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How I treat

How I treat essential thrombocythemia

Philip A. Beer,1-3 Wendy N. Erber,2,3 Peter J. Campbell,3,4 and Anthony R. Green1-3
1Cambridge Institute for Medical Research and 2Department of Haematology, University of Cambridge, Cambridge, United Kingdom; 3Department of

Haematology, Addenbrookes Hospital, Cambridge, United Kingdom; and 4Wellcome Trust Sanger Institute, Hinxton, United Kingdom

In the past 5 years we have witnessed myelofibrosis. In the first part of this rent approach to the treatment of ET,
significant advances in both the diagnos- review, we describe how recent molecu- including risk stratification, choice of cy-
tic process and optimal therapy for pa- lar and histologic studies can be inte- toreductive agent, and a consideration of
tients with essential thrombocythemia grated into a streamlined diagnostic pro- special situations such as the pregnant
(ET). Insights into the underlying molecu- cess that is applicable to everyday clinical or perioperative patient. Areas of contro-
lar mechanisms have been accompanied practice. We also address areas of cur- versy discussed include the identifica-
by the development of new diagnostic rent diagnostic controversy, including het- tion of those at high risk of complications
tests and by an improved understanding erogeneity within ET and the phenotypic and therapeutic decisions in the younger
of the relationship between ET and other overlap between ET, polycythemia vera, patient. (Blood. 2011;117(5):1472-1482)
related myeloproliferative neoplasms, and primary myelofibrosis. In the second
such as polycythemia vera and primary part, we provide an overview of our cur-

Introduction
Essential thrombocythemia (ET) is a clonal stem cell disorder that find blood film examination and assessment of iron status to be
shares phenotypic and pathologic similarities with other myelopro- helpful. A normal hemoglobin count in an iron-replete patient is
liferative neoplasms (MPNs), particularly polycythemia vera (PV) usually sufficient to exclude PV. Although reduced serum ferritin
and primary myelofibrosis (PMF). In the last 5 years there has been and/or absent bone marrow iron stores may occur in patients with
an acceleration in our understanding of these disorders, after the ET,7 we consider the combination of microcytic red cells and a
identification of an acquired JAK2 V617F mutation in approxi- normal hemoglobin count in a JAK2 V617F-positive white patient
mately 50% of ET patients, along with one-half of those with PMF highly suggestive of iron-deficient PV. In our opinion, PMF can
and the majority with PV.1,2 Subsequently mutations in MPL were generally be excluded by the absence of significant splenomegaly,
reported in approximately 4% of patients with ET or PMF,3-5 and unexplained anemia, teardrop poikilocytes, and a leukoerythroblas-
mutations in TET2 have been observed in a variety of myeloid tic blood film. A minority of patients with chronic myelomonocytic
malignancies, including JAK2 V617F-positive and -negative ET.6 leukemia harbor a JAK2 V617F mutation, although such cases
In this article, we explore the impact of recent molecular and generally lack thrombocytosis, with additional features such as
therapeutic advances on the way we diagnose and manage patients leukocytosis, monocytosis, and splenomegaly, suggesting the cor-
with ET. rect diagnosis.8
In patients with suspected ET who lack JAK2 and MPL
mutations, the exclusion of reactive causes is particularly important
How we diagnose ET (Table 1). In studies of unselected patients with thrombocytosis,
fewer than 20% harbored a clonal blood disorder.9,10 Therefore a
We consider a diagnosis of ET when there is an unexplained and careful history, assessment of inflammatory markers (C-reactive
persistent thrombocytosis (platelet count 450 109/L). ET has protein and/or erythrocyte sedimentation rate), and bone marrow
traditionally been a diagnosis of exclusion, requiring the absence of histology are all recommended (Figure 1). Cytogenetic analysis
reactive conditions and other clonal disorders that may present with may also be considered, and we use a panel of fluorescent in situ
thrombocytosis (Table 1). The discovery of mutations in JAK2 and hybridization probes to detect MPN-associated chromosome
MPL now allows for the positive identification of ET in more than abnormalities (detecting additional copies of chromosomes 8
one-half of all cases. In our practice, screening for the JAK2 V617F and 9 and deletions of 20q and 13q). However, chromosomal
mutation is the initial investigation performed in all patients with lesions are present in only 5% of patients at diagnosis and lack
suspected ET, followed by screening for MPL exon 10 mutations in prognostic significance.11 In the absence of a molecular or
V617F-negative cases. TET2 screening is not currently performed cytogenetic marker of clonal hematopoiesis, ET remains a
because mutations are present in a wide range of other myeloid diagnosis of exclusion.
malignancies,6 screening is not straightforward, and the prognostic Diagnostic criteria for ET are presented in Table 2. Criteria from
significance of TET2 mutations in ET is currently unknown. the British Committee for Standards in Haematology (BCSH)12 are
In the presence of a pathogenetic mutation in JAK2 or MPL, a used in our clinic. These criteria are similar to those of the WHO13
diagnosis of ET requires exclusion of PV and PMF. To this end, we but differ in 3 important respects. First, in the presence of a

Submitted August 27, 2010; accepted November 10, 2010. Prepublished 2011 by The American Society of Hematology
online as Blood First Edition paper, November 24, 2010; DOI 10.1182/blood-
2010-08-270033.

