Chapter 84: Polycythemia Vera

Jaroslav F. Prchal; Josef T. Prchal

INTRODUCTION

SUMMARY

Polycythemia vera (PV) is classified in the group of Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) that also includes essential thrombocythemia (ET) and primary myelofibrosis (PMF). Chronic myelogenous leukemia was historically classified as a MPN, but is now considered a separate entity. PV is an acquired primary clonal polycythemic disorder. Primary polycythemias result from abnormal intrinsic properties of erythroid progenitors that proliferate independently or excessively in response to extrinsic regulators; low serum erythropoietin is their hallmark. PV is the most common primary polycythemia. It arises from mutation(s) of a pluripotent hematopoietic stem cell, which results in excess production of erythrocytes and variable overproduction of granulocytes and platelets. It is often accompanied by splenomegaly. Most patients with PV have a somatic mutation of the Janus-type tyrosine kinase-2 gene (JAK2) that is detectable in blood myeloid cells. The mutation results in constitutive hyperactivity of JAK2 kinase stemming from loss-of-function of its negative regulatory domain. The most common mutation is JAK2^V617F, which is present in virtually all cases of PV; a small minority of PV patients have a mutation in other parts of JAK2 (exon 12). The JAK2^V617F mutation is also found in many patients with ET and myelofibrosis (MF), albeit at lower frequency (55 percent in ET and 65 percent in MF). As with other clonal hematologic disorders, PV can undergo a clonal evolution to PMF (JAK2^V617F-positive) or acute leukemia (either JAK2^V617F-negative or positive). In virtually all JAK2^V617F-positive PV patients, at least some progenitors exist that become homozygous for the JAK2^V617F mutation by uniparental disomy-acquired mitotic recombination. The majority of these progenitors account for the erythropoietin-independent erythroid colonies detected in vitro by clonogenic burst-forming unit–erythroid assay. The JAK2^V617F mutation is often not the initial cause of clonal proliferation, but may be preceded by other germline and somatic mutation(s) (e.g., TET2).

Arterial and venous thromboses are a major cause of morbidity and mortality in PV, and a small proportion of patients develop secondary myelofibrosis (sometimes called the spent phase) and/or an invariably fatal acute leukemic transformation. Myelosuppressive therapy has been an effective mode of therapy, with drugs such as hydroxyurea, busulfan, pipobroman, and radioactive phosphorus useful in controlling proliferation of all blood cell lineages. However, while myelosuppressive therapy controls the cellular proliferation and decreases the incidence of thrombotic complications, many of these drugs have leukemogenic potential. In contrast, pegylated interferon-α may lead to complete hematologic remission and restoration of polyclonal hematopoiesis and avoid the leukemogenic complications. Targeted therapy with JAK2 kinase inhibitors is currently being evaluated in clinical trials and, thus far, have been found effective in decreasing the need for phlebotomies, decreasing the number of white cells and splenomegaly, and improving the patient’s quality of life.

Acronyms and Abbreviations

AML, acute myelogenous leukemia; BFU-E, burst-forming unit–erythroid; ECLAP, European Collaboration on Low-Dose Aspirin in Polycythemia Vera; EEC, endogenous erythroid colony; ELN, European Leukemia Net; ET, essential thrombocytosis; HDAC, histone deacetylase; HU, hydroxyurea; IFN-α, interferon-α; IWG-MRT, International Working Group for Myeloproliferative Neoplasms Research and Treatment; JAK2, Janus-type tyrosine kinase 2; MDS, myelodysplastic syndrome; MF, myelofibrosis; MPN, myeloproliferative neoplasm; PCR, polymerase chain reaction; PEG-IFN, pegylated interferon; PFCP, primary familial and congenital polycythemia; PMF, primary myelofibrosis; PV, polycythemia vera; SNP, single nucleotide polymorphism; UPD, uniparental disomy; TET2, a homologue of chromosome 10-11 translocation; WHO, World Health Organization.

DEFINITION AND HISTORY

Listen

The term polycythemia, denoting an increased amount of blood, has traditionally been applied to those conditions in which the mass of erythrocytes is increased. In polycythemia vera (PV), an increase in the erythroid mass is frequently accompanied by an increase in neutrophils and platelets. For a classification of the polycythemias, see Chap. 57 and Chap. 34, Table 34–2. Although several clinical stages of PV are recognized (masked PV, plethoric phase, stable phase, transformation, spent phase, and acute leukemia), it is not clear whether these stages represent a sequential progression of the disease or whether all patients progress through all stages.

PV, the sole clonal form of primary polycythemia, was first described in 1892 by Vaquez.¹ In 1903, Osler reviewed four of his own PV cases and an additional five cases from the literature and wrote, “The condition is characterized by chronic cyanosis, polycythemia, and variable moderate enlargement of the spleen. The chief symptoms have been weakness, prostration, constipation, headache, and vertigo.”² The increased proliferation of granulocyte precursors and megakaryocytes was first described by Türk in 1904.³

EPIDEMIOLOGY

Listen

A recent analysis of 20 studies of PV patients from around the world revealed an annual incidence rate of 0.84 cases per 100,000 people, with no bias for gender.^4,5 The true incidence may be higher, as many cases are asymptomatic and thus not diagnosed. Testing for the Janus-type tyrosine kinase 2 (JAK2)^V617F mutation can uncover hidden cases of PV among subjects with thrombosis or concomitant iron deficiency. The incidence of PV may be higher among Ashkenazi Jews.^6,7

Although most patients with PV do not have a history of polycythemia in the family, familial incidence of the disorder is known to occur^8,9,10 and is very likely underreported. In a large Swedish study of more than 25,000 first-degree relatives of 11,000 myeloproliferative neoplasm (MPN) patients, the incidence of MPNs were five to seven times higher in relatives than in controls.¹¹ In familial cases of PV, an inherited predisposition, perhaps in the form of a germline mutation, presumably facilitates the acquired somatic mutation(s) necessary for disease onset.^9,12

ETIOLOGY AND PATHOGENESIS

Listen

PV arises from the neoplastic transformation of a single normal hematopoietic pluripotent cell, which acquires a selective proliferative and survival advantage, resulting in the development of a variable degree of clonal hematopoiesis. Once large enough, the clone then suppresses and replaces normal polyclonal hematopoiesis. The clonal origin of PV has been demonstrated in women heterozygous for a polymorphic X-chromosome marker such as, glucose-6-phosphate dehydrogenase¹³ as well as by more modern clonality assays (Chap. 10).¹⁴ In both cases, all hematopoietic cell lineages⁹ express either one isoform of the enzyme, or some polymorphic allele encoded by the maternal or paternal X chromosome, whereas T lymphocytes and nonhematopoietic cells are a mosaic of both enzyme types.

In vitro marrow- or blood-derived erythroid colonies of PV patients arise from both normal burst-forming unit–erythroid (BFU-E) precursors and BFU-E precursors that are erythropoietin-independent. Erythropoietin-independent BFU-E precursors form so-called endogenous erythroid colonies (EECs),^15,16,17,18 a characteristic feature of PV. The fibroblasts that accumulate in the marrow of patients with PV as the disease progresses are not part of the abnormal PV clone. Rather, they seem to accumulate in response to cytokines released by megakaryocytes and other cells (Chap. 86).¹⁹

Other abnormalities that have been described include decreased levels of a platelet thrombopoietin receptor,²⁰ deregulation of bcl-x, an inhibitor of apoptosis,²¹ increased expression of protein tyrosine phosphatase activity by red cell precursors,²² and acquired loss-of-heterozygosity of chromosome 9p as a result of uniparental disomy (UPD).⁹ This last observation was one of two routes that led to the discovery of the JAK2 2343G > T mutation encoding the V617F mutation located on chromosome 9p,^12,23 which has improved our understanding of disease pathogenesis, improved the specificity of diagnosis, and led to an explosion of research in MPN (see “JAK2V617F Mutation” below).

There are no specific karyotypic markers occurring with high frequency in PV. Fewer than 25 percent of patients have karyotypic abnormalities at diagnosis,^{24,25,26,27,28,29} but the incidence rises with the increasing duration of the disease,^25,30 suggesting that karyotypic abnormalities represent secondary genetic events.³¹ Cytogenetic abnormalities may potentially herald transformation from PV to myelofibrosis, acute myeloid leukemia, or a myelodysplastic syndrome, but as of now, these associations are weak.²⁹

JAK2^V617F MUTATION

JAK2 kinase is present in all hematopoietic cells and is essential for proliferative intracellular signaling in response to a variety of hematopoietic growth factors (Chaps. 34 and 57). The V617F mutation was first identified in PV in 2004,²³ and was simultaneously reported by several laboratories.^32,33,34 The V617F mutation is present in virtually all patients with PV and in more than 50 percent of patients with essential thrombocytosis (ET; Chap. 85) and myelofibrosis (MF; Chap. 86); rarely is it found in the minority of patients with other myeloproliferative disorders.^35,36 In PV (unlike in ET), it is often in its associated homozygous form as a result of UPD, at least in some of the progenitors.^26,37 Patients bearing homozygous JAK2^V^617F tend to have a longer duration of disease,³³ higher hemoglobin levels, and increased incidence of pruritus³⁸ and are more likely to transform to post-PV MF (Chap. 86).³⁹ The JAK2^V617F allele burden in PV may also be correlated with increased spleen volume, increased leukocytosis, and severity of MF.^39,40,41,42 It should be noted, however, that PV patients can achieve a complete hematologic remission without a significant molecular response (i.e., a decrease in JAK2^V617F allele burden).⁴³ In some of the rare PV patients who are JAK2^V617F-negative, a different JAK2 mutation is present in exon 12.⁴⁴ Several different JAK2 exon 12 mutations, including missense mutations, insertions, and deletions, have been described. Patients with exon 12 mutations may present with different clinical manifestations from those with the classic JAK2^V617F mutation: erythrocytosis only, higher hemoglobin, and differences in marrow morphology.⁴⁵ Disease course and clinical outcome, however, are similar.⁴⁶

Studies of families of MPN patients, in which several different MPNs occur in a single pedigree,⁴⁷ indicate that JAK2 mutations may not be solely responsible for the disease phenotype and may not even represent the disease-initiating event. A number of compelling lines of evidence support this conclusion. First, in familial PV, there is no clear linkage between the disease and chromosome 9p, the genetic site of JAK2, suggesting an independent germline predisposition to PV.¹² Second, in familial PV, affected members can be either JAK2^V617F- positive or negative.⁴⁸ Third, acquisition of the JAK2^V617F mutation may be a late genetic event.⁴⁹ Fourth, in sporadic PV, only a proportion of clonal PV cells are JAK2^V617F-positive.³⁷ And fifth, acute leukemic transformation of any JAK2-positive MPN, including PV, is frequently negative for the JAK2^V617F mutation.^35,50 These diverse observations strongly suggest that the somatic mutation of the JAK2 gene is not the initiating or sole pathogenic process in PV, but in most patients is essential for the clinical phenotype of PV. The pathways leading to acquisition of the JAK2^V617F mutation, homozygosity of JAK2^V617F, and participation of many other genes in the 9p UPD region may have phenotypic and prognostic significance.^51,52 Additional prognostic significance can be ascertained by analysis for clustering of specific genes.⁵³

A genomic chromosome 9p functional variant might also be relevant to the pathogenesis of JAK2^V617F. Independent occurrence of the JAK2^V617F mutation on different haplotypes was found, although a specific constitutional inherited JAK2 haplotype (GGCC, 46/1), associated with the JAK2^V617F somatic mutation, was found in most JAK2^V617F-positive individuals.⁵⁴ The risk of acquiring a JAK2^V617F-positive MPN is three to four fold higher in patients with the JAK2 GGCC (46/1) haplotype.^54,55,56,57 This GGCC haplotype of JAK2 also confers susceptibility to JAK2 exon 12 mutation-positive PV.⁵⁵ These studies suggest that pre-JAK2 hypermutability events exist and that germline genetics play an important role in the early pathogenesis of MPNs.

OTHER MUTATIONS

In addition to the important role of JAK2^V617F and other JAK2 mutations in the etiology of PV and other MPNs, mutations in other genes may be important to the full genesis of these disorders.

TET2 is a homologue of the gene originally discovered at the chromosome ten-eleven translocation (TET) site in a subset of patients with acute leukemia. TET2 mutations were found in hematopoietic cells from a significant proportion of patients with PV and other MPNs.^58,59 It has been established that TET2 loss-of-function mutations originate in pluripotent hematopoietic stem cells but seem to favor myeloid rather than lymphoid proliferation, and that in many patients both TET2 alleles were affected. However, studies in familial PV demonstrated that the TET2 mutation is often not disease-initiating, as the TET2 mutations differ among affected relatives and, in some instances, the TET2 mutations followed, rather than preceded, the appearance of JAK2^V617F.⁶⁰ Additionally, recurrent TET2 mutations have been reported in elderly patients with clonal hematopoiesis but no evidence of hematological malignancy.⁶¹ Several additional genes commonly bear mutations in PV patients, including ASXL1, DNMT3A, and IDH1/2.^62,63 The quantitative proportion of clones carrying different mutations may change during disease progression.⁶⁴

AUTOIMMUNITY AND CHRONIC INFLAMMATION

Although JAK2 kinase is clearly involved in the pathogenesis of PV, immune dysfunction and chronic inflammation may also be implicated. A history of any autoimmune disorder is associated with a 20 percent increased risk of developing an MPN,⁶⁵ and chronic inflammation is suggested to contribute to mutagenesis and clonal evolution in PV.^66,67,68 A recent molecular profiling study found that a number of immune and inflammatory genes were either up- or downregulated in PV patients, among them interleukin-10, interleukin-4, complement 5, short pentraxin C-reactive protein, fibrinogen, orosomucoid, and transforming growth factor-β₁.⁶⁹ The dysregulation of immune and inflammatory genes in PV may represent an additional avenue for future therapeutic development.

CLINICAL FEATURES

Listen

SIGNS AND SYMPTOMS

PV usually has an insidious onset, most commonly during the sixth decade of life, although onset may occur from childhood to old age.⁷⁰ Presenting signs and symptoms may include headache, plethora, pruritus, thrombosis, and gastrointestinal bleeding, but many patients are diagnosed because elevated hemoglobin, and sometimes other cell counts, are found on a periodic medical examination. Others cases may be uncovered during investigation for blood loss, iron-deficiency anemia, or thrombosis. Symptoms are reported by at least 30 percent of patients at the time of diagnosis; other patients may admit to symptoms on direct questioning. The most common symptoms, in decreasing order of frequency, are headache, fatigue, weakness, pruritus, dizziness, and night sweats, but these symptoms are more likely in those PV patients transforming to MF (Chap. 86).⁷⁰

PV generally occurs in older patients, a population who may already have an elevated rate of vascular abnormalities (e.g., coronary artery disease). Development of PV represents an additional increase in the risk of vascular events.

