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How I treat

How I treat polycythemia vera

Francesco Passamonti1
1Division of Hematology, Department of Internal Medicine, University Hospital Ospedale di Circolo e Fondazione Macchi, Varese, Italy

Polycythemia vera (PV) is a clonal disor- Treatment criteria. Different clinical pre- droxyurea is still the gold standard when
der characterized by unwarranted produc- sentations of PV are discussed. Prognos- cytoreduction is needed, even though pegy-
tion of red blood cells. In the majority of tication of PV is tailored to the most lated IFN-alfa-2a and ruxolitinib might be
cases, PV is driven by oncogenic muta- frequent complication during follow-up, useful in particular settings. Results of
tions that constitutively activate the JAK- namely, thrombosis. Age older than phase 1 or 2 studies concerning these
STAT signal transduction pathway, such 60 years and prior history of thrombosis latter agents should however be con-
as JAK2 V617F, or exon 12 mutations or are the 2 main risk factors for disease firmed by the ongoing randomized phase
LNK mutations. Diagnosis of PV is based stratification. Correlations are emerging 3 clinical trials. In this paper, I discuss the
on the WHO criteria. Diagnosis of post-PV between leukocytosis, JAK2(V617F) muta- main problems encountered in daily clinical
myelofibrosis is established according to tion, BM fibrosis, and different outcomes practice with PV patients regarding diagno-
the International Working Group for My- of PV, which need to be confirmed in sis, prognostication, and therapy. (Blood.
eloproliferative Neoplasms Research and prospective studies. In my practice, hy- 2012;120(2):275-284)

Introduction
Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN).1 scenarios: diagnosis by chance (most frequent), diagnosis after a
The abnormal myeloproliferation of PV is sustained by a constitu- thrombotic event ( 30%, 12% severe events),13,24 and diagnosis
tively active JAK-STAT signal transduction pathway, caused by the resulting from disease-related symptoms. Complete blood cell
unique V617F mutation within exon 14 ( 95% of PV)2-5 and by count (CBC) evaluation has a great relevance as a pan-
different mutations within exon 12 ( 4% of PV) of the JAK2 myeloproliferative pattern (erythrocytosis with leukocytosis and/or
gene.6,7 With lower prevalence, loss of negative regulation of JAK thrombocytosis) is more consistent with PV than isolated erythrocy-
activation caused by LNK mutations (hot spot between codons tosis. Blood smear evaluation infrequently adds substantial informa-
208 and 234),8 or by SOCS mutations9 or hypermethylation of CpG tion, even though a look at red cell morphology might help in
islands in SOCS1 and SOCS3,10 have been implicated in PV borderline situations. Splenomegaly is present in approximately
pathogenesis. The current view suggests that several other cooper- 30% to 40% of PV, mainly when PV is pan-myeloproliferative. In
ating genetic hits might be required. Among others, mutations the case of splenomegaly with isolated erythrocytosis, I study the
involving EZH211 or TET2,12 possibly interfering with epigenetic splanchnic district by ultrasound (US) or computed tomography
regulatory mechanisms, have been found in approximately 3% and
(CT) scan to look for splanchnic vein thrombosis (SVT), even in
in approximately 16% of JAK2(V617F)positive PV, respectively.
asymptomatic patients. I do this imaging also in all PV patients
The course of PV is mainly dominated by thrombosis, with an
with mild to severe upper abdominal quadrant pain or vague
incidence estimated at 18 1000 person-years and accounting for 45%
abdominal disturbances, as I have seen many PV patients with
of all deaths, but also evolution to myelofibrosis (post-PV MF) and to
acute myeloid leukemia (AML), both occurring with an incidence of subacute SVT left undiagnosed.
5 1000 person-years and accounting for 13% of deaths,13 warrant
careful consideration. Comprehensive genotypic analyses of post-MPN Which criteria to apply for diagnosis of PV and of its
AML cells identified several mutations14,15 involving IDH1-IDH2,16 evolutions?
TET2,17 IKZF,18 NRAS,19 TP53,20 and RUNX119,21 genes; furthermore,
blasts, even arising in JAK2(V617F)positive PV, have been shown to In all patients with isolated erythrocytosis, I first explore causes of
be JAK2(V617F)negative in a significant proportion of patients,22 secondary polycythemia, such as smoking (by history and oxygen
highlighting the genetic complexity of AML after PV. saturation), pulmonary or cardiac problems (by chest x-ray, lung
In this manuscript, I discuss my approach to patients with PV function tests, echocardiography), overweight with nocturnal dys-
with a focus on specific issues encountered in daily practice pnea (by polysomnography), or hepatic and renal tumors (by US
regarding diagnosis, prognosis, and treatment. scan). Assessing serum erythropoietin (EPO) level is an excellent
discriminatory test, being high in secondary polycythemia and low
in PV.25 To obtain reliable results of EPO measurements, blood
sampling must be performed before the beginning of phlebotomies.
Diagnosis
When a patient displays a pan-myeloproliferative phenotype, I
The median age at presentation is in the sixth decade; patients usually investigate PV first.
younger than 50 years of age account for one-third of PV patients.23 I use the World Health Organization (WHO) criteria to diagnose
Clinical presentation of PV may be recapitulated into 3 main PV,1 as published in 2008, combining 2 major and 1 minor criteria

Submitted February 25, 2012; accepted May 10, 2012. Prepublished online as 2012 by The American Society of Hematology
Blood First Edition paper, May 18, 2012; DOI 10.1182/blood-2012-02-366054.

BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2 275

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276 PASSAMONTI BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2

Table 1. WHO criteria for diagnosis of PV variables (eg, sex and iron status) can interfere with hemoglobin
Major criteria levels. Although allele burden quantification is not mandatory to
1. Hemoglobin 18.5 g/dL in men, 16.5 g/dL in women, or evidence of diagnose PV, I generally analyze the JAK2(V617F) mutation by a
increased red cell volume* quantitative RT-PCRbased allelic discrimination assay,34 studying
2. Presence of JAK2(V617F) or other functionally similar mutation (eg, JAK2 exon the mutation on isolated neutrophils. Outside of a research setting,
12 mutation)
a qualitative test on whole blood leukocytes is a correct approach.37
Minor criteria
1. BM biopsy showing hypercellularity for age with trilineage myeloproliferation
When and why to study JAK2 exon 12 mutations in PV?
2. Serum erythropoietin level below the normal reference range
3. Endogenous erythroid colony formation in vitro
I check exon 12 mutations of JAK26 in case of V617F-negative
The diagnosis of PV requires meeting either both major criteria and 1 minor erythrocytosis with low serum EPO levels or in case of pan-
criterion or the first major criterion and 2 minor criteria. myeloproliferative V617F-negative PV. In a multicenter European
*Hemoglobin or hematocrit 99th percentile of method-specific reference range
study, we found that exon 12 mutations of JAK2 account for 4% of
for age, sex, altitude of residence, or hemoglobin 17 g/dL in men, 15 g/dL in
women if associated with a documented and sustained increase of at least 2 g/dL PV cases and that N542-E543del is the most frequent (30%) among
from a persons baseline value that cannot be attributed to correction of iron the 17 mutations described.7 Irrespective of the underlying muta-
deficiency, or elevated red cell mass 25% above mean normal predicted value. tion, two-thirds of patients had isolated erythrocytosis, whereas the
remaining subjects had erythrocytosis plus leukocytosis and/or
or 1 major and 2 minor (Table 1). Actually, approximately 98% of thrombocytosis. To screen for exon 12 mutations of JAK2, the high
PV diagnoses are covered by the 2 major criteria. Concerning red resolution melting has been recently validated and has demon-
cell mass measurement, I do not use it as a diagnostic tool for PV, strated its strength in routine mutation detection.38
but the WHO classification system allows the diagnostic use of an
Is there the need to investigate other mutations?
elevated red cell mass more than 25% above mean normal
predicted value, when desired. After diagnosis, I check CBC count For the time being, there is no indication to study other PV-related
and I visit patients from 3 to 6 times a year depending on treatment mutations in routine clinical practice, although testing LNK muta-
monitoring need, degree of disease control, and logistics. When a tions8 in the very restricted setting of PV cases without any JAK2
patient develops splenomegaly exceeding more than 5 to 10 cm mutation might be of potential interest. I do not check for mutations
from the costal margin, or reduces the need of phlebotomy or the involving TET2 or evolution-phase mutations involving IDH1-2,
dose of cytotoxic therapy to control PV, or when the blood smear IKZF, NRAS, TP53, ASXL1, and RUNX1,39 given that the former do
reveals leukoerythroblastosis, I check the BM looking for disease not display mutual exclusivity with JAK2 mutations and the latter
evolution. To diagnose post-PV MF, I use the International do not predict evolution during chronic phase. In the case one