1472 BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5

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BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5 ESSENTIAL THROMBOCYTHEMIA 1473

Table 1. Causes of thrombocytosis Table 2. Criteria for the diagnosis of ET

Myeloid malignancy WHO 2008 BCSH 2010
Essential thrombocythemia
Requires A1-A4 Requires A1-A3 or A1 A3-A5
Polycythemia vera
A1: Sustained platelet count A1: Sustained platelet count
Primary myelofibrosis
450 109/L 450 109/L
Chronic myeloid leukemia
A2: Bone marrow showing A2: Presence of an acquired
Refractory anemia with ringed sideroblasts and thrombocytosis
increased numbers of enlarged, pathogenetic mutation (eg, in JAK2
Myelodysplastic syndrome associated with isolated del(5q)
mature megakaryocytes; no or MPL)
Reactive (secondary) thrombocytosis
significant increase of left-shift
Blood loss or iron deficiency
of granulopoiesis or
Infection or inflammation
erythropoiesis*
Disseminated malignancy
A3: Not meeting WHO criteria for A3: No other myeloid malignancy,
Drug effect (vincristine, epinephrine, all-trans-retinoic acid)
PV, PMF, CML, MDS, or other especially PV, PMF, CML, or MDS
Hyposplenism or congenital absence of spleen
myeloid neoplasm
Hemolytic anemia
A4: Acquired mutation or clonal A4: No reactive cause for
Familial thrombocytosis
marker or no reactive cause for thrombocytosis and normal iron
Mutations in TPO, MPL, or unknown genes
thrombocytosis stores
Spurious thrombocytosis
A5: Bone marrow aspirate and trephine
Cryoglobulinemia
biopsy showing increased
Cytoplasmic fragmentation accompanying myeloid or lymphoid neoplasia
megakaryocyte numbers displaying
Red cell fragmentation
a spectrum of morphology with
predominant large megakaryocytes
with hyperlobated nuclei and
pathogenetic mutation a diagnosis of ET does not necessarily abundant cytoplasm.
require bone marrow studies, as other myeloid disorders that
present with thrombocytosis and a JAK2 or MPL mutation can BCSH indicates British Committee for Standards in Haematology; CML, chronic
myeloid leukemia; ET, essential thrombocythemia; MDS, myelodysplastic syn-
generally be excluded by clinical and laboratory features as dromes; MPN, myeloproliferative neoplasm; PMF, primary myelofibrosis; PV, polycy-
outlined above. However, it is our practice to obtain bone marrow themia vera; and WHO, World Health Organization.
aspirate and trephine biopsy samples from most patients at *Increased reticulin fibrosis excludes a diagnosis of ET

diagnosis. This is to provide both confirmatory data (bone marrow

generally showing normal cellularity in the presence of giant tion, specifically the degree of reticulin fibrosis.11 A bone marrow
megakaryocytes with hyperlobated nuclei) and prognostic informa- sample at diagnosis also provides a useful baseline for subsequent

Figure 1. Algorithm for the investigation and diagno-

sis of thrombocytosis. ET indicates essential thrombo-
cythemia; FBC, full blood count; MCV, mean cell volume;
MPN, myeloproliferative neoplasm; and PV, polycythe-
mia vera.
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1474 BEER et al BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5