Thrombosis and Hemorrhage

Thrombotic episodes are the most common and most important complication of PV,^71,72,73 occurring in approximately one-third of PV patients.⁷⁴ From one-half to three-quarters of these events are arterial⁷⁵; ischemic strokes and transient ischemic attacks account for the majority of arterial complications. In some studies, 40 to 60 percent of patients develop at least one thrombotic event over a period of 10 years, the annual incidence being approximately equal throughout this period.⁷⁶ However, in prospective studies, thrombosis was most common just prior to and during the first few years after diagnosis.^74,77,78 The most common serious complication is a cerebrovascular accident, which accounts for approximately one-third of thrombotic events, followed in frequency by myocardial infarction, deep vein thrombosis, and pulmonary embolism.⁷⁶ The allelic burden of the JAK2^V617F mutation has been correlated with activation of thrombotic pathways in PV patients,^79,80 although this idea is not universally accepted.³⁹

Bleeding and bruising is a common complication of PV, occurring in approximately one-quarter of patients in some series.⁷⁴ Although such episodes are usually minor (e.g., gingival bleeding, nose bleeding, easy bruising), serious gastrointestinal and other hemorrhagic complications with a fatal outcome can also occur.^31,75,81,82

Splanchnic Vein Thrombosis Splanchnic vein thrombosis, including hepatic veins, portal vein or a mesenteric vein may occur. Hepatic vein thrombosis (Budd-Chiari syndrome) is the most common site of involvement. Budd-Chiari syndrome is a catastrophic and often fatal complication of PV. In one series, it occurred in 10 percent of 140 PV patients,⁸³ but was less common in a European collaborative study.⁷⁵ Budd-Chiari syndrome is caused by a thrombosis in the hepatic venous outflow, leading to ischemia from reduced perfusion through hepatic arterioles and necrosis of hepatocytes. Budd-Chiari syndrome may present as ascites with or without right-upper-quadrant abdominal pain, hepatosplenomegaly, and jaundice.

Budd-Chiari syndrome may be the first clinical manifestation of PV; endogenous erythroid colony formation and JAK2^V617F mutation have been described in many of these patients before any clinical evidence of polycythemia.^84,85 PV is the most frequent underlying disease associated with Budd-Chiari syndrome. The association of Budd-Chiari syndrome and PV is so strong that many experts advocate screening for PV with JAK2^V617F mutation analysis in all patients who present with hepatic vein thrombosis.^86,87 Budd-Chiari syndrome is a serious condition, often requiring a liver transplant for treatment.^85,88,89

Cutaneous Findings

Pruritus occurs in approximately 40 percent of PV patients.⁹⁰ It is usually aggravated by bathing or showering (aquagenic pruritus), and may be so severe it markedly compromises the quality of life of the patient.^82,91 It has been attributed to increased numbers of mast cells in the skin⁹² and to elevated histamine levels,⁹³ although these associations were not found in other studies.⁹⁴

Several PV patients have developed the dermatologic disorder, acute febrile neutrophilic dermatosis (i.e., Sweet syndrome).^95,96

Erythromelalgia

Erythromelalgia is a syndrome characterized by warmth of the extremities; painful, reddened digits; a burning sensation; and erythema of the fingers, hands, and feet (Fig. 84–1) that is associated with thrombocytosis. It characteristically responds rapidly to low-dose aspirin therapy. In severe cases, it results in ischemic necrosis of the digits and may lead to their amputation. This syndrome occurs in less than 5 percent of PV patients.^75,81 It is not specific to PV or other MPNs, and in one series of 168 patients with erythromelalgia, less than 10 percent had PV.⁹⁷ A causative role for transient microvascular occlusion by platelet aggregates has been proposed (Chap. 112).^98,99

Figure 84–1.

A. Patient with erythromelalgia of hand and fingers. B. Erythromelalgia of feet and toes that progressed to necrosis and amputation of the toes. (Used with permission of Steven Fruchtman, MD, Allos Therapeutics, Princeton, New Jersey.)

View Full Size||Download Slide (.ppt)

Abdominal Findings

Portal hypertension, varices, and abdominal pain are not uncommon,¹⁰⁰ and are often caused by cryptic or overt thrombosis in the hepatic, portal, or mesenteric veins. The former site (Budd-Chiari syndrome) is most common. The occurrence of Budd-Chiari syndrome is noted above (See Splanchnic Vein Thrombosis above). The incidence of peptic ulcer is four to five times greater than in the general population.¹⁰¹ Gastrointestinal bleeding may be the first presenting symptom of PV, with iron deficiency caused by gastrointestinal blood loss frequently masking erythrocytosis.⁸⁷

Cardiovascular Findings

Cardiovascular complications include angina, myocardial infarction, and congestive heart failure, related to a predisposition to thrombosis in the coronary circulation.^31,75,77

Pulmonary Hypertension

Pulmonary hypertension occurs in a higher than expected frequency in patients with PV. The suggested etiologies include smooth muscle hyperplasia induced by the release of platelet-derived growth factor from activated platelets, obstruction of pulmonary circulation by megakaryocytes, extramedullary hematopoiesis, and unrecognized recurrent thrombotic events.^102,103 None of these etiologies are clearly established.

Neurologic Findings

Neurologic symptoms such as dizziness and headache are very common in PV.^{31,75,77,81,104} Spinal cord compression secondary to extramedullary hematopoiesis has been documented.¹⁰⁵

Findings in Other Organ Systems

The increased nucleic acid turnover that results from the excessive proliferation of marrow cells often leads to an increase in blood uric acid concentration; gout can be exacerbated in some patients.³¹

SPECIAL CONSIDERATIONS

Surgery

More than 75 percent of patients with uncontrolled PV develop complications during or after major surgery because both bleeding and thromboses are common.^82,106 Thus, it is advised to normalize blood counts and blood volume before surgical interventions, which may lower the frequency of intraoperative and postoperative complications.

Pregnancy

Chapter 8 discusses the complications of PV in pregnancy.

SPENT PHASE OF POLYCYTHEMIA VERA

The spent phase of PV, also referred to as post-PV MF, is a frequent and often terminal complication of the disease.^75,78,107 It is characterized by a combination of anemia (non–iron deficiency), progressive increase of splenic size (Fig. 84–2), and marrow fibrosis (Chap. 86). The spent phase may first be noticed when phlebotomy requirements decrease. Thrombocytosis and granulocytosis (often with immature myeloid cells) are common. In a minority of cases, thrombocytopenia and granulocytopenia may occur. Affected individuals are frequently symptomatic with anemia, bleeding, splenic enlargement with early satiety, and/or upper abdominal pain secondary to splenic infarcts. Most patients become dependent on transfusions or erythropoietin therapy.^{31,75,77,81,107} Development of the spent phase is associated with an increased risk of leukemic transformation^31,108; in the PV Study Group-01 study, the incidence of acute leukemia was 24 percent in PV patients with MF, compared to 7 percent in those without MF, although it should be noted that a sizable number of the patients in this study had been treated with alkylating agents or ³²P.⁷⁸ Therapy, including use of JAK2 inhibitors, is described in Chap. 86.

Figure 84–2.

Patient with spent phase of PV with a massive increase of splenic size (A) and surgically removed spleen (B). (Used with permission of Steven Fruchtman, MD, Allos Therapeutics, Princeton, New Jersey.)

View Full Size||Download Slide (.ppt)

LEUKEMIC AND MYELODYSPLASTIC TRANSFORMATION OF POLYCYTHEMIA VERA

Patients with PV have an increased risk of developing leukemia.^71,82 This contrasts with other nonclonal polycythemic disorders, wherein progression to leukemia is not part of the disease process. Acute leukemia, usually myelogenous, is an invariably fatal complication of PV. A European multicenter observational study of 1638 patients reported a 6.3 percent relative risk of developing leukemia within 10 years after the diagnosis of PV.⁷⁵ Different treatments can also influence the risk of transformation from PV to leukemia. In the PV Study Group-01 randomized trial, the incidence of acute leukemia at 18 years of followup was 1.5 percent on the phlebotomy-only treatment arm, 10 percent on the ³²P treatment arm, and 13 percent on the chlorambucil treatment arm.⁸¹ In a more recent study of 1638 patients, the risk of transformation to acute myelogenous leukemia (AML) or a myelodysplastic syndrome (MDS) in PV patients also varied by treatment. Treatment-specific risk of transformation, ordered by increasing risk, was: phlebotomy (hazard ratio [HR]: 0.91), hydroxyurea (HR: 1.09), interferon (INF)-α (HR: 1.24), busulfan (HR: 8.64), pipobroman (HR: 4.32), and ³²P (HR: 8.96).¹⁰⁹ Leukemic transformation was not significantly different between phlebotomy, hydroxyurea, and INF-α treatments.¹⁰⁹

Acute leukemia as the terminal PV event may arise from either the JAK2^V617F-positive clone or, more frequently, from a hematopoietic cell that does not carry the JAK2 mutation.^35,47,50

LABORATORY FEATURES

Listen

BLOOD FINDINGS

Erythrocytes

The hemoglobin concentration, erythrocyte count, and hematocrit are usually increased, and the mean cell volume is usually low-normal or low in untreated patients, and low in patients who have undergone phlebotomies or had gastrointestinal bleeding episodes. Red cells are hypochromic and microcytic, with morphology characteristic of iron deficiency. Although increased hemoglobin is generally a diagnostic feature of PV, at times the hemoglobin level may be low, normal, or borderline, a condition termed “masked” PV.^110,111,112

The appearance of significant aniso- and poikilocytosis and teardrop cells (dacryocytes; Chap. 31) heralds the onset of the spent phase and post-PV MF (Chap. 86).

Red Cell Mass Determination

The Polycythemia Vera Study Group employed the direct determination of red cell mass as the sine qua non of the diagnosis of PV for all patients entered into their studies.⁷⁶ Some believe that even in the routine clinical setting, this procedure should be performed on all patients to establish a diagnosis of PV.^76,113 Unfortunately, the determination of red cell mass is expensive, requires the use of radioactive isotopes in patients, and, when performed by the inexperienced, is often inaccurate.¹¹⁴ Red cell mass determination is not useful in distinguishing PV from secondary polycythemia because the red cell mass is increased in both disorders. The principal value of red cell mass determination is to distinguish apparent or spurious polycythemia from PV and secondary polycythemia.^110,111 It could also be useful in distinguishing cases of masked PV from ET.¹¹⁵ The availability of the JAK2 assay has made red cell mass determination only rarely important.

Leukocytes

Absolute neutrophilia occurs in approximately two-thirds of PV patients.⁷⁰ Occasional myelocytes and metamyelocytes are present in the blood, and considerable degrees of cell immaturity are present in patients with longstanding, advanced disease. Again, these abnormalities herald the onset of the spent phase (Chap. 86). Basophilia occurs in approximately two-thirds of patients with uncontrolled disease.^31,81,116 In PV, the proportion of activated neutrophils is increased,¹¹⁷ and it is possible that neutrophils may be an important factor in PV-associated thrombosis.¹¹⁸

The leukocyte alkaline phosphatase level is elevated in approximately 70 percent of patients with PV,⁷⁰ but this assay has now become largely obsolete.

Platelets

The platelet count is increased in approximately 50 percent of PV patients at the time of diagnosis, and in approximately 10 percent of patients it is greater than 1000 × 10⁹/L.⁷⁰ There are no consistent abnormalities of thrombopoietin levels in PV patients.¹¹⁹ A significant proportion of PV patients first present with isolated thrombocytosis without elevated hemoglobin, especially if the patient has a reason for iron deficiency, and are sometimes misdiagnosed with essential thrombocythemia.¹²⁰

Qualitative platelet abnormalities have been described which may play a role in the pathogenesis of thrombotic and hemorrhagic events. In vitro spontaneous platelet aggregation is accelerated. On the other hand, patients with MPNs often display a nearly pathognomonic defect in the primary wave of platelet aggregation induced by epinephrine (Chaps. 112 and 121).¹²¹

There are a number of additional platelet abnormalities associated with PV, including increased platelet thromboxane A₂ generation¹²² and increased excretion of thromboxane metabolites.¹²³ Platelet factor-4 levels are elevated.¹²⁴ Platelet survival may be shortened.^124,125 Fibrinogen binding after stimulation with a platelet-activating factor is diminished,¹²⁶ and there is reduced expression of the thrombopoietin receptor.²⁰ However, none of these changes are specific for PV. In a prospective study, a PI^A2 polymorphism of the platelet glycoprotein IIIa was associated with an increased risk of arterial thrombosis in PV patients,¹²⁷ although this conclusion remains controversial.

Platelet counts greater than 1000 to 1500 × 10⁹/L are associated with progressive decrease of von Willebrand factor (an acquired, type 2 von Willebrand disease) and increased risk of bleeding, but not of thrombosis.¹²⁸

Plasma

Serum lysozyme levels are slightly increased in some patients,¹²⁹ and because of increased leukocyte turnover and increased levels of B₁₂ binding protein, serum B₁₂ determination is usually increased.¹³⁰ Hyperuricemia, a consequence of hyperproliferative myelopoiesis, is frequently encountered.³¹

JAK2^V617F AND EXON 12 MUTATIONS

JAK2 G1849T Creating V617F

Mutations within the JAK2 gene cause deregulation of the hematopoietic process, which is expressed in a wide spectrum of disorders involving the expansion of erythrocytes, granulocytes, or leukocytes. The primary lesion associated with these disorders was discovered in exon 14: A single nucleotide change JAK2 G1849T resulting in the amino acid substitution V617F. Detection of the JAK2^V617F mutation provides a qualitative diagnostic marker for the identification of the Philadelphia-chromosome-negative subgroup of MPNs, and differentiates them from congenital and acquired reactive hematopoietic disorders. In general, the JAK2^V617F allele burden is lower in ET patients than in either PV or primary myelofibrosis (PMF).^131,132 In many, but not all, JAK2^V617F-positive PV patients, at least some progenitors exist that became homozygous for the JAK2^V617F mutation by UPD acquired by mitotic recombination.^37,133

Allele-specific polymerase chain reaction (PCR) is widely used for single nucleotide polymorphism (SNP) genotyping; the technique is based on amplification of DNA by an allele-specific primer matching the polymorphism at the 3′ position. This approach is directly applicable to analysis of JAK2^V617F because the mutation (G1849T) is analogous to a SNP. To improve the specificity, sensitivity, and reliability for quantitating the JAK2^V617F allele burden, two modifications of technique were incorporated: Inclusion of a second mismatch at the –1 position, and substitution of a modified locked nucleic acid at the –2 position. A study comparing 11 different techniques was undertaken and carried out in 16 laboratories using various testing platforms.¹³⁴ Although five of the 11 techniques were similarly reliable for quantification of JAK2^V617F loads that were equal to or greater than1 percent of total JAK2^V617F, the allele-specific quantitative PCR technique could detect 0.2 percent of JAK2^V617F.

The majority of laboratories analyze quantitative assays of JAK2^V617F allele burden from (clonal) granulocytes; nonquantitative analyses use total leukocytes, whole blood, or marrow for screening. A proportion of JAK2^V617F-negative assays are positive using sensitive quantitative analyses.¹³⁴ Plasma has been used for detection of the JAK2^V617F DNA and mRNA mutation and zygosity state,^135,136 but plasma analysis is not reliable.¹³⁷

JAK2 Exon 12 Mutations

Although the most common JAK2 mutation is a single SNP in exon 14, many MPN cases negative for the exon 14 JAK2^V617F mutation may carry one of a number of mutations in exon 12. Almost 40 different mutations in exon 12 have been identified within codons 536 to 547, including substitutions, deletions, and duplications.^{45,138,139,140,141,142} In addition to the various mutations observed in this region, the proportion of mutations within a given sample may be small and therefore difficult to detect in the high background of a normal sequence.⁴⁵ JAK2 exon 12 mutations have been observed primarily in younger patients and in patients with isolated erythrocytosis, and thus may represent a somewhat different phenotype from JAK2^V617F-positive PV.

