INTRODUCTION — Polycythemia vera (PV) is one of the myeloproliferative neoplasms (MPN) (table 1), a group of hematopoietic stem cell-derived malignancies that are characterized by clonal proliferation of myeloid cells with variable degrees of morphologic maturity. PV is distinguished from other MPNs by the presence of an elevated red blood cell mass (ie, erythrocytosis), and is associated with an increased risk for thromboembolic events, leukemic transformation, and/or myelofibrosis. (See "Overview of the myeloproliferative neoplasms".)
Secondary polycythemia refers to erythrocytosis caused by hypoxia, other reasons for elevated serum erythropoietin (EPO; eg, renal artery stenosis, certain tumors), rare inherited conditions (eg, Chuvash polycythemia, congenital methemoglobinemia), and other causes (table 2).
This topic will review the prognosis and treatment of PV and secondary polycythemia.
Evaluation of the patient with erythrocytosis and clinical manifestations and diagnosis of PV are discussed separately. (See "Diagnostic approach to the patient with erythrocytosis/polycythemia" and "Clinical manifestations and diagnosis of polycythemia vera".)
GOALS OF CARE — Survival of patients with PV who receive contemporary treatment is typically decades-long, but symptoms (eg, pruritus, erythromelalgia, splenomegaly), complications (eg, venous or arterial thrombotic events), and hematologic transformation (eg, myelofibrosis, acute myeloid leukemia, myelodysplastic syndromes) cause significant morbidity and limit life expectancy. (See 'Prognosis' below.)
While not curative, modern therapy for PV can relieve symptoms and prolong survival. The goals of care are to reduce the risk of first and/or recurrent thrombosis, prevent bleeding events, ameliorate the symptom burden, and minimize the risk of evolution to post-PV myelofibrosis (MF) and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) [1].
While no drug has been shown to lower the risk of hematologic transformation to MF or AML/MDS, current treatment approaches generally avoid agents known to increase this risk.
PRETREATMENT EVALUATION — All patients with PV should have a complete history and physical examination that documents symptoms, signs, and laboratory studies that may alter prognosis or management strategy.
It is our practice to include an evaluation of the following:
●History of venous or arterial thrombosis
●Presence of symptoms including pruritus, erythromelalgia, fevers, sweats, weight loss, early satiety, fatigue, headaches, lightheadedness, visual disturbances, atypical chest pain, and paresthesias
●Assessment of cardiovascular risk factors, including hypertension, diabetes mellitus, abnormal lipids, obesity, and active tobacco use
●Clinical findings of bleeding or bruising and assessment of spleen and liver size by physical examination
●Laboratory studies, including a complete blood count with differential, review of the peripheral blood smear, chemistries with liver and renal function and electrolytes
●Peripheral blood should be tested for JAK2 V617F mutation and, if negative, for mutations of JAK2 exon 12
●Testing for acquired von Willebrand syndrome in patients with clinical evidence of bleeding or platelet counts >1 million/microL (see "Acquired von Willebrand syndrome", section on 'Laboratory testing')
●Bone marrow biopsy, including assessment of reticulin fibrosis, percent of CD34-positive cells, karyotype, and molecular genetics studies (if not previously performed on peripheral blood)
RISK STRATIFIED MANAGEMENT
Risk stratification — Management of PV is guided by a risk-adapted approach that is based on age (ie, ≤60 versus >60 years) and history of prior thrombosis. Patients who are ≤60 years old with no history of thrombosis are classified as low risk; all others are considered high risk.
The factors that determine risk-stratified management primarily reflect the risk of thrombotic events, which are the leading cause of preventable death in PV. As such, these and other factors also influence overall survival and contribute to other PV-associated complications, which are discussed in greater detail below. (See 'Prognosis' below.)
Additional features that may influence treatment decisions (eg, inadequate symptom control, cardiovascular risk factors, leukocytosis, arterial versus venous thrombosis, pregnancy) are discussed in more detail below.
All patients should be evaluated for their individual risk of complications of PV, including thrombosis and hematologic transformation (eg, post-PV myelofibrosis [MF] and acute myeloid leukemia/myelodysplastic syndrome [AML/MDS]), and counselled regarding therapeutic options for achieving control of red blood cell (RBC) mass, symptom management, and prevention of complications.
Treatment of PV can control symptoms, improve survival, and reduce the risk of thrombotic events. To date, no drug has been shown to lower the risk of hematologic transformation to MF or AML/MDS. (See 'Goals of care' above.)
Management of low-risk PV — Studies of PV have used various definitions of low-risk disease. We consider those patients who are ≤60 years old and have no history of thrombosis to have low-risk PV.
Management of this subgroup includes the following:
●Phlebotomy to maintain the hematocrit <45 percent
●Low-dose aspirin, unless there is a contraindication to its use
●Treatment of aspirin-refractory symptoms, as described below (see 'Management of refractory symptoms' below)
●Assessment and management of cardiovascular risk factors (eg, blood pressure control, weight loss, physical activity) and counselling to stop smoking
These general treatment principles apply to most patients with low-risk PV. Additional considerations in specific clinical scenarios (eg, older/infirm patients, pregnancy) are described below. (See 'Specific clinical scenarios' below.)
Most patients with low-risk PV do not need cytoreductive therapy, because the absolute level of risk reduction does not justify exposure to potential adverse events. (See 'Cytoreductive agents' below and 'Prognosis' below.)
Cytoreductive therapy is usually reserved for those low-risk patients with the following features:
●Uncontrolled PV-associated symptoms
●Progressive increase of leukocyte and/or platelet counts
●Symptomatic or progressive splenomegaly
●Poor tolerance of phlebotomy
Further details about the choice and administration of cytoreductive agents is provided below. (See 'Cytoreductive agents' below.)
Current treatment recommendations are derived from a decades-long series of studies by the Polycythemia Vera Study Group, European Organisation for Research and Treatment of Cancer, French Polycythemia Study Group trials, and ECLAP study, among others [2-11].
Therapeutic phlebotomy — Therapeutic phlebotomy is the mainstay of controlling RBC mass (ie, hematocrit control) in PV.
