Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

nonpregnant adults: low risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])

1st line – phlebotomy

Back
ACUTE
|
nonpregnant adults: low risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
1st line – 

phlebotomy

The main treatment goals for patients with polycythemia vera (PV) are to alleviate symptoms, prevent bleeding events, and prolong survival by reduction of major thrombotic events.

Patients are managed based on their risk for thrombosis. Low-risk patients are those ages <60 years with no history of thrombosis.[54][66][71][97]​​​​​​

Patients without marked thrombocytosis are those with platelet count <1000 × 10³/microliter (<1000 × 10⁹/L).

Some low-risk patients may be considered high risk in the presence of cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, smoking), elevated white blood cell count, or marked thrombocytosis or hematocrit that is uncontrolled with phlebotomy.[66] 

Phlebotomy and low-dose aspirin are the cornerstone of treatment for patients with low-risk PV.

Perform phlebotomy twice weekly (or on alternate days if hematocrit ≥60%); 250-500 mL of blood is replaced with normal saline until hematocrit is <45%.​​​[53][71][108]​​​​​​ In one trial, risk of cardiovascular death or major thromboses was significantly reduced in patients with median hematocrit of 44.4% compared with those with higher hematocrit (median 47.5%).[53]​ Target hematocrit may be individualized if a lower level (e.g., 42%) is preferred (e.g., for women, patients with a low baseline value, to improve symptom control, or in pregnancy).[71][97][108]

Carefully assess patient tolerance to phlebotomy. Adjust volume and frequency to patient size and tolerability; take extra care and proceed slowly when removing blood from patients who are older or infirm. Recommendations vary between guidelines; local guidelines should be consulted.[66]​​[104]

Phlebotomy induces iron-limited hematopoiesis. Iron deficiency can rarely induce symptoms of fatigue or cognitive slowing. Iron supplementation is generally contraindicated. If, however, systemic symptoms of iron deficiency ensue, a short trial of iron replacement is warranted. This should only be attempted by an experienced practitioner. Careful monitoring is required as recurrent polycythemia can emerge rapidly.[66]

Some patients may require long-term intermittent treatment.

Plus – low-dose aspirin or clopidogrel

Back
ACUTE
|
nonpregnant adults: low risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
Plus – 

low-dose aspirin or clopidogrel

Treatment recommended for ALL patients in selected patient group

Phlebotomy and low-dose aspirin are the cornerstone of treatment for patients with low-risk polycythemia vera (PV).

All patients with PV should receive daily low-dose aspirin unless contraindicated. Low-dose aspirin has been shown to modestly decrease thrombotic risk without significantly increasing the risk of bleeding.​[106]​​​ Higher doses of aspirin are associated with an increased risk of bleeding.[149]

Twice-daily low-dose aspirin may be considered for patients with refractory symptoms, or who are at higher risk of arterial thrombosis (including those with cardiovascular risk factors or leukocytosis).​[71][97][107]

There are no data to support the use of other antiplatelet agents when aspirin is contraindicated, except in clinical areas such as transient ischemic attacks, where guidelines exist. Clopidogrel has been suggested as a potential alternative antiplatelet agent.[71][97]​​

Treatment should continue unless a contraindication exists or arises.

Primary options

aspirin: 81-100 mg orally once or twice daily

Secondary options

clopidogrel: 75 mg orally once daily

Plus – intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Back
ACUTE
|
nonpregnant adults: low risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
Plus – 

intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Treatment recommended for ALL patients in selected patient group

Cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, smoking) should be identified and aggressively managed in all patients with polycythemia vera.

Give advice on lifestyle modification (e.g., smoking cessation, weight control) to reduce the risk of developing symptoms, or to moderate the severity of symptoms that may already exist.

Offer supportive care to ensure optimum symptom management.

Consider – cytoreductive therapy

Back
ACUTE
|
nonpregnant adults: low risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
Consider – 

cytoreductive therapy

Treatment recommended for SOME patients in selected patient group

There is limited evidence regarding the use of cytoreductive agents in low-risk patients. Decisions about when to start treatment and which agent to use should be made by an experienced hematologist, taking into account patient preferences, toxicity profiles, and individual treatment goals.

