• Polycythemia vera (PV) should be considered when there is persistent elevation of hemoglobin (> 165 g/L in men and > 160 g/L in women) or hematocrit (> 49% in men and > 48% in women).
• JAK2V617F mutation testing and erythropoietin levels should be performed when PV is suspected.
• Bone marrow biopsy and aspiration may be necessary in some cases to confirm the diagnosis of PV and to distinguish PV from other myeloproliferative neoplasms (MPNs).
• PV is highly likely when JAK2V617F mutation is present and erythropoietin level is subnormal. When JAK2V617F mutation is seen with normal erythropoietin level, PV is possible; bone marrow biopsy is recommended to differentiate PV from other MPNs. When JAK2V617F is normal and erythropoietin is low, consider JAK2 exon 12 mutational analysis or alternative diagnosis of congenital polycythemia. Wildtype JAK2V617F with normal or high erythropoietin level makes PV very unlikely, and patients should be investigated for secondary causes of polycythemia.
• Investigations for secondary polycythemia that may be indicated include:
• Chest x-ray
• Pulse oximetry
• Arterial blood gas including carboxyhemoglobin and methemoglobin levels
• Kidney and liver function tests
• Abdominal imaging studies (ultrasound or computed tomography [CT] scan)
• Oxyhemoglobin dissociation curve
• Sleep studies
• All patients should be treated with phlebotomy and/or cytoreductive therapy with target hematocrit less than 45%.
• Low-dose aspirin1 (acetylsalicylic acid [ASA]) should be used in all patients without a contraindication.
• In high-risk patients with PV (age > 60 years and/or history of thrombosis), cytoreductive therapy should be used in combination with ASA.
• Alkylating agents should be avoided as cytoreductive therapy owing to the risk of acute leukemia.
• Conventional cardiovascular risk factors (diabetes, hypertension, hyperlipidemia) should be aggressively managed, and cigarette smoking should be discouraged.
• Thromboembolic events should be managed according to accepted management guidelines. Thromboprophylaxis should be used after surgery and in other high-risk situations.
1 Not U.S. Food and Drug Administration (FDA) approved for this indication.
Polycythemia vera is a clonal stem cell disorder characterized by an increase in red cell production independent of the stimulation by erythropoietin. PV is the most common of the chronic myeloproliferative neoplasms (MPNs), occurring in approximately 2 to 3 people per 100,000 annually. The median age at diagnosis is 70 years, and it is rare in patients younger than 40 years.
A mutation of the tyrosine kinase Janus kinase 2 (JAK2) is consistently found in PV. This sheds some light on the pathogenesis of the disease and is useful in the diagnosis of PV and other MPNs. A single acquired mutation (V617F) of the gene for the JH-2 domain of JAK2 can be found in 90% to 95% of patients with PV. The JH-2 domain functions to inhibit JAK2 activity. In normal erythropoiesis, binding of erythropoietin to its receptor lifts this inhibition and allows JAK2 stimulation of cell division and differentiation. In mutated JAK2, this inhibitory function is absent, leading to constitutive activity of the tyrosine kinase. This mutation is also present in about half of patients with essential thrombocytosis and primary myelofibrosis. The small number of patients with PV who are negative for the common JAK2V617F mutation have another functionally similar mutation within exon 12.
Many patients with PV are asymptomatic, and PV is diagnosed after the incidental finding of an elevated hemoglobin or hematocrit on routine complete blood count. Splenomegaly is present in 30% to 40% of patients. Up to half of patients experience nonspecific symptoms such as weight loss, sweating, headache, fatigue, epigastric discomfort, visual disturbances, and dizziness. Many of these symptoms are likely caused by decreased blood flow due to an increased blood viscosity from polycythemia.
Generalized pruritus is often described, often after a warm bath or shower (aquagenic pruritus). Although the cause of this is unknown, it is thought to be due to the degranulation of increased numbers of mast cells in the skin of patients, releasing histamine and other inflammatory mediators. However, the symptom responds poorly to antihistamines, and it does not always resolve with treatment of PV.