ERYTHROPOIETIN LEVELS

PV is distinguished by the fact that erythroid cells proliferate even in the absence of normal levels of erythropoietin; thus, one would expect that at high hematocrit levels, the production of erythropoietin would be inhibited and serum levels consequently reduced. Indeed, several studies have documented serum erythropoietin levels below the normal reference range in patients with PV.^143,144,145

Patients with secondary polycythemia usually have normal to elevated erythropoietin levels, although considerable overlap exists in the range of erythropoietin levels between patients with PV and those with secondary polycythemia rendering the test of marginal value in distinguishing between diagnostic possibilties.^144,146 An elevated erythropoietin level generally excludes the diagnosis of PV, but a low erythropoietin level is not pathognomonic of PV; patients with primary familial and congenital polycythemia (PFCP) have levels of erythropoietin that are as low or lower than in PV,¹⁴⁷ and instances of normal erythropoietin levels occur in PV patients without apparent explanation. The latter is more likely to occur in PV patients with exon 12 JAK2 mutations.⁴⁴

ERYTHROID COLONY CULTURES

In vitro assays of erythroid progenitor cells permit the study of their responsiveness to erythropoietin. In PV patient samples, erythroid BFU-E progenitors grow in culture without added erythropoietin,¹⁷ forming colonies that are termed EECs. Detection of EECs in cultures of blood or marrow had previously been the most specific test for PV.^12,14,148 In one study, all patients with PV, but none with secondary or other causes of polycythemia, formed EECs in vitro.¹⁴⁹ Rare EECs may, at times, be observed in PFCP and in congenital disorders of hypoxia sensing, but unlike EECs in PV, these are abrogated by pretreatment with erythropoietin and erythropoietin receptor-blocking antibodies.^150,151

In experienced hands, the EEC assay is a specific and sensitive means for detecting PV. It may be useful in diagnosing patients with unusual presentations of PV, such as Budd-Chiari syndrome,^{85,89,152,153} isolated thrombocytosis, or the rare JAK2^V617F-negative PV patient. It has not been fully standardized, however, and is expensive and laborious, so it is now used primarily in a research setting where it remains informative.

MARROW FINDINGS

In PV, the marrow is characteristically hypercellular, with an increase in erythroid and granulocytic precursor cells and megakaryocytes. Whereas marrow morphology is part of the World Health Organization (WHO) diagnostic criteria of PV,¹⁵⁴ the morphologic features have not yet been validated and may be subject to inter- and intraobserver variation. Marrow morphology in patients with JAK2 exon 12 mutations may be subtly different, with subtle or no megakaryocytic clustering and a lack of panmyelosis.^45,155 Absent or decreased iron stores are seen in the marrow of most PV patients. Various cytogenetic findings have been reported,¹⁵⁶ but they are not sufficiently specific to be of diagnostic utility (Chap. 13).

CLONALITY IN FEMALE SUBJECTS USING ASSAYS EMPLOYING X-CHROMOSOME–BASED POLYMORPHISM

PV results from an acquired mutation in a pluripotent hematopoietic stem cell. Clonality studies based on the phenomenon of X-chromosome inactivation¹⁵⁷ show that red cells, granulocytes, platelets, monocytes, and B lymphocytes are all part of the neoplastic clone.^13,158 The majority of T lymphocytes and natural killer cells are polyclonal, but a small proportion of these cells are also derived from the PV clone⁹; this is presumed to be the result of the presence of long-lived, normal T cells that preceded the development of the clone and younger, clonal cells. Unfortunately, the applicability of X-chromosome inactivation for the differential diagnosis of PV is hampered by the many methodologic and conceptual differences that have drawn conflicting conclusions.¹⁵⁹ Some of these discrepancies result from using two different approaches¹⁶⁰ to distinguish the active from inactive X-chromosomes (Chap. 10).^{161,162,163,164} In a study of approximately 100 female PV patients, their reticulocytes, platelets, and granulocytes were always clonal, with the exception of a few patients who converted to polyclonal hematopoiesis after therapy with IFN-α.¹⁴

DIFFERENTIAL DIAGNOSIS

Listen

Also refer to Chap. 34, Table 34–2, and Chap. 57, Fig. 57–6.

PV has to be differentiated from spurious polycythemia, secondary polycythemias, congenital disorders of hypoxia sensing, and primary congenital polycythemias. The differential diagnostic task has been facilitated by the discovery of the JAK2^V617F mutation that is present in 95 percent or more of all PV patients.^165,166 Thus, the majority of PV patients can be diagnosed with a complete blood count repeated twice and molecular studies to confirm the presence of the JAK2^V617F mutation.

For the remainder of polycythemic patients, additional diagnostic measures need to be undertaken. These may include measuring serum erythropoietin level, measuring venous oxygen saturation to calculate hemoglobin P50, measuring arterial oxygen saturation (less than 92 percent suggests cardiac or pulmonary etiologies), abdominal CT scan (to exclude renal, hepatic, and cerebral tumors), brain magnetic resonance imaging (to rule out a cerebellar hemangioblastoma), and detailed family studies.

If a diagnosis at this point has not yet been made, the patient could be referred to a specialized center for further testing. These studies may include measuring changes in serum erythropoietin levels after phlebotomies, red blood cell and plasma volume studies (to diagnose spurious polycythemia or masked PV), genomic sequencing studies, testing for JAK2 exon 12 mutations, and in vitro studies for EECs. The latter two are used to diagnose JAK2^V617F-negative PV patients (<5 percent of all PVs).

Distinguishing between PV and other polycythemic disorders may, at times, be challenging. Although the diagnosis of PV may be straightforward if patients have the classic features of PV as defined by the most recent WHO guidelines,¹⁵⁴ patients often present with an incomplete phenotype. Some of the clinical and laboratory features that can be helpful for differential diagnosis are summarized in Chap. 34, Table 34–2 and Chap. 57, Fig. 57–6. While the current WHO diagnostic criteria (presented in Table 84–1)¹⁵⁴ represent an improvement over previous guidelines, they do not necessarily discriminate between individual MPNs,¹⁶⁷ and are still a matter of some debate.^168,169 Children with PV are especially unlikely to fit the most recent WHO criteria.¹⁷⁰ Most importantly, often laborious and time-consuming efforts to rule out congenital polycythemia should always be undertaken in patients with atypical presentations; however, the presence of polycythemia in other relatives does not rule out PV.

Table 84–1.World Health Organization Criteria for the Diagnosis of Polycythemia Vera, 2008

View Table||Download (.pdf)

Table 84–1. World Health Organization Criteria for the Diagnosis of Polycythemia Vera, 2008

MAJOR CRITERIA

Hgb >18.5 g/dL (men), >16.5 g/dL (women)

Hgb >17 g/dL (men), >15 g/dL (women)

if associated with a sustained increase of ≥2 g/dL from baseline that cannot be attributed to correction of iron deficiency

Presence of JAK2^V617F or similar mutation

MINOR CRITERIA

Marrow trilineage myeloproliferation

Subnormal serum EPO level

EEC growth

EEC, endogenous erythroid colony; EPO, erythropoietin; Hgb, hemoglobin.

A diagnosis of PV requires the presence of both major criteria and one minor criterion, or the first major criterion and two minor criteria.

TREATMENT

Listen

The major causes of morbidity and mortality in PV are an increased incidence of vascular complications (i.e., thrombosis and/or hemorrhage), and progression to MF or acute leukemia/myelodysplasia. In the first randomized trial of PV patients, a history of previous thrombosis, age, treatment with phlebotomies, and rate of phlebotomies contributed to the increased risk of thrombosis.⁷⁶ Presently, the age of the patient (>60 years) and previous thrombotic events are universally acknowledged major risk factors for major vascular complications in PV.⁷¹

Thus, PV patients are classified as low risk or high risk, with age greater than 60 years and previous thrombotic events (including transient ischemic attacks) defining the high-risk category. The assigned risk classification has a major impact on therapeutic decisions, as high-risk patients are treated with cytoreductive therapies. Other risk factors may also play a role in the pathogenesis of thrombosis, such as hypertension, diabetes, or smoking,¹⁷¹ as well as leukocytosis^{172,173,174,175,176} and JAK2^V617F mutational allele burden.^80,177 There is a need for prospective clinical studies with stratification of patients according to these criteria, but until such evidence is available, patients with high leukocyte levels and/or high JAK2^V617F mutational allele burden should be managed according to conventional criteria.

An elevated platelet count does not increase the risk of thrombosis, but it may increase the risk of hemorrhage.¹²⁸ Bleeding is more frequent in patients with platelet counts in excess of 1500 × 10⁹/L, thought to be the result of an acquired type 2 von Willebrand disease.

Treatment of PV depends on risk evaluation at diagnosis and evolution of the disease over time. Treatment should be given both to alleviate symptoms and prevent complications. Updated consensus-based guidelines for the management of PV and other major MPNs were published by a panel of experts formed by European LeukemiaNet (ELN).¹⁷⁸ Response criteria by which new therapies are evaluated were also updated to facilitate direct comparison of therapeutic efficacy across clinical trials (Table 84–2).¹⁷⁹ This joint effort between ELN and the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) provides updated guidelines incorporating assessment of clinical, hematologic, and histologic response, as well as symptoms, disease progression, and vascular events.¹⁷⁹

Table 84–2.Response Criteria for Polycythemia Vera¹⁷⁹

View Table||Download (.pdf)

Table 84–2. Response Criteria for Polycythemia Vera¹⁷⁹

A. CLINICAL RESPONSE

Response

Criteria

Complete remission

Durable^* resolution of disease-related signs including palpable hepatosplenomegaly, large improvement in symptoms,^† AND

Durable^* blood count remission, defined as hematocrit lower than 45% without phlebotomies; platelet count ≤400 × 10⁹/L, white blood cell count <10 × 10⁹/L, AND

Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND

Marrow histologic remission defined as the presence of age-adjusted normocellularity and disappearance of trilinear hyperplasia, and absence of > grade 1 reticulin fibrosis.

Partial remission

Durable^* resolution of disease-related signs including palpable hepatosplenomegaly, large improvement in symptoms,^† AND

Durable^* blood count remission, defined as hematocrit lower than 45% without phlebotomies; platelet count ≤400 × 10⁹/L, white blood cell count <10 × 10⁹/L, AND

Without progressive disease, and absence of any hemorrhagic or thrombotic event, AND

Without marrow histologic remission defined as persistence of trilinear hyperplasia.

No response

Any response that does not satisfy partial remission.

Progressive disease

Transformation into post-PV myelofibrosis, myelodysplastic syndrome or acute leukemia.

B. MOLECULAR RESPONSE^‡

Response

Criteria

Complete response

Eradication of a preexisting abnormality

Partial response

≥50% decrease in allele burden, in patients with ≥20% allele burden at baseline

^*Lasting at least 12 weeks.

^†Large improvement in symptoms (≥10-point decrease) in MPN Symptom Assessment Form total assessment score.

^‡Evaluation requires analysis in blood granulocytes. Molecular response is not required for assignment as complete response or partial response.

It is useful to consider treatment for the plethoric and spent phases separately. In the plethoric phase, the mainstay of therapy remains nonspecific myelosuppression, which many practitioners supplement with phlebotomies.^82,178,180 Additional measures prevent thrombotic events (i.e., aspirin) and relieve symptoms. Promising therapies include pegylated interferon (PEG-IFN) preparations and JAK2 inhibitors; these are, at the time of this writing, being evaluated by prospective randomized trials. A minority of patients (i.e., low-risk patients) can be treated with phlebotomies and low-dose aspirin alone. PV patients in the spent phase may be treated with a number of therapies (Chap. 86), which may include hydroxyurea, transfusion, erythropoiesis-stimulating drugs, JAK2 inhibitors, splenectomy, or allogeneic stem cell transplantation; only JAK2 inhibitors have been proven to be beneficial in prospective trials.²³⁵

THE PLETHORIC PHASE

Treatment of PV patients in the plethoric phase of the disease is aimed at reducing marrow proliferation and blood counts, thereby ameliorating symptoms and decreasing the risk of thrombosis and bleeding.^180,181 This is best accomplished by myelosuppressive drugs and, in some patients, combination therapy consisting of myelosuppression, phlebotomies, and platelet-reducing agents and/or IFN-α. Table 84–3 summarizes the advantages and disadvantages of various forms of therapy for PV.

Table 84–3.Treatment of Polycythemia Vera

View Table||Download (.pdf)

Table 84–3. Treatment of Polycythemia Vera

Treatment

Advantages

Disadvantages

Phlebotomy

Low Risk. Simple to perform.

Does not control thrombocytosis or leukocytosis.

Hydroxyurea

Controls leukocytosis and thrombocytosis as well as erythrocytosis.

Continuous therapy required. Long-term leukemogenic potential is not completely known.

Busulfan

Easy to administer. Prolonged remissions.

Overdose produces prolonged marrow suppression. Risks of leukemogenesis, long-term pulmonary and cutaneous toxicity.

³²P

Patient compliance not required. Long-term control of thrombocytosis, leukocytosis, and erythrocytosis.

Expensive and relatively inconvenient to administer. Likely leukemogenic risk.

Chlorambucil

Easy to administer. Good control of thrombocytosis and leukocytosis.

High risk of leukemogenesis.

Interferon

Low leukemogenic potential. Beneficial effect on pruritus. Potential deep suppression of the polycythemic clone.

Inconvenient to administer (injectable), costly, and adverse effects are common.

Anagrelide

JAK2 Inhibitors

Selective effect on platelets.

Decreased need for phlebotomy. Improvement in quality of life.

Selective effect on platelets.

Clinical trials experience only. Long-term benefits are unknown.

Myelosuppression

Myelosuppression decreases blood counts, decreases the risk of vascular events, and ameliorates symptoms, thus increasing an overall sense of well-being. Although there may be an impression that it increases patients’ long-term survival, there are no long-term clinical studies to document this.

Hydroxyurea Hydroxyurea (HU) is the most common myelosuppressive agent used in the treatment of PV.^182,183 HU is an effective therapy for controlling erythrocyte, leukocyte, and platelet counts, and it decreases the risk of thrombosis during the first few years of therapy when compared to an historical cohort treated with phlebotomy alone.⁷⁸ Because its suppressive effect is of short duration, continuous rather than intermittent therapy is required. Because it is short acting, it is relatively safe to use even when excessive marrow suppression occurs, as blood counts rise within a few days of decreasing the dose or stopping the drug. Several groups have investigated the effects of HU on JAK2^V617F allele burden, and as of yet, the results have been conflicting.^{184,185,186,187} Interestingly, it has been suggested that the JAK2^V617F allele burden in PV may be a reliable predictor of response to HU, and of the HU dose necessary to control the disease.¹⁸⁸

The leukemogenic risk of HU has been an ongoing debate for many years. Because HU is not an alkylating agent, it has less potential to cause acute leukemic transformation than other myelosuppressive agents, but its leukemogenicity was questioned in some historical studies. A large meta-analysis of patients with sickle cell disease did not find an increased risk of the development of acute leukemia following HU treatment.¹⁸⁹ Two large studies in PV have also suggested a similar low risk associated with HU; analysis of 1638 PV patients enrolled in a prospective observational study¹⁰⁹ and 1545 patients followed under IWG-MRT¹⁹⁰ did not find an increased incidence of leukemic or myelodysplastic transformation with HU treatment.