We recommend that the hematocrit be maintained at <45 percent in all patients with PV; some experts suggest hematocrit targets of <45 percent in men and <42 percent in women [1,2,12,13].
A standard one unit phlebotomy (500 mL) should reduce the hematocrit by 3 percentage points in a normal-sized adult (eg, from 46 to 43 percent). Patients should be encouraged to maintain hydration and avoid vigorous exercise within 24 hours of phlebotomy. Men may tolerate removal of 1.5 to 2 units per week, whereas some women, older adults, and those with low body mass (eg, <50 kg) or cardiopulmonary disease may only tolerate removal of 0.5 units per week (eg, 7 mL/kg). Since phlebotomy controls polycythemia by producing a state of absolute iron deficiency, iron supplementation should not be given.
A prospective trial randomly assigned 365 adults with PV to more intensive treatment (target hematocrit, <45 percent) versus less intensive treatment (target hematocrit, 45 to 50 percent); control of hematocrit could be achieved by phlebotomy, hydroxyurea, or both [2]. After a median follow-up of 31 months, compared with the more intensive therapy group, less intensive therapy was associated with the following [2]:
●Shorter time to death from cardiovascular causes or major thrombotic events (hazard ratio 3.9 [95% CI 1.5-10.5]), with such events reported in 10 percent of the less intensive therapy group and 3 percent in the more intensive treatment group.
●No difference in progression to MF, myelodysplasia, leukemic transformation, or bleeding.
Low-dose aspirin — Low-dose aspirin should be given to all patients with PV unless there is a specific contraindication. We offer low-dose aspirin (ie, 40 to 100 mg by mouth once or twice daily) as a safe and effective treatment for preventing thrombosis in PV [14] and for relieving microvascular symptoms.
An important exception to the use of low-dose aspirin in PV is patients with platelets >1 million/microL, who should be tested for acquired von Willebrand syndrome (aVWS) by directly measuring von Willebrand factor (VWF) activity. Aspirin should not be used in those patients with acquired von Willebrand disease. (See "Acquired von Willebrand syndrome", section on 'Laboratory testing'.)
The use of higher dose aspirin (eg, 900 mg/day) is discouraged because of an increased incidence of gastrointestinal hemorrhage when high-dose aspirin was used in combination with dipyridamole in patients with PV [3,15].
Examples of studies supporting the use of low-dose aspirin in PV include the following:
●The European Collaboration on Low-Dose Aspirin in Polycythemia Vera (ECLAP) trial randomly assigned >500 patients with PV to low-dose aspirin (100 mg daily) versus placebo [6]. Compared with those who received placebo, patients who were treated with aspirin experienced:
•Reduced risk of the combined endpoint of nonfatal myocardial infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis, or death from cardiovascular causes (relative risk, 0.40; 95% CI 0.18-0.91)
•No reduction in the combined endpoint of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes; overall mortality; or cardiovascular mortality
•No increase in the incidence of major bleeding episodes
●An Italian study that randomly assigned 112 patients with PV to either aspirin or placebo reported that aspirin was well tolerated, not associated with increased bleeding, and completely inhibited platelet cyclooxygenase activity [16]. Other studies have also shown that thromboxane synthesis is elevated in PV and is suppressible in vivo with low-dose aspirin [17,18].
Management of high-risk PV — Studies of PV have used variable definitions of high-risk disease. We consider patients who are >60 years old or have a history of thrombosis to be high risk.
Management of this subgroup includes the following:
●Phlebotomy to maintain the hematocrit <45 percent
●Treatment with low-dose aspirin, unless there is a contraindication to its use
●Cytoreductive therapy with hydroxyurea; interferon or busulfan are acceptable alternatives for select patients, as described below (see 'Choice of agent' below)
●Treatment of PV-associated symptoms, as described below (see 'Management of refractory symptoms' below)
●Assessment of cardiovascular risk factors (eg, blood pressure control, weight loss, physical activity) and counselling to stop smoking
●Additional management of specific clinical scenarios is described below (see 'Specific clinical scenarios' below)
Cytoreductive agents — Cytoreductive agents are part of the routine management of patients with high-risk features (ie, age >60 years and/or history of thrombosis), along with phlebotomy and low-dose aspirin therapy. In contrast, most patients with low-risk PV do not need cytoreductive therapy. For low-risk patients, cytoreductive therapy is usually reserved for those with uncontrolled PV-associated symptoms, progressively increasing leukocyte and/or platelet counts, symptomatic or progressive splenomegaly, or who tolerate phlebotomy poorly. (See 'Risk stratification' above.)
Treatment failure is defined as inadequate control of PV-associated symptoms or the inability of cytoreductive therapy to maintain hematocrit <45 percent (with or without ongoing phlebotomy) without causing severe cytopenias.
Choice of agent — Hydroxyurea (HU) is our preferred agent for initial cytoreductive therapy of PV. (See 'Hydroxyurea' below.)
We consider interferon (IFN) alfa or busulfan to be acceptable alternatives for select patients, as described below. Other experts consider HU and IFN to be equally acceptable therapies for initial cytoreductive therapy of patients with PV [1].
Because there are limited comparative efficacy data to guide the choice of initial cytoreductive therapy in PV, selection is influenced by convenience, cost, and toxicity profile, as well as the patient's age, potential fertility, and other factors. We prefer HU for most patients with PV, but we favor initial treatment with pegylated IFN alfa for younger patients (eg, <40 years) and those who might become pregnant, for reasons that are described below. This approach is consistent with that of the European LeukemiaNet (ELN) [1]. (See 'Pegylated interferon' below and 'Pregnancy' below.)
Hydroxyurea — Hydroxyurea (HU; hydroxycarbamide) is our preferred cytoreductive agent for initial treatment of PV because of its efficacy, ease of administration, lower cost, long-term safety data, and favorable toxicity profile. HU is an inhibitor of ribonucleotide reductase that interferes with DNA repair. It is effective at lowering platelet counts and reducing thrombotic risk in PV. For select patients, IFN or busulfan are acceptable alternatives to HU as first-line therapy of PV.