Working Group for Myelofibrosis Research and Treatment criteria claims for the full molecular profile of a patient, I suggest
as published in 2008 (Table 2).26 contacting national referral centers.
What is the practical impact of the JAK2(V617F) mutation?
Is BM histopathology critical in PV?
First, the presence of the JAK2(V617F) mutation helps in the I usually receive 3 questions on this topic. The first is whether BM
diagnostic process of an erythrocytosis and is a major criterion for biopsy is necessary to diagnose PV. In patients with JAK2-mutated
PV diagnosis. Regarding the JAK2(V617F) allele burden,27 al- erythrocytosis and low EPO, BM biopsy is not required, but in all
though no standardized method of analysis is available to date28 other situations BM biopsy is mandatory. Information one wishes
and outcome should probably be adjusted for sex,29 PV patients to obtain from this examination regard age-adjusted cellularity and
have median values ranging from 30% to 40%, similar to those of grade of myelofibrosis.40 The second is how to interpret the
patients with primary myelofibrosis (PMF) and higher than those presence of any grade of BM fibrosis in PV at diagnosis. The rate of
with essential thrombocythemia (ET).30,31 In PV patients, I have grade 1 reticulin fibrosis in PV at diagnosis ranges from 14%41 to
always found interesting correlations between allele burden and 30%,42 and this does not imply per se a diagnosis of myelofibrosis.
clinical phenotype. A higher allele burden correlates unequivocally The third question is whether BM testing should be repeated on a
with enhanced myelopoiesis of the BM, with peripheral blood regular basis in PV patients after diagnosis. I check the BM biopsy
leukocytosis, and with splenomegaly, whereas it inversely corre- only in case of manifest signs of disease evolution, such as
lates with platelet count.32-36 A clear correlation between hemoglo- splenomegaly, leukocytosis, anemia, prolonged fever, weight loss,
bin levels and allele burden is not evident, possibly because many or night sweats. Figure 1 gives pathologic features of PV and
post-PV MF at the corresponding time of diagnosis.
Table 2. International Working Group for Myelofibrosis Research
and Treatment criteria for the diagnosis of post-PV MF Looking for familial cases of erythrocytosis: when?
Required criteria
1. Previous diagnosis of PV (WHO criteria) All MPN patients should be asked about family history of
2. BM fibrosis grade 2 or 3 (on 0-3 scale) erythrocytosis or MPN. Basically, I categorize familial erythrocyto-
Additional criteria (2 are required) sis into 2 main groups on the basis of serum EPO level: low EPO
1. Anemia* or sustained loss of requirement of phlebotomy or cytoreduction (primary familial and congenital polycythemia); and normal-high
2. Leukoerythroblastic peripheral blood picture EPO (disorders of oxygen-sensing mechanisms, altered affinity of
3. Increasing splenomegaly: palpable spleen 5 cm from left costal margin, or hemoglobin for oxygen, congenital cyanotic heart or lung disease).
appearance of a newly palpable splenomegaly Primary familial and congenital polycythemia is an autosomal
4. Development of 1 of 3 constitutional symptoms ( 10% weight loss in 6
dominant disease with mutational lesions (16 described so far)43
months, night sweats, unexplained fever 37.5C)
truncating the EPO receptor with subsequent loss of the negative
*Defined as hemoglobin value 12 g/dL for female and 13.5 g/dL for male. regulatory domain leading to a final activation of the JAK2/STAT
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BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2 POLYCYTHEMIA VERA 277