Unfortunately, despite its safety and effectiveness, approximately 10 percent of PV patients develop HU resistance or intolerance (i.e., skin ulcers or gastrointestinal intolerance).^191,192,193 Resistance to HU is correlated with decreased survival and a higher rate of transformation to AML or MF.¹⁹¹ Effective alternative treatments are available.

Busulfan Busulfan is a useful second-line agent in patients whose disease is difficult to control or who have adverse reactions to HU. The administration of busulfan is a convenient and effective means for treating PV. The marrow suppression produced by this drug is long-lasting and, as a consequence, it can be given intermittently at a dose of 2 to 8 mg daily for a period not exceeding several weeks; blood counts continue to fall for several weeks after drug administration is discontinued. The disease is usually controlled for many months or even years. In one large study, the median first remission duration of busulfan-treated patients was 4 years.¹⁹⁴ The prolonged depression of marrow activity brought about by busulfan is its major advantage in the treatment of PV, but it also poses a hazard of long-term pancytopenia. The incidence of transformation to leukemia may be increased with busulfan treatment. In a large study of 1638 PV patients, busulfan was one of the agents which was associated with an increased rate of transformation to AML/MDS.¹⁰⁹ When tested as a second-line therapy, busulfan robustly reduces the JAK2^V617F allelic burden and causes a complete hematologic response in the majority of patients,^195,196 but also has a higher rate of transformation to leukemia compared to first-line busulfan treatment.¹⁹⁶

Radioactive Phosphorus ³²P therapy was one of the first effective modes of treatment used in PV. Extensive investigations of the long-term outcome of treatment with ³²P have been documented.^76,197 Satisfactory control of the disease usually can be achieved with initial doses of 2 to 4 mCi. It is rarely used at present, but it may be the treatment of choice for older patients and patients who may be difficult to follow.^198,199

Interferon Since the pioneering work of Silver,²⁰⁰ IFN-α treatment has been confirmed to result in clinical and hematologic remission in PV in more than a dozen studies.^{201,202,203,204} Although these studies have many design similarities, they do not lend themselves to accurate meta-analysis; various formulations of IFN were used (INF-α2a and -α2b, PEG-INF-α2a, and -α2b, human leukocyte IFN), and heterogeneous criteria were employed to measure response. Nevertheless, it is clear that IFN-α effectively decreases many PV symptoms, including pruritus, results in a hematologic response in approximately 80 percent of patients, and decreases the need for phlebotomies in approximately 60 percent of patients.^{201,202,203,204}

In addition to clinical and hematologic responses, administration of IFN-α has led to a decrease in JAK2^V617F allelic burden^43,205,206 and conversion from clonal to polyclonal hematopoiesis¹⁴ in the small number of patients studied thus far. Two comparisons of IFN-α2b and HU suggest that IFN-α2b may cause a greater molecular and hematologic response than HU in PV patients.^207,208

However, IFN-α has significant adverse effects. Approximately 25 percent of patients with PV and ET given IFN-α discontinue treatment, half of them within the first year. The hematologic toxicities include anemia, thrombocytopenia, and neutropenia. Other potential untoward effects of IFN-α include depression, mood changes, disabling fatigue, skin toxicity, hair loss, nausea, diarrhea, weight loss, liver function abnormalities, and cardiac and neurologic toxicity. Immunologic abnormalities in the form of autoimmune processes (e.g., hypothyroidism, autoimmune hemolytic anemia, polyarthritis, glomerulonephritis, connective tissue diseases, and asymptomatic antinuclear antibodies) may be consequences of IFN therapy.²⁰⁹ Conceivably, the development of IFN-induced autoimmune processes reflects the immunomodulatory activity of the drug, through which at least part of its antitumor activity is mediated.

A pegylated version of IFN-α (PEG-IFN-α) is better tolerated than standard IFN-α and requires less frequent administration.²¹⁰ A number of phase II trials have shown that PEG-IFN-α2a induces a complete hematologic response in the vast majority of patients and a reduction in JAK2^V617F allelic burden in some.^{211,212,213,214,215} Using JAK2^V617F as a molecular marker, a French group studied 40 PV patients treated with PEG-IFN-α2a; 95 percent of evaluable patients had a complete hematologic remission, 90 percent had a decrease in JAK2^V617F allelic burden, and in 20 percent the JAK2^V617F allelic burden became undetectable.²¹⁴ However, the experience of the authors of this chapter is that we have not seen any true molecular remission in our therapy of more than 50 PV subjects and always detect a small level of JAK2 mutant in those considered in “molecular remission,” albeit it at times at levels of less than 0.2 percent.

Although IFN-α and PEG-IFN-α can be used as first-line therapy in PV, they are more often used as second-line treatments.¹⁹³ PEG-IFN-α is the drug of choice in pregnant patients (Chap. 8).

Phlebotomy

Often, the initial treatment for patients with uncomplicated PV is phlebotomy.^31,197 Together with low-dose aspirin, it is at present the recommended therapy for low-risk PV cases.

When phlebotomy is instituted, the hemoglobin may be reduced to normal or near-normal values by the removal of 450 mL of blood at one time every 2 to 4 days; smaller amounts should be removed from patients who weigh less than 50 kg. Patients with impaired cardiovascular function are better treated with smaller phlebotomies at more frequent intervals.

Phlebotomy is an effective way by which to lower or normalize the elevated blood viscosity of patients with PV. The reduction of hemoglobin levels may result in improvement of symptoms such as headaches or feeling of increased pressure. However, it does not reduce the leukocyte or platelet count, nor does it affect pruritus or gout. Iron deficiency and resulting microcytosis are usual consequences of repeated phlebotomies. An iron-deficient state may help control hemoglobin concentration in the long run, but it may increase platelet counts and fatigue in some patients. Judicious use of oral iron replacement therapy may improve the fatigue associated with iron deficiency without significantly increasing hematocrit.

A randomized study^76,216 of a small number of PV patients comparing phlebotomy to other treatments indicated that the survival of patients treated only with phlebotomy was slightly better than for patients treated with chlorambucil, and no worse than those given ³²P. Patients undergoing phlebotomy did suffer more thrombotic episodes than patients treated with myelosuppressive therapy, although this risk seemed limited to the first 3 years of therapy.⁷⁸ This documented increased risk of thrombosis associated with phlebotomy was balanced by a lower incidence of acute leukemia late in the patient’s course. There was no correlation between platelet count and development of thrombotic complications.²¹⁶

The rationale for phlebotomy in patients with PV is based on a widely quoted study that suggested the risk of thrombosis in PV was proportional to the elevation in hematocrit.²¹⁷ Although the underlying mechanisms causing thrombosis in PV are not fully understood, hematocrit is unlikely to be the only, or even a major risk factor, as the risk of thrombosis is not elevated in patients with non-PV polycythemia or in patients with secondary polycythemia caused by chronic exposure to high altitude, Eisenmenger syndrome,²¹⁸ or other cyanotic heart diseases.^219,220 In patients with Chuvash polycythemia, the risk of stroke is similar regardless of whether hematocrit is controlled by phlebotomies (Chap. 37). Furthermore, the European Collaboration on Low-Dose Aspirin in the Polycythemia Vera study (ECLAP), which included 1638 patients from 12 countries and 94 centers, found no difference in thrombotic complications for patients with hematocrits in the range of 40 to 55 percent.²²¹ An important attempt to clarify this issue was a prospective study of the effect of hematocrit in PV patients, as evaluated by univariate analysis, which reported that patients treated with phlebotomies had a decreased rate of thrombosis.²²² However, patients in the high-hematocrit group received less HU than those in the low-hematocrit group and had higher levels of leukocytes, both independent correlates of thrombotic risk.²²³

Anagrelide

Anagrelide can be used in PV for thrombocytosis, as an adjunct to other treatments. Among 113 PV patients with thrombocytosis, the administration of anagrelide produced a platelet response in 85 cases (75 percent).²²⁴ The starting dose was 0.5 or 1.0 mg given four times daily, and a response was noted in most patients within 1 week. The average dose required to control the platelet count was 2.4 mg per day. Adverse events included headache, palpitations, diarrhea, and fluid retention, and were occasionally sufficiently severe to require discontinuation of the treatment.²²⁵ In patients with ET (Chap. 85), a randomized trial in the United Kingdom indicated superior results for HU plus aspirin compared to anagrelide plus aspirin for control of elevated platelet count, MF, and hemorrhagic complications.²⁶ However, a later randomized trial showed a noninferiority of anagrelide to HU.²²⁶

Symptomatic Therapy for Pruritus

Although some symptoms of PV can be controlled using phlebotomy, control of pruritus is at times achieved using myelosuppression. Pruritus is a major symptom of PV and, in some patients, it is nearly intolerable. When marrow proliferation is well controlled, pruritus becomes milder or disappears entirely. Because bathing or showering usually intensifies the itching, the term aquagenic pruritus is often used. Some level of control of pruritus may be achieved by moisturization of the skin. Photochemotherapy with psoralens and ultraviolet light can be helpful.²²⁷ Antihistamines are often given, but are usually not very effective, and neither is aspirin.²²⁸ Both IFN-α^229,230,231 and the JAK2 inhibitors provide a generally effective treatment modality to alleviate pruritus.^232,233

Aspirin

Because thromboembolic episodes represent a major source of morbidity and mortality in patients with polycythemia, aspirin is an important drug in the arsenal of treatment modalities for PV.

The results of early trials using 300 mg of aspirin daily showed an increase in the incidence of bleeding without a measurable impact on the incidence of thrombotic episodes.²³⁴ Subsequently, several studies showed positive benefits of aspirin use in PV. A pilot-controlled trial found that low-dose aspirin was well tolerated by PV patients and fully inhibited synthesis of the platelet aggregating compound thromboxane, but not the endothelial cell protectant prostacyclin.²³⁵ An ECLAP study showed that daily low-dose aspirin decreased arterial and venous thromboses, albeit incompletely.⁷⁵ Because thrombotic complications were not completely prevented, this study suggested that only a minor fraction of thromboses are attributable to platelets, and additional pathogenetic pathways in PV should be investigated. The increased risk of bleeding with high platelet counts and associated acquired von Willebrand disease is discussed in the preceding section entitled Platelets; aspirin should not be used when the platelet count exceeds 1000 to 1500 × 10⁹/L.

JAK2 Inhibitors

JAK2 inhibitors represent a promising new therapeutic avenue that arose with the discovery of abnormal JAK-STAT signaling in MPNs.²³⁶ Currently available JAK2 inhibitors target the catalytic site of the enzyme and therefore inhibit both wild-type and mutant forms of JAK2, as well as variable inhibition of JAK1, JAK3, and other kinases. A number of JAK2 inhibitors are in clinical testing for PV,^236,237 including ruxolitinib (INCB018424), which is effective and FDA approved for use in patients with PMF.^{238,239,240,241} Ruxolitinib is an oral JAK1/JAK2 inhibitor that has been shown effective in preclinical testing with PV primary cultures²⁴² and in phase II trials in HU-intolerant or refractory PV patients,^233,243,244 ruxolitinib effectively reduced PV-associated symptoms, such as night sweats, pruritus, and bone pain, within 4 weeks, decreased spleen size to nonpalpable in 44 percent of patients by week 24, induced a complete hematologic response in 59 percent of patients, and reduced the JAK2^V617F allelic burden by equal to or greater than 50 percent within the first 3 years of treatment in 24 percent of patients.²³³ Phase III trial showed that patients with HU-intolerant or refractory PV treated with ruxolitinib have a decreased requirement for phlebotomy, decreased spleen size, and improvement in other PV-associated symptoms.²³²

Despite the encouraging advances with JAK2 inhibitors, modulation of the JAK2 pathways may not be the sole optimal treatment for PV and other MPNs. JAK2^V617F may not be the disease-initiating step in patients with MPNs,^37,245 and additional mutations may require specific therapeutic targeting. Additionally, disease progression is characterized by clonal heterogeneity and genetic instability.²⁴⁶ Better characterization of the pathogenesis of PV is needed to facilitate further therapeutic developments.

Epigenetic Modulation

A high incidence of mutation in genes involved in epigenetic modification in MPNs (i.e., TET2, DNMT3A, IDH1/2, PRC2, ASXL1) provides potential targets for therapy.^247,248 One currently used approach in cancer treatment is interference of histone acetylation, as the acetylation status of histones can alter DNA-protein and protein-protein interactions.²⁴⁹ The expression levels of histone deacetylases (HDAC) were found to be altered in all three major MPNs,²⁵⁰ which has made HDAC inhibitors a new therapy of interest in PV. For instance, Givinostat is an HDAC inhibitor which specifically inhibits the proliferation of JAK2^V617F-positive cells compared to normal cells²⁵¹ by inhibiting hematopoietic transcription factors NFE2 and c-MYB.²⁵² It has been found to reduce splenomegaly and pruritus in Phase II trials with PV patients.^253,254

Summary of Therapeutic Approach

The current approach for the management of the majority of PV patients (i.e., high risk) who are not participating in a clinical trial is a combination of therapeutic and preventative approaches:

Myelosuppression with HU daily, both as initial therapy (1500 mg qd) and long-term treatment (500 to 2000 mg qd), aiming to maintain neutrophil counts at low-normal levels. In addition, some patients will require the use of phlebotomies and/or anagrelide to maintain hemoglobin and platelet levels in normal ranges. Myelosuppression can also be achieved by other agents such as IFN-α or PEG-IFN-α. PEG-IFN-α is better tolerated than IFN-α and is the most effective therapy, but it is not as well tolerated as HU.
Low-dose aspirin at 80 mg qd (or 100 mg outside of North America) is given to all patients without history of major bleeding or gastric intolerance, or those with platelets over 1000 to 1500 × 10⁹/L.
Medication to control pruritus and gout may be added if required.
Judicious use of phlebotomies in patients with hematocrits greater than 45 to 55 percent and in patients who find phlebotomy relieves their symptoms, such as headaches, difficulty concentrating, and fatigue.

THE SPENT PHASE

Sometimes after only a few years and usually after 15 years or more, erythrocytosis in patients with PV gradually abates in the absence of iron deficiency, phlebotomy requirements decrease and cease, and anemia develops. During this “spent” phase of the disease, marrow fibrosis becomes more marked and the spleen often becomes greatly enlarged (see Fig. 84–2A). Instead of phlebotomies, transfusions or erythropoietin may be required in such patients.²⁵⁵ The platelet count may remain high or may decline, even to pronounced thrombocytopenic levels. Marked leukopenia or leukocytosis may occur, and immature granulocytes may appear in the blood. At this point, the disease closely mimics PMF (Chap. 86) and is termed post-PV MF. Treatment of this phase of the disease is difficult and requires the judicious use of a combination of therapeutic approaches, including HU, erythropoiesis-stimulating drugs, transfusions, JAK2 inhibitors, and/or allogeneic stem cell transplantation.

Splenectomy

Splenectomy may be warranted (see Fig. 84–2B), particularly in patients with severe fatigue and cytopenias, and in those where a greatly enlarged spleen produces physical discomfort and postprandial fullness.²⁵⁶ However, a large Mayo Clinic series reported significant morbidity and mortality associated with splenectomy at this stage of the disease.²⁵⁷

Hematopoietic Stem Cell Transplantation

Nonmyeloablative allogeneic stem cell transplantation should be considered for otherwise healthy PV patients in the spent phase, even in the seventh decade of life (Chap. 23).^255,258,259 Transplantation is the treatment of choice in patients with early signs of MDS/AML transformation, and the only treatment offering the possibility of a cure.²⁶⁰ The rate of relapse and nonrelapse mortality following allogeneic stem cell transplantation is negatively associated with increased age, a matched but unrelated donor, and a diagnosis of AML.²⁶⁰

COURSE AND PROGNOSIS

Listen

PV is a chronic disease that runs a course over many years. Thrombotic complications, discussed in the preceding sections, are the dominant cause of morbidity and mortality in patients with PV. In contrast to other polycythemic disorders, PV has an increased risk and increased mortality resulting from development of acute leukemia.