Venous and arterial thromboembolic events are a major cause of morbidity and mortality in PV. Thrombosis at presentation occurs in up to 40% of patients. Ischemic stroke, transient ischemic attack, and myocardial infarction are common, especially among elderly patients. These, along with deep venous thrombosis and pulmonary embolus, are the most common thrombotic events and often result in serious morbidity, disability, and even death. Thrombotic events that are considered unusual in the general population, such as Budd-Chiari syndrome; portal, mesenteric, and other abdominal vein thrombosis; and cerebral venous thrombosis, occur more commonly among patients with PV. The possibility of an underlying MPN should be considered when a patient presents with such an event.
PV can manifest with symptoms of peripheral vascular disease.
Patients with erythromelalgia describe a painful burning sensation of the hands and feet; pallor, erythema, or cyanosis of the extremities; and sometimes cutaneous ulceration. Erythromelalgia results from microvascular thrombosis and ischemia due to platelet activation and aggregation and responds well to platelet reduction and antiplatelet agents such as aspirin (ASA).1
Almost all patients with PV are iron deficient at diagnosis, even before the onset of therapeutic phlebotomy. Other manifestations of PV include acute gouty arthritis, peptic ulcer disease, erosive gastritis, and hypertension.
Diagnosis and Differential Diagnosis
The 2016 World Health Organization (WHO) diagnostic criteria for PV are shown in Box 1. The JAK2V617F mutation is present in about 95% of cases of PV. Erythropoietin level is decreased in more than 90% and is rarely elevated. Few patients with PV carry a mutation of exon 12 (~ 4%) of the JAK2 gene instead of the more common JAK2V617F mutation. A JAK2 mutation can also be found in about half of patients with essential thrombocytosis and primary myelofibrosis.
|2016 World Health Organization Diagnostic Criteria for Polycythemia Vera|
|Diagnosis requires three major criteria or first two major criteria and minor criterion.*
1. Hemoglobin > 165 g/L in men, 160 g/L in women,
Hematocrit > 49% in men, > 48% in women,
Other evidence of increased red cell volume†
2. Bone marrow biopsy: hypercellular for age with trilineage growth (panmyelosis)
3. Presence of JAK2V617F or JAK2 exon 12 mutation
1. Subnormal serum erythropoietin level
* Bone marrow biopsy may not be required in sustained erythrocytosis—hemoglobin > 185 g/L (hematocrit > 55.5%) in men or > 165 g/L (hematocrit > 49.5%) in women—if major criterion 3 and minor criterion are present.
† > 25% above mean normal predicted value.
Leukocytosis and thrombocytosis are present in the majority of cases of PV. Red cell mass is increased. A nuclear medicine study measuring red cell mass and plasma volume is rarely required with the availability of JAK2 testing, but it may be useful when relative polycythemia is suspected. Bone marrow biopsy and aspiration are not often needed for a diagnosis of PV but have been included as a major criterion within the revised WHO classification. Bone marrow examination can be important for diagnosing PV in the rare cases where JAK2 is negative and to differentiate PV from other JAK2- positive MPNs when the distinction cannot be made based on peripheral blood counts.
Erythrocytosis can occur as a result of a number of other conditions in the absence of PV (Box 2). A careful history and physical examination with selected investigations can usually distinguish PV from secondary polycythemia and relative polycythemia (see Current Diagnosis). In relative (apparent, spurious) polycythemia, there is usually only a modest increase in the hematocrit, because of a decrease in plasma volume rather than a true increase in red cell mass. Thrombocytosis, leukocytosis, and splenomegaly should be absent.
Causes include smoking, dehydration, and use of diuretics, and it is also described in middle-aged, obese, hypertensive men (Gaisböck syndrome).
|Differential Diagnosis of Polycythemia|
|Normal Red Cell Mass
Elevated Red Cell Mass
• Congenital EPO receptor mutations
• Chuvash polycythemia
• High-affinity hemoglobin
Appropriately elevated EPO (hypoxia driven)
• Chronic hypoxic lung disease
• Cardiac shunts or cyanotic heart disease
• Sleep apnea
• High altitude
• Chronic carbon monoxide poisoning
• Cigarette smoking
• Renal artery stenosis
Inappropriately elevated EPO
• Renal cell carcinoma
• Hepatocellular carcinoma
• Uterine fibroids
• EPO (Epogen) administration
• Androgens (testosterone)
• Kidney transplant
Abbreviation: EPO = erythropoietin.