Figure 1. Bone marrow histopathology in polycythe-

mia and postpolycythemia myelofibrosis. (A) Case of
PV showing hypercellular BM with trilineage proliferation
of all hematopoietic lineages, including prominent mega-
karyocytes (original magnification 350). PAS indicates
periodic acid-Schiff reaction. (B) Case of PV by immuno-
histochemistry revealing red-stained neutrophil granulo-
poiesis and dark-blue nucleated erythropoietic precur-
sors as well as loose clusters of small to large
megakaryocytes (original magnification 350; AS-D-
chloroacetate esterase reaction). (C) Case of post-PV
myelofibrosis showing decrease in overall cellularity and
only a few small and loose erythropoietic islets, abnormal
megakaryocytes, and greatly extended stroma compart-
ment (original magnification 350). PAS indicates peri-
odic acid-Schiff reaction. (D) Case of post-PV myelofibro-
sis revealing effacement of hematopoiesis by dense
bundles of (yellow-brownish) collagen and reticulin fibers
associated with osteosclerosis enclosing few dispersed
megakaryocytes (original magnification 350; Gomori
silver impregnation technique).

pathway.44,45 Patients with primary familial and congenital polycy- Risk factors for thrombosis
themia have isolated erythrocytosis, low EPO, no splenomegaly,
and a predisposition to severe cardiovascular (CV) problems.45 On There is a general agreement among investigators to consider age
older than 60 years at diagnosis and a history of vascular events as
the other hand, the oxygen-sensing pathway consists of different
the 2 prognostic risk factors for thrombosis in PV (Table 3).54,55 The
proteins involved in the regulation of erythropoietin production:
hypoxia inducible factor (HIF), von Hippel Lindau protein (VHL), European Collaboration on Low-Dose Aspirin in Polycythemia
and prolyl hydroxylase domain proteins (PHDs). After the first Vera (ECLAP) study reported that patients younger than 65 years
defect of the oxygen-sensing pathway involving the VHL gene was without prior thrombosis have an incidence of thrombosis of
described,46 different patterns of mutations involving the VHL, 2.5 100 persons/year, those older than 65 years or with prior
thrombosis have an incidence of 5.0 100 persons/year, and
PHD, and HIF genes have been described.47-49 The disease is
patients older than 65 years with prior thrombosis have an
autosomal recessive or dominant, characterized by erythrocytosis,
incidence of 10.9 100 persons/year.56
normal-high EPO, frequent headache, and thrombosis.50 Other
I take CV risk factors (arterial hypertension, smoking, hypercho-
causes of inherited erythrocytosis with high EPO include inherited
lesterolemia, diabetes, obesity) into consideration, even though I do
conditions that increase the affinity of hemoglobin for oxygen,
not include them into a formal risk stratification model for PV.
including high O2 affinity hemoglobin disorders and deficiency of
Among the aforementioned factors, smoking is the only docu-
2,3-DPG (I recommend screening for P50 level on venous blood
mented risk factor associated with an increased risk of thrombosis
samples), methemoglobinemia (I recommend measurement of
in PV.56
arterial blood gases and pulse oxymetry in case of cyanosis), and
cyanotic congenital heart disease (I recommend a cardiology Concerning the CBC count, hematocrit levels up to 50% and
consult). Finally, familial clustering of PV cases may occur with a high platelet count are not associated with thrombosis.13 On the
frequency of approximately 6% to 7%; these cases mimic sporadic other hand, extreme thrombocytosis per se might provoke an
PV in terms of complications and disease evolution.51 I follow the excess of bleeding because of acquired von Willebrand disease. In
the very few patients with platelet counts exceeding 1500 109/L,
flow chart reported in Figure 2.
I consider starting cytoreduction in PV, as well as in ET, although
I tend to use a higher cut-off in young patients. Concerning
Toward a simplified diagnostic algorithm
leukocytosis, an analysis of the ECLAP trial13 showed that patients
Figure 3 reports the steps I undertake to diagnose PV. As some tests with a leukocyte count exceeding 15 109/L have a significant
may not be widely available outside the research setting, I suggest increase of myocardial infarction compared with those having
contacting national referral centers to perform molecular tests and leukocyte counts less than 10 109/L. Regarding mutational status
to obtain instructions for blood sampling and delivery: this and allele burden, I do not consider a high JAK2(V617F) allele
approach should maximize the uniformity of results. burden as a potential risk factor for thrombosis.42-35 Regarding PV
patients who carry exon 12 mutations of JAK2, I apply the same
risk stratification of other PV patients (Table 3).7
Prognostication in PV Risk factors for disease evolution

Life expectancy of PV patients is reduced compared with that of the Approximately 10% of PV patients evolve into post-PV MF
general population, as demonstrated in a study including 396 PV (also referred as spent-phase PV),57 with progressive spleno-
patients followed for a median time of 10 years52 and as recently megaly, MF-related symptoms, anemia, and leukopenia/
confirmed.53 As thrombosis is the most frequent complication, leukocytosis. MF evolution is difficult to be predicted, but
there is rationale for stratifying PV patients according to the risk of leukocyte count greater than 15 109/L has been documented
thrombosis. as a risk factor for disease evolution.57 In a prospective study
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278 PASSAMONTI BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2

Figure 2. Approach to diagnose familial PV.

including 338 PV patients, allele burden greater than 50% instability) and a high leukocyte count (as a sign of myeloproliferation)
implied a higher risk of evolution to MF.42 When BM biopsy is might be of interest.24,58-60
performed, I suggest to consider the recent evidence that PV patients
Risk factors for survival
with fibrosis have an approximately 3-fold higher risk of developing
post-PV MF than those without.41 I check all these parameters, but for A model to predict survival has been reported in PV indicating
the time being, I do not use them for treatment decisions. Evolution to that advanced age, leukocytosis, and prior venous thrombosis
AML is a rare event without any specific risk factor to be looked for at affect survival.61 As an example, based on this model, a
diagnosis. However, I think that advanced age (as a sign of genomic 60-year-old PV patient with leukocytosis has an expected
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BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2 POLYCYTHEMIA VERA 279

Figure 3. Diagnostic approach to erythrocytosis. Note 1 indicates familial erythrocyosis (eg, disorders of O2-sensing mechanisms, altered affinity of hemoglobin for O2);
note 2, primary familial and congenital polycythemia (PFCP).

