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Polycythemia Vera: From New, Modified

Diagnostic Criteria to New Therapeutic


Approaches
Margherita Maffioli, MD, Barbara Mora, MD, and Francesco Passamonti, MD

Drs Maffioli and Mora are hematologists in Abstract: Polycythemia vera (PV) is a Philadelphia chromosome–
the hematology department at ASST Sette negative chronic myeloproliferative neoplasm that is associated with
Laghi - Ospedale di Circolo in Varese, Italy. a Janus kinase 2 (JAK2) mutation in most cases. The most recent
Dr Passamonti is a professor of hematology
update to the World Health Organization diagnostic criteria for PV
in the department of medicine and surgery
at the University of Insubria and head was published in 2016. These were the modifications with the great-
of the hematology department at the est effect: (1) lowering the hemoglobin threshold, allowing a diagno-
ASST Sette Laghi - Ospedale di Circolo in sis of PV at 16.5 g/dL in males and at 16.0 g/dL in females and (2)
Varese, Italy. introducing a hematocrit cutoff (49% in males and 48% in females).
Patients with PV who are older than 60 years or have had a previous
thrombotic event are considered at high risk for thrombosis. Leuko-
Corresponding author:
Francesco Passamonti, MD cytosis and a high allele burden are additional risk factors for throm-
Dipartimento di Medicina e Chirurgia bosis and myelofibrosis, respectively. After disease has progressed
University of Insubria to post–polycythemia vera myelofibrosis (PPV-MF), survival must be
Via Guicciardini 9 assessed according to the recently developed Myelofibrosis Second-
Varese 21100 ary to PV and ET-Prognostic Model (MYSEC-PM). This model is based
Italy
on age at diagnosis, a hemoglobin level below 11 g/dL, a platelet
Tel: (39) 0332 393 648
E-mail: francesco.passamonti@uninsubria.it count lower than 150 × 109/L, a percentage of circulating blasts
of 3% or higher, a CALR-unmutated genotype, and the presence of
constitutional symptoms. Therapy is based on phlebotomy to main-
tain the hematocrit below 45% and (if not contraindicated) aspirin.
When a cytoreductive drug is necessary, hydroxyurea or interferon
can be used as first-line therapy, although the demonstration of an
advantage of interferon over hydroxyurea is still pending. In patients
whose disease fails to respond to hydroxyurea, ruxolitinib is a safe
and effective choice.

Introduction

Polycythemia vera (PV), essential thrombocythemia (ET), and pri-


mary myelofibrosis (PMF) constitute the so-called classic Philadel-
phia chromosome–negative chronic myeloproliferative neoplasms
(MPNs).1-4 PV is characterized by erythrocytosis and, in approxi-
mately 40% of patients, some degree of leukocytosis and thrombo-
Keywords cytosis. Splenomegaly occurs in 30% of cases and is rarely massive.5-8
Interferon, JAK2, myelofibrosis, polycythemia, The estimated incidence of PV is 0.4 to 2.8 × 105 per year in Europe
ruxolitinib, thrombocythemia and 0.8 to 1.3 × 105 per year in United States, and the reported

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Table 1. World Health Organization Criteria for the Diagnosis of Polycythemia Vera

A diagnosis of polycythemia vera requires that either all 3 major criteria, or the first 2 major criteria plus the minor
criterion, be met.
Major criteria
Criterion No. 1 (clinical)
Hemoglobin >16.5 g/dL in men, >16.0 g/dL in women, or
Hematocrit >49% in men, >48% in women, or
Red cell mass 25% increase above mean normal predicted value
Criterion No. 2 (morphologic)
Bone marrow morphologya Hypercellularity for age with trilineage growth (panmyelosis), including prominent
erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic,
mature megakaryocytes (differences in size)
Criterion No. 3 (genetic)
JAK2 V617F mutation or Present
JAK2 exon 12 mutation Present
Minor criterion
Serum erythropoietin level Subnormal

JAK2, Janus kinase 2.


a
Major criterion No. 2 (bone marrow morphology) may not be required in cases with sustained absolute erythrocytosis: hemoglobin levels >18.5 g/
dL in men (hematocrit, 55.5%) or >16.5 g/dL in women (hematocrit, 49.5%) if major criterion No. 3 and the minor criterion are present.
However, initial myelofibrosis (present in up to 20% of patients) can be detected only with a bone marrow biopsy; this finding may predict a more
rapid progression to overt myelofibrosis (post–polycythemia vera myelofibrosis).