While not routinely indicated in low-risk patients, cytoreductive therapy may be considered for symptomatic low-risk PV in certain situations, including: new thrombosis or disease-related major bleeding; progressive thrombocytosis; progressive leukocytosis; splenomegaly; disease-related symptoms (e.g., pruritus, night sweats, fatigue); frequent need for phlebotomy or poor tolerance of phlebotomy.[71]

The target hematocrit for cytoreduction is <45%.

Guidelines recommend ropeginterferon alfa-2b or a clinical trial as preferred options if cytoreduction is indicated for low-risk polycythemia vera (PV).[71] One phase 2 trial suggested that ropeginterferon alfa-2b in combination with standard treatment (phlebotomy and aspirin) is more effective at maintaining hematocrit targets than standard treatment alone in low-risk patients.[109]

Ropeginterferon alfa-2b has a long elimination half-life. It may be an option for younger patients with PV.[97]​ The dose of ropeginterferon alfa-2b should be titrated over several weeks. Blood counts are monitored every 2 weeks initially, then every 3-4 months after optimal dose is identified.[111]

Common adverse effects of ropeginterferon alfa-2b include fatigue, liver function test abnormalities (increased gamma-glutamyltransferase and increased alanine aminotransferase), thrombocytopenia, and leukopenia. Monitoring of toxicity (including regular thyroid function testing) is required during treatment. Ropeginterferon alfa-2b is contraindicated in patients with autoimmune diseases, hepatic impairment, and severe psychiatric disorders, and in immunosuppressed transplant recipients.[111]

Hydroxyurea and peginterferon alfa-2a are alternatives to ropeginterferon alfa-2b for patients with low-risk PV.[71]

Generally, it is safer to titrate the hydroxyurea dose over several weeks to a target hematocrit of <45% (with phlebotomy as required).[53]​ Some physicians titrate to normalize white blood cell count and platelet count.[71]​ Blood counts should be monitored every 1-2 weeks until stable, then as clinically indicated.

Hydroxyurea is uncommonly associated with mild gastrointestinal upset. The most common serious reaction is pancytopenia. Rare skin ulcers, drug fever, and liver toxicity require permanent discontinuation.

Hydroxyurea is teratogenic and therefore should be avoided in those planning to conceive.[119]​ It is also potentially leukemogenic; therefore, an alternative cytoreductive agent may be considered in younger patients.[14][97][105][120][121]​​​ The potential leukemogenicity of hydroxyurea is debated.[122]​​

Peginterferon alfa-2a is an option for younger patients, in particular women of reproductive age and pregnant patients.[71][97]​ Peginterferon alfa 2a is effective (76% to 95% complete hematologic responses [CHRs]) and appears to be better tolerated than nonpegylated interferon alfa.[66][125][126][127]

Toxicity with peginterferon alfa-2a is common and can be severe. Adverse events and discontinuation rates in studies were high; 22% of patients discontinued therapy due to toxicity in one open-label, phase 2 trial.[129][127]​​

Common adverse effects of peginterferon therapy include gastrointestinal upset, fever or flu-like symptoms. Patients may also develop weakness, weight loss, severe depression, cardiovascular symptoms, and autoimmune disease. Patients should be screened for depression and other psychiatric illnesses prior to starting peginterferon. Monitoring of toxicity (including regular thyroid function testing) is required during treatment.

Primary options

ropeginterferon alfa-2b: patients not already on hydroxyurea: 100 micrograms subcutaneously every 2 weeks initially, increase by 50 micrograms every 2 weeks until hematologic parameters are stable, maximum 500 micrograms/dose; patients transitioning from hydroxyurea: 50 micrograms subcutaneously every 2 weeks initially, increase by 50 micrograms every 2 weeks until hematologic parameters are stable, maximum 500 micrograms/dose

More

Secondary options

hydroxyurea: 500-1500 mg orally once daily initially, adjust dose according to response

OR

peginterferon alfa 2a: consult specialist for guidance on dose

nonpregnant adults: high risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])

1st line – cytoreductive therapy

Back
ACUTE
|
nonpregnant adults: high risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
1st line – 

cytoreductive therapy

The main treatment goals for patients with polycythemia vera (PV) are to alleviate symptoms, prevent bleeding events, and prolong survival by reduction of major thrombotic events.

High-risk patients are those ages ≥60 years and/or with a history of thrombosis.[54][66][71][97]​​​​​​​​​ An experienced hematologist should manage all high-risk patients.

