guidelines

A guideline for the diagnosis and management of

polycythaemia vera. A British Society for Haematology Guideline

Mary Frances McMullin,1 Claire N. Harrison,2 Sahra Ali,3 Catherine Cargo,4 Frederick Chen,5 Joanne Ewing,6
Mamta Garg, Anna Godfrey, Steven Knapper S, Donal P. McLornan,2
7 8 9
Jyoti Nangalia,10 Mallika Sekhar,11
12 13
Frances Wadelin, Adam J. Mead and on behalf of the BSH Committee
1
Centre for Medical Education, Queen’s University, Belfast, 2Guy’s and St Thomas’ NHS Foundation Trust, London, 3Castle Hill
Hospital, Hull and East Yorkshire Hospitals NHS Trust, Hull, 4Leeds Teaching Hospitals NHS Trust, Leeds, 5The Royal London
Hospital, Bart’s Health NHS Trust, London, 6Birmingham Heart of England NHS Foundation Trust, Birmingham, 7University
Hospital of Leicester NHS Trust, Leicester (BSH representative), 8Department of Haematology and Haematopathology and Oncology
Diagnostic Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge, 9Cardiff University School of Medicine,
Cardiff, 10Wellcome Trust Sanger Institute, Cambridge, 11Royal Free London NHS Foundation Trust, London, 12Nottingham
University Hospital, Nottingham, and 13MRC Weatherall, Institute of Molecular Medicine, University of Oxford, Oxford, UK

Keywords: Diagnosis, management, polycythaemia to February week 3 2017. Exclusions included articles not in
vera, risk stratification, cytoreductive therapy. English, studies not in humans, single case reports and case
series of under 5 cases. A total of 6062 articles were identi-
fied which, with exclusions and duplications, resulted in
1215 articles which were reviewed.
Methodology
This guideline was compiled according to the British Society Review of manuscript
for Haematology (BSH) process at b-s-h.org.uk. The Grading
of Recommendation Assessment, Development and Evalua- Review of the manuscript was performed by the BSH Guide-
tion (GRADE) nomenclature was used to evaluate levels of lines Committee General Haematology Task Force, the BSH
evidence and to assess the strength of the recommendations. Guidelines Committee and the General Haematology Sound-
The GRADE criteria can be found at http//:www.gradework ing Board of BSH. It was also placed on the members section
inggroup.org. of the BSH website for comment. A patient representative
from MPN-Voice (www.mpnvoice.org.uk) participated in the
guideline writing meeting. The guideline has been reviewed
Literature review details by MPN-Voice; this organisation does not necessarily
The literature review was conducted on 2 March 2017. Data- approve or endorse the contents.
bases searched include MEDLINE(OVID), Embase (OVID)
and CENTRAL(The Cochrane library) using the search terms Introduction
(and relevant MESH terms): polycythaemia vera, erythrocy-
tosis, familial, high oxygen affinity haemoglobin, defects of The previous guideline was published in 2005 (McMullin
oxygen sensing pathway, diagnosis, investigation, molecular, et al, 2005) with an amendment in 2007 (McMullin et al,
mutation, JAK2, MPL, CALR, bone marrow, red cell mass, 2007) to update the diagnostic criteria following the discov-
erythropoietin, risk, management, treatment, cytoreduction, ery of the JAK2 mutation in patients with polycythaemia vera
venesection, hydroxyurea, interferon, busulfan, pipobroman, (PV). Since that time, there has been a considerable amount
radioactive phosphorus, aspirin, anagrelide, ruxolitinib, of research in the area concerning diagnostics, risk stratifica-
thrombosis, haemorrhage, pregnancy, pruritus, surgery and tion, new agents and reinvestigation of existing agents. It was
management. The search covered the period from 2005, the therefore decided to evaluate the literature to formulate guid-
date of last version of the guideline (McMullin et al, 2005), ance on the diagnostic pathway for erythrocytosis, risk strati-
fication of PV, management of PV (including specific
situations) and the management of secondary erythrocytosis.
Here we provide evidence-based guidance on diagnosis, risk
Correspondence: BSH Administrator, British Society for stratification and management of PV. Our review of the evi-
Haematology, 100 White lion Street, London N1, 9PF, UK. dence led us to some differences in diagnostic criteria and
E-mail: [email protected] risk stratification than have been proposed by other

First published online 27 November 2018 ª 2018 British Society for Haematology and John Wiley & Sons Ltd
doi: 10.1111/bjh.15648 British Journal of Haematology, 2019, 184, 176–191
 Guidelines

international organisations. We discuss the reasons for this. and monocytosis, would be indications for bone marrow
An accompanying guideline looks at management of specific assessment.
situations in PV and management of secondary erythrocyto-
sis (McMullin et al, 2018).
Renal and liver function
A number of renal and hepatic diseases can cause erythrocy-
The diagnostic pathway for investigation of an
tosis. Serum calcium levels should also be determined to
erythrocytosis
exclude a parathyroid adenoma/carcinoma, which rarely
Patients with a persistently raised venous haematocrit (Hct) causes secondary erythrocytosis.
(males, >0
52; females, >0
48) should be investigated. As sug-
gested in our previous guideline (McMullin et al, 2005) and
Arterial oxygen saturation (SaO2)/carboxyhaemoglobin
confirmed in recent literature, Hct has been consistently
shown to perform better in identifying patients with a raised Identifying tissue hypoxia, a cause of secondary erythrocyto-
red cell mass (RCM) than haemoglobin concentration sis, can be achieved most simply by using pulse oximetry in
(Alvarez-Larr
an et al, 2012; Ancochea et al, 2014). the clinic. An SaO2 of <92% has been shown to be associated
Patients should be investigated according to the proposed with an absolute erythrocytosis (Berlin, 1975). Clinicians
algorithm (Fig 1). Investigation requires knowledge of diag- should however be aware of three situations of hypoxic ery-
nostic criteria for both PV and potential secondary causes throcytosis where this testing is unreliable and will give a
of erythrocytosis (Tables 1 and 2). A detailed history, exam- normal result. These are: carbon monoxide poisoning, high
ination and stage 1 investigations (listed below) should oxygen affinity haemoglobins and sleep apnoea syndrome.
identify a potential cause in the majority of patients, Those with suspected high oxygen affinity haemoglobins
although a proportion will require more extensive testing should undergo genetic testing as described below. In those
and, in some cases, a cause may not be found (idiopathic with suspected sleep apnoea (heavy snoring with daytime
erythrocytosis). The potential for dual pathology should also somnolence or increased body mass index >30 kg/m2), refer-
be considered. ral should be made to a respiratory or sleep physician.
Carboxyhaemoglobin (COHb) levels are significantly
higher in smokers compared with non-smokers and cigarette
Initial assessment
consumption has been shown to be directly related to COHb
levels (Castleden & Cole, 1975). Testing can therefore be per-
Clinical history and examination
formed at baseline where smoking is suspected.
A detailed clinical history and examination are essential and,
in the absence of a molecular marker of disease, will deter-
Serum ferritin
mine further investigations and management. Particular
attention should be paid to the drug history (prescribed and Low serum ferritin levels are common in PV patients and
recreational), smoking, alcohol consumption and body habi- iron deficiency can mask the presentation of PV, giving a
tus. Systematic questioning should elicit symptoms related to misleadingly low Hct because iron deficiency limits erythro-
other potential secondary causes of erythrocytosis (see poiesis and hypochromic microcytosis develops.
Table 2). A proportion of patients, who have a clear sec-
ondary cause for their erythrocytosis, may not need any fur-
Serum erythropoietin
ther investigations.
Erythrocyte production is controlled by the hormone ery-
thropoietin (EPO). Measurement of serum EPO can provide
Stage 1 Investigations
information on potential causes of erythrocytosis and help
stratify further testing (see Fig 1). EPO levels are commonly
Full blood count/blood film
high in hypoxic conditions or when erythrocytosis is sec-
The full blood count analysis will not only confirm a raised ondary to exogenous administration or endogenous overpro-
Hct but will also identify neutrophilia and thrombocytosis, duction. In contrast EPO levels are typically low in PV,
which are common in JAK2 V617F-positive PV and part of although their diagnostic utility in this setting is limited in
the criteria for JAK2-negative PV (Table 1). As smokers have the era of JAK2 mutation testing (Ancochea et al, 2014).
a significantly higher neutrophil count than non-smokers
(Whitehead et al, 1995), neutrophilia is defined as
JAK2 V617F mutational analysis
>12
5 9 109/l in this patient group.
A blood film should be reviewed in all patients to look for The identification of JAK2 mutations in almost all PV
any atypical features. In those with confirmed PV, abnormal- patients has revolutionised the diagnosis of PV. The JAK2
ities, such as circulating blasts, leucoerythroblastic features V617F mutation can be found in over 95% of PV patients