Table 3. Criteria for the diagnosis of myelofibrosis the second decade, and continuing to increase thereafter.15,16,21
Primary myelofibrosis Myelofibrotic transformation of ET or PV However, studies often included patients who had received mul-
Requires A1 A2 and any 2 B Requires A1 A2 and any 2 B criteria tiple lines of cytoreductive therapy, including alkylating agents,
criteria which are known to increase the rate of leukemic transforma-
A1: Bone marrow fibrosis 3 A1: Bone marrow fibrosis 3 tion,22,23 thus rendering these findings difficult to interpret. Transfor-
(on 0-4 scale) (on 0-4 scale) mation to AML is diagnosed in the presence of 20% blast cells in
A2: Pathogenetic mutation (eg, in A2: Previous diagnosis of ET or PV the blood and/or bone marrow. Of note, patients with JAK2
JAK2 or MPL) or absence of V617F-positive ET may develop AML that is negative for the JAK2
both BCR-ABL1 and reactive
mutation.24-26
causes of bone marrow fibrosis
B1: Palpable splenomegaly B1: New palpable splenomegaly or
increase in spleen size of 5 cm
B2: Unexplained anemia B2: Unexplained anemia with 2 g/dL
decrease from baseline hemoglobin Controversies in the diagnosis of ET
B3: Leukoerythroblastic blood film B3: Leukoerythroblastic blood film
Distinguishing ET from PMF
B4: Teardrop-shaped red cells B4: Teardrop-shaped red cells
B5: Constitutional symptoms* B5: Constitutional symptoms*
ET is heterogeneous with regards to diagnostic, clinical, and
B6: Histological evidence of B6: Histological evidence of
laboratory features, and there has been considerable debate over the
extramedullary hematopoiesis extramedullary hematopoiesis
existence of distinct subgroups. Some of this heterogeneity, such as
Criteria adapted from Campbell and Green.1 variation in diagnostic blood counts and bone marrow cellularity,
ET indicates essential thrombocythemia; and PV, polycythemia vera.
reflects the presence or absence of mutations in JAK2 or MPL,4,7,14,27
*Drenching night sweats, weight loss 10% over 6 months, unexplained fever
(37.5C) or diffuse bone pains. and constitutional genetic differences are also likely to contribute.
The current WHO classification proposes that bone marrow
histology can be used as a tool to subdivide ET into so-called true
comparisons, for example, after myelofibrotic transformation. ET and prefibrotic myelofibrosis13 and suggests that true ET is a
Second, BCSH criteria do not use bone marrow histology to benign and stable condition whereas prefibrotic myelofibrosis
subdivide ET into true-ET and prefibrotic myelofibrosis be- progresses to clinically overt myelofibrosis.28 However many of the
cause the existence of the latter as a distinct entity remains histologic criteria used to define prefibrotic myelofibrosis, such as
controversial and the underlying histologic criteria are difficult to megakaryocyte morphology, are subjective and difficult to apply
apply reproducibly.14 Third, the BCSH classification includes reproducibly, even by experienced hematopathologists.14 We there-
patients with bone marrow reticulin greater than grade 2 (on a 0-4 fore avoid the terms true ET and prefibrotic myelofibrosis in our
scale) who lack other features of PMF or myelofibrotic transforma- practice.
tion. Under current World Health Organization (WHO) criteria, A second area of debate relates to patients with an isolated
such patients cannot be classified as either ET, because they have thrombocytosis who show an increase in bone marrow reticulin
too much reticulin, or PMF, because they have none of the clinical fibrosis at diagnosis but lack any other features of PMF (Figure 2).
features required for this diagnosis. Such patients clearly have an MPN but cannot be classified as
having either ET or PMF according to WHO criteria.13 Importantly,
Myelofibrotic transformation of ET such cases are not unusual, with data from the PT-1 trial indicating
that 15%-20% of ET patients harbor grade 3 or occasionally grade
Evolution to myelofibrosis affects a proportion of ET patients,
4 reticulin fibrosis at diagnosis (on a 0-4 scale, with grade 4
although the reported prevalence varies widely, reflecting differ-
indicating the presence of collagen fibrosis), in the absence of other
ences in study design, therapeutic intervention, and the diagnostic
features of PMF.29 Increased bone marrow fibrosis at diagnosis is
criteria applied. Retrospective studies suggest that myelofibrotic
associated with greater rates of myelofbrotic transformation,
transformation increases with disease duration, affecting 3%-10%
thrombosis, and hemorrhage but no change in overall survival.29
in the first decade after diagnosis and 6%-30% in the second
The lack of a survival difference, together with the small number of
decade.15-17 Given the close relationship of post-ET myelofibrosis
complications even at greater reticulin levels, supports the concept
to PMF, the criteria we use to diagnose these conditions are
that patients presenting with an isolated thrombocytosis but
essentially the same (Table 3). These criteria are similar to other
elevated reticulin have a relatively benign prognosis. We therefore
widely used systems13,18,19 but do not include serum lactate
follow BCSH guidelines according to which such patients are
dehydrogenase (LDH) because a correlation between increasing
diagnosed and treated as ET.
LDH and myelofibrotic transformation has yet to be established
A third area of controversy relates to the traditional view of ET
and increased levels of LDH also are found in most patients with
and PMF as separate entities. More recently it has been suggested
ET or PV.20 It is important to emphasize that the development of
that PMF represents presentation in accelerated phase of a previ-
reticulin fibrosis on its own does not equate to transformation to
ously undiagnosed MPN, usually ET.1,14,30 This concept is sup-
myelofibrosis, and the diagnosis of myelofibrotic transformation is
ported by several lines of evidence: (1) PMF is clinically indistin-
reserved for those patients who demonstrate bone marrow fibrosis
guishable from myelofibrotic transformation of ET; (2) the
in association with accompanying clinical and/or laboratory fea-
prevalence of JAK2 and MPL mutations are similar in ET and PMF;
tures (Table 3).
(3) laboratory (eg, cytogenetic changes) and clinical features (eg,
Leukemic transformation of ET increased rate of leukemic transformation) suggest PMF represents
accelerated phase disease; and (4) patients with PMF may have
Progression to acute myeloid leukemia (AML) occurs in a small thrombocytosis for many years before they are diagnosed (Figure
minority of patients, with retrospective studies suggesting an 3). Of interest, the patient illustrated in Figure 3 had a platelet count
incidence of 1%-2.5% in the first decade after diagnosis, 5%-8% in of 450-500 109/L at diagnosis of PMF but was subsequently
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BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5 ESSENTIAL THROMBOCYTHEMIA 1475

