Curr. Treat. Options in Oncol.

(2018) 19:12
DOI 10.1007/s11864-018-0529-x

Leukemia (PH Wiernik, Section Editor)

Polycythemia Vera
Jerry L. Spivak, MD
Address
Hematology Division, Department of Medicine, Johns Hopkins University School
of Medicine, Traylor 924, 720 Rutland Avenue, Baltimore, MD, 21205, USA
Email: [email protected]

* Springer Science+Business Media, LLC, part of Springer Nature 2018

This article is part of the Topical Collection on Leukemia

Keywords Polycythemia vera I JAK2 V617F I Natural history I Diagnosis I Management

Opinion statement
Polycythemia vera (PV) is the most common myeloproliferative neoplasm (MPN), the
ultimate phenotype of the JAK2 V1617F mutation, the MPN with the highest incidence
of thromboembolic complications, which usually occur early in the course of the disease,
and the only MPN in which erythrocytosis occurs. The classical presentation of PV is
characterized by erythrocytosis, leukocytosis, and thrombocytosis, often with splenomeg-
aly and occasionally with myelofibrosis, but it can also present as isolated erythrocytosis
with or without splenomegaly, isolated thrombocytosis or isolated leukocytosis, or any
combination of these. When PV is present, the peripheral blood hematocrit (or hemoglo-
bin) determination will not accurately represent the actual volume of red cells in the body,
because in PV, in contrast to other disorders causing erythrocytosis, when the red cell
mass increases, the plasma volume usually increases. In fact, unless the hematocrit is
greater than 59%, true erythrocytosis cannot be distinguished from pseudoerythrocytosis
due to plasma volume contraction. Usually, the presence of splenomegaly or leukocytosis
or thrombocytosis establishes the diagnosis. However, when a patient presents with
isolated thrombocytosis and a positive JAK2 V617F assay, particularly a young woman,
the possibility of PV must always be considered because of plasma volume expansion. The
WHO PV diagnostic guidelines are not helpful in this situation, since the hematocrit is
invariably normal and a bone marrow examination will not distinguish ET from PV. Only a
direct measurement of both the red cell mass and plasma volume can establish the correct
diagnosis. In managing a PV patient, it is important to remember that PV is an indolent
disorder in which life span is usually measured in decades, even when myelofibrosis is
present, that chemotherapy is futile in eradicating the disease but does increase the
incidence of acute leukemia and that hydroxyurea is not safe in this regard nor is it
antithrombotic. Phlebotomy to a sex-specific normal hematocrit is the cornerstone of
therapy and there now exist safe remedies for controlling leukocytosis, thrombocytosis,
and extramedullary hematopoiesis and symptoms due to inflammatory cytokines when this
is necessary.
12 Page 2 of 14 Curr. Treat. Options in Oncol. (2018) 19:12

Introduction
Polycythemia vera (PV) is a chronic myeloproliferative one or more of these three genes, it needs to be empha-
neoplasm (MPN), which shares in common with its sized that they are genetically distinct disorders as dem-
companion MPN, essential thrombocytosis (ET), and onstrated by gene expression profiling [8–10], by dis-
primary myelofibrosis (PMF), origin in a hematopoietic tinctly different epidemiologies and natural histories
stem cell (HSC), constitutive activation of hematopoie- [11]. MPN driver mutations dictate clinical phenotype;
sis with overproduction of morphologically normal disease genotype, however, is based on host genetic
blood cells, a tendency to extramedullary hematopoie- variation [12••].
sis, and transformation to bone marrow failure with PV is the most common MPN [13•], the only one in
myelofibrosis or acute leukemia, although at varying which there is an increase in red cell production and the
frequencies in each MPN. These shared phenotypic fea- only one in which there is substantial morbidity and
tures are the consequence of direct or indirect constitu- mortality from venous and arterial thrombosis. First
tive activation of JAK2, the cognate tyrosine kinase for described in 1892, PV is not a new disease. With an
the hematopoietic growth factor receptors for erythro- incidence of 2.5–10/100,000 people, depending on
poietin and thrombopoietin and also utilized by the G- age, PV is not a rare disease, yet, despite 125 years of
CSF receptor. Direct activation of JAK2 is due to a point scrutiny, including an understanding of PV pathophysi-
mutation (V617F in JAK2 exon 14 [1]) or, less common- ology, there is currently no consensus on how to diag-
ly, insertions or deletions in JAK2 exon 12 [2], point nose PV or even how to treat it. There is no reason that
mutations in the thrombopoietin receptor, MPL [3–5], this should be the case since there is abundant evidence
which activate JAK2 indirectly, or insertions or deletions on how to diagnose PV accurately and how to treat it
in the ER chaperone calreticulin (CALR) [6, 7], which that avoids thrombotic complications and unnecessary
allow it to bind MPL, and activate JAK2 indirectly. Al- bone marrow damage that could lead to leukemic trans-
though the three MPN share in common mutations in formation [14, 15].
PV pathophysiology
PV, ET, and PMF are HSC disorders and recent studies of HSC physiology have
explained in part their apparent phenotypic interchangeability, and refuted the
erroneous contention based on clinical phenotype alone that PV and ET are not
separate disorders but rather represent a continuum [16•]. Hematopoiesis is
organized as a hierarchy, with the long-term HSC (LT-HSC), which is respon-
sible for long-term bone marrow repopulation, at its apex [17]. Once consid-
ered the prime contributor to hematopoiesis, it is now clear that the LT-HSC is
primarily quiescent in the marrow endosteal niche [18], while the maintenance
of hematopoiesis on a daily basis is provided by a rapidly multiplying short-
term HSC (ST-HSC) [19]. Furthermore, and most importantly, the LT-HSC not
only gives rise to the multipotent ST-HSC, but can also give rise directly rise to
HSC that are restricted to megakaryocyte differentiation only, megakaryocyte
and erythroid differentiation, or granulocyte, erythrocyte, and megakaryocyte
differentiation [17]. The ability of LT-HSC to give rise to directly to megakar-
yocytic stem cells appears to be linked to the fact that megakaryocytes are
responsible for maintaining LT-HSC in a quiescent state in the marrow endos-
teal niche [20].
An important corollary of this is the fact that some women with JAK2 V617F-
positive ET only express the JAK2 V617F mutation in their platelets [21]. Equally
important, since all MPN driver mutations are expressed in the LT-HSC, is the fact
that the phenotype of an MPN will reflect in part the HSC involved. For example,
although PV is the ultimate consequence of JAK2 V617F expression with a
Curr. Treat. Options in Oncol. (2018) 19:12 Page 3 of 14 12