The Polycythemia Vera Study Group⁷⁶ found that the median survival from the beginning of treatment was 13.9 years for those treated by phlebotomy alone, 11.8 years for ³²P-treated patients, and 8.9 years for chlorambucil-treated patients. Thrombosis was the most common cause of death, accounting for 31 percent of fatalities. Nineteen percent of patients died of acute leukemia, 15 percent from other neoplasms, and approximately 5 percent each from hemorrhage or development of the spent phase.

There is excess mortality attributable to thrombotic complications and acute leukemia transformation as a direct consequence of PV.⁷⁵ Acute leukemia occurs even in patients who have been treated only by phlebotomy, although its incidence is increased by the various forms of cytotoxic therapy employed. While AML is most common, acute lymphoid leukemia²⁶¹ and chronic neutrophilic leukemia²⁶² have occurred as well. The IWG-MRT reported a rate of transformation to leukemia of 2.3 percent at 10 years and 5.5 percent at 15 years,¹⁹⁰ but a unified scoring system that predicts the likelihood of transformation is yet to be developed.^263,264

Although it has been suggested that the overall survival of PV patients is near normal,^265,266 a number of other studies have found reduced survival of PV patients compared to controls.⁴ A recent study of 1545 patients by the IWG-MRT found that survival for PV patients was negatively correlated to leukocytosis, older age, venous thrombosis, and atypical karyotype. The median overall survival ranged from 10.9 and 27.8 years for different PV prognostic risk groups (Fig. 84–3).¹⁹⁰

Figure 84–3.

Survival of PV patients stratified by prognostic low-risk (blue), intermediate-risk (green), and high-risk (red) groups. Patients are scored based on three risk criteria: venous thrombosis (1 point), a leukocyte count ≥15 × 10⁹/L (1 point), and age (≥67 years: 5 points, 57–66 years: 2 points). The sum of these points classifies patients as prognostic low risk (0 points), intermediate risk (1–2 points) or high risk (≥3 points). (Reproduced with permission from Tefferi A, Rumi E, Finazzi G, et al: Survival and prognosis among 1545 patients with contemporary polycythemia vera: An international study. Leukemia 27(9):1874–1881, 2013.)

View Full Size||Download Slide (.ppt)

REFERENCES

Listen

Vaquez MH: Sue une forme spéciale de cyanose s’accompagnant d’hyperglobulie excessive et persistante. CR Soc Biol 44:384, 1892.

Osler W: Chronic cyanosis, with polycythemia and enlarged spleen: A new clinical entity. Am J Med Sci 126:187, 1903.

Türk W: Beitrage zur Kenntnis des Symptomenbildes Polycythamie mit Milztumor und Zyanose. Wien Klin Wochenschr 17:153, 1904.

Anderson LA, McMullin MF: Epidemiology of MPN: What do we know? Curr Hematol Malig Rep 2014.

Titmarsh GJ, Duncombe AS, McMullin MF et al.: How common are myeloproliferative neoplasms? A systematic review and meta-analysis. Am J Hematol 89(6):581–587, 2014. [PubMed: 24971434]

Chaiter Y, Brenner B, Aghai E et al.: High incidence of myeloproliferative disorders in Ashkenazi Jews in northern Israel. Leuk Lymphoma 7(3):251–255, 1992. [PubMed: 1477653]

Modan B, Kallner H, Zemer D et al.: A note on the increased risk of polycythemia vera in Jews. Blood 37(2):172–176, 1971. [PubMed: 5549194]

Bellanne-Chantelot C, Chaumarel I, Labopin M et al.: Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 108(1):346–352, 2006. [PubMed: 16537803]

Kralovics R, Stockton DW, Prchal JT: Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 102(10):3793–3796, 2003. [PubMed: 12829587]

10.

Ranjan A, Penninga E, Jelsig AM et al.: Inheritance of the chronic myeloproliferative neoplasms. A systematic review. Clin Genet 83(2):99–107, 2013. [PubMed: 23094849]

11.

Landgren O, Goldin LR, Kristinsson SY et al.: Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 first-degree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 112(6):2199–2204, 2008. [PubMed: 18451307]

12.

Kralovics R, Guan Y, Prchal JT: Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera. Exp Hematol 30(3):229–236, 2002. [PubMed: 11882360]

13.

Adamson JW, Fialkow PJ, Murphy S et al.: Polycythemia vera: Stem-cell and probable clonal origin of the disease. N Engl J Med 295(17):913–916, 1976. [PubMed: 967201]

14.

Liu E, Jelinek J, Pastore YD et al.: Discrimination of polycythemias and thrombocytoses by novel, simple, accurate clonality assays and comparison with PRV-1 expression and BFU-E response to erythropoietin. Blood 101(8):3294–3301, 2003. [PubMed: 12515724]

15.

Eaves CJ, Eaves AC: Erythropoietin (Ep) dose-response curves for three classes of erythroid progenitors in normal human marrow and in patients with polycythemia vera. Blood 52(6):1196–1210, 1978. [PubMed: 719172]

16.

Prchal JF, Adamson JW, Murphy S et al.: Polycythemia vera. The in vitro response of normal and abnormal stem cell lines to erythropoietin. J Clin Invest 61(4):1044–1047, 1978. [PubMed: 659576]

17.

Prchal JF, Axelrad AA: Bone-marrow responses in polycythemia vera [letter]. N Engl J Med 290(24):1382, 1974. [PubMed: 4827655]

18.

Prchal JF, Adamson JW, Steinmann L et al.: Human erythroid colony formation in vitro: Evidence for clonal origin. J Cell Physiol 89(3):489–492, 1976. [PubMed: 977665]

19.

Groopman JE: The pathogenesis of myelofibrosis in myeloproliferative disorders. Ann Intern Med 92(6):857–858, 1980. [PubMed: 7387029]

20.

Moliterno AR, Hankins WD, Spivak JL: Impaired expression of the thrombopoietin receptor by platelets from patients with polycythemia vera. N Engl J Med 338(9):572–580, 1998. [PubMed: 9475764]

21.

Silva M, Richard C, Benito A et al.: Expression of Bcl-x in erythroid precursors from patients with polycythemia vera. N Engl J Med 338(9):564–571, 1998. [PubMed: 9475763]

22.

Sui X, Krantz SB, Zhao Z: Identification of increased protein tyrosine phosphatase activity in polycythemia vera erythroid progenitor cells. Blood 90(2):651–657, 1997. [PubMed: 9226165]

23.

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

24.

Bench AJ, Nacheva EP, Champion KM et al.: Molecular genetics and cytogenetics of myeloproliferative disorders. Baillieres Clin Haematol 11(4):819–848, 1998. [PubMed: 10640219]

25.

Diez-Martin JL, Graham DL, Petitt RM et al.: Chromosome studies in 104 patients with polycythemia vera. Mayo Clin Proc 66(3):287–299, 1991. [PubMed: 2002687]

26.

Green A, Campbell P, Buck G et al.: The Medical Research Council PT1 Trial in Essential Thrombocythemia. Blood 104(Suppl 1):5a, 2004.

27.

Najfeld V, Montella L, Scalise A et al.: Exploring polycythaemia vera with fluorescence in situ hybridization: Additional cryptic 9p is the most frequent abnormality detected. Br J Haematol 119(2):558–566, 2002. [PubMed: 12406101]

28.

Wurster-Hill D, Whang-Peng J, McIntyre OR et al.: Cytogenetic studies in polycythemia vera. Semin Hematol 13(1):13–32, 1976. [PubMed: 1251221]

29.

Sever M, Quintas-Cardama A, Pierce S et al.: Significance of cytogenetic abnormalities in patients with polycythemia vera. Leuk Lymphoma 54(12):2667–2670, 2013. [PubMed: 23488603]

30.

Swolin B, Weinfeld A, Westin J: A prospective long-term cytogenetic study in polycythemia vera in relation to treatment and clinical course. Blood 72(2):386–395, 1988. [PubMed: 3401588]

31.

Spivak JL: Polycythemia vera: Myths, mechanisms, and management. Blood 100(13):4272–4290, 2002. [PubMed: 12393615]

32.

Baxter EJ, Scott LM, Campbell PJ et al.: Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365(9464):1054–1061, 2005. [PubMed: 15781101]

33.

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

34.

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

35.

Jelinek J, Oki Y, Gharibyan V et al.: JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood 106(10):3370–3373, 2005. [PubMed: 16037387]

36.

Jones AV, Kreil S, Zoi K et al.: Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106(6):2162–2168, 2005. [PubMed: 15920007]

37.

Nussenzveig RH, Swierczek SI, Jelinek J et al.: Polycythemia vera is not initiated by JAK2V617F mutation. Exp Hematol 35(1):32–38, 2007. [PubMed: 17198871]

38.

Tefferi A, Lasho TL, Schwager SM et al.: The clinical phenotype of wild-type, heterozygous, and homozygous JAK2V617F in polycythemia vera. Cancer 106(3):631–635, 2006. [PubMed: 16369984]

39.

Passamonti F, Rumi E, Pietra D et al.: A prospective study of 338 patients with polycythemia vera: The impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications. Leukemia 24(9):1574–1579, 2010. [PubMed: 20631743]

40.

Silver RT, Vandris K, Wang YL et al.: JAK2(V617F) allele burden in polycythemia vera correlates with grade of myelofibrosis, but is not substantially affected by therapy. Leuk Res 35(2):177–182, 2011. [PubMed: 20650526]

41.

Alvarez-Larran A, Bellosillo B, Pereira A et al.: JAK2V617F monitoring in polycythemia vera and essential thrombocythemia: Clinical usefulness for predicting myelofibrotic transformation and thrombotic events. Am J Hematol 89(5):517–523, 2014. [PubMed: 24458835]

42.

Koren-Michowitz M, Landman J, Cohen Y et al.: JAK2V617F allele burden is associated with transformation to myelofibrosis. Leuk Lymphoma 53(11):2210–2213, 2012. [PubMed: 22524513]

43.

Kuriakose E, Vandris K, Wang YL et al.: Decrease in JAK2 V617F allele burden is not a prerequisite to clinical response in patients with polycythemia vera. Haematologica 97(4):538–542, 2012. [PubMed: 22102708]

44.

Scott LM, Tong W, Levine RL et al.: JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. N Engl J Med 356(5):459–468, 2007. [PubMed: 17267906]

45.

Scott LM: The JAK2 exon 12 mutations: A comprehensive review. Am J Hematol 86(8):668–676, 2011. [PubMed: 21674578]

46.

Passamonti F, Elena C, Schnittger S et al.: Molecular and clinical features of the myeloproliferative neoplasm associated with JAK2 exon 12 mutations. Blood 117(10):2813–2816, 2011. [PubMed: 21224469]

47.

Skoda R, Prchal JT: Lessons from familial myeloproliferative disorders. Semin Hematol 42(4):266–273, 2005. [PubMed: 16210040]

48.

Cario H, Schwarz K, Herter JM et al.: Clinical and molecular characterisation of a prospectively collected cohort of children and adolescents with polycythemia vera. Br J Haematol 142(4):622–626, 2008. [PubMed: 18557746]

49.

Kralovics R, Teo SS, Buser AS et al.: Altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of Jak2. Blood 106(10):3374–3376, 2005. [PubMed: 16081684]

50.

Theocharides A, Boissinot M, Girodon F et al.: Leukemic blasts in transformed JAK2-V617F-positive myeloproliferative disorders are frequently negative for the JAK2-V617F mutation. Blood 110(1):375–379, 2007. [PubMed: 17363731]

51.

Wang L, Swierczek SI, Drummond J: Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. 28(4):935–938, 2014.

52.

Wang L, Swierczek SI, Lanikova L et al.: The relationship of JAK2(V617F) and acquired UPD at chromosome 9p in polycythemia vera. Leukemia 28(4):938–941, 2014. [PubMed: 24463469]

53.

Spivak JL, Considine M, Williams DM et al.: Two clinical phenotypes in polycythemia vera. N Engl J Med 371(9):808–817, 2014. [PubMed: 25162887]

54.

Olcaydu D, Harutyunyan A, Jager R et al.: A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms. Nat Genet 41(4):450–454, 2009. [PubMed: 19287385]

55.

Olcaydu D, Skoda RC, Looser R et al.: The “GGCC” haplotype of JAK2 confers susceptibility to JAK2 exon 12 mutation-positive polycythemia vera. Leukemia 23(10):1924–1926, 2009. [PubMed: 19440215]

56.

Kilpivaara O, Mukherjee S, Schram AM et al.: A germline JAK2 SNP is associated with predisposition to the development of JAK2(V617F)-positive myeloproliferative neoplasms. Nat Genet 41(4):455–459, 2009. [PubMed: 19287384]

57.

Jones AV, Chase A, Silver RT et al.: JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms. Nat Genet 41(4):446–449, 2009. [PubMed: 19287382]

58.

Delhommeau F, Dupont S, Della Valle V et al.: Mutation in TET2 in myeloid cancers. N Engl J Med 360(22):2289–2301, 2009. [PubMed: 19474426]

59.

Tefferi A, Pardanani A, Lim KH et al.: TET2 mutations and their clinical correlates in polycythemia vera, essential thrombocythemia and myelofibrosis. Leukemia 23(5):905–911, 2009. [PubMed: 19262601]

60.

Saint-Martin C, Leroy G, Delhommeau F et al.: Analysis of the ten-eleven translocation 2 (TET2) gene in familial myeloproliferative neoplasms. Blood 114(8):1628–1632, 2009. [PubMed: 19564637]

61.

Busque L, Patel JP, Figueroa ME et al.: Recurrent somatic TET2 mutations in normal elderly individuals with clonal hematopoiesis. Nat Genet 44(11):1179–1181, 2012. [PubMed: 23001125]

62.

Cazzola M, Kralovics R: From Janus kinase 2 to calreticulin: The clinically relevant genomic landscape of myeloproliferative neoplasms. Blood 123(24):3714–3719, 2014. [PubMed: 24786775]

63.

Wang L, Swierczek SI, Drummond J et al.: Whole-exome sequencing of polycythemia vera revealed novel driver genes and somatic mutation shared by T cells and granulocytes. Leukemia 28(4):935–938, 2014. [PubMed: 24413320]

64.

Li S, Kralovics R, De Libero G et al.: Clonal heterogeneity in polycythemia vera patients with JAK2 exon12 and JAK2-V617F mutations. Blood 111(7):3863–3866, 2008. [PubMed: 18195094]

65.

Kristinsson SY, Landgren O, Samuelsson J et al.: Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica 95(7):1216–1220, 2010. [PubMed: 20053870]

66.

Hasselbalch HC: Perspectives on chronic inflammation in essential thrombocythemia, polycythemia vera, and myelofibrosis: Is chronic inflammation a trigger and driver of clonal evolution and development of accelerated atherosclerosis and second cancer? Blood 119(14):3219–3225, 2012. [PubMed: 22318201]

67.

Hasselbalch HC: Chronic inflammation as a promotor of mutagenesis in essential thrombocythemia, polycythemia vera and myelofibrosis. A human inflammation model for cancer development? Leuk Res 37(2):214–220, 2013. [PubMed: 23174192]

68.