ª 2018 British Society for Haematology and John Wiley & Sons Ltd 177
British Journal of Haematology, 2019, 184, 176–191
Guidelines

Persistently raised haematocrit M >0·52, F >0·48

Clinical history/examinaon/1 invesgaons

Includes EPO

Clear secondary +
cause JAK2 V617F mutaonal Polycythaemia vera
analysis (PB)

Significant, JAK2-unmutated erythrocytosis

Consider red cell mass to confirm (if Hct<0·6/0·56)
Consider USS abdomen

Is there a likely
+ secondary cause from
Stop Invesgaons
clinical history*,
and correct cause if
stage 1/2 +
possible
invesgaons, USS
abdomen†?

Stafy by serum
erythropoien

+
High Normal Low

Consider further invesgaon for secondary cause if clinically suspected

-referral to respiratory/renal, sleep studies

CT head and neck

-Cerebellar JAK2 exon 12 mutaon analysis
haemangioblastoma Consider bone marrow biopsy
-Meningioma
-Parathyroid
carcinoma/adenoma –

Indicaon for further genec tesng? – Young onset, posive family history

+ –

Sequencing of panel of genes associated with

Idiopathic erythrocytosis
congenital erythrocytosis (NGS)
HBAA, HBB, BPGM, VHL, EGLN1, EPAS1

†USS abdomen –
*Clinical History - Renal disease
Smoking -Hydronephrosis
Alcohol excess -Renal cysts
Chronic lung disease -Renal artery stenosis
Cyanoc heart disease Tumours –
Sleep apnoea/obesity -Hepatocellular
Renal disease carcinoma
Drug Induced – -Renal cell carcinoma
-testosterone -Uterine Leiomyoma
-growth hormone
-EPO
-Diurecs

Figure 1. Algorithm for the investigation of an erythrocytosis. CT, computed tomography; EPO, erythropoietin; F, female; Hct, haematocrit; M,
male; NGS, next generation sequencing; PB, peripheral blood; USS, ultrasound scan.

178 ª 2018 British Society for Haematology and John Wiley & Sons Ltd
British Journal of Haematology, 2019, 184, 176–191
 Guidelines

TABLE 1. Diagnostic criteria for erythrocytosis

Recommended diagnostic criteria for PV
JAK2-positive polycythaemia vera (requires both criteria)
A1 High haematocrit (>0
52 in men, >0
48 in women) OR raised red cell mass (>25% above predicted)
A2 Mutation in JAK2
JAK2-negative polycythaemia vera (requires A1-A4 plus another A or two B criteria) *
A1 Raised red cell mass (>25% above predicted) OR haematocrit ≥0
60 in men, ≥0
56 in women
A2 Absence of mutation in JAK2
A3 No cause of secondary erythrocytosis
A4 Bone marrow histology consistent with polycythaemia vera
A5 Palpable splenomegaly
A6 Presence of an acquired genetic abnormality (excluding BCR-ABL1) in the haematopoietic cells
B1 Thrombocytosis (platelet count >450 3 109/l)
B2 Neutrophil leucocytosis (neutrophil count >10 3 109/l in non-smokers, ≥12
5 3 109/l in smokers)
B3 Radiological evidence of splenomegaly
B4 Low serum erythropoietin

*This is a very rare clinical entity.

