Myeloproliferative neoplasms (MPNs) are a group of clonal myeloid cell–derived disorders characterized by myeloproliferation without dysplasia, bone marrow hypercellularity, and predisposition to thrombosis, hemorrhage, and bone marrow fibrosis. This chapter is focused on the “classical” Philadelphia chromosome–negative MPNs, polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).
The estimated incidence of PMF ranges from 0.8–2.1 per 100,000/year, PV 0.4–2.8 per 100,000/year, and ET 0.4–3.4 per 100,000/year.
The overall incidence of myelofibrosis (MF) is approximately the same in men and women. The prevalence of PV is slightly higher in men than women (male-to-female ratio, 1.8:1), and ET is more prevalent in women than men (male-to-female ratio, 1:2).
Most patients are diagnosed with MPNs after age 60; however, the diseases can occur at any age. Median age of diagnosis of PMF is 65 years; median age of diagnosis of ET is 56 years; and median age of diagnosis of PV is 61 years.
Etiology and Risk Factors
For most cases of MPN, the etiology is unknown.
MPNs are not thought to be inherited; however, some evidence suggests a genetic predisposition to developing MPN in general. A Swedish population-based study found that first-degree relatives of patients with MPN have a 5- to 7-fold increased risk of developing MPN. The 10-fold higher incidence of MPNs in Ashkenazi Jews also indicates a genetic predisposition. The JAK2 46/1 haplotype has been shown to predispose patients to developing JAK2V617F-positive MPN, and an association has been reported between a single nucleotide polymorphism in the TERT gene and risk of developing an MPN.
Exposure to high levels of radiation is a risk factor for developing an MPN. In addition, exposure to petrochemicals, such as benzene and toluene, has been associated with the development of PMF.
Signs and Symptoms
Many of the signs and symptoms of PV are associated with an increased blood viscosity and reduced blood flow. Patients often present with constitutional symptoms, such as headache, fatigue, dizziness, and sweating. Aquagenic pruritus is a common complaint. On physical examination, patients may have a ruddy complexion, and mild splenomegaly is common. Ocular migraine or erythromelalgia associated with erythrocytosis and thrombocytosis can also occur. Transient visual disturbances can be seen. as well.
Pathology and Laboratory Features
The primary feature of PV is an elevated red blood cell mass, reflected in part by elevated hemoglobin levels (> 18.5 g/dL for men or > 16.5 for women). Leukocytosis and thrombocytosis are not uncommon. Red blood cells usually appear normal on peripheral blood smear. Erythroid colony growth in vitro in the absence of exogenous erythropoietin is characteristic of PV.
Bone marrow is typically hypercellular due to myeloid hyperplasia and increased megakaryocytes. Megakaryocytes typically have normal morphology but are often found in clusters.
Some patients may have low-grade bone marrow fibrosis.
Other laboratory findings
Blood viscosity may be five to eight times greater than normal. Serum erythropoietin levels are low in most patients (> 85%). Hyperuricemia is often present. Iron deficiency may be present in some patients, causing low mean corpuscular volume.
Cytogenetic and Molecular Findings
The incidence of chromosomal abnormalities in patients with PV is less than 20%. The most common abnormalities include partial duplication of chromosome 1, trisomy 8 or 9, or deletion of 13q or 20q. While some evidence suggests that trisomy 1 and del(13q) may be correlated with transformation to MF, myelodysplastic syndromes, or acute myeloid leukemia, none of the abnormalities have been shown to be prognostic.
Nearly all patients with PV harbor a JAK2 mutation (95% of patients are positive for JAK2V617F and an additional 3% harbor mutations in JAK2 exon 12). Other mutations have also been identified in some patients (eg, TET2, ASXL2, LNK); however, their prognostic significance is unknown.