HU has been widely adopted as the initial treatment of PV despite a limited base of evidence. Most data for use of HU in PV are extrapolated from randomized trials in essential thrombocythemia. (See "Prognosis and treatment of essential thrombocythemia", section on 'Cytoreductive therapies'.)
Studies that examined efficacy of HU in PV include:
●A study by the Polycythemia Vera Study Group that reported fewer thrombotic events (10 versus 33 percent, respectively) in 51 patients treated with HU compared with 134 historical controls treated with phlebotomy alone [19].
●Two European studies that randomly assigned a total of nearly 600 patients to HU versus the alkylating agent, pipobroman, and reported no significant difference in thrombotic events, but higher rates of leukemic transformation with pipobroman [7,20].
The recommended initial dose of HU is 15 mg/kg per day by mouth (eg, 500 mg twice daily) (table 3). Since it takes at least three to five days for the effect of HU to be seen, dose adjustments should not be made more frequently than once per week. The dose should be adjusted to achieve a platelet count between 100,000 to 400,000/microL, and to limit neutropenia and anemia. Dosing should be based on the patient's actual body weight, and should be reduced in the setting of renal impairment, but does not require adjustment for liver impairment.
Adverse events associated with HU include cytopenias, mucocutaneous ulcers, diarrhea, peripheral neuropathy, skin cancer, potential teratogenicity, and rare cases of severe (including fatal) pulmonary toxicity [21]. Macrocytosis/Megaloblastic erythrocytosis is expected because of its mechanism of action.
Approximately 10 percent of patients develop resistance to HU, based on ELN criteria [22]. Treatment failure is defined as an inability of cytoreductive therapy to maintain hematocrit <45 percent (with or without the need for ongoing phlebotomy) without causing severe cytopenias, or inadequate control of PV-associated symptoms. (See 'Response assessment' below.)
Single-agent HU is not associated with an increased risk of hematologic complications (eg, leukemic transformation, myelofibrosis) in PV. Examples of studies that have addressed the question of potential leukemogenicity of HU include the following:
●An international study of 1545 patients with PV reported that treatment with single-agent HU was not associated with an increased risk of leukemic transformation after a median observation period of 6.9 years, in multivariate analysis [23].
●Reports of the incidence of leukemic transformation in patients treated with HU have ranged from 1 to 17 percent, with the lower values generally obtained at shorter follow-up times [7,19,20,24-30].
●Several studies have suggested leukemia risk rates approaching 30 percent when HU is combined with other agents [8,30-33].
Management of refractory symptoms — Most patients with PV will develop symptoms including pruritus, erythromelalgia, bleeding, or hyperuricemia/gout [34,35]. For many patients, symptoms are fully controlled with low-dose daily aspirin; some patients who fail to achieve adequate control of pruritus or erythromelalgia may respond to twice daily treatment with low-dose aspirin.
For symptomatic patients with PV who have continued symptoms despite low-dose aspirin therapy, additional adjunctive measures (described below) and/or cytoreductive therapy may be beneficial.
We offer ruxolitinib only to patients with PV whose troublesome splenomegaly or symptoms (eg, pain, impaired appetite) are refractory to HU, IFN, or busulfan. (See 'Other agents' below.)
●Severe pruritus – Pruritus occurs in the majority of patients with PV, and is often exacerbated by bathing (so-called aquagenic pruritus), especially with hot water [36]. Symptom management should begin with simple measures such as avoidance of precipitating exposures (eg, attention to temperature of the environment and the water used for bathing; adding laundry starch to bath water; drying the skin by patting, rather than rubbing), moisturizing cream, and antihistamines. General approaches to the management of pruritus are provided separately. (See "Pruritus: Therapies for localized pruritus".)
Low-dose aspirin is generally effective for alleviating pruritus and other symptoms associated with PV. In the setting of symptoms that are resistant to low-dose aspirin, addition of alternative antiplatelet agents (clopidogrel 75 mg per day) may be effective.
Among cytoreductive agents, the most effective for PV-associated pruritus may be ruxolitinib [37]. Other potential treatments include HU, interferon alfa, and narrowband UVB phototherapy [38,39].
●Erythromelalgia – Erythromelalgia is a pathognomonic microvascular complication of PV (or essential thrombocythemia), and refers to a burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis (picture 1). (See "Clinical manifestations and diagnosis of polycythemia vera", section on 'Erythromelalgia'.)
Erythromelalgia typically responds well to low-dose aspirin [17]. Erythromelalgia that is unresponsive to aspirin should be treated with cytoreductive agents [17,40,41]. (See 'Low-dose aspirin' above and 'Cytoreductive agents' above.)
●Bleeding – Extraneous causes for bleeding (eg, use of high-dose aspirin, antiplatelet agents, anticoagulants) should be stopped. Patients with platelet counts >1 million/microL should be evaluated for acquired von Willebrand syndrome (aVWS), and aspirin should not be administered if acquired von Willebrand disease is identified. (See 'Bleeding' below.)
●Gout and/or hyperuricemia – Treatment of acute gout, hyperuricemia, or excessive excretion of uric acid is discussed separately. (See "Treatment of gout flares" and "Asymptomatic hyperuricemia" and "Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout".)
Treatment of PV refractory to initial cytoreductive therapy
Choice of therapy — HU is our preferred agent for initial cytoreductive therapy of PV, as described above. (See 'Hydroxyurea' above.)
Pegylated IFN or busulfan are acceptable alternatives for patients with PV who are intolerant of HU or fail to achieve adequate control of symptoms or hematocrit with HU.
We consider ruxolitinib or pacritinib acceptable for PV only in the specific settings described below. (See 'Other agents' below.)
For patients who are intolerant or refractory to initial therapy with IFN, acceptable alternatives include HU or busulfan.
Pegylated interferon — Interferon (IFN) alpha is a naturally occurring biologic response modifier that has anti-angiogenic, anti-proliferative, pro-apoptotic, immunomodulatory, and differentiating properties [42,43]. IFN alfa is a pharmaceutical product obtained from human leukocytes that contains several naturally occurring subtypes of IFN alpha; in some countries IFN alfa is referred to as IFN alpha. Pegylated interferon alfa-2a (ropeginterferon) provides a more favorable toxicity profile than conventional IFN alfa, and its prolonged activity is compatible with once weekly dosing [44-46].