(James et al, 2005) and an exon 12 mutation in most method for detection. Abdominal ultrasound can also
remaining patients (Scott et al, 2007). Testing for JAK2 exclude secondary causes of erythrocytosis, particularly renal
V617F in peripheral blood is sensitive and bone marrow and hepatic pathology, including hepatocellular carcinoma.
samples are not required to identify this (Takahashi et al, Further testing can be stratified according to the EPO level
2013). Testing for JAK2 V617F is advised as a stage 1 investi- measured during stage 1 investigations.
gation and should confirm the diagnosis the vast majority of
PV patients. Separate guidance is available for assays used for Normal or low EPO level
detection of JAK2 mutations (Bench et al, 2013).
JAK2 exon 12 analysis
Further investigations in JAK2 V617F-negative Compared with JAK2 V617F, patients with exon 12 mutated-
erythrocytosis PV tend to be younger, with higher haemoglobin concentra-
Further investigations are warranted in those patients with a tions, lower white blood cell (WBC) and platelet counts, and
persistent, significant erythrocytosis if JAK2 V617F studies an isolated increase in erythropoiesis without granulocytic or
are negative and a secondary cause is not immediately appar- megakaryocytic morphological abnormalities (Scott et al,
ent (See Fig 1). Secondary causes must be considered because 2007; Passamonti et al, 2011). In contrast to JAK2 V617F
PV is rare in the absence of a JAK2 V617F mutation. testing, a discrepancy between exon 12 mutant allele burden
in bone marrow and peripheral blood has occasionally been
described (Kjær et al, 2012).
Red cell mass studies
Patients with Hct >0
60 (males) or >0
56 (females) can be
Bone marrow biopsy
assumed to have an absolute erythrocytosis, but in others
RCM studies can be helpful to confirm an absolute erythrocy- Bone marrow histology may be helpful in distinguishing PV
tosis. An RCM more than 25% above the mean predicted value from secondary erythrocytosis (Thiele et al, 2005). Bone mar-
is diagnostic of an absolute erythrocytosis (Pearson et al, row aspiration in PV typically reveals markedly increased ery-
1995). Those with a raised Hct but an RCM within the normal thropoiesis with moderate to marked increase in
range have an apparent erythrocytosis. A relative erythrocyto- granulopoiesis and megakaryopoiesis; widely variable
sis, found in states of dehydration, can be confirmed when the megakaryocyte size, including large forms with hyperlobated
RCM is within the normal range and plasma volume is below nuclei; and absent iron stores. The bone marrow trephine
normal. Patients with a relative or apparent erythrocytosis biopsy sections show hypercellularity, trilineage expansion of
require no further investigation. It is noted however, that due haemopoiesis (rarely preferentially erythroid) and normoblas-
to the many drawbacks of this test including cost and labour, tic erythropoiesis. Granulocytic maturation may be left-
access to RCM studies is variable nationally. shifted and disorderly; megakaryocytes show increased varia-
tion in size, often with a predominance of large forms with
uneven or reduced nuclear lobulation, and megakaryocyte
Abdominal ultrasound clusters are common. Reticulin is increased in a minority of
Radiological splenomegaly is a minor criterion for JAK2 patients [up to World Health Organization (WHO) grade 1
V617F-negative PV (Table 1) and ultrasound is the simplest in most cases].

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Guidelines

Table 2. Causes of erythrocytosis High EPO level

Primary Secondary A raised EPO level should lead to a thorough search for sec-
ondary causes of erythrocytosis (Table 2), which may require
Congenital Congenital
EPO receptor Defects in oxygen sensing pathway additional supplementary investigations (Fig 1).
mutations Chuvash erythrocytosis (VHL
mutation)
Imaging
Mutations in EGLN1 or EPAS1
Left shift of Hb-oxygen dissociation curve Further imaging (e.g. head and neck computed tomography)
High oxygen-affinity haemoglobin is indicated in this setting if a cause for the high EPO has
2,3-BPG deficiency (BPGM mutations) not been identified. Imaging should aim to exclude rare
Acquired Acquired tumours, such as a cerebellar haemangioblastoma, pheochro-
Polycythaemia Hypoxia driven
mocytoma, meningioma or a parathyroid tumour, all of
vera Central hypoxic process
which can rarely cause erythrocytosis.
Chronic lung disease
Right-to-left cardiopulmonary vascular
shunts Gene sequencing for congenital erythrocytosis
Carbon monoxide poisoning
Smoker’s erythrocytosis A number of germline mutations in genes involved in
Hypoxic states (sleep apnoea/altitude) oxygen sensing, erythropoiesis and oxygen transport have
Local renal hypoxia now been implicated in patients with otherwise unex-
Renal artery stenosis plained erythrocytosis. These include mutations in the
End-stage renal disease EPO receptor and genes in the oxygen sensing pathway
Hydronephrosis (VHL, EGLN1, EPAS1), high oxygen affinity haemoglobi-
Renal cysts (polycystic kidney disease)
nopathies caused by mutations in the globin genes HBA1,
Pathological EPO production
HBA2, HBB, and 2,3-bisphosphoglycerate deficiency as a
Tumours
result of BPGM mutations (Bento et al, 2014). These
Hepatocellular carcinoma
Renal cell cancer patients can present with low, normal or high EPO levels;
Cerebellar haemangioblastoma high affinity haemoglobins and 2,3-BPG deficiency also
Parathyroid carcinoma/adenoma cause a left shift of the oxygen dissociation curve. In the
Uterine leiomyoma past, this group of mutations was detected by Sanger
Pheochromocytoma sequencing of individual genes, in an order directed by
Meningioma EPO levels and P50 analysis, but this approach is labour-
Drug-associated intensive and time-consuming (Bento et al, 2014). More
Erythropoietin recently, next generation sequencing-based targeted panels
Use of androgen preparations
have been developed to assess established and novel genes
Diuretics
implicated in erythrocytosis (Camps et al, 2016), negating
Alcohol excess
the need for P50 testing. A targeted panel should be per-
Postrenal transplant erythrocytosis
Idiopathic formed in patients in whom congenital erythrocytosis is
erythrocytosis suspected, particularly young patients or those with a
family history.
EPO, erythropoietin.

Diagnostic criteria for polycythaemia vera

Presence of an acquired genetic abnormality is a
Presentation
major criterion for JAK2-negative PV and the presence
of an abnormal karyotype can therefore support this Polycythaemia vera (PV) presents at a median age of
diagnosis. An acquired SH2B3 (LNK) mutation would 60 years with a slight male predominance. Patients can pre-
also support the diagnosis. More recently, mutations in a sent with arterial or venous vascular occlusive events,
number of other genes, most commonly TET2 and microvascular disturbances or, occasionally, haemorrhage.
DNMT3A, have been reported in PV (Delic et al, 2016) Splenic pain and/or enlargement, pruritus, gout and consti-
These gene mutations are not, however, disease-specific tutional symptoms, such as fatigue, may be present. Alterna-
and have also been reported in healthy individuals (Gen- tively, asymptomatic patients may be identified incidentally
ovese et al, 2014; Jaiswal et al, 2014), limiting their following a full blood count. All patients who are newly diag-
application in the diagnostic setting, particularly when nosed with PV should be discussed in a multidisciplinary
found in isolation. team setting.