median age of patients at diagnosis ranges from 65 to 74 patients in the PV category, and rightfully so. However,
years.9,10 The natural history of PV is characterized by an the new hemoglobin and hematocrit cutoffs may lead to
increased risk for thromboembolic complications and a a significant excess in diagnostic examinations if they are
predisposition to the development of post–polycythemia used to define whom to screen for potential PV, especially
vera myelofibrosis (PPV-MF), myelodysplastic syndrome males. A retrospective analysis of 248,839 patients with
(MDS), or acute myeloid leukemia (AML).11-14 presumptively normal complete blood cell count results
showed that 6.48% of the males had hemoglobin levels
Polycythemia Vera: Diagnostic Criteria above 16.5 g/dL or hematocrit levels above 49%, whereas
0.28% of the females had hemoglobin levels above 16.0 g/
The updated World Health Organization (WHO) diag- dL or hematocrit levels above 48%.22 In patients with
nostic criteria for PV, published in 2016 and reported in borderline hemoglobin levels, it is therefore important to
Table 1, introduce several significant changes with respect assess carefully for possible causes of secondary polycy-
to previous criteria.1,2 themia and perform a diagnostic workup for PV in the
The modifications with the greatest effect are presence of clinical features (eg, pruritus, splenomegaly,
probably lowering of the hemoglobin threshold used to previous thrombosis) and/or laboratory features (eg, leu-
diagnose PV (to 16.5 g/dL in males and to 16.0 g/dL in kocytosis, thrombocytosis) associated with MPN.
females) and introduction of a hematocrit cutoff (49% in A recent commentary, however, warned about the
males and 48% in females). These modifications derive risk of missing a PV diagnosis if the presence of additional
from retrospective studies recognizing the existence of MPN-associated clinical and/or laboratory features is
patients with a Janus kinase 2 (JAK2) V617F–mutated deemed mandatory before the clinician can proceed with
MPN, which most often is diagnosed as ET but has diagnostic screening. It should be noted that the patients
PV-consistent bone marrow features, hemoglobin levels included in this analysis had a WHO-defined diagnosis
below 18.5 g/dL in males and 16.5 g/dL in females, an of PV and were not individuals undergoing diagnostic
increased risk for thrombotic complications during fol- screening. Furthermore, the analysis showed that using a
low-up, and a worse disease evolution.15-21 Such patients hemoglobin cutoff of 17 g/dL in males resulted in 14%
are defined as having “masked” or “prodromic” PV.20 of PV diagnoses being missed; however, when males
The current WHO diagnostic criteria place these with lower hemoglobin values (≥16.5-17 g/dL) who had

Clinical Advances in Hematology & Oncology Volume 15, Issue 9 September 2017  701
MAFFIOLI ET AL