Hasselbalch HC: A role of NF-E2 in chronic inflammation and clonal evolution in essential thrombocythemia, polycythemia vera and myelofibrosis? Leuk Res 38(2):263–266, 2014. [PubMed: 23932394]

69.

Skov V, Larsen TS, Thomassen M et al.: Molecular profiling of peripheral blood cells from patients with polycythemia vera and related neoplasms: Identification of deregulated genes of significance for inflammation and immune surveillance. Leuk Res 36(11):1387–1392, 2012. [PubMed: 22877729]

70.

Berlin NI: Diagnosis and classification of the polycythemias. Semin Hematol 12(4):339–351, 1975. [PubMed: 1198126]

71.

Marchioli R, Finazzi G, Landolfi R et al.: Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol 23(10):2224–2232, 2005. [PubMed: 15710945]

72.

Falanga A, Marchetti M: Thrombotic disease in the myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program 2012:571–581, 2012. [PubMed: 23233637]

73.

Falanga A, Marchetti M: Thrombosis in myeloproliferative neoplasms. Semin Thromb Hemost 40(3):348–358, 2014. [PubMed: 24610470]

74.

Wehmeier A, Daum I, Jamin H et al.: Incidence and clinical risk factors for bleeding and thrombotic complications in myeloproliferative disorders. A retrospective analysis of 260 patients. Ann Hematol 63(2):101–106, 1991. [PubMed: 1912029]

75.

Landolfi R, Marchioli R, Kutti J et al.: Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med 350(2):114–124, 2004. [PubMed: 14711910]

76.

Berk PD, Goldberg JD, Donovan PB et al.: Therapeutic recommendations in polycythemia vera based on Polycythemia Vera Study Group protocols. Semin Hematol 23(2):132–143, 1986. [PubMed: 3704665]

77.

Polycythemia vera: The natural history of 1213 patients followed for 20 years. Gruppo Italiano Studio Policitemia. Ann Intern Med 123(9):656–664, 1995. [PubMed: 7574220]

78.

Berk P, Wasserman L, Fruchtman S: Treatment of polycythemia vera. A summary of clinical trials conducted by the Polycythemia Study Group, in Polycythemia Vera and the Myeloproliferative Disorders, edited by Wasserman L, Berk P, Berlin N. WB Saunders, Philadelphia, 1995.

79.

Coucelo M, Caetano G, Sevivas T et al.: JAK2V617F allele burden is associated with thrombotic mechanisms activation in polycythemia vera and essential thrombocythemia patients. Int J Hematol 99(1):32–40, 2014. [PubMed: 24277659]

80.

Carobbio A, Finazzi G, Antonioli E et al.: JAK2V617F allele burden and thrombosis: A direct comparison in essential thrombocythemia and polycythemia vera. Exp Hematol 37(9):1016–1021, 2009. [PubMed: 19559071]

81.

Spivak JL, Barosi G, Tognoni G et al.: Chronic myeloproliferative disorders. Hematology Am Soc Hematol Educ Program 200–224, 2003.

82.

Barbui T, Finazzi G: Special issues in myeloproliferative neoplasms. Curr Hematol Malig Rep 6(1):28–35, 2011. [PubMed: 21181458]

83.

Anger BR, Seifried E, Scheppach J et al.: Budd-Chiari syndrome and thrombosis of other abdominal vessels in the chronic myeloproliferative diseases. Klin Wochenschr 67(16):818–825, 1989. [PubMed: 2796252]

84.

De Stefano V, Fiorini A, Rossi E et al.: Incidence of the JAK2 V617F mutation among patients with splanchnic or cerebral venous thrombosis and without overt chronic myeloproliferative disorders. J Thromb Haemost 5(4):708–714, 2007. [PubMed: 17263783]

85.

De Stefano V, Teofili L, Leone G et al.: Spontaneous erythroid colony formation as the clue to an underlying myeloproliferative disorder in patients with Budd-Chiari syndrome or portal vein thrombosis. Semin Thromb Hemost 23(5):411–418, 1997. [PubMed: 9387199]

86.

Colaizzo D, Amitrano L, Tiscia GL et al.: The JAK2 V617F mutation frequently occurs in patients with portal and mesenteric venous thrombosis. J Thromb Haemost 5(1):55–61, 2007. [PubMed: 17059429]

87.

Reikvam H, Tiu RV: Venous thromboembolism in patients with essential thrombocythemia and polycythemia vera. Leukemia 26(4):563–571, 2012. [PubMed: 22076463]

88.

Srinivasan P, Rela M, Prachalias A et al.: Liver transplantation for Budd-Chiari syndrome. Transplantation 73(6):973–977, 2002. [PubMed: 11923703]

89.

Valla D, Casadevall N, Lacombe C et al.: Primary myeloproliferative disorder and hepatic vein thrombosis. A prospective study of erythroid colony formation in vitro in 20 patients with Budd-Chiari syndrome. Ann Intern Med 103(3):329–334, 1985. [PubMed: 4026081]

90.

Murphy S: Polycythemia vera. Dis Mon 38(3):153–212, 1992. [PubMed: 1587207]

91.

Siegel FP, Tauscher J, Petrides PE: Aquagenic pruritus in polycythemia vera: Characteristics and influence on quality of life in 441 patients. Am J Hematol 88(8):665–669, 2013. [PubMed: 23657863]

92.

Jackson N, Burt D, Crocker J et al.: Skin mast cells in polycythaemia vera: Relationship to the pathogenesis and treatment of pruritus. Br J Dermatol 116(1):21–29, 1987. [PubMed: 3814512]

93.

Steinman HK, Kobza-Black A, Lotti TM et al.: Polycythaemia rubra vera and water-induced pruritus: Blood histamine levels and cutaneous fibrinolytic activity before and after water challenge. Br J Dermatol 116(3):329–333, 1987. [PubMed: 3567071]

94.

Buchanan JG, Ameratunga RV, Hawkins RC: Polycythemia vera and water-induced pruritus: Evidence against mast cell involvement. Pathology 26(1):43–45, 1994. [PubMed: 8165024]

95.

Cox NH, Leggat H: Sweet’s syndrome associated with polycythemia rubra vera. J Am Acad Dermatol 23(6 Pt 1):1171–1172, 1990. [PubMed: 2273125]

96.

Furukawa T, Takahashi M, Shimada H et al.: Polycythaemia vera with Sweet’s syndrome. Clin Lab Haematol 11(1):67–70, 1989. [PubMed: 2706904]

97.

Davis MD, O’Fallon WM, Rogers RS 3rd et al.: Natural history of erythromelalgia: Presentation and outcome in 168 patients. Arch Dermatol[Archives of Dermatology Full Text] 136(3):330–336, 2000. [PubMed: 10724194]

98.

van Genderen PJ, Lucas IS, van Strik R et al.: Erythromelalgia in essential thrombocythemia is characterized by platelet activation and endothelial cell damage but not by thrombin generation. Thromb Haemost 76(3):333–338, 1996. [PubMed: 8883266]

99.

van Genderen PJ, Michiels JJ: Erythromelalgia: A pathognomonic microvascular thrombotic complication in essential thrombocythemia and polycythemia vera. Semin Thromb Hemost 23(4):357–363, 1997. [PubMed: 9263352]

100.

Wanless IR, Peterson P, Das A et al.: Hepatic vascular disease and portal hypertension in polycythemia vera and agnogenic myeloid metaplasia: A clinicopathological study of 145 patients examined at autopsy. Hepatology 12(5):1166–1174, 1990. [PubMed: 2227815]

101.

Tinney WS, Hall BE, Giffin HZ: Polycythemia vera and peptic ulcer. Mayo Clin Proc 18:24, 1943.

102.

Dingli D, Utz JP, Krowka MJ et al.: Unexplained pulmonary hypertension in chronic myeloproliferative disorders. Chest 120(3):801–808, 2001. [PubMed: 11555513]

103.

Garcia-Manero G, Schuster SJ, Patrick H et al.: Pulmonary hypertension in patients with myelofibrosis secondary to myeloproliferative diseases. Am J Hematol 60(2):130–135, 1999. [PubMed: 9929105]

104.

Newton LK: Neurologic complications of polycythemia and their impact on therapy. Oncology (Williston Park) 4(3):59–64; discussion 64–66, 1990. [PubMed: 2144446]

105.

Jackson A, Burton IE: Retroperitoneal mass and spinal cord compression due to extramedullary haemopoiesis in polycythaemia rubra vera. Br J Radiol 62(742):944–947, 1989. [PubMed: 2819366]

106.

Wasserman LR, Gilbert HS: Surgical bleeding in polycythemia vera. Ann N Y Acad Sci 115:122–138, 1964. [PubMed: 14192818]

107.

Gilbert HS: Modern treatment strategies in polycythemia vera. Semin Hematol 40(1 Suppl 1):26–29, 2003. [PubMed: 12682879]

108.

Thiele J, Kvasnicka HM: Diagnostic impact of bone marrow histopathology in polycythemia vera (PV). Histol Histopathol 20(1):317–328, 2005. [PubMed: 15578448]

109.

Finazzi G, Caruso V, Marchioli R et al.: Acute leukemia in polycythemia vera: An analysis of 1638 patients enrolled in a prospective observational study. Blood 105(7):2664–2670, 2005. [PubMed: 15585653]

110.

Cassinat B, Laguillier C, Gardin C et al.: Classification of myeloproliferative disorders in the JAK2 era: Is there a role for red cell mass? Leukemia 22(2):452–453, 2008. [PubMed: 17713549]

111.

Johansson PL, Safai-Kutti S, Kutti J: An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: A study of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol 129(5):701–705, 2005. [PubMed: 15916693]

112.

Barbui T, Thiele J, Gisslinger H et al.: Masked polycythemia vera (mPV): Results of an international study. Am J Hematol 89(1):52–54, 2014. [PubMed: 23996471]

113.

Spivak JL: Diagnosis of the myeloproliferative disorders: Resolving phenotypic mimicry. Semin Hematol 40(1 Suppl 1):1–5, 2003. [PubMed: 12682874]

114.

Beutler E: Polycythemia. Med Grand Rounds 3:142, 1984.

115.

Spivak JL, Silver RT: The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: An alternative proposal. Blood 112(2):231–239, 2008. [PubMed: 18401028]

116.

Gilbert HS, Warner RR, Wasserman LR: A study of histamine in myeloproliferative disease. Blood 28(6):795–806, 1966. [PubMed: 5959473]

117.

Falanga A, Marchetti M, Evangelista V et al.: Polymorphonuclear leukocyte activation and hemostasis in patients with essential thrombocythemia and polycythemia vera. Blood 96(13):4261–4266, 2000. [PubMed: 11110700]

118.

Vannucchi AM: Insights into the pathogenesis and management of thrombosis in polycythemia vera and essential thrombocythemia. Intern Emerg Med 5(3):177–184, 2010. [PubMed: 19789961]

119.

Cerutti A, Custodi P, Duranti M et al.: Thrombopoietin levels in patients with primary and reactive thrombocytosis. Br J Haematol 99(2):281–284, 1997. [PubMed: 9375739]

120.

Shih LY, Lee CT: Identification of masked polycythemia vera from patients with idiopathic marked thrombocytosis by endogenous erythroid colony assay. Blood 83(3):744–748, 1994. [PubMed: 8298136]

121.

Yamamoto K, Sekiguchi E, Takatani O: Abnormalities of epinephrine-induced platelet aggregation and adenine nucleotides in myeloproliferative disorders. Thromb Haemost 52(3):292–296, 1984. [PubMed: 6531753]

122.

Mehta P, Mehta J, Ross M et al.: Decreased platelet aggregation but increased thromboxane A2 generation in polycythemia vera. Arch Intern Med[Archives of Internal Medicine Full Text] 145(7):1225–1227, 1985. [PubMed: 4015270]

123.

Landolfi R, Ciabattoni G, Patrignani P et al.: Increased thromboxane biosynthesis in patients with polycythemia vera: Evidence for aspirin-suppressible platelet activation in vivo. Blood 80(8):1965–1971, 1992. [PubMed: 1327286]

124.

Berild D, Hasselbalch H, Knudsen JB: Platelet survival, platelet factor-4 and bleeding time in myeloproliferative disorders. Scand J Clin Lab Invest 47(5):497–501, 1987. [PubMed: 3477851]

125.

Kutti J, Weinfeld A: Platelet survival in active polycythaemia vera with reference to the haematocrit level. An experimental study before and after phlebotomy. Scand J Haematol 8(5):405–414, 1971. [PubMed: 5134837]

126.

Le Blanc K, Lindahl T, Rosendahl K et al.: Impaired platelet binding of fibrinogen due to a lower number of GPIIB/IIIA receptors in polycythemia vera. Thromb Res 91(6):287–295, 1998. [PubMed: 9772010]

127.

Afshar-Kharghan V, Lopez JA, Gray LA et al.: Hemostatic gene polymorphisms and the prevalence of thrombotic complications in polycythemia vera and essential thrombocythemia. Blood Coagul Fibrinolysis 15(1):21–24, 2004. [PubMed: 15166939]

128.

Landolfi R, Cipriani MC, Novarese L: Thrombosis and bleeding in polycythemia vera and essential thrombocythemia: Pathogenetic mechanisms and prevention. Best Pract Res Clin Haematol 19(3):617–633, 2006. [PubMed: 16781491]

129.

Binder RA, Gilbert HS: Muramidase in polycythemia vera. Blood 36(2):228–232, 1970. [PubMed: 5427457]

130.

Gilbert HS, Krauss S, Pasternack B et al.: Serum vitamin B12 content and unsaturated vitamin B12-binding capacity in myeloproliferative disease. Value in differential diagnosis and as indicators of disease activity. Ann Intern Med 71(4):719–729, 1969. [PubMed: 5360286]

131.

Moliterno AR, Williams DM, Rogers O et al.: Molecular mimicry in the chronic myeloproliferative disorders: Reciprocity between quantitative JAK2 V617F and Mpl expression. Blood 108(12):3913–3915, 2006. [PubMed: 16912229]

132.

Antonioli E, Guglielmelli P, Poli G et al.: Influence of JAK2V617F allele burden on phenotype in essential thrombocythemia. Haematologica 93(1):41–48, 2008. [PubMed: 18166784]

133.

Wang L, Swierczek SI, Lanikova L et al.: The relationship of JAK2(V617F) and acquired UPD at chromosome 9p in polycythemia vera. Leukemia 28(4):938–941, 2014. [PubMed: 24463469]

134.

Lippert E, Girodon F, Hammond E et al.: Concordance of assays designed for the quantification of JAK2V617F: A multicenter study. Haematologica 94(1):38–45, 2009. [PubMed: 19001280]

135.

Ma W, Kantarjian H, Zhang X et al.: Higher detection rate of JAK2 mutation using plasma. Blood 111(7):3906–3907, 2008. [PubMed: 18362222]

136.

Ma W, Kantarjian H, Verstovsek S et al.: Hemizygous/homozygous and heterozygous JAK2 mutation detected in plasma of patients with myeloproliferative diseases: Correlation with clinical behaviour. Br J Haematol 134(3):341–343, 2006. [PubMed: 16787500]

137.

Salama ME, Swierczek SI, Hickman K et al.: Plasma quantitation of JAK2 mutation is not suitable as a clinical test: An artifact of storage. Blood 114(1):223–224; author reply 224, 2009. [PubMed: 19574481]

138.