Figure 2. Isolated thrombocytosis and bone mar-

row fibrosis in the absence of clinical features to
support a diagnosis of primary myelofibrosis.
(A) Bone marrow samples obtained at diagnosis from a
54-year-old female patient with thrombocytosis in the
absence of additional features of PMF: left, bone
marrow aspirate stained with Wright-Giemsa showing a
large megakryocyte with a hyperlobated nucleus;
middle, bone marrow trephine biopsy stained with
hematoxylin and eosin showing loose clusters of
megakaryocytes containing both large megakaryoctes
with hyperlobated nuclei and smaller forms with cloud-
like or hyperchromatic nuclei; right, silver-stained bone
marrow section showing grade 4 reticulin fibrosis (on
0-4 scale). (B) Blood counts during the course of
54 months from diagnosis showing stabilization of the
platelet count and no change in hemoglobin level. Red
and blue shaded areas represent the normal range for
hemoglobin and platelet count, respectively.

found to have had counts lose to 1000 109/L during the and PV therefore form a phenotypic spectrum and there has been
preceding 10 years. This finding indicates that ET patients present- considerable debate over where to draw the line between them.
ing with marginally elevated platelet counts may represent either Indeed, there are inherent problems in the use of continuous
early-phase disease (platelet count on the way up) or late-phase variables, such as hemoglobin, hematocrit, or red cell mass, to
disease (platelet count on the way down). make this binary distinction, because the group of patients with
These various controversies over the boundary between ET and borderline values will inevitably include both disorders, as illus-
PMF are likely to be resolved in time as we gain greater molecular trated in Figure 4A.
insights into these disorders. However, the current lack of a We take a pragmatic approach and base a diagnosis of PV on
universally agreed classification will impair comparisons between the presence of a JAK2 mutation and a raised hematocrit (with or
clinical studies. In our view the WHO criteria place too much without supporting features such a low serum erythropoietin),
reliance on subjective histologic criteria, the variable application of an approach consistent with both WHO and BCSH guide-
which by different centers will result in a lack of comparability lines.13,31 We recognize that, unless markedly elevated, hemato-
between patient cohorts. By contrast, the broader definition of ET crit does not accurately predict an increased red cell mass,32 that
adopted by BCSH guidelines has the advantage that it is easier to serum erythropoietin levels do not distinguish PV from ET,7 and
apply in a reproducible manner. that ET patients, predominantly those with JAK2 V617F-
Distinguishing ET from PV
positive disease, may harbor an increased red cell mass despite a
normal hematocrit.33,34 However, in the presence of a normal
The distinction between ET and PV is, in theory, simplepatients hematocrit and normal iron stores, the clinical significance of a
with PV have an overt erythrocytosis that is lacking in ET. raised red cell mass is unclear, and so we do not measure red cell
Unfortunately, in practice matters are more complex. Mounting mass in our ET patients.
evidence demonstrates that patients with JAK2 V617F-positive ET Further progress in distinguishing ET from PV is likely to
represent a forme fruste of PV and exhibit PV-like features.7,30 ET require a better understanding of their molecular pathogenesis. It
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1476 BEER et al BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5

Figure 3. Presentation with myelofibrotic transfor-

mation of previously undiagnosed ET. (A) Platelet and
hemoglobin levels during a 10-year period before presen-
tation with PMF in a patient at the age of 67 years; a
marked thrombocytosis between 8 and 10 years before
diagnosis is followed by a gradual decrease in platelet
count and progressive anemia in the absence of iron
deficiency or inflammation. (B) At clinical presentation,
left, Wright-Geimsastained blood film showing leuko-
erythroblastosis and tear-drop red cells; middle, hema-
toxylin and eosinstained bone marrow trephine biopsy
showing clusters of dysplastic megakaryocytes; and
right, silver-stained bone marrow trephine biopsy show-
ing grade 4 reticulin fibrosis (on 0-4 scale). Red and blue
shaded areas represent the normal range for hemoglobin
and platelet count, respectively.

