Approach

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

Phlebotomy, low-dose aspirin, and cytoreductive therapy are the mainstays of treatment. Cytoreduction is generally reserved for patients at high risk of thrombosis.[72]​​ The target haematocrit for phlebotomy or cytoreduction is <45%. ​There is no evidence that any of the treatments for PV effectively lower the risk of progression to post-PV myelofibrosis or acute leukaemia.[13]

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

Pregnant patients and children require specialised management, as does the presence of leukocytosis and/or thrombocytosis.

Risk stratification

Patients with PV are managed based on their risk for thrombosis. The following conventional risk stratification is commonly used:[55][67][72]​​​​​​​[98]

  • Low risk: age <60 years and no history of thrombosis

  • High risk: age ≥60 years and/or history of thrombosis

​​Some low-risk patients may be considered high risk in the presence of cardiovascular risk factors (e.g., hypertension, diabetes, hyperlipidaemia, smoking), elevated white blood cell (WBC) count, or marked thrombocytosis or haematocrit that is uncontrolled with phlebotomy.[67]

Low-risk patients

Phlebotomy and low-dose aspirin are the cornerstone of treatment for patients with low-risk PV. Cytoreductive therapy is not routinely recommended in low-risk patients.

Low-dose aspirin

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.[105]

Twice-daily low-dose aspirin may be considered for patients with refractory symptoms, or patients who are at higher risk of arterial thrombosis (including those with cardiovascular risk factors or leukocytosis).[72][98][106]

For patients with marked thrombocytosis (platelet count ≥1000 × 10⁹/L [≥1000 × 10³/microlitre]), perform coagulation tests to assess for acquired von Willebrand' syndrome. Aspirin should be used with caution or withheld in patients with acquired von Willebrand's disease because of increased risk of bleeding.[98][105]​​​​​​​​​​​

There are no data to support the use of other antiplatelet agents when aspirin is contraindicated, except in clinical settings such as transient ischaemic attacks, where guidelines exist. Clopidogrel has been suggested as a potential alternative antiplatelet agent.[72][98]

Phlebotomy

Recommended in all low-risk patients. Perform phlebotomy twice weekly (or on alternate days if haematocrit ≥60%); 250-500 mL of blood is replaced with normal saline until haematocrit is <45%.​[54][72][107]​​​​​​​ In one trial, risk of cardiovascular death or major thromboses was significantly reduced in patients with median haematocrit of 44.4% compared with those with higher haematocrit (median 47.5%).[54]​ Target haematocrit may be individualised 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).[72][98][107]

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.[67]​​[108]

Phlebotomy induces iron-limited haematopoiesis. 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 polycythaemia can emerge rapidly.[67]

Some patients may require long-term intermittent treatment.

Cytoreductive therapy

While not routinely indicated in low-risk patients, cytoreductive therapy may be considered for symptomatic low-risk PV in certain situations, including:[72]​​

  • 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

The target haematocrit for cytoreduction is <45%.

Guidelines recommend ropeginterferon alfa-2b or a clinical trial as preferred options if cytoreduction is indicated for low-risk PV.[72] One phase 2 trial suggested that ropeginterferon alfa-2b in combination with standard treatment (phlebotomy and aspirin) is more effective at maintaining haematocrit targets than standard treatment alone in low-risk patients.[109]​ After 2 years of ropeginterferon alfa-2b treatment, 83% of patients achieved a response (haematocrit <45%) compared with 59% of patients receiving standard treatment. Patients who responded to ropeginterferon alfa-2b had a 23% decrease in JAK2 V617F variant allele frequency. Treatment-related adverse effects occurred in 55% of patients in the ropeginterferon alfa-2b group compared with 6% in the standard treatment group.[110][111][112]​​​​

Hydroxycarbamide and peginterferon alfa-2a are alternatives to ropeginterferon alfa-2b for patients with low-risk PV.[72]

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 haematologist, taking into account patient preferences, toxicity profiles, and individual treatment goals.

High-risk patients: cytoreductive therapy

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 haematocrit control, concurrent with cytoreductive therapy, in the acute setting).​​​[67][72][98][108]​​​​​​​​​​ An experienced haematologist should manage all high-risk patients.

Hydroxycarbamide and ropeginterferon alfa-2b are recommended as first-line cytoreductive therapy; peginterferon alfa-2a is an option for younger patients and pregnant patients.[72] Ruxolitinib may be a second-line or salvage option. Choice of agent should take into account toxicity profiles and individual treatment goals.​[98]​​​

Systemic anticoagulation is recommended (in addition to cytoreductive therapy) for patients with active thrombosis.[72][98] 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 individualised, taking into account the risks and benefits.