a platelet value of at least 440 × 109/L were included, Aspirin in Polycythemia Vera) trial was the first random-
only 3% of diagnoses were missed.23 Notwithstanding ized study to assess prospectively the efficacy of low-dose
these considerations, the focus should clearly remain on aspirin in reducing thrombotic events in patients with
diagnosing PV correctly according to the current WHO PV.32 The results of this pivotal trial led to the use of
classification because doing so has significant prognostic prophylactic low-dose aspirin in all patients with PV and
and therapeutic implications. no contraindications. Furthermore, the ECLAP study
A second important modification introduced by the showed that the incidence of thrombosis in patients
2016 WHO criteria is the upgrade of histopathologic younger than 65 years without prior thrombosis was
features to major diagnostic criteria. Bone marrow mor- 2.5% persons per year, the incidence in those older than
phology in PV is characterized by age-adjusted hypercel- 65 years or with prior thrombosis was 5.0% persons per
lularity and panmyelosis. Approximately 20% of patients year, and the incidence in patients older than 65 years
with PV have grade 1 bone marrow reticulin fibrosis at with prior thrombosis was 10.9% persons per year.
diagnosis, which does not necessarily imply a diagnosis Accordingly, patients older than 60 years or with a previ-
of myelofibrosis but is associated with a higher risk for ous thrombotic event are considered to be at high risk for
myelofibrosis evolution.24 A recent retrospective study thrombosis (the presence of either factor defines high-risk
that included 262 patients with PV whose disease was patients, whereas the absence of these risk factors defines
diagnosed according to the 2016 WHO criteria confirmed low-risk patients), and therapeutic choices are often made
the association between bone marrow reticulin fibrosis solely on this basis.33 However, a growing amount of data
of at least grade 1 at diagnosis (present in this study in show that an elevated leukocyte count,34,35 the presence of
as many as 48% of patients) and subsequent fibrotic cardiovascular risk factors,36 a high (>50%) JAK2 V617F
progression.25 It should be noted that the presenting allele burden,8 and the presence of bone marrow fibrosis24
clinical and laboratory features did not differ significantly may affect the likelihood of thrombosis, progression, and
between patients with and without bone marrow fibrosis. survival.
The prognostic information derived from a bone marrow A multicenter, retrospective, observational study
biopsy performed at diagnosis may translate in a more conducted in a cohort of 1545 patients with PV (diag-
careful follow-up strategy and may be an additional reason nosed according to the 2008 WHO criteria) focused on
to undertake such an analysis beyond strictly adherence the evaluation of survival patterns.37 In multivariable
to the WHO diagnostic criteria, especially in younger analysis, survival was negatively affected by older age, leu-
male patients with hemoglobin values above 18.5 g/dL or kocytosis, venous thrombosis, and abnormal karyotype;
female patients with hemoglobin values above 16.5 g/dL. a prognostic model that included the first 3 factors (with
The third major diagnostic criterion is the muta- older age bearing significant weight) identified risk groups
tional characterization. JAK2 mutations, which result in with median survival times of 10.9 to 27.8 years (hazard
JAK-STAT pathway activation, are present in the vast ratio [HR], 10.7; 95% CI, 7.7-15.0).
majority of patients (the V617F mutation is present in A recent study that included 271 patients with
95% to 97% of patients,26,27 and exon 12 mutations are PV (diagnosed according to the 2008 WHO criteria)
present in most of the remaining patients).28,29 reported a 20% incidence of abnormal karyotype with
The new diagnostic criteria allow a diagnosis of sole del(20q); double abnormalities and complex karyo-
JAK2-unmutated PV, which is exceedingly rare. Few cases type negatively affected survival.38
of CBL or LNK mutations have been described, and diag-
nostic testing for these mutations is not widely available.30 Post–Polycythemia Vera Myelofibrosis:
For patients without evident causes of secondary polycy- Diagnosis, Genetics, and Prognosis
themia and without a JAK2 mutation, careful follow-up
is recommended. PPV-MF is currently diagnosed according to the 2008
A reduced serum erythropoietin (EPO) level is the International Working Group-Myeloproliferative Neo-
only minor diagnostic criterion that has been retained in plasms Research and Treatment (IWG-MRT) Criteria
the 2016 WHO criteria. However, a significant propor- (Table 2),39 with histopathology clearly playing a prom-
tion of patients with PV—ranging from 7% to approx- inent role. Because the therapeutic needs and available
imately 40%—seem to have normal serum EPO values, strategies in PV and PPV-MF differ significantly, bone
pointing to a low negative predictive value for this test.31 marrow biopsy is mandatory when disease evolution is
suspected.
Prognosis of Patients With Polycythemia Vera Patients with PPV-MF or post–essential thrombo-
cythemia myelofibrosis (PET-MF) are often included in
The ECLAP (European Collaboration on Low-Dose interventional studies along with those who have PMF.

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Table 2. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) Criteria for the
Diagnosis of Secondary Myelofibrosis

A diagnosis of post–polycythemia vera myelofibrosis requires that the 2 major criteria and at least 2 minor criteria be met.
Major criteria
Criterion No. 1
Documentation of a previous diagnosis of Met
polycythemia vera (WHO criteria)
Criterion No. 2
Bone marrow morphology Reticulin fibrosis grade 2/3 (on scale of 0-3), or
reticulin fibrosis grade 3/4 (on scale of 0-4)
Minor criteria
Anemiaa or sustained loss of requirement for Present
phlebotomy or cytoreduction
Leukoerythroblastosis Present
Spleen size Increasing splenomegaly, defined as either an increase in palpable
splenomegaly of ≥5 cm (from left costal margin) or the appearance of
newly palpable splenomegaly
Constitutional symptomsb Development of ≥1 of 3

WHO, World Health Organization.


a
Defined as a hemoglobin value <12 g/dL for men and <13.5 g/dL for women.
b
Defined as weight loss of ≥10% in 6 months, night sweats, and unexplained fever (temperature >37.5°C).

