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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
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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 leukocytosis172,173,174,175,176 and JAK2V617F 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 JAK2V617F mutational allele burden should be managed according to conventional criteria.
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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.
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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
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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
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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.
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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.
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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 JAK2V617F allele burden, and as of yet, the results have been conflicting.184,185,186,187 Interestingly, it has been suggested that the JAK2V617F allele burden in PV may be a reliable predictor of response to HU, and of the HU dose necessary to control the disease.188
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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.
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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.
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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 JAK2V617F 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
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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
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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
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In addition to clinical and hematologic responses, administration of IFN-α has led to a decrease in JAK2V617F allelic burden43,205,206 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
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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.
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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 JAK2V617F allelic burden in some.211,212,213,214,215 Using JAK2V617F 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 JAK2V617F allelic burden, and in 20 percent the JAK2V617F 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.
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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).
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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.
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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.
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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.
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A randomized study76,216 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
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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
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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
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Symptomatic Therapy for Pruritus
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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-α229,230,231 and the JAK2 inhibitors provide a generally effective treatment modality to alleviate pruritus.232,233
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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.
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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.
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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 JAK2V617F 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
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Despite the encouraging advances with JAK2 inhibitors, modulation of the JAK2 pathways may not be the sole optimal treatment for PV and other MPNs. JAK2V617F 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.
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Epigenetic Modulation
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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 JAK2V617F-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
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Summary of Therapeutic Approach
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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:
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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.
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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.
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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
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Hematopoietic Stem Cell Transplantation
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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