PV is diagnosed according to 2008 World Health Organization (WHO) criteria on the basis of clinical, histological, and molecular characteristics (Table 1). Major diagnostic criteria for PV include elevated hemoglobin and presence of a JAK2 mutation (either V617F or exon 12). The presence of a JAK2 mutation, along with elevated red blood cell mass (or abnormally high hemoglobin) and low erythropoietin levels, is strongly suggestive of PV.
Several studies have confirmed that age older than 60 and previous thrombosis are the main risk factors for thrombosis, the most common cause of death in patients with PV. The estimated 15-year cumulative risk of thrombosis is 27%, and the 15-year risks of transformation to either acute leukemia or MF are 7% and 6%, respectively.
Life expectancy for patients with PV is predicted to be slightly shorter than that of age- and gender-matched healthy individuals. The International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) developed a prognostic model that includes age (≥ 67 years: 5 points; 57–66 years: 2 points), leukocyte count (≥ 15 × 109/L: 1 point), and history of venous thrombosis (1 point) as independent predictors of poor prognosis. Patients with 0 points, defined as low risk, had a median survival of 28 years; patients with 1 to 2 points, defined as intermediate risk, had a median survival of 19 years; and patients with 3 or more points, defined as high risk, had median survival time of 11 years. Independent risk factors for shorter leukemia-free survival time are age > 61 years, abnormal karyotype, and leukocyte count ≥15 × 109/L. Bone marrow fibrosis in patients with PV may increase the risk of transformation to post-PV MF. However, the usefulness of these prognostic models awaits further validation in additional patient populations.
The current treatment approach for PV is focused on preventing thrombotic events and reducing constitutional symptoms (Table 2). In addition to treating the signs and symptoms of PV, cardiovascular risk factors should be aggressively managed when present.
Phlebotomy and low-dose aspirin
Phlebotomy to reduce the hematocrit to below 45% for men and below 42% for women is a safe and effective treatment indicated for all patients. Phlebotomy induces iron deficiency, which is thought to reduce hematopoiesis and has not been shown to be detrimental in the absence of anemia. Low-dose aspirin should also be administered to all patients to reduce the risk of thrombosis, unless aspirin is contraindicated.
Hydroxyurea. Hydroxyurea (HU) is the most widely used cytoreductive therapy for reducing blood counts in patients with PV and has not been proven to increase the risk of AML. However, up to 20% of patients can develop resistance to or be intolerant of HU.
Interferon-a. Interferon-a (IFN-a) is effective in suppressing erythrocytosis, reducing spleen size and alleviating pruritus in 80% to 90% of patients with PV. However, up to 50% of patients discontinue treatment due to side effects including flu-like symptoms, fatigue, and depression. More recently, pegylated forms of IFN-a have been shown to be equally as effective, but with fewer adverse effects. In some patients, pegylated IFN-a has been shown to significantly reduce the JAK2 allele burden, suggesting that it may suppress the malignant clone. A phase III randomized study comparing a longer-acting form of pegylated IFN-a (PEG-proline-IFN-a-2b) with HU in patients with PV is currently being conducted in Europe (Clinical.Trials.gov identifier: NCT01259856). IFN-a is currently recommended as a first-line therapy, as is HU, but is particularly useful in women of childbearing age.
Pipobroman, busulfan, and radioactive phosphorus. Pipobroman (Vercyte), busulfan (Busulfex), and radioactive phosphorus have been used as second-line agents for patients after failure of primary therapy with either HU or IFN-a. However, due to their potential leukemogenicity, they should generally be reserved for older patients with a short life expectancy.
JAK2 inhibitors. In December 2014, the oral JAK1/2 inhibitor ruxolitinib (Jakafi) was approved in the US by the Food and Drug Administration for treating patients with PV who have an inadequate response or cannot tolerate HU. In the pivotal phase III RESPONSE trial, which randomized patients to either ruxolitinib (at 10 mg bid) or best available therapy (BAT), 77% of patients in the ruxolitinib arm achieved hematocrit control without phlebotomy and/or ≥ 35% reduction in spleen volume at week 32, compared with only 1% of those in the BAT arm. Most patients had symptom improvement, and 49% had a ≥ 50% improvement in the MPN-Symptom Assessment Form (MPN-SAF) total symptom score, a validated measure of patient-reported symptoms. Anemia and thrombocytopenia were the main toxicities observed but these could be managed with dose reductions.