phenotype of erythrocytosis, thrombocytosis, and granulocytosis, in some PV

patients, however, the phenotype is restricted to erythrocytosis and
thrombocytosis. At the same time, HSC involvement is not fixed: PMF patients
can evolve to PV, and ET patients to PV. Transformations such as these usually
occur within 12 years of diagnosis but can take much longer. While the PMF to
PV transformation is uncommon, the ET to PV transformation, particularly in
woman occurs in approximately 20–30% of JAK2 V617F-positive ET patients.
These types of de novo phenotypic shifts need to be distinguished from a
different type of disease transformation in which the development of bone
marrow failure with myelofibrosis occurs during the course of PV or ET, can be
seen with any driver mutation, and reflects intrinsic HSC failure, usually with the
acquisition of additional mutations. They also need to be distinguished from
simply misdiagnosing PV for ET, which can occur because the hematocrit in PV,
drawn from a peripheral vein, is not an accurate representation of the actual red
cell mass in the patient as discussed below [14, 22, 23].

PV diagnosis
PV is the ultimate phenotypic expression of JAK 2 V617F since all HSC and their
progeny utilize this tyrosine kinase, in their hematopoietic growth factor recep-
tors. In contrast to JAK2 V617F, which can cause ET or PMF, JAK2 exon 12
mutations only cause PV and not infrequently just cause erythrocytosis alone as
opposed to “polycythemia” [5]. CALR mutations can rarely cause PV [24] but
MPL mutations apparently cannot. This is paradoxical since the
thrombopoietin receptor, MPL, is the oncogene of the MPLV retrovirus, which
causes a fulminant PV-like syndrome in mice [25], and is the only hematopoi-
etic growth factor receptor in the LT-HSC. Regardless, it is clear that neither JAK2
V617F nor CALR mutations are specific for PV, ET, or PMF and only the
presence of erythrocytosis can distinguish PV from its companion MPN. Fur-
thermore, there are also rare PV patients with no identified driver mutations. It
is also important to note that PV can also present as isolated thrombocytosis
[26], isolated leukocytosis [27], or with myelofibrosis [28]. Therefore, since PV
is the most common MPN and the one with the highest morbidity and
mortality rates due to thrombotic events, it should be the first disorder consid-
ered when an MPN is a diagnostic possibility.
It is important to emphasize that since there is no molecular marker specific
for PV, the diagnosis of PV is clinically based regardless of the mutation causing
it. Stated differently, 125 years of clinical experience have provided accurate
clinical guidelines for the diagnosis of PV, that do not involve the need to
examine a bone marrow specimen [28] or obtain a serum erythropoietin level
[14, 29], though recently these clinical guidelines have been eschewed by a
WHO expert committee in preference for guidelines [30, 31] that, unfortunate-
ly, do not guarantee diagnostic accuracy for PV [14, 15, 22, 32, 33], or even for
distinguishing PV from ET or PMF. This is obviously not a trivial issue, since
mistaking PV for ET can result in thrombotic episodes, and mistaking PV for
PMF can not only lead to the same problem but also because the prognosis for
post-PV myelofibrosis is better than that of de novo PMF, which has important
therapeutic implications [34•]. Finally, since PV can present as isolated
erythrocytosis, it becomes an important consideration in the differential
12 Page 4 of 14 Curr. Treat. Options in Oncol. (2018) 19:12

diagnosis of any patient presenting with an elevated hematocrit (Table 1),

which as the table indicates, is not a trivial exercise.
When a patient has an elevation of the hematocrit, hemoglobin level or red
cell count in conjunction with a neutrophilic leukocytosis and thrombocytosis,
with or without splenomegaly, the diagnosis of polycythemia vera is
established. This is also true if there is erythrocytosis and splenomegaly [14,
23]. The presence of myelofibrosis does not change the diagnosis [28]. Many PV
patients will present with only erythrocytosis and thrombocytosis, while fewer
will present with erythrocytosis and leukocytosis [15]. These definitions do not,

Table 1. Causes of absolute and relative erythrocytosis

Causes of absolute erythrocytosis Causes of relative erythrocytosis

Hypoxia Loss of fluid from the vascular space
Carbon monoxide intoxication (tobacco abuse, Emesis, diarrhea, diuretics, sweating, polyuria, hypodipsia,
environmental) hypoalbuminemia, capillary leak syndromes, burns, peritonitis
High affinity hemoglobins Chronic plasma volume contraction
High altitude Hypoxia from any cause
Pulmonary disease Androgen therapy
Right to left shunts Recombinant erythropoietin therapy
Sleep apnea syndrome Hypertension
Neurologic disease Tobacco use
Renal disease Pheochromocytoma
Renal artery stenosis Ethanol abuse
Focal sclerosing of membranous glomerulonephritis Sleep apnea
Renal transplantation
Tumors
Hypernephroma
Hepatoma
Cerebellar hemangioblastoma
Uterine fibromyoma
Adrenal tumors
Meningioma
Pheochromocytoma
Drugs
Androgenic steroids
Recombinant erythropoietin
Familial (with normal hemoglobin function; Chuvash;
EPO receptor mutations; 2,3 BPG deficiency)
Polycythemia vera
JAK2 V617F
JAK2 exon 12 mutations
Curr. Treat. Options in Oncol. (2018) 19:12 Page 5 of 14 12