median survival of approximately 11 years, showing the limits

of available treatments. Therapy

Risk factors for survival after diagnosis of post-PV MF

The goal of therapy is to prevent thrombosis occurrence and
recurrence, to delay, if possible, evolution into MF or AML, and to
When PV progresses to post-PV MF, my prediction of survival control disease-related symptoms. On behalf of the European
is based on the dynamic prognostic score we developed in LeukemiaNet, different levels of response have been defined in PV,
post-PV MF patients.57 This model is based on 3 risk factors: namely, clinicohematologic, molecular, and histologic responses.65
hemoglobin level lower than 10 g/dL, leukocyte count greater However, because these criteria were established to standardize
than 30 109/L, and platelet count lower than 100 109/L. design of clinical studies and reporting of results, they should not
The low-risk group includes patients without risk factors, be applied in clinical practice.
whereas higher-risk categories include patients with 1, 2, or I continue to consider 45% as the cut-off hematocrit value to
3 risk factors. When a patient acquires 1 risk factor during control PV, although the ECLAP13 and PVSG-0166 studies did not
follow-up, his/her survival worsens (4.2-fold). However, many disclose any advantage in maintaining hematocrit values less than
investigators are more confident applying prognostic systems 50% to 52%. The multicenter randomized and controlled
developed in PMF, International Prognostic Scoring System, Cytoreductive therapy in PV trial67 is aimed at defining the
Dynamic International Prognostic Scoring System, or Dynamic benefit/risk profile of cytoreductive therapy given to maintain
International Prognostic Scoring System-plus.62-64 hematocrit less than 45% versus 45% to 50%. The Cytoreduc-
tive therapy in PV will clarify the best cut-off for hematocrit in
PV. Besides hematocrit control, the aim of therapy should be to
normalize leukocyte count, platelet count, and spleen size,
Table 3. Risk categories in PV
whenever increased. Indeed, hematocrit response seems not to
Category Characteristics
result in better survival or lower thrombosis and bleeding
Low risk Age 60 y and no history of thrombosis rates.68 On the contrary, having no response in terms of
High risk Age 60 y or history of thrombosis
leukocyte count was associated with a higher risk of death
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280 PASSAMONTI BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2

(hazard ratio 2.7), whereas lack of response in platelet count Cytoreductive therapies: the conventional approach
involved a higher risk of thrombosis and bleeding.68
I consider cytoreductive therapy at diagnosis when patients are at
high risk of thrombosis (age older than 60 years and/or prior
thrombosis), or in the presence of symptomatic splenomegaly,
My treatment strategy platelet count higher than 1500 109/L, unexplained leukocytosis
exceeding 20 to 25 109/L, or disease-related symptoms. I also
The treatment strategy in PV patients consists of combining begin cytoreductive therapy during the course of the disease in
4 elements: modification of CV risk factors, antiplatelet therapy, low-risk patients who shift to the high-risk category or develop
phlebotomy, and cytoreduction. progressive leukocytosis or thrombocytosis, enlargement of spleen,
uncontrolled symptoms, or intolerance to or high need of
phlebotomy.
Correction of CV risk factors
I use HU, an oral antimetabolite that prevents DNA synthesis by
A definitive causative/contributory role for CV risk factors on the inhibiting the enzyme ribonucleoside reductase, in all age PV
incidence of vascular events in PV is not yet defined, except for patients who need cytoreductive therapy. The starting dose of HU is
smoking.69 However, one may assume that arterial hypertension, 15 to 20 mg/kg per day until response is obtained. In general, I give
diabetes, smoking, hypercholesterolemia, and obesity can modify HU at a dose ranging from 1000 mg daily to 1500 mg daily
the vascular risk in PV patients in (at least) the same way as in according to the extent of myeloproliferation (the higher dose in
non-PV subjects. Given that CV risk factors are PV-independent, I case of leukocytosis, thrombocytosis, and splenomegaly), to the
do not use cytotoxic therapy in patients harboring them, but I treat symptomatic burden and to the urgency (critical situation, surgery).
CV risk factors according to the corresponding guidelines and I I recommend female patients on HU to avoid pregnancies. After
check patients adherence to these indications during follow-up. obtaining a response, a maintenance dose should be administered to