Cytoreductive therapy is the mainstay treatment of high-risk patients, with the aim of replacing phlebotomy in the long term. High-risk patients should receive cytoreductive therapy along with low-dose aspirin, with phlebotomy performed as required (e.g., to achieve rapid hematocrit control, concurrent with cytoreductive therapy, in the acute setting).​​[66][71][97][104]​​​​​

Hydroxyurea and ropeginterferon alfa-2b are recommended as first-line cytoreductive therapy; peginterferon alfa-2a is an option for younger patients and pregnant patients.[71] Ruxolitinib may be a second-line or salvage option. Choice of agent should take into account toxicity profiles and individual treatment goals.[71][97]

Hydroxyurea is a preferred first-line cytoreductive agent.[71]​ Hydroxyurea decreases the rate of thrombosis in high-risk patients.[113][114][115][116][117][118]

Generally, it is safer to titrate the hydroxyurea dose over several weeks to a target hematocrit of <45% (with phlebotomy as required).[53]​ Some physicians titrate to normalize white blood cell count and platelet count.[71]​ Blood counts should be monitored every 1-2 weeks until stable, then as clinically indicated.

Hydroxyurea is uncommonly associated with mild gastrointestinal upset. The most common serious reaction is pancytopenia. Rare skin ulcers, drug fever, and liver toxicity require permanent discontinuation.

Hydroxyurea is teratogenic and therefore should be avoided in those planning to conceive.[119]​ It is also potentially leukemogenic; therefore, an alternative cytoreductive agent may be considered in younger patients.[14][97][105][120]​​​​​​​​​​​​​​​​​​[121]​​ The potential leukemogenicity of hydroxyurea is debated.[122]

Ropeginterferon alfa-2b, a monopegylated interferon alfa-2b with a long elimination half-life, is a preferred first-line cytoreductive agent.[71] It may be an option for younger patients with PV.[97] 

The dose of ropeginterferon alfa-2b should be titrated over several weeks. Blood counts are monitored every 2 weeks initially, then every 3-4 months after optimal dose is identified.[111]

In phase 3 trials, ropeginterferon alfa-2b was noninferior to hydroxyurea in terms of complete hematologic response (CHR) rate at 12 months, and superior to hydroxyurea at 2 and 3 years follow-up.[123]

Common adverse effects of ropeginterferon alfa-2b include fatigue, liver function test abnormalities (increased gamma-glutamyltransferase and increased alanine aminotransferase), thrombocytopenia, and leukopenia. Monitoring of toxicity (including regular thyroid function testing) is required during treatment. Ropeginterferon alfa-2b is contraindicated in patients with autoimmune diseases, hepatic impairment, and severe psychiatric disorders, and in immunosuppressed transplant recipients.[111]

Peginterferon alfa-2a is a preferred option for younger patients, in particular women of reproductive age and pregnant patients.[71][97]​​​​​ Peginterferon alfa-2a is effective (76% to 95% complete hematologic responses [CHRs]) and appears to be better tolerated than nonpegylated interferon alfa.[66][125][126][127]

Results from a phase 3 trial of first-line management for high-risk patients found no meaningful differences in any end point between peginterferon alfa-2a and hydroxyurea after 2 years' follow-up.[128]​ Peginterferon alfa 2a has demonstrated efficacy in hydroxyurea-resistant or -intolerant patients with PV.[129]

Toxicity with peginterferon alfa-2a is common and can be severe. Adverse events and discontinuation rates in studies were high; 22% of patients discontinued therapy due to toxicity in one open-label, phase 2 trial.[127][129]

Common adverse effects of peginterferon therapy include gastrointestinal upset, fever or flu-like symptoms. Patients may also develop weakness, weight loss, severe depression, cardiovascular symptoms, and autoimmune disease. Patients should be screened for depression and other psychiatric illnesses prior to starting peginterferon. Monitoring of toxicity (including regular thyroid function testing) is required during treatment.