The main goal of treatment is to reduce symptoms and prevent thrombotic complications. A prospective randomized trial in 365 patients with PV (the CYTO-PV study) found that strict control of hematocrit levels significantly reduced the risk of death caused by cardiovascular risk factors or thrombotic events. Current guidelines ask treating physicians to aim to reduce and maintain the hematocrit at < 45% for men and 42% for women.
All patients should receive phlebotomy and low-dose ASA, unless contraindicated. Patients at high risk for thrombosis (those over 60 years of age or with a history of thrombosis) should receive cytoreductive therapy. Hydroxyurea is the currently preferred agent, although IFN-a can be considered, especially for younger patients or those who are pregnant. Patients who are resistant to or intolerant of HU should be treated with ruxolitinib. Patients who do not respond to treatment, experience toxicity, or relapse after receiving standard therapies should be considered for inclusion in clinical trials of novel targeted agents.
Signs and Symptoms
Some patients with essential thrombocythemia (ET) are asymptomatic and are diagnosed after abnormal findings on a routine blood count screening. In symptomatic patients, vasomotor symptoms can be seen in 30% to 40% of patients and often manifest as headache, lightheadedness, syncope, erythromelalgia, acral paresthesia, livedo reticularis, atypical chest pain, and transient visual disturbance. Up to 40% of patients have mild splenomegaly (< 5 cm), 30% to 40% have leukocytosis, and 10% to 20% have mild anemia. Thrombosis and hemorrhage are common complications that have been reported in 18% to 26% and 4% to 11% of patients, respectively. The risk of hemorrhage increases in patients with platelet counts > 1.5 × 109/L, due to acquired Von Willebrand factor deficiency. Constitutional symptoms are uncommon. Transformation to acute leukemia or MF is the most serious complication of ET. The estimated 15-year cumulative risk of transformation to acute leukemia is about 2%, while the 15-year cumulative risk of transformation to MF is about 9%.
Pathology and Laboratory Features
A primary feature of ET is elevated platelet counts (> 450 × 109/L). A markedly increased number of platelets are also seen on peripheral blood smear. Leukocytosis or, rarely, mild anemia may also be present.
Bone marrow biopsy typically shows slight hypercellularity, myeloid hyperplasia, and an increased number of large mature megakaryocytes with hyperlobulated nuclei. Fibrosis should not be present.
Cytogenetic and Molecular Findings
Karyotypic abnormalities in ET are uncommon (< 5% to 10% of cases). Trisomy 8 or 9, del(13q), and del(20q) are most common abnormalities.
Nearly 90% of patients with ET have mutations in one of three genes that drive the disease process. Approximately 50% to 60% of patients harbor the JAK2V617F mutation, while an additional 3% to 5% harbor a mutation in the gene for the thrombopoietin receptor (MPLW151L/K). Mutations in the CALR gene have been identified in 67% to 71% of ET cases that are both JAK2- and MPL-negative (25% of all ET cases).
ET is diagnosed according to 2008 WHO criteria on the basis of clinical, histological, and molecular characteristics (Table 1). The diagnosis of ET is one of exclusion. While major criteria include elevated platelets (≥ 450 × 109/L), exclusion of chronic myelogenous leukemia, PV, PMF, or myelodysplastic syndrome is required for proper diagnosis.
The survival duration of patients with ET overall is not significantly shorter than that of the healthy population. Thrombosis and hemorrhage are the most common disease-related complications. The main risk factors for thrombosis are age older than 60 years and a history of thrombosis. Platelet count has not been shown to correlate with risk of thrombosis.