180 ª 2018 British Society for Haematology and John Wiley & Sons Ltd
British Journal of Haematology, 2019, 184, 176–191
 Guidelines

The recommended diagnostic criteria for JAK2-positive and myelofibrotic or leukaemic transformation and survival, but
the very rare JAK2-negative PV are given in full in Table 1. no difference in rate of thrombosis. Hct thresholds of 0
48/
0
49 (females/males) were subsequently proposed to discrimi-
nate ET from PV in the WHO 2016 revision (Arber et al,
Role of the bone marrow biopsy in JAK2
2016).
V617F-positive patients
The proposed BSH Hct-based thresholds have good speci-
Although the WHO classification considers histology to be ficity but will miss a minority of patients with a raised RCM.
useful in distinguishing PV from other myeloproliferative By lowering the Hct threshold it may be possible to identify
neoplasms (MPNs) (Arber et al, 2016), several studies have patients with histology more typical of PV who may have
reported high rates of non-consensus or failure to reach a certain adverse outcomes, but these findings have not yet
histological diagnosis in patients with PV (Koopmans et al, been reproduced independently. It is unknown whether man-
2011; Madelung et al, 2013) (Alvarez-Larr
an et al, 2014a) agement of any of these patients using a strict Hct target
Given the uncertain utility of bone marrow histology in the benefits their vascular risk. However, in patients with a JAK2
diagnosis of uncomplicated PV, it is not mandatory in all V617F mutation and borderline Hct levels (especially males
patients, but should be considered if there are atypical fea- with Hct 0
48–0
52), the possibility of true erythrocytosis
tures, such as marked splenomegaly or a history of splanch- should be considered, especially if the patient is at high risk
nic vein thrombosis, where it is necessary to establish if there of vascular events. Options in this group include performing
is an occult MPN. The degree of baseline fibrosis can also be an RCM study to clarify the diagnosis or, pragmatically,
ascertained, which, as discussed below, may have a prognos- managing the patient with a Hct target as for PV.
tic role. Bone marrow biopsy may nonetheless be useful in It should also be noted that Hct is a poor surrogate of
those patients likely to have a long disease history, as a base- RCM in patients who have had splanchnic vein thrombosis
line sample for comparison in the event of suspected disease (Lamy et al, 1997), and these high-risk patients are best
transformation. Abnormal karyotype and other molecular managed with standard blood count targets regardless of
abnormalities (e.g. TET2 mutations) have been reported in blood count parameters at diagnosis. Hct is also reduced by
PV and some may have prognostic value (Delic et al, 2016; pregnancy and gestation-specific ranges should be used when
Cerquozzi et al, 2017) but these tests are not routinely considering the distinction between PV and ET in a patient
required at diagnosis. presenting during pregnancy.

Differentiation of JAK2 V617F-positive PV from JAK2 V617F allele burden

other MPNs
Quantitative assessments of the JAK2 V617F allele burden in
In patients with a JAK2 V617F mutation, haemoglobin con- peripheral blood granulocytes have shown that this parame-
centration and/or Hct are currently used as a surrogate for ter tends to be higher in PV than ET. A higher mutant allele
RCM to distinguish between PV and essential thrombo- burden correlates with certain clinical features at presenta-
cythaemia (ET) (Arber et al, 2016), but Hct has the better tion, including higher haemoglobin levels, higher WBC
accuracy in predicting RCM (Alvarez-Larr
an et al, 2012; counts, lower platelet counts, lower mean cell volume
Ancochea et al, 2014). Concerns have however been raised (MCV), lower serum ferritin and EPO, more splenomegaly
that distinguishing PV from ET based on blood count and more pruritus (Dupont et al, 2007; Tefferi et al, 2007;
thresholds alone may fail to identify a subgroup of patients Vannucchi et al, 2007; Passamonti et al, 2010). However,
with “masked” PV, who may be better managed as PV rather there is no validated threshold at which JAK2 V617F allele
than ET. burden can confirm or refute a diagnosis of PV and this
The definition of masked PV has been inconsistent across investigation is not recommended routinely.
studies. When using a raised RCM to define an erythrocyto-
sis, studies have shown that a Hct threshold of 0
52 in males
Low level JAK2 V617F allele burden
will fail to identify approximately 20% of male patients with
a raised RCM, whilst the threshold of 0
48 in women is more A low level JAK2 V617F mutation (allele burden <1–3%)
sensitive (Alvarez-Larr
an et al, 2012). These ‘‘masked’’ PV should be interpreted in the context of clinical, haematologi-
patients were reported to have similar outcomes to those cal and other laboratory findings (Bench et al, 2013). If the
with “overt” PV when managed equivalently (Alvarez-Larr
an result is reproducible and does not represent a false positive,
et al, 2016). this finding may provide support for a diagnosis of a PV in
By contrast, other studies have defined masked PV as a patient with otherwise unexplained, significant erythrocyto-
those patients who did not meet the haemoglobin-based sis (Perricone et al, 2017). However, the JAK2 V617F muta-
thresholds for PV but did meet the other WHO criteria, tion has been identified in normal individuals, often at a low
mainly bone marrow histology and JAK2 status. Patients allele burden, with a frequency that increases with age (Gen-
meeting this definition had poorer outcomes in terms of ovese et al, 2014; Jaiswal et al, 2014). Caution is therefore

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British Journal of Haematology, 2019, 184, 176–191
Guidelines