Pegylated IFN alfa is an acceptable alternative to HU for initial cytoreductive treatment of PV in select patients. For younger patients with PV (eg, <40 years) and in those who might become pregnant, we favor initial therapy with IFN rather than HU; reasons for this preference include the possibility of achieving cytogenetic remission with IFN, and the teratogenicity of HU. This suggestion is consistent with that of the ELN [1]. IFN is more expensive and is generally less well tolerated than HU. Up to one-third of patients have discontinued IFN alfa therapy because of side effects such as fever, malaise, nausea, and vomiting [43,47-49].
IFN achieves control of erythrocytosis, reduction of spleen size, and relief from intractable pruritus in approximately 80 percent of patients with PV [47,50-53]. Results from nonrandomized long-term studies suggest that IFN may provide better control of splenomegaly, thrombocytosis, pruritus, and thrombohemorrhagic complications than phlebotomy alone or phlebotomy plus HU [43,54,55]. A potential advantage of IFN is its ability to suppress clonal hematopoiesis and reports of molecular remissions in PV, although the relevance of remissions to disease outcomes, and long-term rates of thrombotic events and mortality with IFN treatment are currently uncertain [9,56-61].
●Administration
•Ropeginterferon:
-For patients not already on hydroxyurea (HU) – Ropeginterferon is started at 100 mcg subcutaneously once every two weeks, and the dose is increased by 50 mcg every two weeks to a maximum of 500 mcg, until hematologic parameters are stabilized (ie, hematocrit <45 percent, platelets <400,000/microL, and leukocytes <10,000/microL).
The two-week dosing interval should be maintained for at least one year. After one year of hematologic stability on a stable dose, the dosing interval may be increased to once every four weeks.
-For patients transitioning from HU – Ropeginterferon is started at 50 mcg subcutaneously once every two weeks (in combination with HU) and the dose is increased by 50 mcg every two weeks to a maximum of 500 mcg, until hematologic parameters are stabilized (as above). Gradually taper the total biweekly HU dose by 20 to 40 percent every two weeks during weeks 3 to 12 and discontinue HU by week 13.
Duration and intervals of treatment are as above.
•IFN alfa: If ropeginterferon is not available, the usual starting dose of IFN alfa is 3 million units subcutaneously three times per week.
●Outcomes
•In a phase 2 study of pegylated IFN alfa-2a, 35 of 37 evaluable patients achieved complete hematologic remission and 7 of those 35 patients achieved molecular complete remission (ie, undetectable JAK2 V617F) [9]. Responses were durable, and 35 patients remained in complete hematologic remission at one year. Only three patients stopped treatment during the first year because of side effects.
•Similar results were achieved in a second study in 43 patients with advanced PV [59,62]. The planned dose (450 mcg/week) was poorly tolerated. Most patients with PV were controlled on 45 to 90 mcg/week with grade 1 or 2 toxicity. At a median follow-up of 42 months, the complete hematologic response rate was 76 percent, while the complete molecular response rate was 19 percent.
•A multicenter study that included 50 patients with PV that was refractory to HU reported 60 percent overall response rate (22 percent complete response) at 12 months to pegylated IFN alfa-2a [63]. Grade ≥3 toxicity included cytopenias, myalgia/arthralgia, depression, dyspnea, and headache (all of which were reported in <10 percent of patients); adverse events led to discontinuation of therapy in 14 percent.
A prospective, randomized evaluation of pegylated IFN alfa versus HU in PV and essential thrombocythemia is ongoing (NCT01259856) [64].
Ropeginterferon is approved by the US Food and Drug Administration (FDA) for treatment of adults with polycythemia vera.
Busulfan — Busulfan is an alkylating agent that is an acceptable second-line agent for PV, but data regarding its efficacy and toxicity are limited [1].
Busulfan has been used for decades in the treatment of PV, but it fell out of favor because of associations with long-lasting cytopenias, marrow aplasia, skin pigmentation, pulmonary fibrosis, and/or leukemia [5,65-68]. However, it appears that busulfan is leukemogenic only when used in combination with other agents, and not when used alone [23]. Furthermore, long-lasting cytopenias may be lessened by use of lower doses given for shorter periods of time.
Use of busulfan is best reserved for older patients (especially those ≥60 years) who require myelosuppression but have failed treatment with other agents (eg, HU, IFN). A reasonable starting dose is 2 to 4 mg/day, with adjustments made based on weekly monitoring of complete blood counts; the dose is reduced to 2 mg/day for a platelet count <200,000/microL or a white blood cell count <5000/microL, and is temporarily withheld for counts <100,000/microL and <3000/microL, respectively [69].
Other agents — Other agents that may be considered for patients with PV that failed to respond adequately to first-line therapy include ruxolitinib, anagrelide, pipobroman, and radioactive phosphorus (32P). None is appropriate as a first-line treatment for PV, but some are included among options by the ELN [1]. 32P is not available in the United States.
Examples of other agents that may be considered for refractory PV include:
●Ruxolitinib – Ruxolitinib is an inhibitor of Janus associated kinases (JAKs) that is approved by the US FDA for treatment of PV in HU-resistant or HU-intolerant patients, and is approved by the European Medicines Agency for post-PV myelofibrosis.
We suggest treatment of PV with HU, IFN, or busulfan rather than ruxolitinib because of their known efficacy, toxicities, and long-term effects.
We offer ruxolitinib to patients with PV only in the following settings:
•Markedly symptomatic splenomegaly that failed to respond to HU, IFN, or busulfan
•Severe, protracted pruritus that failed to respond to IFN and other measures
•Post-PV myelofibrosis with indications that are expected to be improved by ruxolitinib therapy
Long-term effects of ruxolitinib in PV are uncertain, and there is no evidence that it reduces the malignant clone (measured by the allele frequency of JAK2 V617F in the bone marrow) or alters the natural history of PV (ie, leukemic transformation, myelofibrosis).
Use of ruxolitinib in patients with myelofibrosis is discussed in detail separately. (See "Management of primary myelofibrosis", section on 'Ruxolitinib'.)