however, encompass all possible presentations of PV [23] because of its unique

pathophysiology as discussed below.
Blood volume physiology
Understanding blood volume physiology is central to understanding PV path-
ophysiology and how to diagnose this disorder. The most important principle is
that with disease, a peripheral blood hematocrit, hemoglobin level, or red cell
count cannot provide an accurate estimation of the red cell mass and the
situation is further confounded by splenomegaly or pregnancy, which cause
plasma volume expansion. An important corollary is that until the hematocrit is
≥ 60% [35], it is not possible to distinguish plasma volume contraction from
true erythrocytosis without an independent measurement of the red cell mass
and plasma volume by isotope dilution. Equally important is to recognize what
the WHO does not—that the hematocrit can appear to be normal in untreated
PV and generally when the disease is complicated by hepatic vein thrombosis.
It is also important to note that the hematocrit, not the hemoglobin level, is
the most clinically significant measurement because blood viscosity is a func-
tion of red cell number not their hemoglobin content [36]. Furthermore, when
there is a paucity of available iron, the body defends the red cell MCHC and
makes many smaller red cells with an MCHC as close as possible to normal
[37••]. This is not a trivial fact because when the hematocrit is normal or even
low due to iron deficiency or a thalassemia gene, microcytic erythrocytosis can
be an important clue to the presence of either [38, 39•]. Indeed, in PV, with iron
deficiency, the erythrocyte count can increase to greater than 7 million while the
hematocrit remains normal; in thalassemia, the hematocrit is low due to a
much lower MCV, while the red cell number is increased [40].
A high hematocrit or red cell count can be due to either plasma volume
contraction or an increase in the number of red cells. As mentioned above, it is
impossible to determine this from a peripheral venous hematocrit. This is
illustrated in (Fig. 1). With erythrocytosis due to hypoxia or inappropriate
erythropoietin production, as the red cell mass increases, the plasma volume
decreases because the body tries to keep the total blood volume the same. By
hematocrit determination, absolute erythrocytosis and plasma contraction are
indistinguishable [12••]. In PV, where neither tissue hypoxia nor excess eryth-
ropoietin production are present, the opposite occurs, as the red cell mass
expands autonomously, the plasma volume expands or stays the same, masking
the increase in red cell numbers as determined by the hematocrit. Table 2
provides examples of this in patients with PV and secondary erythrocytosis.
Figure 2 is a diagnostic algorithm for evaluating a high hematocrit, hemo-
globin, or red cell count, since in recent years, fewer institutions offer red cell
mass and plasma volume measurements. A history of prior blood counts is
important for distinguishing between an acquired and a hereditary abnormal-
ity; a family history is also important in this regard. Hopefully, however, now
that the WHO has added red cell mass and plasma volume measurements to
their PV diagnostic criteria [31], more academic institutions will reoffer these
useful tests and avoid the conflation of PV with ET.
12 Page 6 of 14 Curr. Treat. Options in Oncol. (2018) 19:12

Fig. 1. Changes in the red cell mass and plasma volume in secondary erythrocytosis and polycythemia vera.

Table 2. Examples of changes in the red cell mass and plasma volume in polycythemia vera and secondary erythrocytosis

Observed Expected Excess

An asymptomatic 48-year-old woman presenting with massive splenomegaly and a hematocrit of 39%
Red cell mass 2600 mL 1250 mL +1350 mL
Plasma volume 3550 mL 1750 mL +1800 mL
Total blood volume 6150 mL 3000 mL
Hematocrit 42.2% 41.7%
A 30-year-old woman with polycythemia vera, hepatic vein thrombosis, and a hematocrit of 44.8%
Red cell mass 2847 mL 1379 mL +1468 mL
Plasma volume 3507 mL 2232 mL +1275 mL
Total blood volume 6354 mL 3611 mL
Hematocrit 44.8% 38.7%
A 68-year-old man with sleep apnea and a hematocrit of 55.8%
Observed Expected Excess/deficit
Red cell mass 3769 mL 2979 mL +790 mL
Plasma volume 2980 mL 4040 mL −1060 mL
Total blood volume 6749 mL 7019 mL
Hematocrit 55.8% 42.4%
Curr. Treat. Options in Oncol. (2018) 19:12 Page 7 of 14 12

Fig. 2. Algorithm for the diagnosis of erythrocytosis.

Table 3. The complications of polycythemia vera and their management

• Erythrocytosis • Phlebotomy
• Pruritus • Antihistamines, ruxolitinib, pegylated interferon, PUVA light therapy,
hydroxyurea
• Ocular migraine, transient ischemic attacks • Aspirin; ruxolitinib, anagrelide; pegylated interferon; hydroxyurea (TIA
(TIA), erythromelalgia only)
• Thrombosis (arterial, venous) • Anticoagulation
• Thrombocytosis • Ruxolitinib, pegylated interferon; anagrelide; hydroxyurea
• Hemorrhage (due to thrombocytosis) • Tranexamic acid, EACA (Amicar), anagrelide, pegylated interferon
• Leukocytosis • Ruxolitinib, pegylated interferon, hydroxyurea
• Hyperuricemia • Allopurinol (uric acid ~ 10 mg%)
• Splenomegaly • Ruxolitinib, pegylated interferon, thalidomide, hydroxyurea,
irradiation, Gleevec, splenectomy
12 Page 8 of 14 Curr. Treat. Options in Oncol. (2018) 19:12