Jones AV, Cross NC, White HE et al.: Rapid identification of JAK2 exon 12 mutations using high resolution melting analysis. Haematologica 93(10):1560–1564, 2008. [PubMed: 18698085]

139.

Percy MJ, Scott LM, Erber WN et al.: The frequency of JAK2 exon 12 mutations in idiopathic erythrocytosis patients with low serum erythropoietin levels. Haematologica 92(12):1607–1614, 2007. [PubMed: 18055983]

140.

Pietra D, Li S, Brisci A et al.: Somatic mutations of JAK2 exon 12 in patients with JAK2 (V617F)-negative myeloproliferative disorders. Blood 111(3):1686–1689, 2008. [PubMed: 17984312]

141.

Rapado I, Grande S, Albizua E et al.: High resolution melting analysis for JAK2 Exon 14 and Exon 12 mutations: A diagnostic tool for myeloproliferative neoplasms. J Mol Diagn 11(2):155–161, 2009. [PubMed: 19225136]

142.

Schnittger S, Bacher U, Haferlach C et al.: Detection of JAK2 exon 12 mutations in 15 patients with JAK2V617F negative polycythemia vera. Haematologica 94(3):414–418, 2009. [PubMed: 19252176]

143.

Birgegard G, Wide L: Serum erythropoietin in the diagnosis of polycythaemia and after phlebotomy treatment. Br J Haematol 81(4):603–606, 1992. [PubMed: 1390249]

144.

Messinezy M, Westwood NB, El-Hemaidi I et al.: Serum erythropoietin values in erythrocytoses and in primary thrombocythaemia. Br J Haematol 117(1):47–53, 2002. [PubMed: 11918532]

145.

Mossuz P, Girodon F, Donnard M et al.: Diagnostic value of serum erythropoietin level in patients with absolute erythrocytosis. Haematologica 89(10):1194–1198, 2004. [PubMed: 15477203]

146.

Remacha AF, Montserrat I, Santamaria A et al.: Serum erythropoietin in the diagnosis of polycythemia vera. A follow-up study. Haematologica 82(4):406–410, 1997. [PubMed: 9299851]

147.

Prchal JT: Classification and molecular biology of polycythemias (erythrocytoses) and thrombocytosis. Hematol Oncol Clin North Am 17(5):1151–1158, vi, 2003. [PubMed: 14560779]

148.

Weinberg RS: In vitro erythropoiesis in polycythemia vera and other myeloproliferative disorders. Semin Hematol 34(1):64–69, 1997. [PubMed: 9025164]

149.

Shih LY, Lee CT, See LC et al.: In vitro culture growth of erythroid progenitors and serum erythropoietin assay in the differential diagnosis of polycythaemia. Eur J Clin Invest 28(7):569–576, 1998. [PubMed: 9726038]

150.

Fisher MJ, Prchal JF, Prchal JT et al.: Anti-erythropoietin (EPO) receptor monoclonal antibodies distinguish EPO-dependent and EPO-independent erythroid progenitors in polycythemia vera. Blood 84(6):1982–1991, 1994. [PubMed: 8081000]

151.

Kralovics R, Sokol L, Prchal JT: Absence of polycythemia in a child with a unique erythropoietin receptor mutation in a family with autosomal dominant primary polycythemia. J Clin Invest 102(1):124–129, 1998. [PubMed: 9649565]

152.

Acharya J, Westwood NB, Sawyer BM et al.: Identification of latent myeloproliferative disease in patients with Budd-Chiari syndrome using X-chromosome inactivation patterns and in vitro erythroid colony formation. Eur J Haematol 55(5):315–321, 1995. [PubMed: 7493678]

153.

Pagliuca A, Mufti GJ, Janossa-Tahernia M et al.: In vitro colony culture and chromosomal studies in hepatic and portal vein thrombosis—Possible evidence of an occult myeloproliferative state. Q J Med 76(281):981–989, 1990. [PubMed: 2236481]

154.

Tefferi A, Thiele J, Vardiman JW: The 2008 World Health Organization classification system for myeloproliferative neoplasms: Order out of chaos. Cancer 115(17):3842–3847, 2009. [PubMed: 19472396]

155.

Lakey MA, Pardanani A, Hoyer JD et al.: Bone marrow morphologic features in polycythemia vera with JAK2 exon 12 mutations. Am J Clin Pathol 133(6):942–948, 2010. [PubMed: 20472853]

156.

Wang X, LeBlanc A, Gruenstein S et al.: Clonal analyses define the relationships between chromosomal abnormalities and JAK2V617F in patients with Ph-negative myeloproliferative neoplasms. Exp Hematol 37(10):1194–1200, 2009. [PubMed: 19615425]

157.

Beutler E, Yeh M, Fairbanks VF: The normal human female as a mosaic of X-chromosome activity: Studies using the gene for C-6-PD-deficiency as a marker. Proc Natl Acad Sci U S A 48:9–16, 1962. [PubMed: 13868717]

158.

Prchal JT: Pathogenetic mechanisms of polycythemia vera and congenital polycythemic disorders. Semin Hematol 38(1 Suppl 2):10–20, 2001. [PubMed: 11242597]

159.

Swierczek SI, Piterkova L, Jelinek J et al.: Methylation of AR locus does not always reflect X chromosome inactivation state. Blood 119(13):e100–e109, 2012. [PubMed: 22286197]

160.

Swierczek SI, Agarwal N, Nussenzveig RH et al.: Hematopoiesis is not clonal in healthy elderly women. Blood 112(8):3186–3193, 2008. [PubMed: 18641369]

161.

Vogelstein B, Fearon ER, Hamilton SR et al.: Use of restriction fragment length polymorphisms to determine the clonal origin of human tumors. Science 227(4687):642–645, 1985. [PubMed: 2982210]

162.

Allen RC, Zoghbi HY, Moseley AB et al.: Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am J Hum Genet 51(6):1229–1239, 1992. [PubMed: 1281384]

163.

Curnutte JT, Hopkins PJ, Kuhl W et al.: Studying X inactivation. Lancet 339(8795):749, 1992. [PubMed: 1347621]

164.

Prchal JT, Guan YL, Prchal JF et al.: Transcriptional analysis of the active X-chromosome in normal and clonal hematopoiesis. Blood 81(1):269–271, 1993. [PubMed: 8093348]

165.

McMullin MF, Reilly JT, Campbell P et al.: Amendment to the guideline for diagnosis and investigation of polycythaemia/erythrocytosis. Br J Haematol 138(6):821–822, 2007. [PubMed: 17672880]

166.

Bench AJ, White HE, Foroni L et al.: Molecular diagnosis of the myeloproliferative neoplasms: UK guidelines for the detection of JAK2 V617F and other relevant mutations. Br J Haematol 160(1):25–34, 2013. [PubMed: 23057517]

167.

Samuelson SJ, Parker CJ, Prchal JT: Revised criteria for the myeloproliferative disorders: Too much too soon? Blood 111(3):1741; author reply 1742, 2008. [PubMed: 18223175]

168.

Barbui T, Thiele J, Vannucchi AM et al.: Rethinking the diagnostic criteria of polycythemia vera. Leukemia 28(6):1191–1195, 2014. [PubMed: 24352199]

169.

Silver RT, Chow W, Orazi A et al.: Evaluation of WHO criteria for diagnosis of polycythemia vera: A prospective analysis. Blood 122(11):1881–1886, 2013. [PubMed: 23900239]

170.

Teofili L, Giona F, Martini M et al.: The revised WHO diagnostic criteria for Ph-negative myeloproliferative diseases are not appropriate for the diagnostic screening of childhood polycythemia vera and essential thrombocythemia. Blood 110(9):3384–3386, 2007. [PubMed: 17644735]

171.

Finazzi G, Barbui T: Evidence and expertise in the management of polycythemia vera and essential thrombocythemia. Leukemia 22(8):1494–1502, 2008. [PubMed: 18596737]

172.

Barbui T, Carobbio A, Rambaldi A et al.: Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: Is leukocytosis a causative factor? Blood 114(4):759–763, 2009. [PubMed: 19372254]

173.

Caramazza D, Caracciolo C, Barone R et al.: Correlation between leukocytosis and thrombosis in Philadelphia-negative chronic myeloproliferative neoplasms. Ann Hematol 88(10):967–971, 2009. [PubMed: 19214510]

174.

Landolfi R, Di Gennaro L, Barbui T et al.: Leukocytosis as a major thrombotic risk factor in patients with polycythemia vera. Blood 109(6):2446–2452, 2007. [PubMed: 17105814]

175.

Gangat N, Strand J, Li CY et al.: Leucocytosis in polycythaemia vera predicts both inferior survival and leukaemic transformation. Br J Haematol 138(3):354–358, 2007. [PubMed: 17614822]

176.

De Stefano V, Za T, Rossi E et al.: Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia. Am J Hematol 85(2):97–100, 2010. [PubMed: 20052743]

177.

Vannucchi AM, Antonioli E, Guglielmelli P et al.: Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: A critical reappraisal. Leukemia 22(7):1299–1307, 2008. [PubMed: 18496562]

178.

Barbui T, Barosi G, Birgegard G et al.: Philadelphia-negative classical myeloproliferative neoplasms: Critical concepts and management recommendations from European LeukemiaNet. J Clin Oncol 29(6):761–770, 2011. [PubMed: 21205761]

179.

Barosi G, Mesa R, Finazzi G et al.: Revised response criteria for polycythemia vera and essential thrombocythemia: An ELN and IWG-MRT consensus project. Blood 121(23):4778–4781, 2013. [PubMed: 23591792]

180.

Harrison C: Rethinking disease definitions and therapeutic strategies in essential thrombocythemia and polycythemia vera. Hematology Am Soc Hematol Educ Program 2010:129–134, 2010. [PubMed: 21239782]

181.

Tefferi A: Polycythemia vera and essential thrombocythemia: 2013 Update on diagnosis, risk-stratification, and management. Am J Hematol 88(6):507–516, 2013. [PubMed: 23695894]

182.

Dingli D, Tefferi A: Hydroxyurea: The drug of choice for polycythemia vera and essential thrombocythemia. Curr Hematol Malig Rep 1(2):69–74, 2006. [PubMed: 20425334]

183.

Barbui T, Finazzi G: Evidence-based management of polycythemia vera. Best Pract Res Clin Haematol 19(3):483–493, 2006. [PubMed: 16781485]

184.

Antonioli E, Carobbio A, Pieri L et al.: Hydroxyurea does not appreciably reduce JAK2 V617F allele burden in patients with polycythemia vera or essential thrombocythemia. Haematologica 95(8):1435–1438, 2010. [PubMed: 20418246]

185.

Ricksten A, Palmqvist L, Johansson P et al.: Rapid decline of JAK2V617F levels during hydroxyurea treatment in patients with polycythemia vera and essential thrombocythemia. Haematologica 93(8):1260–1261, 2008. [PubMed: 18519514]

186.

Spanoudakis E, Bazdiara I, Kotsianidis I et al.: Hydroxyurea (HU) is effective in reducing JAK2V617F mutated clone size in the peripheral blood of essential thrombocythemia (ET) and polycythemia vera (PV) patients. Ann Hematol 88(7):629–632, 2009. [PubMed: 19096846]

187.

Zalcberg IR, Ayres-Silva J, de Azevedo AM et al.: Hydroxyurea dose impacts hematologic parameters in polycythemia vera and essential thrombocythemia but does not appreciably affect JAK2-V617F allele burden. Haematologica 96(3):e18–e20, 2011. [PubMed: 21357711]

188.

Sirhan S, Lasho TL, Hanson CA et al.: The presence of JAK2V617F in primary myelofibrosis or its allele burden in polycythemia vera predicts chemosensitivity to hydroxyurea. Am J Hematol 83(5):363–365, 2008. [PubMed: 18266209]

189.

Lanzkron S, Strouse JJ, Wilson R et al.: Systematic review: Hydroxyurea for the treatment of adults with sickle cell disease. Ann Intern Med 148(12):939–955, 2008. [PubMed: 18458272]

190.

Tefferi A, Rumi E, Finazzi G et al.: Survival and prognosis among 1545 patients with contemporary polycythemia vera: An international study. Leukemia 27(9):1874–1881, 2013. [PubMed: 23739289]

191.

Alvarez-Larran A, Pereira A, Cervantes F et al.: Assessment and prognostic value of the European LeukemiaNet criteria for clinicohematologic response, resistance, and intolerance to hydroxyurea in polycythemia vera. Blood 119(6):1363–1369, 2012. [PubMed: 22160617]

192.

Barosi G, Birgegard G, Finazzi G et al.: A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythaemia vera and primary myelofibrosis: Results of a European LeukemiaNet (ELN) consensus process. Br J Haematol 148(6):961–963, 2010. [PubMed: 19930182]

193.

Sever M, Newberry KJ, Verstovsek S: Therapeutic options for patients with polycythemia vera and essential thrombocythemia refractory/resistant to hydroxyurea. Leuk Lymphoma 55(12):2685–2690, 2014. [PubMed: 24524340]

194.

Treatment of polycythaemia vera by radiophosphorus or busulphan: A randomized trial. “Leukemia and Hematosarcoma” Cooperative Group, European Organization for Research on Treatment of Cancer (E.O.R.T.C.). Br J Cancer 44(1):75–80, 1981. [PubMed: 7020738]

195.

Kuriakose ET, Gjoni S, Wang YL et al.: JAK2V617F allele burden is reduced by busulfan therapy: A new observation using an old drug. Haematologica 98(11):e135–e137, 2013. [PubMed: 24186314]

196.

Alvarez-Larrán A, Martínez-Avilés L, Hernández-Boluda JC et al.: Busulfan in patients with polycythemia vera or essential thrombocythemia refractory or intolerant to hydroxyurea. Ann Hematol 93(12):2037–2043, 2014. [PubMed: 24981691]

197.

Tefferi A: Polycythemia vera: A comprehensive review and clinical recommendations. Mayo Clin Proc 78(2):174–194, 2003. [PubMed: 12583529]

198.

Balan KK, Critchley M: Outcome of 259 patients with primary proliferative polycythaemia (PPP) and idiopathic thrombocythaemia (IT) treated in a regional nuclear medicine department with phosphorus-32—A 15 year review. Br J Radiol 70(839):1169–1173, 1997. [PubMed: 9536909]

199.

Roberts BE, Smith AH: Use of radioactive phosphorus in haematology. Blood Rev 11(3):146–153, 1997. [PubMed: 9370045]

200.

Silver RT: Recombinant interferon-alpha for treatment of polycythaemia vera. Lancet 2(8607):403, 1988. [PubMed: 2899816]

201.

Hasselbalch HC: A new era for IFN-alpha in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Expert Rev Hematol 4(6):637–655, 2011. [PubMed: 22077528]

202.

Hasselbalch HC, Larsen TS, Riley CH et al.: Interferon-alpha in the treatment of Philadelphia-negative chronic myeloproliferative neoplasms. Status and perspectives. Curr Drug Targets 12(3):392–419, 2011. [PubMed: 21143149]

203.

Silver RT, Kiladjian JJ, Hasselbalch HC: Interferon and the treatment of polycythemia vera, essential thrombocythemia and myelofibrosis. Expert Rev Hematol 6(1):49–58, 2013. [PubMed: 23373780]

204.

Kiladjian JJ, Mesa RA, Hoffman R: The renaissance of interferon therapy for the treatment of myeloid malignancies. Blood 117(18):4706–4715, 2011. [PubMed: 21389325]

205.