Ruxolitinib is orally administered at doses up to 20 mg twice daily, and dosing is adjusted for efficacy and tolerance. Dose adjustments are required for impaired renal and hepatic function, and for patients taking strong inhibitors of CYP3A4 (table 4).
Adverse effects include cytopenias; dizziness, headache, and fatigue (in approximately 15 percent of patients); bruising; elevated serum cholesterol; and viral, bacterial, mycobacterial, and fungal infections.
Discontinuation of ruxolitinib can be associated with a relapse of disease symptoms and/or clinical findings (eg, fever, hypotension, hypoxia) suggestive of systemic inflammatory response syndrome that may require resumption of ruxolitinib and other medical management. Patients should be counseled about the ruxolitinib withdrawal syndrome before starting on therapy. (See "Management of primary myelofibrosis", section on 'Ruxolitinib'.)
An open-label trial (RESPONSE) evaluated ruxolitinib in 222 patients with PV who were either resistant (46 percent) or intolerant to HU (54 percent) [70,71]. Patients were randomly assigned to receive ruxolitinib (10 mg twice daily) or best available therapy (BAT), which included HU, IFN alfa or pegylated IFN alfa, anagrelide, other therapy, or observation. An important limitation of this trial was the widespread use of HU for those assigned to BAT, despite documented resistance or intolerance to this agent. Other concerns include the choice of clinical endpoints rather than the major goals of therapy (ie, reduction of thrombotic complications, myelofibrosis, and disease transformation), and the open-label design (which might affect subjective measures of symptom assessment).
When compared with BAT, ruxolitinib resulted in:
•Improvement in the primary endpoint of combined phlebotomy independence and reduction in spleen size (21 versus 1 percent, respectively)
•Fewer patients requiring phlebotomy (20 versus 62 percent, respectively) and fewer patients requiring ≥2 phlebotomy sessions (7 versus 34 percent, respectively)
•Greater reduction in splenomegaly (38 versus 1 percent, respectively)
•Greater control of PV symptoms, including fatigue, itching, night sweats (49 versus 5 percent, respectively)
•Fewer thromboembolic events in the first 32 weeks (one versus six events)
A preplanned analysis reported outcomes once all patients had completed 80 weeks of therapy or discontinued treatment [71]. The majority of patients assigned to ruxolitinib remained on therapy (83 percent); none of the patients assigned to BAT remained on that therapy and 88 percent crossed over to ruxolitinib. The majority of responses with ruxolitinib were durable (92 percent for primary response and 89 percent for hematocrit control).
Ruxolitinib was associated with an increased rate of herpes zoster infection (5.3 per 100 patient-years of exposure versus none) and nonmelanoma skin cancer (4.4 versus 2.7 cases per 100 patient-years of exposure) [71]. Estimated rates of long-term PV-associated complications did not appear to be increased, but the number of events was small.
●Pacritinib – Pacritinib is a kinase inhibitor that is approved by the US FDA for treatment of post-polycythemia myelofibrosis with a platelet count <50,000/microL [72].
●Anagrelide – Anagrelide is approved for use in essential thrombocythemia, where it can reduce the platelet count. It is not suggested for treatment of PV because its use is associated with an increased risk of arterial thrombosis, major bleeding, and fibrotic progression [73]. (See "Prognosis and treatment of essential thrombocythemia", section on 'Anagrelide'.)
●Pipobroman – Pipobroman is an alkylating agent that is available in Europe. In a French study, 292 patients with PV under the age of 65 were randomly assigned to treatment with HU or pipobroman [7]. At a median follow-up of 16.3 years, treatment with pipobroman resulted in shorter median survival (15 versus 20 years) and a doubling of the incidence of transformation to AML/MDS [20].
RESPONSE ASSESSMENT — Response to therapy should be monitored by following blood counts and assessing symptoms and signs of disease. This assessment includes periodic clinical evaluation and monitoring of complete blood count, as guided by the patient's clinical status and the nature of treatment. There is no need to routinely monitor bone marrow or molecular response (eg, sequential assessment of the JAK2 V617F allele burden) for clinical follow up, unless findings from clinical assessment, complete blood count, or other findings suggest a change in the underlying disease process.
Response criteria that were developed for clinical trials (eg, European LeukemiaNet and International Working Group – Myeloproliferative Neoplasms Research and Treatment) [22] are applicable to the clinical management of PV, as follows:
●Complete response (CR):
•Resolution of disease signs and improved symptoms (10-point decrease in the MPN-SAF TSS) for at least 12 weeks
•Normalization of peripheral blood counts (white blood cell count ≤10,000/microL, platelets ≤400,000/microL, hematocrit <45 without phlebotomy) for at least 12 weeks
•Absence of vascular events and disease progression
•Disappearance of bone marrow histological abnormalities
●Partial response (PR):
•The first three criteria of CR are achieved in the absence of bone marrow histologic remission
Molecular complete remission (ie, clearance of JAK2 V617F clone) is not incorporated into this definition of remission.
SPECIFIC CLINICAL SCENARIOS — The goals of therapy in PV are to prevent thrombohemorrhagic complications, control vasomotor symptoms, and avoid treatments that are associated with increased risk of transformation to myelofibrosis and/or acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). (See 'Goals of care' above.)
Thrombotic complications — Thromboembolic events are the major cause of morbidity and mortality in PV. (See 'Thrombotic events' below.)
Patients with PV and venous thrombotic events should be treated with appropriate doses and intensity of anticoagulation, but there are no randomized studies that have examined the optimal duration of anticoagulation in a patient with PV and a first episode of venous thromboembolism [74-76]. General management of venous thromboembolism is discussed separately. (See "Venous thromboembolism: Initiation of anticoagulation" and "Venous thromboembolism: Anticoagulation after initial management".)
Patients with PV and arterial thrombotic events (eg, cerebrovascular accidents, myocardial infarction, limb ischemia) should be treated as described separately. (See "Initial assessment and management of acute stroke" and "Initial evaluation and management of suspected acute coronary syndrome (myocardial infarction, unstable angina) in the emergency department".)