has recently been reported that the distinct phenotypes of JAK2 of one recent study suggested that low-risk patients may not derive
V617F-positive ET and PV reflect differential STAT1 activation,35 benefit from antiplatelet therapy.39 On the basis of current evidence,
an observation that could lead to clinically useful biomarkers. we recommend aspirin for all ET patients unless contraindicated.
Although there are few data concerning the use of newer antiplate-
let agents such as clopidogrel, their proven track record in
How we treat ET atherosclerotic disease suggests they are appropriate for ET
patients unable to tolerate aspirin.
Modification of cardiovascular risk factors
Indications for cytoreductive therapy
In our practice, all patients are screened for the presence of
established cardiovascular risk factors, including hypertension, The best established risk factors for thrombotic complications in
diabetes, smoking, hypercholesterolemia, and obesity, and treated ET are age older than 60 years or a history of previous thrombo-
where indicated according to local guidelines. The broad efficacy sis,16,40,41 and patients with these risk factors probably benefit from
of the cholesterol-lowering statin drugs in the prevention of cytoreductive therapy.42 Risk factors for atherosclerotic disease
atherosclerotic disease has raised the possibility that such agents also predict for thrombosis in ET patients,41,43,44 although it is
may be useful in ET, although this has yet to be tested in a unclear whether their presence necessitates cytoreductive therapy
prospective study. in the absence of high-risk ET (age 60 years or history of
thrombosis). The degree of thrombocytosis is not a reliable
Antiplatelet therapy
indicator of thrombotic risk, although very high levels may predict
A large randomized trial in PV demonstrated a reduction in for hemorrhagic complications.16,41,45-48 Meta-analysis has con-
thrombotic events in those taking aspirin, without a concomitant firmed an increased risk of venous and arterial thrombosis in JAK2
increase in the risk of hemorrhage.36 Retrospective studies have V617F-positive compared with V617F-negative ET.49,50 Studies
suggested a similar protective effect in ET,37,38 although the authors have also suggested that the size of the JAK2-mutant clone may be
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BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5 ESSENTIAL THROMBOCYTHEMIA 1477

Figure 4. Distribution of hematocrit level in JAK2

V617F-positive disease. (A) Diagrammatic representa-
tion of hemoglobin levels in patients with JAK2 V617F-
negative ET, V617F-positive ET and V617F-positive PV,
showing mean hemoglobin levels for patients with V617F-
positive and negative ET (from Campbell et al7) and
V617F-positive PV (from Cambridge cohort); hemoglobin
levels in the mid-range will include patients with both ET
and PV. (B) Hematocrit levels at diagnosis from a cohort
of patients attending the Cambridge MPN clinic and
diagnosed with JAK2 V617F-positive ET or PV, showing
considerable overlap in hematocrit between ET and PV in
both male and female patients.

of prognostic significance in MPN patients, although data for ET poorly controlled diabetes or a strong family history of early onset
patients are limited27 Increased leukocyte count or increased bone atherosclerotic disease. The role of the platelet count in directing
marrow fibrosis at diagnosis are also independent predictors of cytoreductive therapy remains contentious. Many physicians still
thrombotic complications.15,29,48 recommend cytoreductive therapy in patients with platelets
We stratify ET patients on the basis of thrombotic risk (Table 4) 1500 109/L, although it may be reasonable to use a greater
and recommend cytoreductive therapy for all high-risk patients. cut-off in younger patients. There are, as yet, no prospective
Cytoreduction is also considered in those with previous serious clinical data on the utility of novel thrombotic risk factors, such as
hemorrhage (eg, requiring hospitalization or red cell transfusion) JAK2 mutation status, mutant allele burden, leukocyte count, and
that is thought to be related to ET. Microvascular complications, bone marrow fibrosis. We therefore do not currently use these
such as erythromelalgia, generally settle with antiplatelet therapy factors to guide therapeutic decisions.
alone,38 and cytoreductive therapy is only considered for refractory Patients without high-risk features can be divided into low risk (age
cases. Those with indicators of atherosclerotic disease in the 40 years) and intermediate risk (age 40-60 years). Cytoreductive
absence of high-risk ET are assessed on a case-by-case basis, therapy is unlikely to offer a significant protective effect for those with
taking into account the severity of each cardiovascular risk. For low risk of disease, in whom the a priori risk of thrombosis is small.
example in the absence of high-risk features, cytoreductive therapy There is currently little evidence available to guide treatment decisions
would not generally be recommended for a patient with well- in the intermediate risk group. The ongoing PT-1 trials (http://
controlled hypertension but would be considered in someone with www.haem.cam.ac.uk/pages/pt1/), which comprise a randomized trial
of hydroxycarbamide and aspirin versus aspirin alone for intermedi-
ate-risk patients and an observational study of low-risk patients
Table 4. Risk stratification for patients with essential
thrombocythemia treated with aspirin alone, will provide prospective data to help
No high-risk features
clarify therapeutic decisions for these patients.
Intermediate
High risk Low risk risk Choice of cytoreductive agent
Age 60 y Age 40 y Age 40-60 y Hydroxycarbamide (also known as hydroxyurea) is the only
Prior thrombosis
cytoreductive agent proven to reduce thrombotic events in a
Platelets 1500 109/L
randomized controlled trial42 and remains our recommended first-
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1478 BEER et al BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5