Hydroxycarbamide

  • A preferred first-line cytoreductive agent.[72] Hydroxycarbamide decreases the rate of thrombosis in high-risk patients.[113][114][115][116][117][118]

  • ​Generally, it is safer to titrate the hydroxycarbamide dose over several weeks to a target haematocrit of <45% (with phlebotomy as required).[54] Some physicians titrate to normalise WBC count and platelet count.[72] Blood counts should be monitored every 1-2 weeks until stable, then as clinically indicated.

  • Hydroxycarbamide 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.

  • Hydroxycarbamide is teratogenic and therefore should be avoided in pregnant patients (particularly in the first trimester) and in those planning to conceive.[119]​ It is also potentially leukaemogenic; therefore, an alternative cytoreductive agent (e.g., a pegylated interferon) may be considered in younger patients.​[14][98][120][121][122]​​​​ The potential leukaemogenicity of hydroxycarbamide is debated.[123]

Ropeginterferon alfa-2b

  • A monopegylated interferon alfa-2b with a long elimination half-life, ropeginterferon alfa-2b is a preferred first-line cytoreductive agent.[72] It may be an option for younger patients with PV.[98]

  • The dose of ropeginterferon alfa-2b should be titrated over several weeks to a target haematocrit of <45%. 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 non-inferior to hydroxycarbamide in terms of complete haematological response at 12 months, and superior to hydroxycarbamide at 2 and 3 years follow-up.[124]​ Reduction in the frequencies of non-Janus kinase 2 (JAK2) mutant alleles was reported. Analysis of patient-specific treatment goals at 6 years found that 81% of patients receiving ropeginterferon alfa-2b had a haematocrit of <45% without the need for phlebotomy, compared with 60% receiving the control (mostly hydroxycarbamide). A JAK2 allele burden of <1% was recorded in approximately 21% of patients in the ropeginterferon alfa-2b group compared with 1% of patients in the control group.[125]

  • 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

  • A preferred option for younger patients, in particular women of reproductive age and pregnant patients.[72][98] 

  • Peginterferon alfa-2a is effective (76% to 95% complete haematological responses [CHRs]) and appears to be better tolerated than non-pegylated interferon.[67][126][127][128]

  • 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 hydroxycarbamide after 2 years' follow-up.[129]

  • Peginterferon alfa-2a has demonstrated efficacy in hydroxycarbamide-resistant or -intolerant patients with PV.[130]

  • Clonal (molecular) remissions have been reported with peginterferon alfa-2a, including some (18% to 19%) that are complete.[126][127]​​ However, it is less effective at reducing mutant allele burden in patients with non-JAK2-mutant clones, such as mutations in TET2 or other epigenetic regulators (e.g., ASXL1, EZH2, DNMT3A, or IDH1/2).[131][132]

  • 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.[128][130]

  • 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.

High-risk patients: resistance or intolerance to initial cytoreductive therapy

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:[72]

  • 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

Formal consensus criteria for resistance or intolerance to hydroxycarbamide have been developed, which are used in clinical trials.[99][104]​​​​ See Criteria. However, these thresholds might not be suitable in practice, and clinical judgment should be used for response assessment focused on symptom improvement and quality of life.[72][133][134]​​​​

Second-line treatment options include ruxolitinib or, if not used already, a pegylated interferon or hydroxycarbamide.[72][98]​​​[108][135]​​​​

Ruxolitinib

  • A JAK1/2 inhibitor approved for second-line use after hydroxycarbamide failure.

  • Open-label phase 3 studies found ruxolitinib to be superior to standard therapy with respect to haematocrit control, splenic shrinkage, and relief of PV-associated symptoms.[92][136]​​​​​​​ The benefits of ruxolitinib were maintained at 5 years.[137][138]

  • Switching patients with well-controlled PV, but persistent symptoms, from hydroxycarbamide to ruxolitinib failed to improve PV-related symptoms in a phase 3 randomised, double-blind, double-dummy study.[139]

  • One meta-analysis reported numerically lower, but not statistically significant, rates of thrombotic events with ruxolitinib than with comparator (best available therapy).[140]

  • There are reports of complete molecular remission with ruxolitinib in a minority of patients with PV.[141] In one open-label randomised phase 2 trial of patients intolerant or resistant to hydroxycarbamide, molecular response (>50% reduction in JA2V617F variant allele frequency) was larger, and more frequent, in ruxolitinib-treated patients than in patients assigned to best available therapy (56%; median follow-up 48 months vs. 25%; 36 months, respectively).[135]​ Molecular response was associated with improved event-free, progression-free, and overall survival in the entire study cohort and in patients treated with ruxolitinib, but not in the best available therapy group.