PV natural history
PV is a chronic disorder whose clinical course in the majority of patients is
measured in decades [11, 14]. In approximately 15% of patients, a clinical
picture phenocopying PMF develops, though the clinical course is usually much
more prolonged compared to PMF [41]. A small fraction of patients (~ 1.5%)
spontaneously develop acute leukemia; these patients are usually older than
60 years. Acquisition of the JAK2 V617F mutation is not age-dependent [42••]
but increases exponentially after age 60 [43]. Thus, PV can be acquired at any
age but is rare in the pediatric age group and below age 60 is most common in
women; thereafter, the sex ratio is equal.
Initially in most PV patients, only one JAK2 allele is mutated and the
neutrophil JAK2 V617F allele burden is usually between 15 and 30% [12••].
It is important to note that neutrophil allele burden does not correlate with the
HSC (CD34+ cell) allele burden. The neutrophil JAK2 V617F allele burden
usually rises slowly over time [44] and concomitantly, there are increases in the
white cell and platelet counts. This does not necessarily reflect disease progres-
sion as opposed to the expected expansion of the hematopoietic progenitor cell
pool, which is sensitive to the constitutively active JAK2; HSC are less affected by
this mutation and expand more slowly [45].
Characteristically, involvement of the unaffected JAK2 allele on chromo-
some 9 (uniparental disomy) is a feature of PV in contrast to JAK2 V617F-
positive ET [46]. This is associated with neutrophil JAK2 V617F allele burdens
greater than 50% and a more active disease. As the HSC JAK2 V617F population
increases, extramedullary hematopoiesis ensues with enlargement of the spleen
and sometimes the liver. As a general rule, when the neutrophil JAK2 V617F
allele burden is ≥ 70%, it reflects the HSC (CD34+) JAK2 V617F allele burden
[45], homozygosity for JAK2 V617F, and identifies the presence of clonal
dominance by the affected HSC clone over normal HSC [44]. Recent gene
expression studies in PV have indicated that the acquisition of a PMF phenotype
during the course of PV is not random but is associated with a distinct gene
expression profile [8].
The complications of PV are listed in Table 3. PV is an indolent disease with
life span that can exceed four decades and should be treated accordingly. Most
thrombotic complications occur before diagnosis or early in the course of the
disease [47]. This is particularly true in young woman who frequently present
with hepatic vein thrombosis; for unknown reasons, portal vein thrombosis is
more common in men. Not all PV patients experience ocular migraine, severe
itching, or erythromelalgia. The development of a PMF phenotype can take
decades and must be distinguished from myelofibrosis as a histologic phenom-
enon due to the high plasma thrombopoietin level in PV [48]. Bone marrow
fibrosis in PV is a reactive and reversible condition, which does not affect
marrow function; bone marrow failure in this disorder is due to defective HSC.

PV therapy
The first principle of therapy is “prima non nocere.” If the diagnosis is incorrect,
therapy will be ineffective and possibly harmful, and currently due to the
Curr. Treat. Options in Oncol. (2018) 19:12 Page 9 of 14 12

inaccurate WHO PV diagnostic guidelines as well as the consistent conflation of

PV with ET [49•, 50•], PV is underdiagnosed. Second, although PV is a hema-
topoietic malignancy, it usually has an indolent clinical course in most patients
and should be treated accordingly. In this regard, it is important to remember
that most clinical manifestations of PV represent over production of normal
blood cells since the disease involves the inappropriate activation of physiolog-
ic signal transduction pathways in hematopoietic cells, making chemotherapy
inappropriate in most patients. Furthermore, myeloproliferation is a feature of
committed hematopoietic progenitor cells, not the HSC, for whom accumula-
tion is slow. Consequently, the advice of William Dameshek is worth remem-
bering. “There is a tendency in medical practice by no means limited to
hematologists to treat almost any condition as vigorously as possible. In
hematology, this consists in attempting to change an abnormal number –
whether this number is the hematocrit, white cell count or platelet count to
get normal values, whether the patient needs it or not!” [51]
Table 3 lists the currently available therapies for the various complications of
PV. Phlebotomy is the mainstay of therapy since if performed properly by
lowering the hematocrit to the appropriate sex-specific level (G 45% in a man
and G 42% in woman) [52, 53], it will prevent thrombosis, the major compli-
cation of PV. Women with PV are not small men; woman normally have a
smaller red cell mass than men and common sense dictates that they should be
phlebotomized accordingly. With respect to the appropriate hematocrit target,
it is important to remember that pregnancy, splenomegaly with portal hyper-
tension and hepatic vein thrombosis cause expansion of the plasma volume
(Fig. 1 and Table 2) [12••, 14, 23]. In these situations, a “normal” hematocrit
will actually be inappropriately high and reduction of the hematocrit below
35% will be necessary to avoid thrombotic complications [15]. This is, unfor-
tunately and inexplicably, not discussed in the literature. It is also important to
remember that an inappropriately high hematocrit can lead to spuriously high
PT values, under-anticoagulation with warfarin, and loss of protection against
thrombosis. Claims that phlebotomy can activate coagulation or cause further
increase in blood cell production are also unfounded since blood production in
PV is already autonomous. Finally, claims that iron deficiency in the absence of
anemia is harmful in adults are equally unfounded [54].
Aspirin is the drug of choice for erythromelalgia [55] and ocular migraine
unless the platelet count is high enough to cause acquired von Willebrand
disease [56]. This is usually seen with platelet counts greater than 1,000,000/
μL, which is associated with platelet-induced proteolysis of high molecular
weight von Willebrand multimers and a reduction in ristocetin co-factor activity
to less than 50%. This syndrome is not usually associated with spontaneous
hemorrhage and bleeding is easily prevented or treated with an antifibrinolytic
agent like epsilon aminocaproic acid (Amicar) [57] or tranexamic acid; for
dental procedures, oral Amicar mouth washes are usually sufficient. There is
no evidence to support the contention [58] that aspirin is beneficial in PV when
given prophylactically [59, 60] in asymptomatic patients without cardiovascu-
lar risk factors. Sometimes ocular migraine is intractable despite aspirin therapy
unless the platelet count is lowered. The neutrophilic leukocytosis occurring in
PV is harmless unless it causes hyperuricemia and has never been convincingly
shown to be associated with thrombosis [61]. This is also true for
thrombocytosis [62]. Interestingly, PV patients are prone to Helicobacter pylori
12 Page 10 of 14 Curr. Treat. Options in Oncol. (2018) 19:12