An alternative cytoreductive agent may be required in patients who are resistant or intolerant to initial treatment. Possible indications for a change of cytoreductive therapy include: new thrombosis or disease-related major bleeding; progressive thrombocytosis; progressive leukocytosis; splenomegaly; disease-related symptoms (e.g., pruritus, night sweats, fatigue); frequent need for phlebotomy or poor tolerance of phlebotomy.[71]

Second-line treatment options include ruxolitinib or, if not used already, a pegylated interferon or hydroxyurea.[71][97][104][134]​​ 

Ruxolitinib, a JAK1/2 inhibitor, is approved for second-line use after hydroxyurea failure. Open-label phase 3 studies found ruxolitinib to be superior to standard therapy with respect to hematocrit control, splenic shrinkage, and relief of PV-associated symptoms.[91][135]​​​ The benefits of ruxolitinib were maintained at 5 years.[136][137]​ 

Herpes zoster infections and nonmelanoma skin cancer occurred more frequently in the ruxolitinib group of phase 3 studies.[91][136][137]

Primary options

hydroxyurea: 500-1500 mg orally once daily initially, adjust dose according to response

OR

ropeginterferon alfa-2b: patients not already on hydroxyurea: 100 micrograms subcutaneously every 2 weeks initially, increase by 50 micrograms every 2 weeks until hematologic parameters are stable, maximum 500 micrograms/dose; patients transitioning from hydroxyurea: 50 micrograms subcutaneously every 2 weeks initially, increase by 50 micrograms every 2 weeks until hematologic parameters are stable, maximum 500 micrograms/dose

More

Secondary options

peginterferon alfa 2a: consult specialist for guidance on dose

Tertiary options

ruxolitinib: 10 mg orally twice daily for 4 weeks initially, adjust dose according to response, maximum 50 mg/day

Plus – low-dose aspirin or clopidogrel

Back
ACUTE
|
nonpregnant adults: high risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
Plus – 

low-dose aspirin or clopidogrel

Treatment recommended for ALL patients in selected patient group

All patients with polycythemia vera should receive daily low-dose aspirin, unless contraindicated. Low-dose aspirin has been shown to modestly decrease thrombotic risk without significantly increasing the risk of bleeding.​[106]​​​​​​ Higher doses of aspirin are associated with an increased risk of bleeding.[149]

Twice-daily low-dose aspirin may be considered for patients with refractory symptoms or who are at higher risk of arterial thrombosis (including those with cardiovascular risk factors or leukocytosis).[71][97][107]

There are no data to support the use of other antiplatelet agents when aspirin is contraindicated, except in clinical areas such as transient ischemic attacks, where guidelines exist. Clopidogrel has been suggested as a potential alternative antiplatelet agent.[71][97]

Treatment should continue unless a contraindication exists or arises.

Primary options

aspirin: 81-100 mg orally once or twice daily

Secondary options

clopidogrel: 75 mg orally once daily

Plus – intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Back
ACUTE
|
nonpregnant adults: high risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
Plus – 

intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Treatment recommended for ALL patients in selected patient group

Cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, smoking) should be identified and aggressively managed in all patients with polycythemia vera (PV).

Give advice on lifestyle modification (e.g., smoking cessation, weight control) to reduce the risk of developing symptoms, or to moderate the severity of symptoms that may already exist.

Offer supportive care to ensure optimum symptom management.

Systemic anticoagulation is recommended (in addition to cytoreductive therapy) for patients with active thrombosis.[71][97]​​​​ The use of aspirin plus anticoagulation is associated with an increased risk of bleeding; close monitoring is required. Evidence is limited and decisions about anticoagulant therapy should be individualized, taking into account the risks and benefits.

Consider – phlebotomy

Back
ACUTE
|
nonpregnant adults: high risk for thrombosis without marked thrombocytosis (platelet count <1000 × 10³/microliter [<1000 × 10⁹/L])
Consider – 

phlebotomy

Treatment recommended for SOME patients in selected patient group

In the acute setting, phlebotomy may be combined with cytoreductive therapy to achieve rapid hematocrit control.[97]

Perform phlebotomy twice weekly (or on alternate days if hematocrit ≥60%); 250-500 mL of blood is replaced with normal saline until hematocrit is <45%.​[53][71][108]​​​​​​​

In one trial, risk of cardiovascular death or major thromboses was significantly reduced in patients with median hematocrit of 44.4% compared with those with higher hematocrit (median 47.5%).[53] Target hematocrit may be individualized if a lower level (e.g., 42%) is preferred (e.g., for women, patients with a low baseline value, to improve symptom control, or in pregnancy).[71][97][108]