Red cell mass can be elevated owing to increased stimulation of erythropoiesis by high levels of erythropoietin. Erythropoietin can be increased as an appropriate response to chronic hypoxia (sleep apnea, right-to-left cardiac shunts, chronic lung disease, high altitude, smoking, methemoglobinemia), and it can be inappropriately elevated owing to erythropoietin-secreting tumors (renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioma, uterine fibroids) or decreased kidney perfusion (renal artery stenosis). Familial causes of polycythemia include high-affinity hemoglobins, erythropoietin receptor mutations, and Chuvash polycythemia. Polycythemia occurs in 10% to 15% of patients following kidney transplantation, and this may be due to erythropoietin secretion by the native kidneys or increased sensitivity to erythropoietin. Polycythemia can be drug induced, such as with the use of performance-enhancing drugs (erythropoietin [Epogen], androgens) in athletes and testosterone replacement in men.
Patients with PV have a reduced life expectancy compared with the general population with a median survival of approximately 14 years, or 24 years if younger than age 60 at diagnosis.
Despite therapy, thrombosis remains an important cause of mortality. Cardiac disease, ischemic stroke, pulmonary embolus, and other thrombotic events account for 40% of deaths among patients with PV. Nonfatal thrombosis is common, occurring in almost 4% of patients annually. Age and a history of prior thromboembolic events are independent risk factors for thrombosis and can be used to predict a patient’s risk of future events (Box 3). Low-risk patients are younger than 60 years and have no history of thrombosis. They experience new events at a rate of 2% per year. For patients older than 60 years or with a past history of thrombosis, this rate is 5% annually, but it can be as high as 11% when both risk factors are present.
|Thrombotic Risk in Polycythemia Vera|
Age < 60 years and no history of thrombosis
Age ≥ 60 years and/or history of thrombosis
The contribution of other cardiovascular risk factors (smoking, diabetes, hypertension, hyperlipidemia) to thrombotic risk in PV has been studied, with inconclusive results. However, because these are major contributors to the development of cardiovascular disease in the general population, they should also be considered when assessing risk in patients with PV. Leukocytosis (white blood cell count > 15 × 109/L) has been associated with a higher risk of arterial thrombosis.
Conversely, the risk of major hemorrhage is low, with fatal bleeding responsible for less than 5% of all deaths. However, there is considerable excess mortality from malignancy, in particular transformation to a myelodysplastic syndrome, myelofibrosis, or acute leukemia. The rate of leukemic transformation is less than 10% at 20 years. Risk factors for leukemic transformation include advanced age, leukocytosis, and abnormal karyotype. Approximately 10% of patients transform to myelofibrosis (post-PV myelofibrosis). Risk factors for post-PV myelofibrosis include leukocytosis and JAK2V617F allele burden of greater than 50%.
The goals of treatment in PV are to lower the risk of thrombosis while minimizing toxicity. This is achieved by a combination of phlebotomy, aspirin,1 and hydroxyurea (Hydrea)1 or other cytoreductive agents.
The use of these therapies can be individualized based on a patient’s risk of developing future thromboembolic events. Risk stratification (Box 3) aims at identifying patients with PV at higher risk of thrombotic events who require cytoreductive therapy. Because cerebrovascular and cardiovascular disease are among the main causes of morbidity and mortality for these patients, careful attention should be paid to the management of conventional cardiovascular risk factors. Hypertension, diabetes, and hyperlipidemia should be controlled with standard measures based on current guidelines, and patients should be encouraged to stop smoking. As the hematocrit increases in PV, there is a dramatic increase in blood viscosity.
Phlebotomy is the fastest, most effective way to normalize a patient’s hematocrit, and it should be initiated immediately in those with newly diagnosed PV. Blood volume should be reduced as rapidly as possible. Usually, 500 mL of blood is removed every 1 or 2 days until the hematocrit is less than 45%. The frequency of phlebotomy or volume of blood removed can be decreased in elderly patients, those with cardiovascular disease, or others who do not tolerate this schedule. The optimal target in patients with PV is to maintain a hematocrit less than 45% to lower the risk of major thrombotic events and death from cardiovascular causes. Regular phlebotomy eventually results in iron deficiency, at which point most patients’ phlebotomy needs decrease dramatically. Iron replacement should be avoided.