keep the CBC within the normal range using the lowest possible
Antiplatelet therapy dose. I check CBC monthly and, in steady state, every 3 months. I
do not expect particular toxicities, and I warn patients about skin
Aspirin is my preferred antiplatelet drug in PV for different and nail alterations, potential leg ulcers, and macrocytosis of red
reasons. An increased biosynthesis of thromboxane has been blood cells. In my practice, I have seen very few cases of
reported in PV, and 1 of the cellular effects of aspirin on platelet HU-induced fever and gastrointestinal toxicity, such as diarrhea or
aggregation is the reduction of thromboxane biosynthesis.70 The vomiting.
ECLAP trial studied 518 PV patients randomized to low-dose I prescribe HU because it is effective in preventing thrombosis,
aspirin (100 mg/day) or placebo.13 This study demonstrated a although this notion is derived from randomized clinical trials in
significant advantage for aspirin in terms of nonfatal myocardial ET. A pivotal trial performed in 114 ET patients at high risk for
infarction, nonfatal stroke, pulmonary embolism, major venous thrombosis compared HU with no therapy.71 After 27 months of
thrombosis, or death from CV causes (relative risk 0.40) with a follow-up, patients receiving HU had less thrombotic episodes
higher risk of any bleeding (relative risk 1.82), although the
(3.6%) than controls (24%). In another trial in ET, HU plus
latter did not reach statistical significance. On the basis of this
low-dose aspirin (100 mg daily) was compared with anagrelide
information, I use low-dose aspirin (100 mg/day) in PV patients at
(selective platelet-lowering agent) plus low-dose aspirin in
any risk unless contraindicated, and I withdraw aspirin in case of
809 high-risk patients observed for a median follow-up of
bleeding or gastric intolerance.
39 months.72 Patients randomized to HU had less major thromboses
(arterial or venous) than those treated with anagrelide.
Phlebotomy In PV, HU (51 patients) was compared with phlebotomy
(134 patients) in a PVSG trial.73 There were no significant
I recommend phlebotomy in all patients with PV and as single
differences in outcomes between the 2 groups, although the
treatment for hematocrit control in those at low-risk for thrombosis
HU-treated patients developed more AML (9.8% vs 3.7%) and less
without overt signs of myeloproliferation. A Polycythemia Vera
MF (7.8% vs 12.7%). In PV, large studies have focused on the risk
Study Group (PVSG) randomized trial compared phlebotomy
alone with radiophosphorus plus phlebotomy or chlorambucil plus of AML. I generally discuss the following studies with my patients.
phlebotomy.66 Although comparators are obsolete treatments in PV, (1) The ECLAP trial was conducted on 1638 PV and found that the
patients treated with phlebotomy alone had a better survival but incidence of AML was 0.29 100 patient/years for HU and
displayed an excess of mortality within the first 2 to 4 years, 1.8 100 patient/years for other cytotoxic drugs (median observa-
principally caused by thrombotic complications. I start phlebotomy tion before study enrollment 3.5 years, after enrollment 2.8 years)
at diagnosis by withdrawing 250 to 400 mL of blood every other and did not disclose any difference between HU and no therapy.58
day (lower quantity and frequency in older patients or in case of CV (2) Mayo Clinic investigators found that in 459 PV patients HU
disease) until hematocrit reaches 40% to 45%. Once hematocrit does not increase the rate of AML compared with no therapy.59
normalization has been obtained, I check CBC every 4 to 8 weeks. (3) The last update of the prospective randomized French Polycy-
Overusing phlebotomy, iron deficiency might be induced resulting themia Study Group trial74 showed that the cumulative incidence of
in abnormal RBC morphology and eventually reactive thrombocy- AML/myelodysplastic syndrome at 20 years was 16.6% for
tosis. In these cases, I generally do not supplement with iron, with patients treated with HU and 49.4% for patients treated with
the exception of very few patients with symptomatic iron defi- pipobroman.53 (4) I find of relevance the Swedish population-based
ciency who I treat with no more than 5 to 10 days of iron. I do not study on 11 039 MPN patients with 162 post-MPN AML cases.75
consider secondary iron deficiency as a reason for starting hy- Investigators found that 25% of AML patients were never exposed
droxyurea (HU). to cytotoxic drugs, that HU at any dose is not associated with an
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BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2 POLYCYTHEMIA VERA 281