Prevention of thrombotic complications includes phlebotomy to maintain hematocrit <45 percent, low-dose aspirin (unless there is a contraindication to its use), and/or cytoreductive agents (based on risk stratification). (See 'Risk stratification' above and 'Risk stratified management' above.)
Bleeding — Bleeding is commonly seen in PV, but major bleeding episodes are relatively rare. Such episodes may be associated with excessively high platelet counts, the use of aspirin in doses greater than 100 mg/day and/or the use of anticoagulants or antiplatelet agents [76].
Extreme thrombocytosis/acquired von Willebrand syndrome — Acquired von Willebrand syndrome (aVWS) may be present in some patients with PV and platelet counts >1 million/microL, likely due to increased binding of large von Willebrand factor multimers to platelets and their consequent removal from the plasma. Such patients may have increased bleeding, especially when treated with aspirin. Cytoreduction usually corrects both the clinical and laboratory abnormalities. (See "Diagnosis and clinical manifestations of essential thrombocythemia", section on 'Thrombosis and hemorrhage' and "Acquired von Willebrand syndrome" and "Pathophysiology of von Willebrand disease", section on 'Causes of reduced VWF in acquired VWS'.)
Aspirin should not be used in the setting of aVWS.
Post-PV myelofibrosis — Progression to myelofibrosis (MF) is one of the most common complications of PV.
Treatment of patients who develop post-PV MF is similar to that of patients with primary MF and is discussed separately. (See "Management of primary myelofibrosis".)
Transformation to myelodysplasia or acute leukemia — Prognosis of patients who develop post-PV secondary to MDS or AML is generally poor. Treatment is similar to that of patients with primary MDS or AML, and is discussed separately. (See "Acute myeloid leukemia: Management of medically-unfit adults" and "Therapy-related myeloid neoplasms: Epidemiology, causes, evaluation, and diagnosis" and "Overview of the treatment of myelodysplastic syndromes".)
In one study in 21 patients with PV who developed MDS or AML and were treated with palliative chemotherapy (azacitidine, initial dose: 75 mg/m2/day subcutaneously for 7 days every 28 days), the overall response rate was 33 percent, with a median survival of only seven months from the onset of treatment with this agent [77]. The best survival has been found in those who have attained complete remission following chemotherapy and received subsequent allogeneic hematopoietic cell transplantation. (See "Overview of the myeloproliferative neoplasms", section on 'Treatment of MPN-associated acute leukemia'.)
Elderly/Infirm patients — For patients of advanced age and/or limited life expectancy, the risk of thrombosis greatly exceeds the risk of hematologic transformation to MF or AML/MDS. The relative ease of treatment with alkylating agents makes them acceptable agents in older (eg, >80 years), or infirm patients for whom the risk of thrombosis greatly outweighs that of transformation.
Pregnancy — There is an increased risk of miscarriages and other complications of pregnancy (eg, abruptio placentae, pre-eclampsia, intrauterine growth retardation) in patients with PV and other myeloproliferative neoplasms [78-80]. However, there are only limited data regarding the occurrence and outcomes of pregnancy in PV patients, and we do not consider pregnancy to be contraindicated in women with PV. A meta-analysis that included women with PV reported that aspirin and interferon are associated with reduced rates of pregnancy loss [81], as described separately. (See "Prognosis and treatment of essential thrombocythemia", section on 'Pregnant women or those who desire to become pregnant'.)
Patients should be closely monitored for pregnancy-induced hypertension.
Pregnancy is associated with an increase in plasma volume, and an expanded red cell mass may be masked by an apparently normal hematocrit in some pregnant patients with PV [82]. The European LeukemiaNet has suggested that the target hematocrit in the pregnant woman with PV should be either <45 percent or the normal midgestation hematocrit range, whichever is lower [1]. Low-dose aspirin should be administered.
Interferon alfa is the preferred cytoreductive agent in pregnant women with PV and in those of childbearing potential because of the potential teratogenicity of hydroxyurea, ruxolitinib, and alkylating agents [83].
We do not recommend the use of low molecular weight heparin (LMWH) in pregnant women with PV unless there is evidence for active thrombosis. However, some experts suggest the use of LMWH throughout pregnancy for women with a previous major thrombotic complication of PV, and prophylactic LMWH for the first six weeks following delivery for low-risk pregnant women with PV [1,12,84]. There are no data confirming the safety and utility of these prophylactic approaches in pregnant women with PV.
PROGNOSIS — PV is associated with reduced overall survival, an increased incidence of thromboembolic events, and various hematologic complications.
Survival — Median survival of untreated symptomatic patients with PV has been estimated as 18 months [85], but survival is at least 13 years in patients who are treated [24]. Nevertheless, overall survival of treated patients with PV is inferior to that of an age- and sex-matched normal population [23,24,86,87].
The most comprehensive analysis of factors that influence survival in PV was an international study of 1545 patients with PV who were treated with a variety of therapeutic agents [23]. This study identified age, leukocytosis, history of venous thrombosis, and abnormal karyotype as independent risk factors for survival. Patients with PV who were ≤61 years of age with a white blood cell count ≤10,500/microL had a median survival of 23 years, in contrast to median survival of 9 years in those without either or both of those characteristics.
This study led to the following prognostic model for survival in PV (figure 1) [23]:
●Age: ≥67 years = 5 points; 57 to 66 years = 2 points
●Leukocytosis: ≥15,000 white blood cells/microL = 1 point
●History of venous thrombosis = 1 point
Risk groups and median survivals were calculated as follows:
●Low risk (0 points) – 28 years
●Intermediate risk (1 to 2 points) – 19 years
●High risk (≥3 points) – 11 years
A long-term study (median follow-up: 11 years) using registry data from 327 patients with PV made the following observations [88]:
●The median age at diagnosis was 71 years (range: 21 to 95), while the median age at death was 81 years. Death was attributed to thrombotic events (21 percent), secondary AML (17 percent), solid tumors (17 percent), and chronic heart failure (15 percent).