warranted and comprehensive investigations should exclude established. In the ECLAP study, age >65 years was associ-
an alternative secondary or congenital cause of erythrocyto- ated with inferior survival and age >70 years was associated
sis. The test should preferably be repeated within 3– with increased incidence of leukaemia/myelodysplasia
6 months, and clinical assessment for other features of an (Marchioli et al, 2005). In the International Working Group-
MPN, e.g. splenomegaly, bone marrow histological features, Myeloproliferative Neoplasms Research and Treatment
and screening for an additional mutation in JAK2 exon 12 (IWG-MRT) study, age>61 years was associated with inferior
may be helpful. overall and leukaemia-free survival (Tefferi et al, 2013).
Longer disease duration has been associated with increased
risk of myelofibrotic transformation (Marchioli et al, 2005).
Recommendations
Leucocytosis with WBC count ≥15 9 109/l is associated with
• In patients with persistent, significant and unexplained an inferior leukaemia-free survival. A prior history of venous
erythrocytosis, testing for JAK2 V617F is recommended, thrombosis also impacts negatively on overall survival. The
using a peripheral blood sample and an assay sufficiently IWG-MRT Prognostic Score uses these three parameters
sensitive to detect a mutant allele burden as low as 1–3%. (age, WBC count and thrombotic history) to delineate dis-
(GRADE 1B) tinct risk groups for overall survival (Tefferi et al, 2013), but
this prognostic score has not been independently validated in
prospective studies.
Risk stratification in PV Several other clinical and laboratory variables have been
reported to influence overall survival and/or risk of disease
The principal aims of risk stratification in PV are a) to select
transformation. The presence of splenomegaly in PV patients
patients at higher risk of thrombosis for consideration of
has been associated with shorter overall survival and
cytoreductive therapy and b) to provide the most accurate
increased risk of transformation to both myelofibrosis (MF)
information to patients on the risks and implications of a
and acute myeloid leukaemia (AML) (Abdulkarim et al,
diagnosis of PV.
2011). The presence of an abnormal karyotype adversely
impacts overall and leukaemia-free survival (Tefferi et al,
Thrombosis and bleeding risk 2013). A raised lactate dehydrogenase (LDH) level and the
presence of reticulin fibrosis at diagnosis predict a higher rate
At diagnosis, in the largest prospective study to date, the of transformation to MF but not to AML (Alvarez-Larr
an
European Collaboration on Low-Dose Aspirin in Poly- et al, 2009) (Barbui et al, 2012). Prospective analysis indi-
cythaemia Vera (ECLAP), age ≥65 years and a prior history cates that a JAK2 mutant allele burden of >50% is also asso-
of thrombosis were found to be the most important predic- ciated with increased risk of MF (but not of AML or
tors of cardiovascular events (Marchioli et al, 2005). A base- thrombosis) (Passamonti et al, 2010) but the clinical utility
line WBC count of >15
0 9 109/l is a significant predictor of of this measurement is not yet well-established. Although
thrombosis, particularly an increased risk of myocardial JAK2 exon12-mutated disease has a subtly different clinical
infarction (Landolfi et al, 2007); however, prognostic models phenotype to JAK2 V617F-driven PV (higher haemoglobin
including leucocytosis have not been prospectively validated. concentration, lower WBC count), there appears to be no
Cardiovascular risk factors (smoking, diabetes mellitus, arte- difference in long-term prognosis (Passamonti et al, 2011).
rial hypertension, hypercholesterolaemia) also contribute to Targeted gene sequencing is a rapidly advancing area;
thrombotic risk in PV (Barbui et al, 2017) (Landolfi et al, approximately 15% of PV patients have mutations of ≥1 of
2007) (Gangat et al, 2007). Once treatment is initiated, car- ASXL1, SRSF2 and IDH2 and these patients have a reduced
diovascular events occur more frequently in patients with less rate of overall survival in univariate analysis (Tefferi et al,
stringent Hct control (Marchioli et al, 2013) and when the 2016).
WBC count remains elevated >11 9 109/l (Barbui et al,
2015). A relationship between thrombocytosis (either at diag-
nosis or follow-up) and thrombotic risk has not been estab- Recommendations: risk stratification
lished in PV (Di Nisio et al, 2007), but extreme • Age and thrombotic history should be used to define
thrombocytosis (≥1500 9 109/l) is associated with increased risk groups for thrombosis in polycythaemia vera (PV)
risk of bleeding due to acquired von Willebrand disease and (GRADE 1A).
should be considered an indication for initiation of cytore- • ‘High risk’: age ≥65 years and/or prior PV-associated
ductive therapy (Budde & van Genderen, 1997). arterial or venous thrombosis (GRADE 1A)
• ‘Low risk’: age <65 years and no PV-associated throm-
botic history (GRADE 1A)
Survival and transformation risk
• Some ‘low risk patients’ may be to be considered at
The impact of age, degree of leucocytosis and prior history higher risk in the presence of cardiovascular risk factors,
of venous thrombosis on long term prognosis are well- elevated white blood cell (WBC) count, extreme

182 ª 2018 British Society for Haematology and John Wiley & Sons Ltd
British Journal of Haematology, 2019, 184, 176–191
 Guidelines

thrombocytosis or haematocrit (Hct) uncontrolled with investigators who assessed the impact of stringent Hct reduc-
venesection (GRADE 1B) tion to <0
45 compared with a more liberal target range of
• A number of variables including age, prior thrombosis, 0
45–0
50 (Marchioli et al, 2013). Patients with a Hct target
the presence of splenomegaly, serum lactate dehydroge- of < 0
45 had a significantly lower rate of cardiovascular
nase (LDH) level, degree of reticulin staining, presence death and major thrombosis than those with a target of
of an abnormal karyotype and JAK2 mutant allele bur- 0
45–0
50 (Marchioli et al, 2013). It was noted that the med-
den may be utilised when counselling the patient on ian WBC count was significantly lower in the low Hct group,
longer term prognosis including overall survival and dis- which may have been related to variation in the use of
ease transformation risk (GRADE 2B). cytoreductive therapy between the groups. The impact of this
• Deep sequencing for ‘high risk mutations’ e.g. ASXL1, parameter on the difference in outcome between the groups
SRSF2, IDH1/2 is not yet ‘standard of care’ but may be has been debated (McMullin et al, 2013).
considered in selected cases where their presence may The European LeukaemiaNet (ELN) has, by consensus,
influence management. (GRADE 2B). recommended response criteria for PV. There is, however,
little evidence that stringent achievement of these contributes
to improved outcomes apart from the Hct target. These are a
Management of polycythaemia vera valuable set of measures to assess treatment outcome with
consistency across clinical trials but are not as useful in clini-
Patients with PV may present with thrombosis or cardiovas-
cal practice (Barosi et al, 2015).
cular disease. Disease-related PV symptoms, such as
microvascular disturbance, pruritus (which may be excruciat-
ing), migraine-type headache and fatigue, may also be pre-
Platelet and leucocyte target
senting features which can significantly impact on quality of
life (Harrison et al, 2017). However, patients may be asymp- There is considerable published evidence of an association
tomatic at presentation. between increased WBC count and thrombosis risk in PV
The goals of treatment are to reduce complications and (Barbui et al, 2009; Caramazza et al, 2009) ((De Stefano
therefore improve survival. (Table 3). Mortality is chiefly et al, 2010; Barbui et al, 2015) (Cerquozzi et al, 2017). In
related to thromboembolic events and the principal aim of contrast, one prospective study did not find such an asso-
therapy is to reduce this risk. Targeted assessment and man- ciation (Passamonti et al, 2010). An analysis of long-term
agement of cardiovascular risk factors, such as hypertension, outcome of patients enrolled into the ECLAP study
hypercholesterolaemia, diabetes mellitus and smoking, is demonstrated that in patients with WBC counts
essential. Reduction in symptom burden is also a valid target >15 9 109/l there was increased incidence of thrombosis
for treatment. There is evidence that patients with inade- in comparison with those with WBC counts <10 9 109/l,
quately controlled PV, as determined by hydroxycarbamide largely related to an increase in myocardial infarction
(HC) use, splenomegaly and venesection requirements, have (Landolfi et al, 2007). In a retrospective study of PV to
a significantly higher symptom score measured by the determine whether blood counts influenced the complica-
Myeloproliferative Neoplasm Symptom Assessment Form tion rate and survival, older age and elevated LDH level
(MPN-SAF) (Geyer et al, 2016). Frequent requirement for at diagnosis were found to be risk factors for vascular
concurrent venesection may indicate the need for dose complications. When the vascular complication occurred,
alteration and or change of treatment. 41% of the patients with a complication had elevated
WBC counts compared with 20% of patients without a
complication (Enblom-Larsson et al, 2017).The CYTO-PV
Haematocrit target
study treatment arms, which showed a lower thrombotic
The target for Hct control in PV was originally based on data risk in those intensively managed to Hct <0
45, showed a
from assessment of numbers of vascular events at different comparatively lower WBC count, which may have con-
Hct levels and it was estimated that a target below 0
45 tributed to the lower rate of thrombotic events (Marchioli
should be maintained (Pearson & Wetherley-Mein, 1978). et al, 2013) (McMullin et al, 2013). There is no evidence
This target has now been validated in a randomised clinical from randomised trials to determine whether treatment
trial by the Cytoreductive Therapy in PV (CYTO-PV) targeted at reducing leucocyte count impacts on overall