increased risk of AML, and that only an increasing cumulative dose will clarify the role of ruxolitinib in the setting of PV patients
of alkylators is associated with AML. intolerant or resistant to HU.
During follow-up, patients may become resistant to HU: the The majority of PV patients are well maintained over time with
figure has been estimated at 11.5% after a median of 5.8 years from HU, and for them I do not favor any investigative trial unless the
diagnosis and this implies a 5.6-fold increase in the risk of death.68 experimental drug provides evidence of clonal suppression. On the
On the basis of these data, I start considering this cohort of patients other hand, some patients may lose or not achieve response,
as potential candidates for investigative trials. However, in my develop symptomatic splenomegaly without evidence of evolution
day-to-day clinical practice, I shift patients resistant or intolerant to into post-PV MF, or have uncontrolled pruritus. These patients may
HU to IFN if younger or to pipobroman24 or busulphan if older benefit from ruxolitinib independently of the not yet demonstrated
following the European LeukemiaNet recommendations.55 suppressive potential on the PV-clone.

Is IFN an alternative to HU?

IFN is contraindicated in patients with thyroid and/or mental Critical situations

disorders. IFN is commonly administered subcutaneously at the SVT
dose of 3 million units daily until achievement of response. CBC
should be recorded monthly. Pegylated (Peg) IFN-alfa-2a is given In patients with SVT, the diagnosis of PV might be masked by
at a starting dose of 45 g weekly; and in patients who fail to coexisting hypersplenism and bleeding; and in most cases, the CBC
achieve a response after 12 weeks, the dose is increased to 90 g is normal.81 Medical treatment of SVT includes low molecular
and subsequently to 135 g weekly. Afterward, therapy has to be weight heparin (LMWH) followed by long-life oral anticoagulation
adjusted at the lowest dose that maintains response and monitored (to keep the international normalized ratio between 2.0 and 3.0).
following IFN-specific guidelines. For PV control, I use HU as in high-risk PV cases modulating the
European LeukemiaNet55 recommended HU or IFN as first-line dose on the CBC. Warning about pregnancy is recommended in this
cytoreductive therapy at any age. Peg-IFN-alfa-2a was considered context,55 and decision should be taken on a case-by-case basis
on the basis of the potential advantage in terms of JAK2(V617F) balancing the spleen volume impact on the uterus, the risk of
allele burden reduction.76 Indeed, peg-IFN has been reported to additional vascular complications for the mother, with the possibil-
reduce the V617F load in 48% and to fully abrogate it in 24% of ity to follow pregnancy with LMWH and IFNs. A team of expert in
37 PV patients at diagnosis. Overall hematologic responses was MPN, thromboembolism, obstetrics, and hepatology is required for
excellent (95%), whereas 24% of patients discontinued Peg-IFN the discussion. In cases of PV with SVT, I recommend considering
for toxicity. Similar results were also obtained in 40 patients treated intensive management in agreement with the local hepatology team
after a median time of approximately 5 years from PV diagnosis.77 guidelines (transjugular intrahepatic portosystemic shunt, angio-
Overall hematologic response rate was 80%, and abrogation of the plasty with or without stenting, surgical shunts, and liver
V617F clone occurred in 14%. transplantation).
I think that only ongoing trials comparing HU with Peg-IFN
Surgery
will clarify the indication of IFN in the clinical practice of PV
patients. For the time being, I suggest using IFN in particular I consider this situation at high risk as approximately 8% of PV and
situation of PV: (1) high-risk females with childbearing potential, ET patients develop fatal thrombosis or hemorrhage after surgery.82
avoiding peg-IFN while pregnant; (2) high-risk young patients who In elective surgery, I prepare my patients trying to achieve the best
refuse HU because of the inflexible fear that HU favors leukemic possible CBC (normalization or near-normalization) with HU,
evolution; and (3) second-line therapy after HU intolerance/ even in low risk PV patients treated solely with phlebotomy. I use
resistance in high-risk young people. In all these cases, I inform my prophylactic LMWH according to guidelines for the specific
patients that IFNs are not approved for PV, at least in my country. intervention.

JAK inhibitors in PV: a potential opportunity for some patients Pregnancy

Ruxolitinib is an oral JAK1-2 inhibitor now approved in the United Differently from ET,83 pregnancy in PV is not usual because of the
States for myelofibrosis.78 Ruxolitinib-results in PV can be summa- higher median age of patients. I explain to both patient and partner
rized as follows79: (1) 34 patients with advanced PV (median PV that PV may increase the risk of abortion and that it might be better
duration, 10 years) received ruxolitinib over a median time of for the fetus to avoid any type of cytotoxic agent to control PV, with
21 months; (2) ruxolitinib-treated patients achieved a hematocrit the exception of IFN. I follow ELN recommendations,55 by
less than 45% in 97% of cases, more than 50% spleen reduction in maintaining hematocrit less than 45% with phlebotomy, adding
80%, leukocytosis normalization in 73%, thrombocytosis normal- aspirin if not contraindicated and LMWH after delivery until
ization in 69%, and a complete response (normal hematocrit, 6 weeks postpartum, adding LMWH during pregnancy in the case
platelets, leukocytes, spleen size)65 in 50%. Patients also obtained of previous major thrombosis or severe pregnancy complications,
rapid improvement in patient-reported symptom scores; (3) 82% of and considering IFN if platelet count is greater than 1500 109/L
patients were still on treatment at 21 months of therapy; (4) no or prior severe bleeding.
grade 4 adverse events have been reported; (5) at the time of Pruritus
reporting, a few patients obtained a reduction of the V617F load
exceeding 50%; and (6) ruxolitinib down-regulates leukocyte No effective therapies are available for pruritus, a seriously
alkaline phosphatase expression in patients with PV or ET, and this debilitating although short-living symptom. Antihistamines are
is compatible with a decrease of leukocyte activation and a largely ineffective. In selected cases, photochemotherapy using
potential effect on thrombosis.80 A randomized phase 3 trial psoralen and ultraviolet A light, may be successful. IFNs84 and
comparing ruxolitinib to best available therapy is ongoing and ruxolitinib78 are effective in controlling pruritus.
 From www.bloodjournal.org by guest on July 26, 2016. For personal use only.