infections [63]. Pulmonary hypertension is an uncommon but serious and

often unrecognized complication of PV, usually in patients who have trans-
formed to myelofibrosis [64]. Due to massive splenomegaly, they are also the
same patients who develop portal hypertension.
Current treatment recommendations for PV define its risk factors as extreme
thrombocytosis (9 1,000,000/μL), prior thrombosis, and age 9 65 [65]. How-
ever, no prospective study has ever established the validity of these claims.
Asymptomatic thrombocytosis requires no treatment, thrombosis in PV is
almost always provoked by a high hematocrit and the complications of PV
are the same over age 65 as under age 45 [66, 67]. Furthermore, hydroxyurea is
recommended as the drug of choice for treating PV when in fact no prospective
study has ever established this, but a randomized prospective, controlled clin-
ical trial showed that hydroxyurea, like every other form of chemotherapy or
irradiation [47, 68], caused acute leukemia and did not prolong survival [69,
70]. Considering that hydroxyurea is a dermal tumor promoter in combination
with UV irradiation [71], causes DNA copy number changes [71], and impairs
P53 function [72], it is difficult to recommend hydroxyurea as first line therapy
for young patients and equally difficult to recommend it for older patients since
they are at greater risk for leukemic transformation simply by virtue of their age.
[43] Interestingly, hydroxyurea-induced leukemia in PV often arises in a JAK2
V617F-negative HSC [73], while spontaneous leukemic transformation usually
occurs after PV transforms to a PMF phenotype.
Based on an abundance of data, therefore, hydroxyurea cannot be consid-
ered a first line agent in the treatment of any MPN and its use should be limited
to situations in which a rapid reduction in a blood count is deemed necessary.
Importantly, with the recognition that MPN driver mutations constitutively
activate JAK2, we now have a nonmyelotoxic, targeted form of therapy for
inhibiting this kinase, ruxolitinib, which should make hydroxyurea use obso-
lete [37••, 74].
In evaluating a PV patient for therapy, the most appropriate form of staging
is measurement of the JAK2 V617F neutrophil allele burden. This does not
require a marrow examination since the results are the same using peripheral
blood. Indeed, a marrow examination is not only unnecessary for the diagnosis
of PV but also unnecessary for its management unless there is peripheral blood
evidence of marrow failure, since myelofibrosis per se does not impair marrow
function [41]. In most PV patients, as long as the JAK2 V617F neutrophil allele
burden is less than 50%, the disease will not be aggressive and supportive care is
all that is usually necessary. Ruxolitinib, a nonselective JAK1/2 has been dem-
onstrated to effectively alleviate symptoms in PV due to inflammatory cytokine
production such as pruritus and to control splenomegaly [37••, 74]. It can also
control the blood counts but with respect to hematocrit control, phlebotomy is
more effective and less expensive. Two clinical trials have indicated that
ruxolitinib is superior to hydroxyurea with respect to hematocrit control and
symptom control [37••, 74], including pruritus [75], and reduction of spleno-
megaly. The effects of ruxolitinib are durable but it does cause immunosup-
pression with an increase in Herpes zoster and in some patients, deep-seated
tissue infections or pneumonia, particularly with advanced disease. The drug
can partially reduce the JAK2 V617F neutrophil allele burden in some patients
[76] but its effect on the HSC JAK2 V617F allele burden is less effective but not
Curr. Treat. Options in Oncol. (2018) 19:12 Page 11 of 14 12

well studied nor, for unknown reasons, is ruxolitinib effective in every patient
[37••, 74].
Reduction in the JAK2 V617F neutrophil and HSC allele burden can be
achieved with pegylated interferon, and in approximately 20% of patients, a
complete molecular remission can be obtained [77]. Pegylated interferon is less
toxic than its recombinant congener and has the advantage that it can be given
weekly. It is effective in alleviating symptoms in the majority of PV patients and
reducing splenomegaly [78, 79••]. While it appears to be selective for the
involved HSC [80], it is not always effective in controlling erythrocytosis since
paradoxically it activates erythroid gene expression [80]. Interferon appears to
be most effective in PV when there is a low JAK2 V617F allele burden [77]. It
does, of course, have a side effect profile similar to recombinant interferon with
respect to immunosuppression, thyroid toxicity, atrial fibrillation, neuropathy,
liver toxicity, depression, and suicidal ideation.
In PV patients intolerant to or refractory to ruxolitinib or pegylated interfer-
on, low-dose thalidomide and prednisone can be effective [81], although
thalidomide is also an immunosuppressant; lenalidomide has no role in PV
therapy [82]. The role of bone marrow transplantation in PV has not yet been
defined, given the chronic nature of the disease but should be considered in PV
patients who have transformed to a PMF phenotype [83].

Compliance with ethical standards

Conflict of interest
Jerry L. Spivak has received compensation from Incyte for service as a consultant.

Human and animal rights and informed consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. James C, Ugo V, Le Couedic JP, et al. A unique clonal 4. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a
JAK2 mutation leading to constitutive signalling causes novel somatic activating mutation in myelofibrosis
polycythaemia vera. Nature. 2005;434(7037):1144–8. with myeloid metaplasia. PLoS Med. 2006;3(7):e270.
2. Scott LM, Tong W, Levine RL, et al. JAK2 exon 12 5. Williams DM, Kim AH, Rogers O, Spivak JL, Moliterno
mutations in polycythemia vera and idiopathic AR. Phenotypic variations and new mutations in JAK2
erythrocytosis. N Engl J Med. 2007;356(5):459–68. V617F-negative polycythemia vera, erythrocytosis, and
3. Ding J, Komatsu H, Iida S, et al. The Asn505 mutation idiopathic myelofibrosis. Exp Hematol.
of the c-MPL gene, which causes familial essential 2007;35(11):1641–6.
thrombocythemia, induces autonomous 6. Nangalia J, Massie CE, Baxter EJ, et al. Somatic CALR
homodimerization of the c-Mpl protein due to strong mutations in myeloproliferative neoplasms with
amino acid polarity. Blood. 2009;114(15):3325–8. nonmutated JAK2. N Engl J Med. 2013;369(25):2391–
405.
12 Page 12 of 14 Curr. Treat. Options in Oncol. (2018) 19:12