Carefully assess patient tolerance to phlebotomy. Adjust volume and frequency to patient size and tolerability; take extra care and proceed slowly when removing blood from patients who are older or infirm. Recommendations vary between guidelines; local guidelines should be consulted.[66]​​[104]

Phlebotomy induces iron-limited hematopoiesis. Iron deficiency can rarely induce symptoms of fatigue or mental slowing. Iron supplementation is generally contraindicated. If, however, systemic symptoms of iron deficiency ensue, a short trial of iron replacement is warranted. This should only be attempted by an experienced practitioner. Careful monitoring is required as recurrent polycythemia can emerge rapidly.[66]

nonpregnant adults: with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L])

1st line – cytoreductive therapy

Back
ACUTE
|
nonpregnant adults: with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L])
1st line – 

cytoreductive therapy

The main treatment goals for patients with polycythemia vera (PV) are to alleviate symptoms, prevent bleeding events, and prolong survival by reduction of major thrombotic events.

Cytoreductive therapy should be considered for patients with marked thrombocytosis (≥1000 × 10³/microliter [≥1000 × 10⁹/L]) as this may be associated with an increased risk of bleeding due to acquired von Willebrand disease.

The target hematocrit for cytoreduction is <45%.

No particular level of thrombocytosis has been demonstrated to correlate accurately with the risk of thrombosis.[60][61][62]​​​​​​ Therefore, strict control of platelets to a specific level cannot be endorsed for this purpose.[13][47]​​​​​​

Hydroxyurea is the preferred first-line cytoreductive agent in patients with marked thrombocytosis. Peginterferon alfa-2a may be a reasonable alternative option, but it acts slowly.

Generally, it is safer to titrate the hydroxyurea dose over several weeks to a target hematocrit of <45% (with phlebotomy as required).[53] Some physicians titrate to normalize white blood cell count and platelet count.[71] Blood counts should be monitored every 1-2 weeks until stable, then as clinically indicated.​

Hydroxyurea is uncommonly associated with mild gastrointestinal upset. The most common serious reaction is pancytopenia. Rare skin ulcers, drug fever, and liver toxicity require permanent discontinuation.

Hydroxyurea is teratogenic and therefore should be avoided in those planning to conceive.[119]​ It is also potentially leukemogenic; therefore, an alternative cytoreductive agent may be considered in younger patients.[14][97][105][120][121]​​​ The potential leukemogenicity of hydroxyurea is debated.[122]

Peginterferon alfa-2a or ruxolitinib may be considered for patients who are intolerant to, or with disease that is resistant to, hydroxyurea.

Results from a phase 3 trial of first-line management for high-risk patients found no meaningful differences in any end point between peginterferon alfa-2a and hydroxyurea after 2 years' follow-up.[128]​​ Peginterferon alfa 2a has demonstrated efficacy in hydroxyurea-resistant or -intolerant patients with PV.[129]

Peginterferon alfa-2a is a preferred option for younger patients, in particular women of reproductive age and pregnant patients.[71][97]​ Peginterferon alfa 2a is effective (76% to 95% complete hematologic responses [CHRs]) and appears to be better tolerated than nonpegylated interferon alfa.[66][125][126][127]

Toxicity with peginterferon alfa-2a is common and can be severe. Adverse events and discontinuation rates in studies were high; 22% of patients discontinued therapy due to toxicity in one open-label, phase 2 trial.[127][129]

Common adverse effects of peginterferon therapy include gastrointestinal upset, fever or flu-like symptoms. Patients may also develop weakness, weight loss, severe depression, cardiovascular symptoms, and autoimmune disease. Patients should be screened for depression and other psychiatric illnesses prior to starting peginterferon. Monitoring of toxicity (including regular thyroid function testing) is required during treatment.

Ruxolitinib, a JAK1/2 inhibitor, is approved for second-line use after hydroxyurea failure. Open-label phase 3 studies found ruxolitinib to be superior to standard therapy with respect to hematocrit control, splenic shrinkage, and relief of PV-associated symptoms.[91][135]​ The benefits of ruxolitinib were maintained at 5 years.[136][137]

Herpes zoster infections and nonmelanoma skin cancer occurred more frequently in the ruxolitinib group of phase 3 studies.[91][136][137]

Primary options

hydroxyurea: 500-1500 mg orally once daily initially, adjust dose according to response