Studies of a series of 891 patients published by the IWG-MRT reported a 6% incidence of major bleeding (0.79% of patients per year) and a 25% incidence of thrombosis (1.9% of patients per year). Arterial thrombosis (1.9% of patients per year) was more common than venous thrombosis (0.6% of patients per year). The International Prognostic Score of thrombosis in ET (IPSET-thrombosis) was recently proposed (Table 2). The prognostic score includes four risk factors: age ≥ 60 years, previous thrombosis, cardiovascular risk factors (diabetes, hypertension, smoking), and presence of the JAK2V617F mutation. Patients could be stratified into three risk categories with an annual risk of thrombosis ranging from 1.03% of patients per year to 3.56% of patients per year. A prognostic score predicting overall survival at diagnosis (IPSET) included age ≥ 60 years, leukocyte count ≥ 11 × 109/L, and prior thrombosis as independent risk factors for survival. Patients could be stratified into three risk groups with median survival ranging from 14.7 years (high risk) to > 25 years (low risk) (Table 2). While prognostic scoring systems need to be tested in prospective studies to determine their usefulness in clinical practice, the data suggest that patients with these risk factors should be monitored more closely.
Most patients with ET have a normal life expectancy and, therefore, the main goal of treatment is to prevent thromboembolic events. Antiplatelet therapy and cytoreductive therapy are the two major classes of drugs currently used to treat ET. A recommended treatment algorithm is summarized in Table 3.
Low-dose aspirin: Low-dose aspirin is safe and effective for reducing microvascular symptoms in most patients, but its role in reducing or preventing thrombotic events is unclear. The use of aspirin in patients with very high platelet counts (> 1,500 × 109/L) should be avoided due to an increased risk of bleeding caused by von Willebrand disease. Therefore, patients with very high platelet counts should be screened for von Willebrand disease and possibly considered for cytoreductive therapy to decrease bleeding risk.
Hydroxyurea. HU is the currently recommended first-line treatment for patients with high-risk ET (age > 60 years or history of thrombosis). It can also be considered for patients with platelet counts above 1,500 × 109/L, to reduce the risk of bleeding. HU has been shown to reduce platelet counts and significantly reduce the incidence of thrombosis compared with placebo.
Anagrelide. Recommended as a second-line treatment for patients with high-risk ET, anagrelide blocks megakaryocyte differentiation and proliferation. In a large, randomized study comparing anagrelide plus aspirin to HU plus aspirin (UK MRC PT-1), anagrelide plus aspirin was associated with increased rates of arterial thrombosis, serious hemorrhage, and transformation to MF. However, a more recent randomized study of anagrelide monotherapy vs HU monotherapy (ANAHYDRET) showed noninferiority of anagrelide to HU.
Interferon-alpha. Studies of conventional IFN-a in patients with ET have shown hematologic responses rates > 75%; however, up to 50% of patients discontinued treatment due to intolerable side effects. Pegylated IFN-a-2a has been shown to have a better toxicity profile than standard IFN-a, with neutropenia being the main adverse event in patients with ET. In a phase II study of pegylated IFN-a-2a in patients with ET, 76% of patients achieved a complete hematologic response (normalization of platelet counts in the absence of thromboembolic events), and 38% had reductions in JAK2 allele burden.
The main goal of therapy for patients with ET is prevention of thromboembolic events. However, because overall survival in ET is similar to that of the general population, overtreatment should be avoided. Low-dose aspirin can be safely used to treat microvascular symptoms in all patients unless contraindicated. HU is recommended as a frontline therapy to treat patients with high-risk ET (ie, those over 60 years of age or with a history of thrombosis), though recent data suggest that anagrelide may also be a good first-line treatment option. Pegylated IFN-a-2a should be reserved as a second-line therapy for those who are intolerant of or resistant to HU or for women who are pregnant or of childbearing potential.