Previous studies did not support the routine use of aspirin to prevent thrombosis in PV. However, high doses of aspirin were used in these early studies, resulting in excess bleeding in the treatment arm. The results of a recent large randomized trial show that low-dose aspirin (100 mg/day) reduces major thrombotic events (nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis). This was accomplished without an increase in bleeding risk. Although there was a trend suggesting more minor bleeding events in those receiving aspirin, the rates of major bleeding were identical for those receiving aspirin or placebo. The benefit from aspirin was seen even though this study included many low-risk patients without a prior history of thromboembolism. Low-dose aspirin (75–100 mg daily)1 should be started in all patients without a contraindication to the drug (history of bleeding or intolerance).
Because of the risk of bleeding from acquired von Willebrand disease that can occur with extreme thrombocytosis, aspirin should be held when platelets are more than 1500 × 109/L until the count can be lowered by cytoreduction.
Cytoreductive therapy is recommended for high-risk patients with PV (Box 3). Hydroxyurea (HU)1 is the cytoreductive agent most commonly used to treat PV. Hydroxyurea can safely control blood counts and decreases spleen size in PV and other MPNs. Randomized data are limited, but hydroxyurea also appears to reduce thrombotic complications. A starting dosage of 15 to 20 mg/kg daily (1000–1500 mg daily) is used. Occasional phlebotomy is still required to maintain hematocrit less than 45%, but the frequency usually decreases. Myelosuppression is the main toxicity. The lowest dosage that provides therapeutic effect should be used, and excess myelosuppression should be avoided. The dosage can be 1titrated to ensure that the white cell count remains higher than 3.0 × 109/L, neutrophils are higher than 2.0 × 109/L, and platelets are in the normal range.
Hydroxyurea has been associated with leg ulcers and other skin changes, especially after long-term use. There is growing evidence that hydroxyurea does not contribute to the excess rates of acute leukemia seen in PV; rates are no different than in those treated with phlebotomy alone. However, transformation is clearly associated with the use of other chemotherapeutic agents such as chlorambucil (Leukeran),1 busulfan (Myleran),1 and pipobroman (Vercyte),2 accounting for one third of the deaths among patients with PV treated with these agents. The use of these agents should be avoided.
Hydroxyurea resistance can occur in up to 11% of patients and is associated with increased risk of death. Both hydroxyurea resistance and intolerance are defined according to the European Leukemia Net (ELN) criteria.
Interferon-α2b (IFN-α2) (Intron A)1 is an alternative treatment option in the setting of hydroxyurea resistance and/or intolerance and often is considered in young patients with PV. IFN-αb is available in both short-acting and controlled-release (pegylated) formulations.
IFN-α is commonly administered subcutaneously with a starting dose of 3 million units daily, or pegylated IFN-α (Peg-Intron)1 is given at 45 to 90 µg weekly. Studies have shown its efficacy in controlling blood counts in addition to achieving complete hematologic and molecular responses. The inconvenience of its administration and its side effects including mood disturbances and flulike illness make it a less desirable therapy. Controlled studies are comparing hydroxyurea with pegylated forms of IFN-α. At present, both are first-line cytoreductive treatment options with recommendations that IFN-α be used in females with childbearing potential.
Ruxolitinib (Jakafi), a JAK1/2 inhibitor, was originally approved in patients with myelofibrosis, including myelofibrosis evolving from PV. There was a significant reduction in spleen size and constitutional symptoms in almost half of these patients. In the phase III RESPONSE trial, ruxolitinib illustrated its effectiveness in controlling hematocrit (< 45%), reducing spleen size (≥ 35%), and improving symptoms in patients with PV who had hydroxyurea intolerance or resistance, resulting in its approval as a second-line cytoreductive agent in PV. The most common side effects are anemia and thrombocytopenia.
Other Treatment Issues
Hyperuricemia is common in myeloproliferative neoplasms and occasionally results in kidney stones or gout. Allopurinol (Zyloprim) 300 mg daily can be used to reduce uric acid levels in patients with these complications. For those with intractable pruritus, several agents have been used with variable success. Some patients respond to aspirin,1 hydroxyurea, cimetidine (Tagamet),1 cyproheptadine (Periactin),1 and paroxetine (Paxil)1 20 mg daily. Both IFN-α1 and ruxolitinib have been successful in the majority of cases.