7. Klampfl T, Gisslinger H, Harutyunyan AS, et al. So- 22. Cassinat B, Laguillier C, Gardin C, et al. Classification
matic mutations of calreticulin in myeloproliferative of myeloproliferative disorders in the JAK2 era: is there
neoplasms. N Engl J Med. 2013;369(25):2379–90. a role for red cell mass? Leukemia. 2008;22:452–3.
8. Spivak JL, Considine M, Williams DM, et al. Two clin- 23. Lamy T, Devillers A, Bernard M, et al. Inapparent
ical phenotypes in polycythemia vera. N Engl J Med. polycythemia vera: an unrecognized diagnosis. Am J
2014;371(9):808–17. Med. 1997;102(1):14–20.
9. Catani L, Zini R, Sollazzo D, et al. Molecular profile of 24. Broseus J, Park JH, Carillo S, Hermouet S, Girodon F.
CD34+ stem/progenitor cells according to JAK2V617F Presence of calreticulin mutations in JAK2-negative
mutation status in essential thrombocythemia. Leuke- polycythemia vera. Blood. 2014;124(26):3964–6.
mia. 2009;23(5):997–1000. 25. Wendling F, Varlet P, Charon M, Tambourin P. MPLV:
10. Guglielmelli P, Zini R, Bogani C, et al. Molecular pro- a retrovirus complex inducing an acute myeloprolifer-
filing of CD34+ cells in idiopathic myelofibrosis iden- ative leukemic disorder in adult mice. Virology.
tifies a set of disease-associated genes and reveals the 1986;149(2):242–6.
clinical significance of Wilms’ tumor gene 1 (WT1). 26. Janssen JW, Anger BR, Drexler HG, Bartram CR,
Stem Cells. 2007;25(1):165–73. Heimpel H. Essential thrombocythemia in two sisters
11. Tefferi A, Guglielmelli P, Larson DR, et al. Long-term originating from different stem cell levels. Blood.
survival and blast transformation in molecularly an- 1990;75(8):1633–6.
notated essential thrombocythemia, polycythemia 27. Taylor KM, Shetta M, Talpaz M, et al. Myeloprolifera-
vera, and myelofibrosis. Blood. 2014;124(16):2507– tive disorders: usefulness of X-linked probes in diag-
13. nosis. Leukemia. 1989;3(6):419–22.
12.•• Spivak JL. Myeloproliferative neoplasms. N Engl J Med. 28. Ellis JT, Peterson P, Geller SA, Rappaport H. Studies of
2017;376(22):2168–81. the bone marrow in polycythemia vera and the evolu-
A comprehensive review of the genetics, pathophysiology, di- tion of myelofibrosis and second hematologic malig-
agnosis and management of the MPN. nancies. Semin Hematol. 1986;23(2):144–55.
13.• Anderson LA, McMullin MF. Epidemiology of MPN: 29. Wasserman LR. The management of polycythaemia
what do we know? Curr Hematol Malig Rep. vera. Br J Haematol. 1971;21(4):371–6.
2014;9(4):340–9. 30. Tefferi A, Thiele J, Orazi A, et al. Proposals and ratio-
A comprehensive review of the epidemiology of the MPN. nale for revision of the World Health Organization
14. Spivak JL. Polycythemia vera: myths, mechanisms, and diagnostic criteria for polycythemia vera, essential
management. Blood. 2002;100(13):4272–90. thrombocythemia, and primary myelofibrosis: recom-
15. Spivak JL, Silver RT. The revised World Health Organi- mendations from an ad hoc international expert panel.
zation diagnostic criteria for polycythemia vera, essen- Blood. 2007;110:1092–7.
tial thrombocytosis, and primary myelofibrosis: an al- 31. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revi-
ternative proposal. Blood. 2008;112(2):231–9. sion to the World Health Organization classification of
16.• Cazzola M, Kralovics R. From Janus kinase 2 to myeloid neoplasms and acute leukemia. Blood.
calreticulin: the clinically relevant genomic landscape 2016;127(20):2391–405.
of myeloproliferative neoplasms. Blood. 32. Johansson PL, Safai-Kutti S, Kutti J. An elevated venous
2014;123(24):3714–9. haemoglobin concentration cannot be used as a sur-
A review of the driver mutations of the MPN. rogate marker for absolute erythrocytosis: a study of
17. Yamamoto R, Morita Y, Ooehara J, et al. Clonal anal- patients with polycythaemia vera and apparent poly-
ysis unveils self-renewing lineage-restricted progenitors cythaemia. Br J Haematol. 2005;129(5):701–5.
generated directly from hematopoietic stem cells. Cell. 33. Alvarez-Larran A, Ancochea A, Angona A, et al. Red cell
2013;154(5):1112–26. mass measurement in patients with clinically suspected
18. Yoshihara H, Arai F, Hosokawa K, et al. diagnosis of polycythemia vera or essential
Thrombopoietin/MPL signaling regulates hematopoi- thrombocythemia. Haematologica.
etic stem cell quiescence and interaction with the os- 2012;97(11):1704–7.
teoblastic niche. Cell Stem Cell. 2007;1(6):685–97. 34.• Hernandez-Boluda JC, Pereira A, Gomez M, et al. The
19. Busch K, Klapproth K, Barile M, et al. Fundamental International Prognostic Scoring System does not ac-
properties of unperturbed haematopoiesis from stem curately discriminate different risk categories in pa-
cells in vivo. Nature. 2015;518(7540):542–6. tients with post-essential thrombocythemia and post-
20. Zhao M, Perry JM, Marshall H, et al. Megakaryocytes polycythemia vera myelofibrosis. Haematologica.
maintain homeostatic quiescence and promote post- 2014;99(4):e55–7.
injury regeneration of hematopoietic stem cells. Nat Myelofibrosis is a histologic diagnosis but it, per se, does not
Med. 2014;20(11):1321–6. confer prognosis. That is the purview of the underlying.
21. Pemmaraju N, Moliterno AR, Williams DM, Rogers O, 35. Pearson TC, Botterill CA, Glass UH, Wetherley-Mein G.
Spivak JL. The quantitative JAK2 V617F neutrophil Interpretation of measured red cell mass and plasma
allele burden does not correlate with thrombotic risk in volume in males with elevated venous PCV values.
essential thrombocytosis. Leukemia. Scand J Haematol. 1984;33(1):68–74.
2007;21(10):2210–2.
Curr. Treat. Options in Oncol. (2018) 19:12 Page 13 of 14 12