Table 5. Choice of cytoreductive agent in essential with anagrelide was observed in V617F-positive and negative
thrombocythemia patients.
Age group First line Second line Preliminary reports of the final results of the ANAHYDRET
40 y Interferon Hydroxycarbamide (Anagrelide versus Hydroxyurea in ET) trial claim to show that
Anagrelide anagrelide is not inferior to hydroxycarbamide in the treatment of
40-75 y Hydroxycarbamide Interferon ET.65 However, compared with PT-1, the number of patients
Anagrelide enrolled was small, the duration of follow-up relatively short
75 y Hydroxycarbamide Anagrelide
(539 patient-years compared with 2653 patient-years in PT-1), and
Pipobroman
considerably fewer end-point events were recorded.30 It therefore
Busulphan
Radioactive phosphorus
seems highly unlikely that the ANAHYDRET study had the
statistical power necessary to detect the differences observed in the
PT-1 study. In addition, the noninferiority design of the ANAHY-
DRET study seems inappropriate, especially after the marked
line therapy for the majority of patients requiring treatment (Table inferiority documented by the PT-1 trial. Such designs define
5). Concerns have been raised, however, about a possible increased noninferiority up to a predetermined limit of tolerable inferiority,
risk of leukemic transformation with this agent. Clinical studies but often this limit is entirely arbitrary or selected with an eye on
have given conflicting results,23,51-54 further confounded by inclu- obtaining regulatory approval, and risks failing to detect clinically
sion of patients who have received multiple cytotoxic agents, lack relevant differences between the treatment arms. Indeed, the whole
of proper controls, retrospective data collection, and relatively ethical basis for conducting noninferiority trials has recently been
short follow-up. Further evidence cited in support of a mutagenic called into question.66
role for hydroxycarbamide includes a possible association with Recombinant interferon is free from leukemogenic or terato-
deletions of 17p (harboring the TP53 locus),51,55-57 increased risk of genic effects, is effective at controlling the platelet count in ET, and
skin neoplasia during prolonged therapy,58 and possible clastogenic may reduce JAK2 mutant allele burden.67,68 It should be noted,
activity in vitro.59 By contrast, hydroxycarbamide appears nonleu- however, that interferon has not been shown to protect from
kemogenic in the treatment of sickle cell disease60 and does not thrombotic complications, and the PT-1 trial reminds us that
appear to increase in vivo mutation rates in sickle cell or MPN 2 agents that result in equivalent control of the platelet count may
patients.61 At this time it is unclear whether single agent hydroxy- nonetheless be associated with very different thrombotic risk.19
carbamide is leukemogenic; however, any increased risk is likely to Interferon therapy is still considered by many as experimental, and
be small and should be balanced against the reduction in throm- its use in the MPN is not licensed in Europe or North America.
botic complications because thrombosis remains the major source Therapy is often associated with significant side-effects, and
of morbidity in ET. although pegylated interferon may be more convenient, toxicity
Anagrelide reduces the platelet count by inhibition of appears similar to the native compound.67,69 Interferon is used in
megakaryocyte differentiation,62 and we currently use it as second- our clinic for young patients (typically those 40 years), for those
line therapy for patients in whom hydroxycarbamide is inadequate wishing to start a family, or for those in whom hydroxycarbamide
or not tolerated. Combined therapy with anagrelide and hydroxycar- may be inappropriate. We try and avoid the use of interferon in
bamide has also been used successfully in our clinic in circum- older patients, who are generally less able to tolerate this agent.
stances in which hydroxycarbamide alone has failed to control the Radioactive phosphorus and alkylating agents such as busul-
platelet count. Anagrelide does not affect the white cell count, but phan are effective at controlling the platelet count but are associ-
anemia is common and often progressive.29 Up to one-third of ated with an increased risk of progression to acute leukemia,
patients cannot tolerate anagrelide because of side effects, many of particularly when used sequentially with hydroxycarbamide.23,52
which result from its vasodilatory and positive inotropic actions, Both agents can be given intermittently with long intervals between
including palpitations and arrhythmias, fluid retention, heart fail- doses and may be useful in treating older patients who are unable to
ure, and headaches.19,63 The use of this drug requires particular attend the clinic on a regular basis. Pipobroman, a piperazine
caution in elderly patients or those with pre-existing cardiac derivative, is effective at reducing the platelet count in ET, although
disease. Although anagrelide is not cytotoxic and therefore unlikely there is little direct evidence for thrombosis prevention.70 Pipobro-
to be leukemogenic, the PT-1 trial demonstrated that anagrelide man is chemically similar to the alkylating agents and is associated
plus aspirin was inferior to hydroxycarbamide plus aspirin in with an increased risk of leukemic transformation when used in the
high-risk ET patients. Despite equivalent control of the platelet long-term treatment of PV.71 In our clinic, the use of pipobroman
count, anagrelide-treated patients experienced greater rates of and other alkylating agents is restricted to older patients (typically
arterial thrombosis, major hemorrhage, and progression to myelofi- those 75 years), where they are used as second- or third-line
brosis and were more likely to be intolerant of their therapy.19 In agents for those who are unable to tolerate hydroxycarbamide, for
contrast to hydroxycarbamide, anagrelide therapy was also associ- example, because of nonhealing leg ulcers.
ated with an increase in bone marrow reticulin over time.29 Response to therapy
Comparison of patients in the PT-1 (comparison of hydroxycarbam-
ide vs anagrelide19) and Italian (comparison of hydroxycarbamide The traditional goal of cytoreductive therapy in ET has been
vs no cytoreductive therapy42) prospective studies suggests that resolution of symptoms and normalization of the platelet count.
anagrelide provides partial protection from thrombosis.64 The However, retrospective studies have identified an association
reduced efficacy of anagrelide compared with hydroxycarbamide between leukocytosis and thrombosis,48 raising the possibility that
in thrombosis prevention was limited to those with JAK2 V617F- controlling the white cell count may be important. Recent prospec-
positive ET, probably reflecting increased sensitivity of these tive data from the PT-1 trial have shed further light on this issue,
patients to the cytoreductive effects of hydroxycarbamide.7 How- with analysis of blood counts revealing that a leukocyte (but not
ever, the increased risk of myelofibrotic transformation associated platelet) count above the normal range during follow-up predicted
 From www.bloodjournal.org by guest on January 16, 2017. For personal use only.

BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5 ESSENTIAL THROMBOCYTHEMIA 1479

for thrombosis in the subsequent 60 days (P.J.C., C. MacLean, receiving cytoreductive treatment, temporary therapy is considered
P.A.B., G. Buck, K. Wheatley, C. N. Harrison, A.R.G., manuscript on a case-by-case basis, after assessment of the patients throm-
in preparation). We now use freedom from ET-related symptoms botic risk profile, degree of thrombocytosis (because greater
together with normal platelet and leukocyte counts as our primary platelet counts may predict for hemorrhage47), and the nature of the
therapeutic endpoints, although it should be noted that this surgery. Splenectomy in ET patients generally results in a sharp
approach has yet to be validated in a prospective clinical study. increase in platelet count that may lead to thrombotic and
hemorrhagic complications. Unless otherwise contraindicated, we
Special considerations: pregnancy commence cytoreductive therapy before splenectomy in ET pa-
First-trimester fetal loss complicates 25%-50% of pregnancies in tients with an increased or high-normal platelet count, aiming for a
ET patients, with other complications such as intrauterine growth platelet count in the mid-normal range before surgery. Postopera-
retardation, stillbirth, and preeclampsia also occurring more fre- tive thromboprophylaxis and daily monitoring of bloods counts are
quently.72-77 Such complications occur irrespective of the platelet also recommended.
count before conception but appear to be more common in those
with JAK2 V617F-positive disease.74,77 Whether the use of aspirin How we treat advanced-phase disease
or cytoreductive agents can improve pregnancy outcome is uncer- The problems and complications associated with myelofibrotic
tain; researchers have reported contradictory results.72-77 Moreover, transformation of ET are similar to de novo PMF, and we manage
the use of aspirin during pregnancy does not benefit non-ET the conditions in the same way. Therapy of post-ET AML is often
patients with a history of recurrent miscarriage.78 However, a large limited by the age and comorbidities and supportive treatment is
meta-analysis of non-ET preeclampsia patients suggested that often the most appropriate strategy. Overall the prognosis of AML
aspirin use in pregnancy is safe for mother and fetus,79 and we secondary to an MPN is very poor. Younger patients who achieve
therefore recommend aspirin for all pregnant ET patients (unless remission with AML induction therapy are considered for alloge-
otherwise contraindicated). neic bone marrow transplantation.
We consider the use of cytoreductive therapy for all pregnant
women with a history of thrombosis. We also consider cytoreduc-
tive therapy for those with previous obstetric complications, such
as stillbirth or recurrent miscarriage. Because the platelet count Controversies in the management of ET
often decreases during pregnancy, we do not consider a platelet The choice of cytoreductive therapy in the younger patient
count of greater than 1500 109/L as an absolute indication for
cytoreductive therapy, and such patients are considered on a Hydroxycarbamide has proven efficacy in the prevention of
case-by-case basis. thrombosis, the major source of morbidity in this condition, but
Although hydroxycarbamide has been used during pregnancy, concerns remain about potential leukemogenicity.57 Because the
usually without adverse effects for mother or fetus, it is teratogenic incidence of leukemic transformation in ET increases with disease
in nonhuman mammals80 and should therefore be avoided. duration,15,16 this concern is particularly relevant to younger
Anagrelide can cross the placenta with unknown effects on fetal patients who may require therapy for several decades. Interferon
development and should also be avoided. Interferon is nonterato- is not leukemogenic, but efficacy data are lacking, and some
genic and is the agent of choice should cytoreductive therapy be patients experience intolerable side-effects. Anagrelide is not
required. Although studies in ET are lacking, thromboprophylaxis cytotoxic and likely not mutagenic. However, the PT-1 trial
appears safe in pregnancy81 and may be considered for patients demonstrated inferiority of anagrelide to hydroycarbamide in the
with a history of thrombosis or recurrent pregnancy loss; in those prevention of thrombosis and identified an increased risk of
with a previous occurrence of thrombosis, treatment should be myelofibrotic transformation with anagrelide therapy.19
continued for at least 6 weeks postpartum. Overall, pregnancy does It is our current practice to recommend a trial of interferon to
not appear to affect the natural history of ET.72 Pregnant ET patients younger than the age of 40 years who require therapy.
patients should ideally be managed in a center at which regular Approaches to maximizing tolerance include slow escalation from
fetal monitoring can be performed, with good communication a low starting dose (eg, 1MU 3 times a week initially), administra-
between the obstetric, hematology, and anesthetic departments. In tion at bedtime with prophylactic acetaminophen (paracetamol),
animal studies, hydroxycarbamide is associated with reduced dose reduction once control is achieved (to the lowest dose that
spermatogenesis and genetic damage to spermatogonia.80 We affords blood count control), and support from specialist nursing
therefore advise male patients requiring cytoreductive treatment to staff between visits to the clinic. If interferon is not tolerated, the
switch to interferon before attempted conception. pros and cons of hydroxycarbamide versus anagrelide are dis-
cussed in detail with each patient. For those receiving anagrelide,
Special considerations: surgery we recommend baseline bone marrow studies to assess reticulin
fibrosis with follow-up bone marrow histology every 2-3 years
Although perioperative thrombotic and bleeding complications while therapy continues. Cessation of anagrelide should be consid-
appear increased in ET patients, it is not clear whether this can be ered in those with increasing reticulin fibrosis because anagrelide-
ameliorated by therapeutic intervention.82 In general, we stop associated fibrosis is reversible in some cases.29
antiplatelet agents 7-10 days before major surgery or surgery to
critical sites and reintroduce as soon as the surgeon is confident of
Indications for cytoreductive therapy in ET versus PV
hemostasis. Postoperative thromboprophylaxis is recommended
according to usual guidelines for the specific procedure. For As outlined previously in this article, ET and PV form a phenotypic
patients receiving cytoreductive therapy who are undergoing continuum with significant overlap in hemoglobin and platelet
elective surgery, the blood count is optimized preoperatively, and levels. These observations call into question the rationale for
interruptions in therapy are kept to a minimum. For patients not different therapeutic strategies in these 2 disorders, particularly the
 From www.bloodjournal.org by guest on January 16, 2017. For personal use only.