Secondary options

peginterferon alfa 2a: consult specialist for guidance on dose

OR

ruxolitinib: 10 mg orally twice daily for 4 weeks initially, adjust dose according to response, maximum 50 mg/day

Plus – low-dose aspirin or clopidogrel (post-platelet reduction)

Back
ACUTE
|
nonpregnant adults: with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L])
Plus – 

low-dose aspirin or clopidogrel (post-platelet reduction)

Treatment recommended for ALL patients in selected patient group

For patients with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L]), perform coagulation tests to assess for acquired von Willebrand syndrome. Aspirin should be used with caution or withheld in patients with acquired von Willebrand disease because of increased risk of bleeding.​[97]​​​​​​​[106] 

Once the platelet count is reduced to <1000 × 10³/microliter (<1000 × 10⁹/L) and there is no evidence of acquired von Willebrand disease (i.e., ristocetin cofactor activity >30%), patients should receive daily low-dose aspirin.​[106]​​

Low-dose aspirin has been shown to modestly decrease thrombotic risk without significantly increasing the risk of bleeding.[106]​​ Higher doses of aspirin are associated with an increased risk of bleeding.[149]

There are no data to support the use of other antiplatelet agents when aspirin is contraindicated, except in clinical areas such as transient ischemic attacks, where guidelines exist. Clopidogrel has been suggested as a potential alternative antiplatelet agent.​[71][97]​ 

Treatment should continue unless a contraindication exists or arises.

Primary options

aspirin: 81-100 mg orally once daily

Secondary options

clopidogrel: 75 mg orally once daily

Plus – intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Back
ACUTE
|
nonpregnant adults: with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L])
Plus – 

intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Treatment recommended for ALL patients in selected patient group

Cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, smoking) should be identified and aggressively managed in all patients with polycythemia vera (PV).

Give advice on lifestyle modification (e.g., smoking cessation, weight control) to reduce the risk of developing symptoms, or to moderate the severity of symptoms that may already exist.

Offer supportive care to ensure optimum symptom management.

Systemic anticoagulation is recommended (in addition to cytoreductive therapy) for patients with thrombosis.[71][97]​​​​​ The use of aspirin plus anticoagulation is associated with an increased risk of bleeding; close monitoring is required. Evidence is limited and decisions about anticoagulant therapy should be individualized, taking into account the risks and benefits. 

Consider – anagrelide

Back
ACUTE
|
nonpregnant adults: with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L])
Consider – 

anagrelide

Treatment recommended for SOME patients in selected patient group

Anagrelide can be considered as an adjunct to hydroxyurea in patients with marked thrombocytosis if hydroxyurea alone does not adequately normalize platelet counts or is not tolerated at the required dose.[66]

Data on the use of anagrelide in polycythemia vera are limited; one retrospective case series supports its efficacy in combination with hydroxyurea.[145]

Primary options

anagrelide: 0.5 mg orally four times daily or 1 mg twice daily for at least 1 week initially, adjust dose according to response, maximum 10 mg/day

Consider – phlebotomy

Back
ACUTE
|
nonpregnant adults: with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L])
Consider – 

phlebotomy

Treatment recommended for SOME patients in selected patient group

In the acute setting, phlebotomy may be combined with cytoreductive therapy to achieve rapid hematocrit control.[97]​​

Perform phlebotomy twice weekly (or on alternate days if hematocrit ≥60%); 250-500 mL of blood is replaced with normal saline until hematocrit is <45%.​​​[53][71][108]​​​​​​​

In one trial, risk of cardiovascular death or major thromboses was significantly reduced in patients with median hematocrit of 44.4% compared with those with higher hematocrit (median 47.5%).[53] Target hematocrit may be individualized if a lower level (e.g., 42%) is preferred (e.g., for women, patients with a low baseline value, to improve symptom control, or in pregnancy).[71][97][108]

Carefully assess patient tolerance to phlebotomy. Adjust volume and frequency to patient size and tolerability; take extra care and proceed slowly when removing blood from patients who are older or infirm. Recommendations vary between guidelines; local guidelines should be consulted.[66]​​[104]

Phlebotomy induces iron-limited hematopoiesis. Iron deficiency can rarely induce symptoms of fatigue or mental slowing. Iron supplementation is generally contraindicated. If, however, systemic symptoms of iron deficiency ensue, a short trial of iron replacement is warranted. This should only be attempted by an experienced practitioner. Careful monitoring is required as recurrent polycythemia can emerge rapidly.[66]

pregnant

1st line – low-dose aspirin

Back
ACUTE
|
pregnant
1st line – 

low-dose aspirin

Patients with polycythemia vera who become pregnant should be under the joint care of a hematologist and an obstetrician experienced in high-risk care. Pregnant patients should be stratified by risk and receive individualized treatment accordingly.