282 PASSAMONTI BLOOD, 12 JULY 2012 VOLUME 120, NUMBER 2

Disease evolution JAK2(V617F) mutation, of exon 12 mutations of JAK2 and of

LNK mutations, but a minority ( 1%-2%) of patients with PV
I treat post-PV MF as PMF tailoring treatment to anemia,
still remains without a known molecular alteration. In 2008, the
splenomegaly, and constitutional symptoms, which are considered
WHO provided useful criteria to define PV; and in 2008, the
pressing issues in MF.55 I use steroids or danazol to treat anemia.
Pomalidomide seems a promising agent for anemia.85-88 For the International Working Group for Myeloproliferative Neoplasms
control of myeloproliferation and symptoms in post-PV MF, HU is Research and Treatment defined post-PV MF diagnostic criteria.
mostly ineffective almost all in patients treated with HU during Advances have also been made in terms of prognostication,
PV phase. although we still use age older than 60 years and prior
Among JAK2 inhibitors, ruxolitinib (JAK1, JAK2 inhibitor, thrombosis as the 2 risk factors to predict thrombosis. Leuko-
orally bioavailable)78,89,90 has been extensively studied, and it is cyte count, V617F allele burden, and BM histopathology seem
now approved for MF in United States. SAR30250391 is currently really promising, but they need to be validated in prospective
under placebo-controlled phase 3 randomized trial, whereas other studies. Concerning therapy, HU is still my gold standard,
molecules are being evaluated in phase 1 or 2 trials.40 Of 152 MF although peg-IFN and ruxolitinib may be useful in particular
patients treated with ruxolitinib in a phase 1 or 2 trial, 48 had settings of patients, with the cautionary note that results of phase
post-PV MF.76 Clinical improvement of spleen size ( 50% 1 or 2 studies still need to be confirmed by the ongoing
reduction from baseline) was obtained in 44% of patients randomized clinical trials.
at 3 months, and responses were maintained at 12 months in more
than 70% of patients. The majority of patients had more than 50%
improvement in constitutional symptoms. Nonhematologic toxicity
occurred in less than 6% and was usually grade 2. At a dose of Acknowledgments
15 mg twice a day, grade 3 reversible thrombocytopenia occurred
in 3% of patients and anemia in 8% of red blood cell transfusion- The author thanks Prof Mario Lazzarino, past Director of the
independent patients. Two randomized trials with ruxolitinib were Division of Hematology of the University of Pavia, where the
conducted in MF: COMFORT I,88 comparing ruxolitinib with author worked for many years, for all aspects of his scientific
placebo (115 MF: 32 post-PV MF), and COMFORT II,89 compar- work in the field of MPN. He has been a great teacher and
ing ruxolitinib with best available therapy BAT (146 MF: advisor and, without his contribution and guidance in his career,
33 post-PV MF). The primary endpoint was the number of subjects the author would not have the opportunity to write this paper.
achieving more than or equal to 35% reduction in spleen volume The author also thanks Prof Jurgen Thiele and Prof Hans
from baseline to week 24 for COMFORT I and to week 48 for Michael Kvasnicka for providing BM figures and helpful
COMFORT II. The primary endpoint was achieved in 41.9%
interpretation and Dr Margherita Maffioli and Dr Domenica
(ruxolitinib) versus 0.7% (placebo) in COMFORT I and in 28.5%
Caramazza from the authors Division of Hematology for many
(ruxolitinib) versus 0% (BAT) in COMFORT II. A reduction of
helpful discussions.
total symptom score was obtained in 45.9% of ruxolitinib-treated
F.P. was supported by Associazione Italiana contro Leucemie,
patients and in 5.3% of placebo-treated patients. Finally, COM-
FORT II demonstrated that ruxolitinib was more effective than Linfomi, Mieloma, Varese Onlus.
BAT in post PV-MF as well as in PMF.90 I will use ruxolitinib in all
post-PV MF patients with splenomegaly and/or with disease-
related symptoms, except in younger patients candidates to alloge-
neic hematopoietic stem cell transplantation.92-97 Authorship
AML post-PV is an aggressive phase of the disease, which is not
Contribution: F.P. wrote the manuscript.
curable in the majority of patients.98 Experimental therapies should
be considered. I generally apply a de novo AML-like induction Conflict-of-interest disclosure: F.P. serves as coinvestigator on
chemotherapy only in young patients potentially candidates for many clinical trials, including those that are industry-sponsored,
allogeneic hematopoietic stem cell transplantation. such as pomalidomide (Celgene), INCB018424 (Incyte), rux-
olitinib (Novartis), panobinostat (Novartis), and SAR302503
(Sanofi-Aventis).
Future directions Correspondence: Francesco Passamonti, Division of Hematol-
ogy, Department of Internal Medicine, University Hospital Osped-
In recent years, great insight has been gained into the understand- ale di Circolo e Fondazione Macchi, Viale L. Borri 57, 21100
ing of the pathogenesis of PV with the identification of the Varese, Italy; e-mail [email protected].

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 From www.bloodjournal.org by guest on July 26, 2016. For personal use only.

2012 120: 275-284

doi:10.1182/blood-2012-02-366054 originally published
online May 18, 2012

How I treat polycythemia vera

Francesco Passamonti

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