●Median survivals for those <65 or ≥65 years at the time of diagnosis were 17.5 and 6.5 years, respectively. Relative survival that focused on deaths directly attributable to PV was 93, 72, and 46 percent, respectively, after 5, 10, and 20 years of disease duration, respectively.
●Age >70 years, white blood cell count >13,000 cells/microL (>13 x 109/L), and thrombosis at the time of diagnosis were predictors of survival in multivariate analysis. Relative survivals were 84, 59, and 26 percent for those with none, one, or two to three of these risk factors at the time of PV diagnosis, respectively.
Other studies that have examined survival of patients with PV include the following:
●A study of 226 patients reported that treatment of PV is associated with 10-year projected rates for survival, leukemic transformation, and fibrotic progression of >75 percent, <5 percent, and <10 percent, respectively [89]. The risk of thrombosis exceeds 20 percent and a substantial portion of patients experience vasomotor disturbances (eg, headache lightheadedness acral paresthesias, erythromelalgia, atypical chest pain, pruritus) [36,90].
●In a prospective multinational study of 1638 patients, the overall mortality rate was 3.7 deaths per 100 persons/year [25]. Cardiovascular mortality, solid tumors, and hematologic transformation accounted for 45, 20, and 13 percent of the deaths, respectively.
●A study of 459 patients with PV reported that age ≥60 years and leukocytosis (≥15,000/microL), along with arterial thrombosis at the time of diagnosis, were independent predictors of inferior survival in multivariate analysis, and reported similar median survival data [91].
●Abnormal karyotype (eg, +9, +8, 20q-), which is seen in approximately 20 percent of patients with PV, is associated with inferior survival [92,93].
Thrombotic events — Thromboembolic events are the major cause of morbidity and mortality in PV [94].
Older age and a history of prior thrombosis are predictors of thromboembolic risk in PV [25,85,86,95]. Examples include the following:
●In two large studies of patients with PV, age over 65 to 70 years, and a history of previous thrombosis were the most powerful predictors of recurrent thrombosis and cardiovascular events [25,86].
The annual incidence of thrombosis in PV ranged from 1.8 percent in patients <40 years of age to 5.1 percent in those >70 years [86]; for perspective, the latter figure (5.1 percent) is similar to the annual stroke risk of a 75-year-old person with atrial fibrillation and a prior thromboembolic event (5.3 percent) or to the annual cardiovascular risk of a 75-year-old smoker with hypertension and diabetes (5.6 percent).
Other risk factors, including leukocytosis and thrombocytosis, are less conclusively associated with vascular events in PV. Examples include:
●Some studies have reported that leukocytosis is associated with vascular events in PV [91,96-98].
●One study reported that the frequency of vascular occlusive episodes was 1.5 times higher in patients with a platelet count >400,000/microL, although neither the degree of thrombocytosis nor the presence of platelet function abnormalities has been consistently correlated with thrombotic risk [26,99,100].
Reduced thrombotic risk is associated with maintaining hematocrit below 45 percent [2]. (See 'Therapeutic phlebotomy' above.)
Hematologic complications — A major cause of death in PV is disease transformation to post-PV myelofibrosis and/or evolution to acute myeloid leukemia/myelodysplastic syndrome [26,86,101,102].
A large prospective study reported that the rate of such hematologic complications was 1.3 episodes per 100 patient-years (21 cases of AML, one case of myelodysplasia, and 38 cases of myelofibrosis among 1,638 patients) [25].
●Myelofibrosis – Progression to myelofibrosis (MF) occurs in 12 to 21 percent of patients with PV [24].
The Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus for primary myelofibrosis (table 5) may be useful for defining prognosis in secondary myelofibrosis (calculator 1) [103]. Risk factors that are associated with an increased risk for progression to MF include disease duration, age, and white blood cell count [25,91,104].
Other factors have been reported to be associated with a higher risk for development of post-PV MF include [105-111]:
•Homozygosity for the JAK2 V617F mutation
•Elevated serum levels of lactate dehydrogenase (LDH)
•Presence of >grade 1 bone marrow fibrosis at presentation
•Endogenous megakaryocyte colony formation in vitro
In an Italian study, median survival was 5.7 years among 68 patients who developed post-PV MF [104]. In multivariate analysis, adverse risk factors for survival after the onset of post-PV MF included the following:
•Hemoglobin <10.0 g/dL
•Platelet count <100,000/microL
•White blood cell count >30,000/microL
Median survivals were >108, 51, 15, and 3 months, respectively, for those who developed none, one, two, or all three of these adverse risk factors at some time in their disease course.
●Acute myeloid leukemia (AML)/Myelodysplastic neoplasms/syndrome (MDS) – Transformation to AML or MDS is a major cause of death in PV. Examples include:
•In a large international study, approximately 7 percent of patients with PV developed AML/MDS within 20 years [24].
•In a study of 1545 patients with PV, the 50 cases of AML (3.2 percent) occurred at a median time of 10.8 years (range: 0.5 to 22 years) from diagnosis, and the cumulative risk was 2.3, 5.5, and 7.9 percent at 10, 15, and 20 years, respectively (figure 2) [23].
Risk factors for development of AML include older age, the type of the treatment for PV, and leukocytosis at the time of diagnosis of PV. Examples of studies of risk factors for development of AML include:
•In two reports, development of acute leukemia/MDS was associated with [25,65]:
-Age >70 (relative risk 4.3 to 5.0)
-Treatment with cytoreductive agents other than hydroxyurea and interferon (relative risk 5.5 to 11)
•In one study, the incidence of leukemia was associated with the type of treatment given, as follows [91]:
-No cytoreductive therapy (or exposure to anagrelide or interferon only) – 2.4 percent
-Hydroxyurea (with or without anagrelide or interferon) – 4 percent
-Single-agent cytotoxic agent other than hydroxyurea – 12 percent
-Two or more cytotoxic agents – 17 percent
•Another study reported the following hazard ratios for development of AML after specific treatments for PV [23]:
-No increased risk for single-agent hydroxyurea or busulfan
-3.9 – pipobroman alone
-4.1 – pipobroman + either hydroxyurea or busulfan
-4.8 – 32P or chlorambucil alone
The prognosis is dismal for AML that arises in the setting of PV and other myeloproliferative neoplasms [112-114]. In one report of 74 such patients, median survival was five months from the time of blastic transformation [114]. Complete remissions were noted in about one-half of the patients treated with induction chemotherapy, but remissions were not durable and median progression-free survival was five months. Long-term survival was seen only in patients who received allogeneic hematopoietic cell transplantation as initial therapy or during first remission.
