.1186/1752-1947-7-131. PMC 3668271. PMID 23683307.CS1 maint: PMC format (link)
↑ Buzas C, Sparchez Z, Cucuianu A, Manole S, Lupescu I, Acalovschi M (2009). “Budd-Chiari syndrome secondary to polycythemia vera. A case report”. J Gastrointestin Liver Dis. 18 (3): 363–6. PMID 19795034.
↑ Biagioni E, Pedrazzi P, Marietta M, Di Benedetto F, Villa E, Luppi M; et al. (2013). “Successful liver transplantation in a patient with splanchnic vein thrombosis and pulmonary embolism due to polycythemia vera with Jak2v617f mutation and heparin-induced thrombocytopenia”. J Thromb Thrombolysis. 36 (3): 352–4. doi:10.1007/s11239-012-0832-5. PMID 23277116.
↑ Reikvam H, Tiu RV (2012). “Venous thromboembolism in patients with essential thrombocythemia and polycythemia vera”. Leukemia. 26 (4): 563–71. doi:10.1038/leu.2011.314. PMID 22076463.
↑ “Erratum: Borderud SP, Li Y, Burkhalter JE, Sheffer CE and Ostroff JS. Electronic cigarette use among patients with cancer: Characteristics of electronic cigarette users and their smoking cessation outcomes. Cancer. doi: 10.1002/ cncr.28811”. Cancer. 121 (5): 800. 2015. PMID 25855820.
↑ ^12.0 ^12.1 ^12.2 ^12.3 Tefferi A, Vannucchi AM, Barbui T (2018). “Essential thrombocythemia treatment algorithm 2018”. Blood Cancer J. 8 (1): 2. doi:10.1038/s41408-017-0041-8. PMC 5802626. PMID 29321520.
↑ Spivak JL, Considine M, Williams DM, Talbot CC, Rogers O, Moliterno AR; et al. (2014). “Two clinical phenotypes in polycythemia vera”. N Engl J Med. 371 (9): 808–17. doi:10.1056/NEJMoa1403141. PMC 4211877. PMID 25162887.

Diagnosis

Treatment

Case Studies

Case #1

[pmid18779404-1] 1.0 ^1.1 ^1.2 ^1.3 Levine RL, Gilliland DG (2008). “Myeloproliferative disorders”. Blood. 112 (6): 2190–8. doi:10.1182/blood-2008-03-077966. PMC 2962533. PMID 18779404.

[pmid27884974-2] 2.0 ^2.1 Vannucchi AM (2017). “From leeches to personalized medicine: evolving concepts in the management of polycythemia vera”. Haematologica. 102 (1): 18–29. doi:10.3324/haematol.2015.129155. PMC 5210229. PMID 27884974.

[3] Dameshek W (1951). “Some speculations on the myeloproliferative syndromes”. Blood. 6 (4): 372–5. PMID 14820991.

[pmid15837627-4] Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ; et al. (2005). “Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis”. Cancer Cell. 7 (4): 387–97. doi:10.1016/j.ccr.2005.03.023. PMID 15837627.

[5] Baxter EJ, Scott LM, Campbell PJ; et al. (2005). “Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders”. Lancet. 365: 1054–1061. PMID 15781101.

[6] James C, Ugo V, Le Couedic JP; et al. (2005). “A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera”. Nature. 434 (7037): 1144–1148. PMID 15793561.

[7] Levine RL, Wadleigh M, Cools J; et al. (2005). “Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis”. Cancer Cell. 7 (4): 387–397. PMID 15837627.

[8] Kralovics R, Passamonti F, Buser AS; et al. (2005). “A gain-of-function mutation of JAK2 in myeloproliferative disorders”. N Engl J Med. 352 (17): 1779–1790. PMID 15858187.

[9] Campbell PJ, Scott LM, Buck G; et al. (2005). “Definition of subtypes of essential thrombocythaemia and relation to polycythaemia vera based on JAK2 V617F mutation status: a prospective study”. Lancet. 366 (9501): 1945–1953. PMID 16325696.

[pmid16834459-10] 10.0 ^10.1 Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M; et al. (2006). “MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia”. PLoS Med. 3 (7): e270. doi:10.1371/journal.pmed.0030270. PMC 1502153. PMID 16834459.

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Myeloproliferative neoplasm

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Myeloproliferative Neoplasm from Other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

Chest X-Ray

CT

MRI

Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Future of Investigational Therapies

References

Overview

Historical Perspective

References

Overview

Classification

References

Overview

Pathophysiology

Physiology

Pathophysiology

Gallery

References

Overview

Causes

References

Overview

Differentiating Myeloproliferative Neoplasm from other Diseases

Differentiating Myeloproliferative neoplasm from other Diseases

References

Overview

Epidemiology and Demographics

Incidence

Prevalence

Age

Gender

Race

References

Overview

Risk factors

References

Overview

Screening

References

Overview

Natural History

Complications

Prognosis

References

Diagnosis

Treatment

Case Studies

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