Less than 60% of pregnancies occurring in patients with PV are successful. First-trimester fetal loss is the most common complication, and third-trimester fetal loss, preterm birth, and intrauterine growth restriction are also common. Phlebotomy should be used to keep the hematocrit at less than 45%. Interferon-α2b1 is recommended for those requiring cytoreductive therapy during pregnancy; other cytoreductive agents are contraindicated owing to possible teratogenic effects. There is some evidence that the use of low-dose aspirin1 throughout pregnancy improves live birth rate. It is recommended that prophylactic low-molecular-weight heparin (LMWH) be used for 6 weeks postpartum.
Surgery in patients with PV has a high risk of both operative bleeding and postoperative thromboembolism. Elective surgeries should be delayed until cytoreductive measures and phlebotomy can be used to achieve good control of blood counts. Aspirin should be held for 1 week before surgery to reduce the risk of hemorrhage.
LMWH should be given after surgery to prevent deep venous thrombosis. Mechanical compression stockings are an option for patients with bleeding that prevents the use of anticoagulation. When thromboembolic events do occur, treatment should be according to current management guidelines. Venous thromboembolism is treated with LMWH and warfarin (Coumadin). Indefinite anticoagulation should be considered because of the high risk of recurrent events.
Low-dose aspirin is indicated in those with a history of arterial events such as stroke and myocardial infarction.
1. Arber D.A., Orazi A., Hasserjian R., et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405.
2. Barosi G., Birgegard G., Finazzi G., et al. A unified definition of clinical resistance and intolerance to hydroxycarbamide in polycythemia vera and primary myelofibrosis: Results of a European LeukemiaNet (ELN) consensus process. Br J Haematol. 2010;148:961–963.
3. Finazzi G., Caruso V., Marchioli R., et al. for the ECLAP Investigators: Acute leukemia in polycythemia vera: An analysis of 1638 patients enrolled in a prospective observational study. Blood. 2005;105(7):2664–2670.
4. Kiladjian J.J., Cassinat B., Chevret S., et al. Pegylated interferon- alfa-2a induces complete hematologic and molecular responses with low toxicity in polycythemia vera. Blood. 2008;112:3065–3072.
5. Landolfi R., Marchioli R., Kutti J., et al. Efficacy and safety of low-dose aspirin in polycythemia vera. N Engl J Med. 2004;350:114–124.
6. Marchioli R., Finazzi G., Landolfi R., et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. J Clin Oncol. 2005;23(10):2224–2232.
7. Marchioli R., Finazzi G., Specchia G., et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368:22–33.
8. Passamonti F. How I, treat polycythemia vera. Blood. 2012;120(2):275–284.
9. Passamonti F., Rumi E., Caramella M., et al. A dynamic prognostic model to predict survival in post-polycythemia vera myelofibrosis. Blood. 2008;111(7):3383–3387.
10. Quintas-Cardama A., Kantarjian H., Manshouri T., et al. Pegylated interferon alfa-2a yields high rates of hematologic. and molecular response in patients with advanced essential thrombocythemia and polycythemia vera. J Clin Oncol. 2009;27:5418–5424.
11. Vannucchi A.M., Kiladjian J.J., Griesshammer M., et al. Ruxolitinib versus standard therapy for the treatment of polycythemia vera. N Engl J Med. 2015;372:426–435.
12. Tefferi A., Barbui T. Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management. Am J Hematol. 2015;90(2):163–173.
13. Tefferi A., Rumi E., Finazzi G., et al. Survival and prognosis among 1545 patients with contemporary polycythemia vera: An international study. Leukemia. 2013;27:1874–1881.
14. Tefferi A., Guglielmelli P., Larson D.R., et al. Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014;124(16):2507–2513.
1 Not FDA approved for this indication.
1 Not FDA approved for this indication.
1 Not FDA approved for this indication.
1 Not FDA approved for this indication.
2 Not available in the United States.
1 Not FDA approved for this indication.
1 Not FDA approved for this indication.