●Chronic myeloid leukemia (CML) – Clonal evolution of PV to chronic myeloid leukemia (CML) is a rare phenomenon, occurring either when a stem cell carrying the JAK2 V617F mutation acquires the BCR-ABL1 translocation, or when PV and CML have evolved from separate clones [1,3,113,114].
SECONDARY POLYCYTHEMIA — Secondary polycythemia refers to an increase of red blood cell (RBC) mass caused by hypoxia, other reasons for elevated serum erythropoietin (EPO; eg, renal artery stenosis, certain tumors), rare inherited conditions (eg, Chuvash polycythemia, congenital methemoglobinemia), and other causes (table 2). (See "Diagnostic approach to the patient with erythrocytosis/polycythemia", section on 'Secondary polycythemia'.)
Management of secondary polycythemia is generally directed at ameliorating the underlying cause and contributing factors, alleviating symptoms, and/or reducing the risk of thrombosis [115]:
●Lessen contributing factors – Remediable causes should be addressed, when possible. Examples include improving oxygenation in patients with pulmonary or heart disease, providing continuous positive airway pressure (CPAP) for obstructive sleep apnea, correcting renal artery stenosis, removing EPO-producing tumors, considering angiotensin converting enzyme (ACE) inhibitors for post-renal transplant syndrome, and re-evaluating the need for anabolic steroids.
All patients with secondary polycythemia should be encouraged to discontinue smoking.
●Symptom relief – For patients with symptoms attributable to secondary polycythemia (eg, fatigue, headache, dizziness, mental slowing, visual changes, paresthesias, atypical chest pain, dyspnea, palpitations), we provide therapeutic phlebotomy only if this ameliorates symptoms. The target hematocrit is based on the threshold that provides symptom relief; in such settings, cautious phlebotomy (eg, removal of 250 mL blood, replaced by an equal volume of crystalloid) to modestly reduce the Hb may relieve these symptoms. However, reduction of Hct to <55 percent range is likely to exacerbate dyspnea or other hypoxic symptoms. (See 'Therapeutic phlebotomy' above.)
We do not treat secondary polycythemia with cytoreductive agents.
●Thrombosis prophylaxis – There is no persuasive evidence that prophylactic phlebotomy or cytoreduction reduces the risk of thrombosis in patients with secondary polycythemia.
We offer once-daily low-dose aspirin to patients with cardiovascular risk factors, twice-daily low-dose aspirin for patients with a history of arterial thrombosis, and systemic anticoagulation for those with a history of venous thromboembolism. (See 'Low-dose aspirin' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Polycythemia vera (PV) (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by increased red blood cell mass that is associated with increased risk for thrombotic events, leukemic transformation, and/or myelofibrosis.
Diagnostic criteria for PV and evaluation of thrombocytosis are presented separately. (See "Clinical manifestations and diagnosis of polycythemia vera" and "Diagnostic approach to the patient with erythrocytosis/polycythemia".)
●Goals of care – The goals of care for the patient with PV are to reduce the risk of thrombosis, alleviate symptoms, and minimize evolution to post-PV myelofibrosis and acute myeloid leukemia (AML). (See 'Goals of care' above.)
●Pretreatment evaluation
•Clinical – History should evaluate prior venous and arterial thrombotic events, PV-associated symptoms (eg, pruritus, erythromelalgia, bleeding), splenomegaly, and cardiovascular (CV) risk factors. (See 'Pretreatment evaluation' above.)
•Laboratory
-Complete blood count (CBC)
-For platelet count >1 million/microL on CBC or clinical bleeding, we measure ristocetin cofactor (RCo) activity; RCo <30 percent is considered acquired von Willebrand syndrome (vWS). (See 'Extreme thrombocytosis/acquired von Willebrand syndrome' above.)
-JAK2 V617F
●Risk stratification – Patients are stratified according to risk factors for survival (eg, age >60, prior thrombosis, leukocytosis) (figure 1). (See 'Risk stratification' above.)
●Management – Phlebotomy is the mainstay of management of red blood cell mass in PV. (See 'Therapeutic phlebotomy' above.)
•Treatment target – For all patients with PV, we recommend maintenance of hematocrit <45 percent, rather than higher levels (Grade 1A). (See 'Therapeutic phlebotomy' above.)
•Aspirin – For all patients, except those with a contraindication (eg, acquired vWS), we recommend low-dose aspirin (Grade 1B). (See 'Low-dose aspirin' above.)
•Risk-stratified therapy
-Low-risk – For patients with low-risk PV (≤60 years and no history of thrombosis), we suggest phlebotomy, rather than cytoreductive agents (Grade 2C). (See 'Management of low-risk PV' above.)
-High-risk – For patients with high-risk PV (>60 years and/or history of thrombosis), we recommend phlebotomy plus cytoreductive therapy, rather than phlebotomy alone. (Grade 1C). (See 'Management of high-risk PV' above.)
●Cytoreductive agents – For most patients who require cytoreductive agents, we suggest hydroxyurea (HU), rather than pegylated interferon alfa (IFN), ruxolitinib, or other agents (Grade 2C). (See 'Choice of agent' above.)
In selected patients (eg, <40 years and those who might become pregnant), we favor initial therapy with pegylated IFN rather than HU because of the possibility of achieving cytogenetic remission with IFN and potential teratogenicity of HU. (See 'Pegylated interferon' above.)
We treat with ruxolitinib only for severe pruritus, symptomatic splenomegaly, or symptoms of post-PV myelofibrosis that failed to respond adequately to first-line therapies. (See 'Other agents' above.)
●Secondary polycythemia – Management of secondary polycythemia is generally directed at ameliorating the underlying cause and contributing factors, alleviating symptoms, and/or reducing the risk of thrombosis. (See 'Secondary polycythemia' above.)
ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