1480 BEER et al BLOOD, 3 FEBRUARY 2011 VOLUME 117, NUMBER 5

use of a target hematocrit level to guide treatment in PV but not ET. studies. With regards to therapy, direct comparison of interferon
The primary aim of therapeutic intervention in both ET and PV is and hydroxycarbamide seems timely. JAK2 inhibitors may prove
the prevention of thrombosis. Whereas thrombotic risk appears useful for accelerated-phase disease88 but given the excellent
greater in V617F-positive compared with V617F-negative ET,49,50 prognosis of chronic phase ET, it is unclear whether there is likely
retrospective data suggest comparable thrombosis rates in V617F- to be a role for JAK2 inhibitors in the majority of ET patients.
positive ET and PV.83 Common predictors of thrombosis in ET and
PV include older age, thrombotic history, and increased white cell
count,16,40,41,84,85 with hematocrit identified by some but not all Acknowledgments
studies as an important predictor of thrombosis in PV.86,87 Given the
similarities between V617F-positive ET and PV, the time may be We thank Dr Penny Wright for helpful comments on bone marrow
approaching when these disorders are stratified and managed as a histology and our colleagues in the NCRI MPN study group for
single disease entity, with older age, history of previous thrombo- many helpful discussions.
sis, or an increased hematocrit indicating high-risk disease and Work in the authors laboratories is supported by Leukemia and
mandating cytoreductive therapy. Given the lower thrombosis rates Lymphoma Research UK, Cancer Research UK, the Kay Kendal
in V617F-negative ET, it may be that indications for therapy could Leukemia Fund, the National Institute for Health Research Cam-
safely be relaxed in this group. Clearly further prospective trials are bridge Biomedical Research Center, and the Leukemia & Lym-
necessary before these goals can be realized, with studies enrolling phoma Society of America. P.J.C. is supported by a Wellcome Trust
both ET and PV patients allowing for prospective comparison of Senior Clinical Research Fellowship and P.A.B. by a Kay Kendall
complication rates and assessment of novel risk factors such as Leukemia Fund Intermediate Fellowship.
mutation status, leukocyte count and bone marrow fibrosis.

Authorship

Future directions Contribution: P.A.B. and A.R.G. wrote the manuscript; P.J.C.
contributed to the writing of the manuscript; W.N.E. contributed to
In the past 5 years we have witnessed dramatic advances in our the writing of the How we diagnose ET section; and all authors
understanding of the pathogenesis, classification, and therapy of reviewed and revised the final manuscript.
ET. The identification of additional molecular markers is likely to Conflict-of-interest disclosure: The authors declare no compet-
be needed to clarify the overlap between ET, PV, and PMF. Novel ing financial interests.
risk factors such as leukocyte count, JAK2 mutation status, and Correspondence: Prof Tony Green, Cambridge Institute for
bone marrow fibrosis may provide more precise therapeutic Medical Research, Hills Rd, Cambridge CB2 0XY, United King-
stratification, an approach that awaits validation in prospective dom; e-mail: [email protected].

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2011 117: 1472-1482

doi:10.1182/blood-2010-08-270033 originally published
online November 24, 2010

How I treat essential thrombocythemia

Philip A. Beer, Wendy N. Erber, Peter J. Campbell and Anthony R. Green

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