36. Wells RE, Merrill EW. Influence of flow properties of Detailed analysis of the clinical features of JAK2 V617F and
blood upon viscosity-hematocrit relationship. J Clin CALR mutations with thrombocytosis but with conflation with
Investig. 1962;41(8):1591–8. PV.
37.•• Vannucchi AM, Kiladjian JJ, Griesshammer M, et al. 50.• Rotunno G, Mannarelli C, Guglielmelli P, et al. Impact
Ruxolitinib versus standard therapy for the treatment of calreticulin mutations on clinical and hematological
of polycythemia vera. N Engl J Med. 2015;372(5):426– phenotype and outcome in essential
35. thrombocythemia. Blood. 2014;123(10):1552–5.
Ruxolitinib was superior to supportive therapy, including hy- Detailed analysis of the clinical features of JAK2 V617F and
droxyurea, in the treatment of polycythemia vera. CALR mutations with thrombocytosis but with conflation with
38. Rongvaux A, Willinger T, Takizawa H, et al. Human PV.
thrombopoietin knockin mice efficiently support hu- 51. Dameshek W. The case for phlebotomy in polycythe-
man hematopoiesis in vivo. Proc Natl Acad Sci U S A. mia vera. Blood. 1968;32(3):488–91.
2011;108(6):2378–83. 52. Pearson TC, Weatherly-Mein G. Vascular occlusive ep-
39.• Silver RT, Gjoni S. The hematocrit value in polycythe- isodes and venous haematocrit in primary proliferative
mia vera: caveat utilitor. Leuk Lymphoma. polycythaemia. Lancet. 1978;2:1219–21.
2015;56(5):1540–1. 53. Marchioli R, Vannucchi AM, Barbui T. Treatment target
The hematocrit cannot be relied on as an indicator of in polycythemia vera. N Engl J Med.
erythrocytosis if polycythemia vera is a diagnostic 2013;368(16):1556.
consideration. 54. Rector WG, Fortuin NJ, Conley CL. Non-hematologic
40. Bessman JD. Microcytic polycythemia. Frequency of effects of chronic iron deficiency. A study of patients
nonthalassemic causes. JAMA. 1977;238(22):2391–2. with polycythemia vera treated solely with venesec-
41. Passamonti F, Rumi E, Caramella M, et al. A dynamic tions. Medicine (Baltimore). 1982;61(6):382–9.
prognostic model to predict survival in post- 55. Michiels JJ, Berneman Z, Schroyens W, et al. Platelet-
polycythemia vera myelofibrosis. Blood. mediated erythromelalgic, cerebral, ocular and coro-
2008;111(7):3383–7. nary microvascular ischemic and thrombotic manifes-
42.•• Xie M, Lu C, Wang J, et al. Age-related mutations asso- tations in patients with essential thrombocythemia
ciated with clonal hematopoietic expansion and ma- and polycythemia vera: a distinct aspirin-responsive
lignancies. Nat Med. 2014;20(12):1472–8. and coumadin-resistant arterial thrombophilia. Plate-
JAK2 V617F can be acquired at any age but the incidence lets. 2006;17(8):528–44.
increases over age 60 as does the incidence of mutations in 56. Budde U, Scharf RE, Franke P, Hartmann-Budde K,
genes such as DNMT3a and TET2. Dent J, Ruggeri ZM. Elevated platelet count as a cause
of abnormal von Willebrand factor multimer distribu-
43. RJ MN, Rowland D, Roman E, Cartwright RA. Age and
tion in plasma. Blood. 1993;82(6):1749–57.
sex distributions of hematological malignancies in the
U.K. Hematol Oncol. 1997;15(4):173–89. 57. Bartholomew JR, Salgia R, Bell WR. Control of bleeding
in patients with immune and nonimmune thrombo-
44. Stein BL, Williams DM, Wang NY, et al. Sex differences
cytopenia with aminocaproic acid. Arch Intern Med.
in the JAK2 V617F allele burden in chronic myelopro-
1989;149(9):1959–61.
liferative disorders. Haematologica. 2010;95(7):1090–
7. 58. Landolfi R, Marchioli R, Kutti J, et al. Efficacy and safety
of low-dose aspirin in polycythemia vera. N Engl J
45. Moliterno AR, Williams DM, Rogers O, Isaacs MA,
Med. 2004;350(2):114–24.
Spivak JL. Phenotypic variability within the JAK2
59. Spivak J. Daily aspirin—only half the answer. N Engl J
V617F-positive MPD: roles of progenitor cell and neu-
Med. 2004;350(2):99–101.
trophil allele burdens. Exp Hematol.
2008;36(11):1480–6. 60. Patrono C, Rocca B, De SV. Platelet activation and
inhibition in polycythemia vera and essential
46. Wang L, Swierczek SI, Drummond J, et al. Whole-
thrombocythemia. Blood. 2013;121(10):1701–11.
exome sequencing of polycythemia vera revealed novel
driver genes and somatic mutation shared by T cells 61. Passamonti F, Rumi E, Pietra D, et al. A prospective
and granulocytes. Leukemia. 2014;28(4):935–8. study of 338 patients with polycythemia vera: the im-
pact of JAK2 (V617F) allele burden and leukocytosis
47. Gruppo Italiano SP. Polycythemia vera: the natural
on fibrotic or leukemic disease transformation and
history of 1213 patients followed for 20 years. Ann
vascular complications. Leukemia. 2010;24(9):1574–
Intern Med. 1995;123(9):656–64.
9.
48. Moliterno AR, Hankins WD, Spivak JL. Impaired ex- 62. Tefferi A, Gangat N, Wolanskyj AP. Management of
pression of the thrombopoietin receptor by platelets extreme thrombocytosis in otherwise low-risk essential
from patients with polycythemia vera. N Engl J Med. thrombocythemia; does number matter? Blood.
1998;338(9):572–80. 2006;108(7):2493–4.
49.• Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mu- 63. Torgano G, Mandelli C, Massaro P, et al. Gastroduo-
tation status defines subtypes of essential denal lesions in polycythaemia vera: frequency and
thrombocythemia with substantially different clinical role of Helicobacter pylori. Br J Haematol.
course and outcomes. Blood. 2014;123(10):1544–51. 2002;117(1):198–202.
12 Page 14 of 14 Curr. Treat. Options in Oncol. (2018) 19:12