TABLE 3. Treatment goals

o Reduce thrombosis and haemorrhage risk
o Minimise complications and symptomatology
o Minimise risk of transformation to myelofibrosis and acute leukaemia
o Manage specific situations such as pregnancy and surgery
o Achieve good haematocrit control to <0
45

ª 2018 British Society for Haematology and John Wiley & Sons Ltd 183
British Journal of Haematology, 2019, 184, 176–191
Guidelines

outcome and therefore no recommendation to target WBC may warrant an alternative approach, such as cytoreductive
counts as a treatment goal can be made. Indeed, no evi- therapy.
dence for improved survival or lower thrombosis risk was
seen in patients achieving complete or partial response
Aspirin
according to ELN criteria in an analysis of PV patients
treated with HC, whereas a better prognosis was seen The value of low-dose aspirin in patients with PV was
when there was a WBC and platelet response (Alvarez- demonstrated in the ECLAP study. In this double blind, pla-
Larr
an et al, 2012). There is evidence that, at extremes of cebo-controlled randomised trial, those randomised to
platelet count, there is a risk for bleeding and haemor- aspirin 100 mg daily had significantly fewer vascular events
rhage which may necessitate cytoreductive treatment in at 3 years compared to placebo. There was a 60% decrease in
those with high counts. the risk of the combined primary end-point, which was of
thrombotic events and death from cardiovascular causes.
Major bleeding events were not significantly increased (Lan-
Allele burden reduction
dolfi et al, 2004).
There is currently no indication to monitor allele burden
sequentially outside the clinical trial setting. Whilst many
Cytoreductive therapy
studies have used allele burden reduction to assess
impact of treatment, there is currently no clear clinical High-risk patients should be considered for cytoreductive
impact of this as a target. Allele burden over 50% may therapy. Low-risk patients who may benefit from cytoreduc-
correlate with progression to MF (Passamonti et al, tion include those with progressive splenomegaly, progressive
2010) but there is no evidence that this alters outcome leucocytosis (e.g. WBC count >15 9 109/l) thrombocytosis
and no evidence that lowering allele burden alters out- (e.g. platelet count>1500 9 109/l) and poor tolerance of
come. venesection.

Bone marrow response Hydroxycarbamide

There is no indication that serial monitoring of bone marrow Hydroxycarbamide is a cytoreductive agent, a non-alkylating
morphology or fibrosis grade is of value but this should be antimetabolite which acts through inhibition of ribonu-
undertaken if there is suspected progression from blood cleotide reductase thereby regulating the rate of DNA synthe-
counts or symptomatology. sis. HC has a dose-dependent effect and needs to be
individually titrated to achieve optimal count control. The
efficacy of HC in controlling blood counts and preventing
Venesection
thrombosis has been extrapolated from the evidence in ET
Randomised trial data supports that venesection of 200– (Cortelazzo et al, 1995) and HC has been used in the man-
500 ml blood at intervals suitable for patient size/tolerabil- agement of PV. A recent retrospective study of PV demon-
ity should be used to achieve and maintain a Hct of strated that patients treated with HC experienced
<0
45 (Marchioli et al, 2013). In low risk patients this is significantly fewer vascular complications (11%) than
usually adequate to maintain target Hct. Where frequent patients treated with venesection only, with a survival advan-
venesection is needed to achieve this target then an alter- tage for patients treated with HC when adjusted for variables
native approach using a cytoreductive agent may need to supporting the use of this agent in first-line treatment
be considered. High levels of venesection requirement have (Enblom-Larsson et al, 2017).
been reported to have an association with higher thrombo-
sis risk in patients on HC, specifically in those patients
Side effects
requiring 3 or more venesections per year (Alvarez-Larr
an
et al, 2017). HC is generally well tolerated. Macrocytosis is expected and
No study has explicitly defined a gender difference in Hct myelosuppression is seen in some patients. Mucocutaneous
target. A different target Hct in males and females is not rec- side effects occur, including ulceration in perimalleolar areas,
ommended. oral aphthous ulceration, actinic keratosis, squamous cell
Iron deficiency may result from venesection. Whilst gen- cancer and other skin lesions. Gastrointestinal side effects
erally this is asymptomatic, restless legs, concentration have been reported.
problems, impaired cognitive function, dizziness, fatigue,
headaches and inactivity and other symptoms may warrant
Leukaemogenic risk and risk of secondary malignancy
a different treatment approach. Iron administration must
be undertaken with extreme caution and with close super- There has been much debate and concern over the potential
vision and monitoring of blood counts. Severe symptoms leukaemogenic risk of treatments used for PV and also the

184 ª 2018 British Society for Haematology and John Wiley & Sons Ltd
British Journal of Haematology, 2019, 184, 176–191
 Guidelines