Unless contraindicated, treating all patients with daily low-dose aspirin during the pregnancy, and with 6 weeks of prophylactic low molecular weight heparin (LMWH) postpartum, is appropriate. Low-dose aspirin can be resumed after LMWH is finished.[71]​​​[119][147]

Low-dose aspirin has been shown to modestly decrease thrombotic risk without significantly increasing the risk of bleeding.[106] Higher doses of aspirin are associated with an increased risk of bleeding.[149]

For patients with marked thrombocytosis (platelet count ≥1000 × 10³/microliter [≥1000 × 10⁹/L]), perform coagulation tests to assess for acquired von Willebrand syndrome. Aspirin should be used with caution or withheld in patients with acquired von Willebrand disease because of increased risk of bleeding.​[97][106]

Cytoreductive therapy should be considered for patients with marked thrombocytosis.

Once the platelet count is reduced to <1000 × 10³/microliter (<1000 × 10⁹/L) and there is no evidence of acquired von Willebrand disease (i.e., ristocetin cofactor activity >30%), patients should receive daily low-dose aspirin.[106]

There are no data to support the use of other antiplatelet agents when aspirin is contraindicated, except in clinical areas such as transient ischemic attacks, where guidelines exist.

Treatment should continue unless a contraindication exists or arises.

Primary options

aspirin: 81-100 mg orally once daily

Plus – intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Back
ACUTE
|
pregnant
Plus – 

intensive management of cardiovascular risk factors + lifestyle modification + supportive care

Treatment recommended for ALL patients in selected patient group

Cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidemia, smoking) should be identified and aggressively managed in all patients with polycythemia vera.

Give advice on lifestyle modification (e.g., smoking cessation, weight control) to reduce the risk of developing symptoms, or to moderate the severity of symptoms that may already exist.

Offer supportive care to ensure optimum symptom management.

Consider – low molecular weight heparin

Back
ACUTE
|
pregnant
Consider – 

low molecular weight heparin

Treatment recommended for SOME patients in selected patient group

Unless contraindicated, treating low-risk patients with 6 weeks of prophylactic low molecular weight heparin (e.g., enoxaparin) postpartum is appropriate.​[119][147]

In pregnant patients with a history of severe pregnancy complications or thrombosis, low molecular weight heparin should be used throughout pregnancy.​[119][147]​​​

Data are lacking to indicate which low molecular weight heparins are best for use in these patients.

Primary options

enoxaparin: 40 mg subcutaneously once daily

OR

dalteparin: 5000 international units subcutaneously once daily

Consider – phlebotomy

Back
ACUTE
|
pregnant
Consider – 

phlebotomy

Treatment recommended for SOME patients in selected patient group

All patients should have well-controlled polycythemia vera (hematocrit <45%) before pregnancy. A lower target hematocrit is recommended during pregnancy, consistent with lower gestational ranges (e.g., first trimester <41%, second trimester <38%, third trimester <39%).[71]

If acute hematocrit control is required during pregnancy (which is less likely, owing to increased plasma volume), judicious phlebotomy may be appropriate.[119]

Carefully assess that the mother and fetus can safely tolerate phlebotomy during pregnancy. Adjust volume and frequency to tolerability.

Consider – cytoreductive therapy

Back
ACUTE
|
pregnant
Consider – 

cytoreductive therapy

Treatment recommended for SOME patients in selected patient group

All patients should have well-controlled polycythemia vera (PV; hematocrit <45%) before pregnancy. A lower target hematocrit is recommended during pregnancy, consistent with lower gestational ranges (e.g., first trimester <41%, second trimester <38%, third trimester <39%).[71]

Pregnancy is considered high risk in women with PV and any of: history of venous and/or arterial thrombosis; previous hemorrhage due to PV; previous pregnancy complications (e.g., unexplained death of a fetus at >10 weeks gestation, premature delivery at <34 weeks due to severe pre-eclampsia or eclampsia or recognized features of placental insufficiency, ≥3 unexplained consecutive miscarriages at <10 weeks gestation without abnormalities [anatomic, hormonal, chromosomal], unexplained intrauterine growth restriction, significant antepartum or postpartum hemorrhage).[71]