Jones AV, Silver RT, Waghorn K et al.: Minimal molecular response in polycythemia vera patients treated with imatinib or interferon alpha. Blood 107(8):3339–3341, 2006. [PubMed: 16352805]

206.

Larsen TS, Moller MB, de Stricker K et al.: Minimal residual disease and normalization of the bone marrow after long-term treatment with alpha-interferon2b in polycythemia vera. A report on molecular response patterns in seven patients in sustained complete hematological remission. Hematology 14(6):331–334, 2009. [PubMed: 19941739]

207.

Zhang ZR, Duan YC: Interferon apha 2b for treating patients with JAK2V617F positive polycythemia vera and essential thrombocytosis. Asian Pac J Cancer Prev 15(4):1681–1684, 2014. [PubMed: 24641389]

208.

Huang BT, Zeng QC, Zhao WH et al.: Interferon alpha-2b gains high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation. Leuk Res 38(10):1177–1183, 2014. [PubMed: 25069759]

209.

Steegmann JL, Requena MJ, Martin-Regueira P et al.: High incidence of autoimmune alterations in chronic myeloid leukemia patients treated with interferon-alpha. Am J Hematol 72(3):170–176, 2003. [PubMed: 12605388]

210.

Quintas-Cardama A, Kantarjian HM, Giles F et al.: Pegylated interferon therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders. Semin Thromb Hemost 32(4 Pt 2):409–416, 2006. [PubMed: 16810616]

211.

Jabbour E, Kantarjian H, Cortes J et al.: PEG-IFN-alpha-2b therapy in BCR-ABL-negative myeloproliferative disorders: Final result of a phase 2 study. Cancer 110(9):2012–2018, 2007. [PubMed: 17849460]

212.

Samuelsson J, Hasselbalch H, Bruserud O et al.: A phase II trial of pegylated interferon alpha-2b therapy for polycythemia vera and essential thrombocythemia: Feasibility, clinical and biologic effects, and impact on quality of life. Cancer 106(11):2397–2405, 2006. [PubMed: 16639737]

213.

Samuelsson J, Mutschler M, Birgegard G et al.: Limited effects on JAK2 mutational status after pegylated interferon alpha-2b therapy in polycythemia vera and essential thrombocythemia. Haematologica 91(9):1281–1282, 2006. [PubMed: 16956836]

214.

Kiladjian JJ, Cassinat B, Chevret S et al.: Pegylated interferon-alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood 112(8):3065–3072, 2008. [PubMed: 18650451]

215.

Kiladjian JJ, Cassinat B, Turlure P et al.: High molecular response rate of polycythemia vera patients treated with pegylated interferon alpha-2a. Blood 108(6):2037–2040, 2006. [PubMed: 16709929]

216.

Berlin NI, Wasserman LR: Polycythemia vera: A retrospective and reprise. J Lab Clin Med 130(4):365–373, 1997. [PubMed: 9358074]

217.

Pearson TC, Wetherley-Mein G. Vascular occlusive episodes and venous haematocrit in primary proliferative polycythaemia. Lancet 2(8102):1219–1222, 1978. [PubMed: 82733]

218.

Vongpatanasin W, Brickner ME, Hillis LD et al.: The Eisenmenger syndrome in adults. Ann Intern Med 128(9):745–755, 1998. [PubMed: 9556469]

219.

Thorne SA: Management of polycythaemia in adults with cyanotic congenital heart disease. Heart 79(4):315–316, 1998. [PubMed: 9616333]

220.

Perloff JK, Marelli AJ, Miner PD: Risk of stroke in adults with cyanotic congenital heart disease. Circulation 87(6):1954–1959, 1993. [PubMed: 8504509]

221.

Di Nisio M, Barbui T, Di Gennaro L et al.: The haematocrit and platelet target in polycythemia vera. Br J Haematol 136(2):249–259, 2007. [PubMed: 17156406]

222.

Marchioli R, Finazzi G, Specchia G et al.: Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med 368(1):22–33, 2013. [PubMed: 23216616]

223.

Prchal JT, Gordeuk VR: Treatment target in polycythemia vera. N Engl J Med 368(16):1555–1556, 2013. [PubMed: 23594015]

224.

Petitt RM, Silverstein MN, Petrone ME: Anagrelide for control of thrombocythemia in polycythemia and other myeloproliferative disorders. Semin Hematol 34(1):51–54, 1997. [PubMed: 9025162]

225.

Storen EC, Tefferi A: Long-term use of anagrelide in young patients with essential thrombocythemia. Blood 97(4):863–866, 2001. [PubMed: 11159509]

226.

Gisslinger H, Gotic M, Holowiecki J et al.: Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: The ANAHYDRET Study, a randomized controlled trial. Blood 121(10):1720–1728, 2013. [PubMed: 23315161]

227.

Swerlick RA: Photochemotherapy treatment of pruritus associated with polycythemia vera. J Am Acad Dermatol 13(4):675–677, 1985. [PubMed: 4078060]

228.

Bircher AJ: Water-induced itching. Dermatologica 181(2):83–87, 1990. [PubMed: 2242790]

229.

de Wolf JT, Hendriks DW, Egger RC et al.: Alpha-interferon for intractable pruritus in polycythaemia vera. Lancet 337(8735):241, 1991. [PubMed: 1670870]

230.

Foa P, Massaro P, Caldiera S et al.: Long-term therapeutic efficacy and toxicity of recombinant interferon-alpha 2a in polycythaemia vera. Eur J Haematol 60(5):273–277, 1998. [PubMed: 9654155]

231.

Ozturk A, Gunay A, Uskent N: Therapeutic efficacy of recombinant interferon-alpha in polycythaemia vera. Acta Haematol 99(2):89–91, 1998. [PubMed: 9554456]

232.

Verstovsek S, Kiladjian JJ, Grieshammer M et al.: Results of a Prospective, Randomized, Open-Label Phase 3 Study of Ruxolitinib (RUX) in Polycythemia Vera (PV) Patients Resistant to or Intolerant of Hydroxyurea (HU): The RESPONSE Trial, abstract #7026. American Society of Clinical Oncology (ASCO), Chicago, 2014.

233.

Verstovsek S, Passamonti F, Rambaldi A et al.: A phase 2 study of ruxolitinib, an oral JAK1 and JAK2 Inhibitor, in patients with advanced polycythemia vera who are refractory or intolerant to hydroxyurea. Cancer 120(4):513–520, 2014. [PubMed: 24258498]

234.

Tartaglia AP, Goldberg JD, Berk PD et al.: Adverse effects of antiaggregating platelet therapy in the treatment of polycythemia vera. Semin Hematol 23(3):172–176, 1986. [PubMed: 3749927]

235.

Landolfi R, Marchioli R: European Collaboration on Low-dose Aspirin in Polycythemia Vera (ECLAP): A randomized trial. Semin Thromb Hemost 23(5):473–478, 1997. [PubMed: 9387206]

236.

Mascarenhas JO, Cross NC, Mesa RA: The future of JAK inhibition in myelofibrosis and beyond. Blood Rev 28(5):189–196, 2014. [PubMed: 25043171]

237.

Scherber R, Mesa RA: Future therapies for the myeloproliferative neoplasms. Curr Hematol Malig Rep 6(1):22–27, 2011. [PubMed: 21080242]

238.

Harrison C, Kiladjian JJ, Al-Ali HK et al.: JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. N Engl J Med 366(9):787–798, 2012. [PubMed: 22375970]

239.

Santos FP, Verstovsek S: Efficacy of ruxolitinib for myelofibrosis. Expert Opin Pharmacother 15(10):1465–1473, 2014. [PubMed: 24856675]

240.

Verstovsek S, Kantarjian H, Mesa RA et al.: Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N Engl J Med 363(12):1117–1127, 2010. [PubMed: 20843246]

241.

Verstovsek S, Mesa RA, Gotlib J et al.: A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med 366(9):799–807, 2012. [PubMed: 22375971]

242.

Quintas-Cardama A, Vaddi K, Liu P et al.: Preclinical characterization of the selective JAK1/2 inhibitor INCB018424: Therapeutic implications for the treatment of myeloproliferative neoplasms. Blood 115(15):3109–3117, 2010. [PubMed: 20130243]

243.

Garber K: JAK2 inhibitors: Not the next imatinib but researchers see other possibilities. J Natl Cancer Inst 101(14):980–982, 2009. [PubMed: 19584324]

244.

Mesa RA, Tefferi A: Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis. Expert Opin Emerg Drugs 14(3):471–479, 2009. [PubMed: 19552608]

245.

Kralovics R, Teo SS, Li S et al.: Acquisition of the V617F mutation of JAK2 is a late genetic event in a subset of patients with myeloproliferative disorders. Blood 108(4):1377–1380, 2006. [PubMed: 16675710]

246.

Plo I, Nakatake M, Malivert L et al.: JAK2 stimulates homologous recombination and genetic instability: Potential implication in the heterogeneity of myeloproliferative disorders. Blood 112(4):1402–1412, 2008. [PubMed: 18515659]

247.

Nguyen HM, Gotlib J: Insights into the molecular genetics of myeloproliferative neoplasms. Am Soc Clin Oncol Educ Book 411–418, 2012.

248.

Reuther GW: Recurring mutations in myeloproliferative neoplasms alter epigenetic regulation of gene expression. Am J Cancer Res 1(6):752–762, 2011. [PubMed: 22016825]

249.

Mascarenhas J, Roper N, Chaurasia P et al.: Epigenetic abnormalities in myeloproliferative neoplasms: A target for novel therapeutic strategies. Clin Epigenetics 2(2):197–212, 2011. [PubMed: 22704337]

250.

Skov V, Larsen TS, Thomassen M et al.: Increased gene expression of histone deacetylases in patients with Philadelphia-negative chronic myeloproliferative neoplasms. Leuk Lymphoma 53(1):123–129, 2012. [PubMed: 21806350]

251.

Guerini V, Barbui V, Spinelli O et al.: The histone deacetylase inhibitor ITF2357 selectively targets cells bearing mutated JAK2(V617F). Leukemia 22(4):740–747, 2008. [PubMed: 18079739]

252.

Amaru Calzada A, Todoerti K, Donadoni L et al.: The HDAC inhibitor Givinostat modulates the hematopoietic transcription factors NFE2 and C-MYB in JAK2(V617F) myeloproliferative neoplasm cells. Exp Hematol 40(8):634–645 e10, 2012. [PubMed: 22579713]

253.

Andersen CL, McMullin MF, Ejerblad E et al.: A phase II study of vorinostat (MK-0683) in patients with polycythaemia vera and essential thrombocythaemia. Br J Haematol 162(4):498–508, 2013. [PubMed: 23758082]

254.

Rambaldi A, Dellacasa CM, Finazzi G et al.: A pilot study of the histone-deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms. Br J Haematol 150(4):446–455, 2010. [PubMed: 20560970]

255.

Hoffman R, Prchal JT, Samuelson S et al.: Philadelphia chromosome-negative myeloproliferative disorders: Biology and treatment. Biol Blood Marrow Transplant 13(1 Suppl 1):64–72, 2007. [PubMed: 17222772]

256.

Rosenthal DS: Clinical aspects of chronic myeloproliferative diseases. Am J Med Sci 304(2):109–124, 1992. [PubMed: 1503110]

257.

Tefferi A, Mesa RA, Nagorney DM et al.: Splenectomy in myelofibrosis with myeloid metaplasia: A single-institution experience with 223 patients. Blood 95(7):2226–2233, 2000. [PubMed: 10733489]

258.

Devine SM, Hoffman R, Verma A et al.: Allogeneic blood cell transplantation following reduced-intensity conditioning is effective therapy for older patients with myelofibrosis with myeloid metaplasia. Blood 99(6):2255–2258, 2002. [PubMed: 11877308]

259.

Anderson JE, Sale G, Appelbaum FR et al.: Allogeneic marrow transplantation for primary myelofibrosis and myelofibrosis secondary to polycythaemia vera or essential thrombocytosis. Br J Haematol 98(4):1010–1016, 1997. [PubMed: 9326205]

260.

Lussana F, Rambaldi A, Finazzi MC et al.: Allogeneic hematopoietic stem cell transplantation in patients with polycythemia vera or essential thrombocythemia transformed to myelofibrosis or acute myeloid leukemia: A report from the MPN Subcommittee of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Haematologica 99(5):916–921, 2014. [PubMed: 24389309]

261.

Camos M, Cervantes F, Montoto S et al.: Acute lymphoid leukemia following polycythemia vera. Leuk Lymphoma 32(3–4):395–398, 1999. [PubMed: 10037041]

262.

Higuchi T, Oba R, Endo M et al.: Transition of polycythemia vera to chronic neutrophilic leukemia. Leuk Lymphoma 33(1–2):203–206, 1999. [PubMed: 10194140]

263.

Shariff F, Harrison C: Polycythemia vera: Can we do better? Expert Opin Pharmacother 14(6):687–689, 2013. [PubMed: 23496342]

264.

Hensley B, Geyer H, Mesa R: Polycythemia vera: Current pharmacotherapy and future directions. Expert Opin Pharmacother 14(5):609–617, 2013. [PubMed: 23480062]

265.

Passamonti F, Malabarba L, Orlandi E et al.: Polycythemia vera in young patients: A study on the long-term risk of thrombosis, myelofibrosis and leukemia. Haematologica 88(1):13–18, 2003. [PubMed: 12551821]

266.

Rozman C, Giralt M, Feliu E et al.: Life expectancy of patients with chronic nonleukemic myeloproliferative disorders. Cancer 67(10):2658–2663, 1991. [PubMed: 2015567]

Pop-up div Successfully Displayed

This div only appears when the trigger link is hovered over. Otherwise it is hidden from view.

Send Email

Jump to a Section

JAK2V617F MUTATION

OTHER MUTATIONS

AUTOIMMUNITY AND CHRONIC INFLAMMATION

SIGNS AND SYMPTOMS

Thrombosis and Hemorrhage

Cutaneous Findings

Erythromelalgia

Figure 84–1.

Abdominal Findings

Cardiovascular Findings

Pulmonary Hypertension

Neurologic Findings

Findings in Other Organ Systems

SPECIAL CONSIDERATIONS

Surgery

Pregnancy

SPENT PHASE OF POLYCYTHEMIA VERA

Figure 84–2.

LEUKEMIC AND MYELODYSPLASTIC TRANSFORMATION OF POLYCYTHEMIA VERA

BLOOD FINDINGS

Erythrocytes

Red Cell Mass Determination

Leukocytes

Platelets

Plasma

JAK2V617F AND EXON 12 MUTATIONS

JAK2 G1849T Creating V617F

JAK2 Exon 12 Mutations

ERYTHROPOIETIN LEVELS

ERYTHROID COLONY CULTURES

MARROW FINDINGS

CLONALITY IN FEMALE SUBJECTS USING ASSAYS EMPLOYING X-CHROMOSOME–BASED POLYMORPHISM

THE PLETHORIC PHASE

Myelosuppression

Phlebotomy

Symptomatic Therapy for Pruritus

JAK2 Inhibitors

Epigenetic Modulation

Summary of Therapeutic Approach

THE SPENT PHASE

Splenectomy

Hematopoietic Stem Cell Transplantation

Figure 84–3.

Pop-up div Successfully Displayed

JAK2^V617F MUTATION

JAK2^V617F AND EXON 12 MUTATIONS