64. Popat U, Frost A, Liu E, et al. High levels of circulating 75. Mesa R, Vannucchi AM, Yacoub A, et al. The efficacy
CD34 cells, dacrocytes, clonal hematopoiesis, and and safety of continued hydroxycarbamide therapy
JAK2 mutation differentiate myelofibrosis with mye- versus switching to ruxolitinib in patients with poly-
loid metaplasia from secondary myelofibrosis associ- cythaemia vera: a randomized, double-blind, double-
ated with pulmonary hypertension. Blood. dummy, symptom study (RELIEF). Br J Haematol.
2006;107(9):3486–8. 2017;176(1):76–85.
65. Tefferi A, Barbui T. Polycythemia vera and essential 76. Vannucchi AM, Verstovsek S, Guglielmelli P, et al.
thrombocythemia: 2015 update on diagnosis, risk- Ruxolitinib reduces JAK2 p.V617F allele burden in
stratification and management. Am J Hematol. patients with polycythemia vera enrolled in the RE-
2015;90(2):162–73. SPONSE study. Ann Hematol. 2017;96(7):1113–20.
66. Passamonti F, Malabarba L, Orlani E, et al. Polycythe- 77. Kiladjian JJ, Cassinat B, Chevret S, et al. Pegylated
mia vera in young patients: a study on the long-term interferon-alfa-2a induces complete hematological and
risk of thrombosis, myelofibrosis and leukemia. molecular responses with low toxicity in polycythemia
Haematologica. 2003;88(1):13–8. vera. Blood. 2008;108(2037):2040.
67. Stein BL, Saraf S, Sobol U et al. Age-related differences in 78. Silver RT, Kiladjian JJ, Hasselbalch HC. Interferon and
disease characteristics and clinical outcomes in polycy- the treatment of polycythemia vera, essential
themia vera. Leuk Lymphoma. 2013;54(9):1989–95 thrombocythemia and myelofibrosis. Expert Rev
68. Berk PD, Goldberg JD, Silverstein MN, et al. Increased Hematol. 2013;6(1):49–58.
incidence of acute leukemia in polycythemia vera as- 79.•• Gowin K, Jain T, Kosiorek H, et al. Pegylated interferon
sociated with chlorambucil therapy. N Engl J Med. alpha-2a is clinically effective and tolerable in myelo-
1981;304(8):441–7. proliferative neoplasm patients treated off clinical trial.
69. Najean Y, Rain J. Treatment of polycythemia vera: the Leuk Res. 2017;54:73–7.
use of hydroxyurea and pipobroman in 292 patients
Pegylated interferon is an effective therapy in PV, which in
under the age of 65 years. Blood. 1997;90(9):3370–7.
contrast to ruxolitinib and hydroxyurea, specifically attacks the
70. Spivak JL. An inconvenient truth. Blood.
malignant stem cells.
2010;115(14):2727–8.
71. Arlt MF, Ozdemir AC, Birkeland SR, Wilson TE, Glover 80. Mullally A, Bruedigam C, Poveromo L, et al. Depletion
TW. Hydroxyurea induces de novo copy number vari- of Jak2V617F myeloproliferative neoplasm-
ants in human cells. Proc Natl Acad Sci U S A. propagating stem cells by interferon-alpha in a murine
2011;108(42):17,360–5. model of polycythemia vera. Blood.
72. Spivak JL, Hasselbalch H. Hydroxycarbamide: a user’s 2013;121(18):3692–702.
guide for chronic myeloproliferative disorders. Expert 81. Mesa RA, Steensma DP, Pardanani A, et al. A phase 2
Rev Anticancer Ther. 2011;11(3):403–14. trial of combination low-dose thalidomide and pred-
73. Beer PA, Delhommeau F, Lecouedic JP, et al. Two nisone for the treatment of myelofibrosis with myeloid
routes to leukemic transformation following a JAK2 metaplasia. Blood. 2003;101(7):2534–41.
mutation-positive myeloproliferative neoplasm. 82. Spivak JL. Lenalidomide and the 3 Ms.: déjà vu all over
Blood. 2010;115:2891–900. again? Blood. 2006;108:1118–9.
74. Passamonti F, Griesshammer M, Palandri F, et al. 83. Kroger NM, Deeg JH, Olavarria E, et al. Indication and
Ruxolitinib for the treatment of inadequately con- management of allogeneic stem cell transplantation in
trolled polycythaemia vera without splenomegaly primary myelofibrosis: a consensus process by an
(RESPONSE-2): a randomised, open-label, phase 3b ebmt/eln international working group. Leukemia.
study. Lancet Oncol. 2017;18(1):88–99. 2015;29(11):2126–33.