potential for secondary malignancies. The natural history of cytopenias identifying a group with poorer outcome
PV is that a proportion of patients will experience progres- (Alvarez-Larr
an et al, 2012, 2017).
sion to acute leukaemia and MF. There is currently no con-
clusive evidence that this risk is exacerbated by the use of
Interferons
HC alone. A recent large study European ET trial, the EXELS
study, compared anagrelide-treated patients versus those Numerous single centre studies have observed that IFN-a
treated with other cytoreductive therapies and found there can be successfully used to normalise blood counts, reduce
was a higher incidence of leukaemia and increased incidence splenomegaly and prevent thrombosis in PV (Silver, 2006) It
of other cancers in those treated with other cytoreductive is also effective in many patients in reducing pruritus (Taylor
therapies, including HC alone (Besses et al, 2013) (Birgeg ard et al, 1996). This agent is of particular interest due to its
et al, 2018). A Swedish population-based study with a anti-clonal activity as demonstrated by molecular (as assessed
nationwide MPN cohort identified those who developed by mutation burden of JAK2 V617F) and histological remis-
AML/myelodysplastic syndrome (MDS) and matched con- sions (Larsen et al, 2009) (Stauffer Larsen et al, 2013). No
trols, and performed a retrospective case record analysis. leukaemogenic effect has been identified. However, side
Whilst the risk of AML/MDS was increased in patients effects often limit use and most commonly include flu-like
exposed to high doses of 32P and alkylators or 2 or more symptoms and mood changes. In a minority of patients,
cytoreductive agents, this was not seen in those patients trea- endocrine and autoimmune disorders also occur, warranting
ted exclusively with HC (Bj€orkholm et al, 2011). A long-term regular monitoring of thyroid function and additional inves-
assessment from the ECLAP study showed no increased tigations where indicated. Treatment with IFN-a is usually
MDS/AML in those treated with HC alone (Finazzi et al, continuous but occasionally it can be stopped for prolonged
2005) and a retrospective analysis showed no association periods of time.
between HC or busulfan and AML (Tefferi et al, 2013). Longer acting pegylated IFN-a-2a (PEG-a-2a) requires less
A higher incidence of second malignancies has been seen frequent administration and is generally better tolerated. Two
in a small cohort of patients treated with HC compared to Phase II studies of PEG-a-2a demonstrated complete
interferon (IFN) alone (Hansen et al, 2017), particularly responses of 70–95% as well as complete molecular remis-
non-melanoma skin cancers, and this has been seen in popu- sions of 14–24%, with treatment discontinuation due to
lation-based studies with increased risk of non-melanotic side-effects observed in only 8–10% of patients (Kiladjian
skin cancer in patients treated with HC, especially in older et al, 2006) (Quint
as-Cardama et al, 2009) Comparable
patients of male sex (G
omez et al, 2016). Another study results have been noted in single-centre studies (Crisa et al,
looked at treatment characteristics of a large number of 2017; Gowin et al, 2017) A Phase III study of PEG-a-2a ver-
patients with ET, diagnosed and followed during a 30-year sus HC as first-line treatment for high-risk PV is underway
period. The different therapies administered, comprising HC and interim analysis shows no significant advantage for PEG-
and alkylating agents, did not appear to have any impact on a-2a over HC (Mascarenhas et al, 2016).
the development of secondary malignancy with a similar rate PEG-a-2b has also been assessed in two studies that
of secondary malignancies in untreated patients. Male gender included PV patients and, whilst it has been shown to be
and age >60 years were the only factors that were correlated effective in controlling disease, clinical use has been limited
with higher risk (Santoro et al, 2017). by high discontinuation rates due to side effects (Samuelsson
HC is recommended as a first line cytoreductive treatment et al, 2006) (Jabbour et al, 2007). Recently, interim analysis
option for all patients for whom this is required. The risk from a phase III study of proline-PEG-a-2b (Ropeginter-
benefit profiles need to be discussed with patients. HC is not feron) has demonstrated complete haematological responses
safe in pregnancy and it is recommended that it be stopped in 71% of PV patients, sustained reductions in mutation bur-
3 months prior to intended conception. Adequate contracep- den of JAK2 V617F, good tolerability and confirmed non-
tion should be used by patients receiving this medication. inferiority (or no significant advantage) to HC as first line
treatment for patients with high risk PV (Gisslinger et al,
2017).
Hydroxycarbamide intolerance and resistance
There has been an attempt to define the criteria to suggest
Ruxolitinib
failure of HC as first line therapy for PV. The ELN have by
consensus suggested a unified definition of resistance to Following early studies of the JAK1/2 inhibitor, ruxolitinib,
intolerance or HC. This classification identifies a group of in MF, this agent was tested in PV and ET, in patients resis-
patients who have a poorer prognosis who may require or tant or intolerant to HC. The majority of PV patients
benefit from a change of treatment (Barosi et al, 2010) became phlebotomy-independent and had an improvement
(Table 4). In retrospective studies resistance is associated in symptoms and splenomegaly (>50%) (Verstovsek et al,
with worse survival, with development of anaemia or 2014).

ª 2018 British Society for Haematology and John Wiley & Sons Ltd 185
British Journal of Haematology, 2019, 184, 176–191
Guidelines

TABLE 4. European LeukaemiaNet criteria for hydroxycarbamide intolerance and resistance

1. Need for phlebotomy to keep haematocrit <0
45 after 3 months of at least 2 g/day of hydroxycarbamide OR
2. Uncontrolled myeloproliferation, i.e. platelet count >400 9 109/l AND white blood cell count >10 9 109/l after 3 months of at least 2 g/day
of hydroxycarbamide OR
3. Failure to reduce massive* splenomegaly by more than 50% as measured by palpation OR failure to completely relieve symptoms related to
splenomegaly, after 3 months of at least 2 g/day of hydroxycarbamide OR
4. Absolute neutrophil count <1
0 9 109/l OR platelet count <100 9 109/l OR haemoglobin <100 g/l at the lowest dose of hydroxycarbamide
required to achieve a complete or partial clinico-haematological response OR
5. Presence of leg ulcers or other unacceptable hydroxycarbamide -related non-haematological toxicities, such as mucocutaneous manifestations,
gastrointestinal symptoms, pneumonitis or fever at any dose of hydroxycarbamide.

Reproduced from: Barosi, G., Birgegard, G., Finazzi, G., Griesshammer, M., Harrison, C., Hasselbalch, H., Kiladijan, J., Lengfelder, E., Mesa, R.,
Mc Mullin, M.F., Passamonti, F., Reilly, J.T., Vannucchi, A.M. and Barbui, T. (2010), A unified definition of clinical resistance and intolerance to
hydroxycarbamide in polycythaemia vera and primary myelofibrosis: results of a European LeukemiaNet (ELN) consensus process. British Journal
of Haematology, 148: 961–963. © 2010 John Wiley & Sons, Inc.
*Organ extending by more than 10 cm from the costal region.