  • Herpes zoster infections and non-melanoma skin cancer occurred more frequently in the ruxolitinib group of phase 3 studies.[92][137][138]

Salvage therapy for high-risk patients

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.[72]

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.[108] The leukaemogenicity of busulfan is unclear as studies have reported conflicting results.[14]​​[98]​​[121][142][143][144]​​​​​​ ​Long-term follow-up of a randomised controlled trial suggests that sequential use of busulfan and hydroxycarbamide may significantly increase the risk of secondary malignancies.[144] The National Comprehensive Cancer Network (NCCN) guidelines do not recommend the use of busulfan for PV.[72]​ 

Radioactive phosphorus, chlorambucil, and pipobroman should not be used; these treatments are associated with a high risk of leukaemic transformation.[118][121][143]​​

Patients with leukocytosis

A correlation between thrombosis risk and leukocytosis in patients with PV has been reported in some analyses; however, uncertainty remains.[56][60][145]​

Some clinicians attempt to use hydroxycarbamide to normalise WBC count in high-risk patients, but this approach has not been evaluated in prospective trials. There is no evidence to support the use of cytoreduction to normalise the WBC count in low-risk patients.[13]

Patients with thrombocytosis

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

No particular level of thrombocytosis has been demonstrated to correlate accurately with the risk of thrombosis.[61][62][63]​​​​​​​ Therefore, strict control of platelets to a specific level cannot be endorsed for this purpose.[13][48]​​​​​​​

Hydroxycarbamide 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.

Anagrelide can be considered as an adjunct to hydroxycarbamide in patients with marked thrombocytosis if hydroxycarbamide alone does not adequately normalise platelet counts or is not tolerated at the required dose.[67] Data on the use of anagrelide in PV are limited; one retrospective case series supports its efficacy in combination with hydroxycarbamide.[146]

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

Low-dose aspirin and phlebotomy

Patients with marked thrombocytosis (platelet count ≥1000 × 10⁹/L [≥1000 × 10³/microlitre]) should avoid aspirin; aspirin increases the risk of bleeding due to acquired von Willebrand's disease.​[105]​​​​

Once the platelet count is reduced, and there is no evidence of acquired von Willebrand's disease (i.e., ristocetin cofactor activity >30%), patients should receive daily low-dose aspirin.​[105]​​​​​ 

In the acute setting, phlebotomy may be combined with cytoreductive therapy to achieve rapid haematocrit control.[98]​​​

Pregnant patients

PV more commonly affects those who are middle-aged or older; therefore, pregnancy in PV patients is uncommon.[11][147]

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

All patients should have well-controlled PV (haematocrit <45%) before pregnancy. A lower target haematocrit is recommended during pregnancy, consistent with lower gestational ranges (e.g., first trimester <41%, second trimester <38%, third trimester <39%).[72]

If acute haematocrit control is required during pregnancy (which is less likely, owing to increased plasma volume), judicious phlebotomy may be appropriate.[119] Carefully assess whether the mother and fetus can safely tolerate phlebotomy during pregnancy, and adjust volume and frequency to tolerability.

Unless contraindicated, treating all patients with daily low-dose aspirin during the pregnancy, and with 6 weeks of prophylactic low molecular weight heparin (LMWH; e.g., enoxaparin, dalteparin) postnatal, is appropriate. Low-dose aspirin can be resumed upon completion of LMWH course.[72][119][148]​ 

High-risk pregnant patients

Pregnancy is considered high risk in women with PV and any of the following:[72]

  • History of venous and/or arterial thrombosis

  • Previous haemorrhage due to PV

  • Previous pregnancy complications

    • Unexplained death of a fetus at >10 weeks gestation

    • Premature delivery at <34 weeks due to severe pre-eclampsia or eclampsia or recognised features of placental insufficiency

    • ≥3 unexplained consecutive miscarriages at <10 weeks gestation without abnormalities (anatomical, hormonal, chromosomal)

    • Unexplained intrauterine growth restriction

    • Significant antepartum or postnatal haemorrhage

In pregnant patients with a history of severe pregnancy complications or thrombosis, LMWH should be used throughout pregnancy and pegylated interferon used as needed to control the haematocrit or marked thrombocytosis.[119][148]​ 

Peginterferon alfa-2a is the cytoreductive therapy of choice for high-risk patients who are pregnant.[72][98][119][148]​​​ Peginterferon alfa-2a should be used as needed throughout pregnancy to control the haematocrit or marked thrombocytosis.[119][148]

Hydroxycarbamide 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.[148]​ Patients receiving hydroxycarbamide before pregnancy should be switched to pegylated interferon. Hydroxycarbamide is excreted in breast milk and should be avoided in women who are breastfeeding.

Children

Because 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.[149] Phlebotomy may be performed until haematocrit is reduced to <45%, then repeated at regular intervals as needed. Hydroxycarbamide or pegylated interferon may be used as a last resort in high-risk paediatric 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’s syndrome.[149]

Use of this content is subject to our disclaimer