Peginterferon alfa-2a is the cytoreductive therapy of choice for high-risk patients who are pregnant.​[71][97]​​[119][147]​​​​ Peginterferon alfa-2a should be used as needed throughout pregnancy to control the hematocrit or marked thrombocytosis.​[119][147]​​

Toxicity with peginterferon alfa-2a is common and can be severe. Adverse events and discontinuation rates in studies were high; 22% of patients discontinued therapy due to toxicity in one open-label, phase 2 trial.[127][129]

Common adverse effects of peginterferon therapy include gastrointestinal upset, fever or flu-like symptoms. Patients may also develop weakness, weight loss, severe depression, cardiovascular symptoms, and autoimmune disease. Patients should be screened for depression and other psychiatric illnesses prior to starting peginterferon. Monitoring of toxicity (including regular thyroid function testing) is required during treatment.

Hydroxyurea should not be used in pregnant patients (particularly in the first trimester) as it is teratogenic. If possible, it should be discontinued at least 3 months before planned conception.[119] Patients receiving hydroxyurea before pregnancy should be switched to pegylated interferon. Hydroxyurea is excreted in breast milk and should be avoided in women who are breast-feeding.

High-risk obstetric care is strongly recommended.

Primary options

peginterferon alfa 2a: consult specialist for guidance on dose

children

1st line – specialist consultation

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ACUTE
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children
1st line – 

specialist consultation

Because polycythemia vera (PV) is very rare in children, there is little evidence to guide treatment.

Expert opinion suggests that the main challenge in the management of PV in children and young adults is to avoid recurrence of major thrombosis by selecting those patients who will benefit from cytoreductive and antithrombotic therapy without increasing the incidence of drug-induced adverse effects.

In asymptomatic low-risk patients no therapy is prescribed, while in high-risk patients low-dose aspirin may be used.[148] Phlebotomy may be performed until hematocrit is reduced to <45%, then repeated at regular intervals as needed. Hydroxyurea or pegylated interferon may be used as a last resort in high-risk pediatric patients, but cytoreductive therapy is seldom indicated.

Adverse effects of pegylated interferon (e.g., flu-like syndrome, neuropsychiatric symptoms, and autoimmune phenomena) can be particularly dangerous for children. Extreme caution should be exercised when prescribing aspirin to children under 12 years because of the risk of Reye syndrome.[148] Consult a specialist for guidance.

ONGOING

nonpregnant adults: high risk of thrombosis and intolerant or resistant to first- and second-line cytoreductive therapy

1st line – salvage therapy

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ONGOING
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nonpregnant adults: high risk of thrombosis and intolerant or resistant to first- and second-line cytoreductive therapy
1st line – 

salvage therapy

Options for patients unable to tolerate first- and second-line cytoreductive drugs are limited.

Enrollment in a clinical trial is preferred. Ruxolitinib (if not used previously) may be an option.[71]

Ruxolitinib is a JAK1/2 inhibitor approved for second-line use after hydroxyurea failure. Open-label phase 3 studies found ruxolitinib to be superior to standard therapy with respect to hematocrit control, splenic shrinkage, and relief of polycythemia vera-associated (PV-associated) symptoms.[91][135]​​​ The benefits of ruxolitinib were maintained at 5 years.[136][137]

Herpes zoster infections and nonmelanoma skin cancer occurred more frequently in the ruxolitinib group of phase 3 studies.[91][136][137]

Busulfan is sometimes considered for patients who are intolerant of first- and second-line drugs, or who are of a very advanced age, or with short life expectancy.[104]

The leukemogenicity of busulfan is unclear as studies have reported conflicting results.[14][97]​​​​​[120][141][142][143]​ Long-term follow-up of a randomized controlled trial suggests that sequential use of busulfan and hydroxyurea may significantly increase the risk of secondary malignancies.[143]

The National Comprehensive Cancer Network (NCCN) guidelines do not recommend the use of busulfan for PV.[71]

Primary options

ruxolitinib: 10 mg orally twice daily for 4 weeks initially, adjust dose according to response, maximum 50 mg/day

Secondary options

busulfan: consult specialist for guidance on dose

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