Following this, a phase III trial RESPONSE evaluated the Here, ruxolitinib showed good responses in controlling Hct
efficacy and safety of ruxolitinib in a specific subgroup of PV and PV-related symptoms. However, the follow-up for the
patients who were both refractory to, or intolerant of, HC study is short, the majority of patients had received HC pre-
and who required ongoing phlebotomy and had splenome- viously and HC was part of BAT options.
galy (Vannucchi, 2015). Patients were randomized between RELIEF was a randomized study focusing on PV-related
ruxolitinib and best available therapy (BAT), which could symptoms for patients on a stable dose of HC (Mesa et al,
include any therapy, and crossover was permitted. Patients 2017) with crossover to ruxolitinib allowed after week 16.
on ruxolitinib achieved good Hct control and spleen The primary endpoint, the percentage of patients with ≥50%
response, although only 21% of patients achieved both. reduction in symptoms, was seen in significantly more
Improvements in disease-related symptoms were described. patients in the ruxolitinib arm. A statistically significant
Anaemia and thrombocytopenia were the main haematologi- reduction in itching was also noted in the ruxolitinib arm.
cal adverse events. Herpes zoster infection was described in This study was perhaps underpowered, but showed that rux-
patients on ruxolitinib. Non-melanoma skin cancer was olitinib improves symptoms in patients with controlled PV.
reported in both arms. Thromboembolic events were more The evidence from these trials suggests that ruxolitinib has
frequent in the BAT arm but this was not a pre-determined a role in the treatment of HC-resistant or intolerant PV.
outcome. Data published from this study also suggested that
molecular responses can occur, perhaps to the same extent as
Other treatments
with IFN (Pieri et al, 2015; Vannucchi et al, 2017) and that
even profoundly iron deficient patients can normalise their There are several cytotoxic agents that are effective in con-
iron parameters with ruxolitinib therapy (Verstovsek et al, trolling blood counts but have been associated with increased
2017). Disease transformation occurred and there is no infor- rates of leukaemic transformation. Busulfan, a cell cycle non-
mation to suggest that ruxolitinib therapy impacts these specific alkylating agent, has such an association. However,
events. retrospective studies show that it is an effective therapy for
However, the RESPONSE study had some inherent bias: MPNs (Begna et al, 2016) although an actuarial probability
first, the population of the study is highly selected as they of leukaemia transformation of 10% at 3 years was reported
had to be venesection-dependent. Second, patients on the in one study (Alvarez-Larr
an et al, 2014b). Busulfan is useful
BAT arm were allowed to receive HC and many did so, in treating PV in those with limited life expectancy. It can be
reflecting the lack of therapy options in this setting. Finally, given in dosing regimens of 2–4 mg/day until counts are
as patients received other treatments before ruxolitinib and controlled, but patients need to be seen frequently to check
crossed between the treatment arms it is difficult to establish for neutropenia or thrombocytopenia so that treatment can
if the events, such as skin cancer, or disease transformation be interrupted. An alternative regimen is pulsed single 25–
could be an effect of the ruxolitinib or occur as an accumu- 50 mg doses at intervals of approximately 6 weeks.
32
lative effect of other cytoreductive therapies. P is has a leukaemogenic potential but a single intra-
Following RESPONSE, a second randomized open label venous dose can be effective for long term control. One ret-
phase 3b study (RESPONSE-2) was developed to determinate rospective study showed its efficacy with remission rates of
the efficacy of ruxolitinib versus BAT in a similar population 90% (Lawless et al, 2016). Doses can be repeated if the
of PV patients as RESPONSE but the patients were not response is lost but the leukaemogenic risk increases with the
required to have splenomegaly (Passamonti et al, 2017). cumulative exposure. 32P is a suitable treatment for those

186 ª 2018 British Society for Haematology and John Wiley & Sons Ltd
British Journal of Haematology, 2019, 184, 176–191
 Guidelines

with limited life expectancy who are self-caring (so that there • Persistent leucocytosis (e.g. WBC count >15 3 109/l)
is no risk for carers). • Uncontrolled haematocrit (or poor tolerability of vene-
Pipobroman, a bromide derivative of piperazine similar to section)
alkylating agents, has been compared to HC in randomised • Extreme/progressive thrombocytosis (e.g. ≥ 1500 3 109/
trials and shown to be effective but has continuing leukae- l) and/or haemorrhagic symptoms
mogenic potential (Kiladjian et al, 2011) and therefore • Progressive/symptomatic splenomegaly
should only be used in those with limited life expectancy. • Uncontrolled or progressive disease-related symptoms,
Anagrelide, a megakaryocyte differentiation inhibitor, is e.g. weight loss, sweats
licensed as second line therapy in ET. Retrospective reports • (GRADE 1B)
of anagrelide used in combination with HC in PV have
shown that it is effective at lowering the platelet count and it
may be useful in combination when an elevated platelet Recommendations: Management options in high-risk
count is an issue (Ahn et al, 2013). patients
A number of other agents have been used for cytoreduc-
• First Line: hydroxycarbamide (HC) or interferon (prefer-
tion in PV with varying efficacy. A small study investigated
ably pegylated interferon)
the use of imatinib. The complete response rate was 30%
• Second line: in patients treated with HC as first line, inter-
with frequent side effects. This has not been studied further
feron as second line treatment, or, where treated with inter-
and is not recommended for the treatment of PV (Silver
feron as first line, recommend HC as second line treatment
et al, 2012).
• Consider pegylated interferon as second line in those
Histone-deacetylase inhibitors (HDACi) inhibit prolifera-
patients who have had non-pegylated interferon first line
tion of cells with a JAK2 V617F mutation. Two HDACi have
and could not tolerate it
been tested in PV in phase 2 trials: vorinostat in a trial of
• Ruxolitinib second/third line in HC resistant or intoler-
PV and ET achieved a response rate of 35% but with a very
ant patients
high drop-out rate because of adverse events (Andersen et al,
(GRADE 1A)
2013). Givinostat was assessed in a phase 2 study of PV
unresponsive to HC monotherapy with response rates in the Third-line or further treatment options
order of 50% and with high rates of improvement in pruri-
• Busulfan or 32P or pipobroman in those with limited life
tus (Finazzi et al, 2013). HDACi need to be assessed further
expectancy (GRADE 1B).
in trials before they can be recommended for clinical use.
• Anagrelide in combination with HC may be helpful in
Following the evaluation of all recent evidence, it is rec-
those where platelet control is difficult (GRADE 2C)
ommended that all patients, including those stratified as low-
risk, should be venesected to a Hct target of 0
45 and given
low dose aspirin if there are no specific contraindications.
Acknowledgements
High-risk patients should, in addition, be treated with
cytoreductive therapy. However, low-risk patients with any The authors would like to the BSH task forces and the BSH
of the criteria listed below, may also need to be considered sounding boards for their support in preparing this guide-
for cytoreductive therapy. line. They also wish to thank Jacky Wilson for help in under-
taking the initial literature review. All authors reviewed the
literature search, formulated and agreed guidance and con-
Recommendations: management options for ALL PV
tributed to drafting writing and editing of the manuscript.
including low-risk patients
• Target haematocrit of <0
45 in all patients (GRADE 1A)
Declaration of interest
• Low dose aspirin (75–100 mg) in all patients (GRADE 1A)
• Targeted intervention to reduce cardiovascular risk factors The BSH paid the expenses incurred during the writing of
this guidance. All authors have made a declaration of inter-
Consider cytoreductive therapy in low-risk patients with:
ests to the BSH and Task Force Chairs, which may be viewed
• History of treated arterial hypertension, ischaemic heart on request.
disease or diabetes mellitus

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