However, clinical, molecular, and prognostic information SMF, especially when one considers the differences that
specific to patients with PPV-MF or PET-MF (together are emerging with respect to PMF.
referred to as secondary myelofibrosis [SMF]) has been The prognostic assessment of patients with PPV-MF
lacking for some time, in contrast to the growing body has in recent years relied on tools that were originally
of knowledge regarding PMF. The need for further developed in patients with PMF, such as the Interna-
information about SMF led to the development of the tional Prognostic Scoring System (IPSS),45 the Dynamic
MYSEC (Myelofibrosis Secondary to PV and ET) proj- IPSS (DIPSS),46 and DIPSS Plus.47 Retrospective studies
ect, an international effort generated in 2014 to collect have shown, however, that such tools may not be ideal
retrospective data on SMF. In an initial analysis of 685 to analyze prognosis in PPV-MF and PET-MF.48-50
molecularly annotated SMF cases, all patients with The MYSEC project has provided an ideal framework
PPV-MF carried the JAK2 V617F mutation, and the to develop a prognostic system specifically tailored for
driver mutation distribution in PET-MF appeared similar PPV-MF and PET-MF, named the MYSEC Prognostic
to that in PMF, although a direct comparison was clearly Model (MYSEC-PM). A cohort of 685 patients with
not feasible.40 Furthermore, the analysis disclosed that SMF (333 with PET-MF and 352 with PPV-MF) and
survival varied significantly according to genotype, with a known phenotype driver mutational status were ana-
patients who had CALR-mutated PET-MF living longer lyzed.51 Median survival in patients with SMF was 9.3
than those who had JAK2-mutated PPV-MF or PET-MF. years (95% CI, 8-not reached). Cox regression models
PPV-MF and PET-MF appear to have a higher muta- and least absolute shrinkage and selection operator were
tional load (JAK2 V617F–mutated and CALR-mutated employed to select the following subset of significant
allele burden) compared with PV and ET, suggesting a covariates: hemoglobin level below 11 g/dL, platelet
role for the accumulation of mutated alleles in the pro- count below 150 × 109/L, at least 3% circulating blasts,
gression to SMF.41-43 With regard to additional, nondriver CALR-unmutated genotype, and the presence of constitu-
mutations, 25% of patients with SMF have been found tional symptoms. Age at diagnosis was also found to be an
to harbor a mutation in ASXL1, EZH2, SRSF2, IDH1, important predictor of survival according to multivariate
or IDH2.44 Only mutations in SRSF2 appear to correlate models and was retained as a continuous covariate. Each
with reduced survival, which is different from what occurs discrete variable was assigned a risk point (obtained by
in PMF. Further molecular insight is clearly warranted in rounding the risk coefficients): 2 points for hemoglobin

Clinical Advances in Hematology & Oncology Volume 15, Issue 9 September 2017  703
MAFFIOLI ET AL

level below 11 g/dL, at least 3% circulating blasts, and patient’s risk profile.33,53,54 Thrombocytosis (platelet count
CALR-unmutated genotype; 1 point for platelet count >1000 × 109/L) constitutes a risk factor. In the event of
below 150 × 109/L and for the presence of constitutional thrombocytosis, it is therefore advisable to consider the use
symptoms. Age-related risk, calculated on the points scale, of low-dose aspirin with caution. Extreme thrombocyto-
accounted for approximately 0.15 points per year of age. sis (platelet count >1500 × 109/L), although rare in PV,
The sum of risk points and age-related risk was mapped is regarded as an indication for cytoreductive treatment.
into 4 risk categories with different median overall sur- Symptomatic splenomegaly or disease-related symptoms
vivals: low risk (score <11), median survival not reached; may be an indication to start cytoreduction.9,55,56
intermediate 1 risk (score ≥11 and <14), median survival The objective of reducing the risk for evolution
of 9.3 years (95% CI, 8.1-not reached); intermediate 2 risk to myelofibrosis, MDS, and/or AML remains elusive,
(score ≥14 and <16), median survival of 4.4 years (95% although certain therapeutic agents are thought to have
CI: 3.2-7.9); and high risk (score ≥16), median survival some disease-modifying effect.
of 2 years (95% CI, 1.7-3.9). A nomogram to facilitate For cytoreduction, hydroxyurea, an oral antimetabo-
the use of the model has been developed. The large set of lite that prevents DNA synthesis by inhibiting the enzyme
patients with SMF included in the MYSEC project made ribonucleoside reductase, is the most commonly used
it possible to develop a model with superior discrimina- first-line agent. Hydroxyurea is generally well tolerated
tory power with respect to the IPSS in this specific subset and only rarely associated with the development of sig-
of myelofibrosis. nificant side effects, such as leg ulcers and gastrointestinal
toxicity (eg, nausea, diarrhea). However, it is necessary to
Treatment of Polycythemia Vera warn patients about possible skin and nail changes and
to recommend strict dermatologic surveillance in the case
To date, patients with PV have been treated with the of new skin lesions. No definitive association has been
aim of reducing the risk for vascular complications. The demonstrated between the use of hydroxyurea (as a single
aforementioned ECLAP study provided high-quality data agent, not as part of a sequence of cytotoxic drugs) and
that supported the use of low-dose aspirin in all patients the development of AML.57 Furthermore, a large popu-
who do not have clear contraindications.32 Furthermore, lation-based study has shown that 25% of people with
it aided the identification of low-risk patients (ie, those post-MPN AML were never exposed to cytoreductive
<60 years and without a history of thrombosis) and high- treatment, that hydroxyurea at any dose was not associ-
risk patients (ie, those not considered low risk). Low-risk ated with an increased risk for AML, and that only an
patients are commonly treated with phlebotomy and increasing cumulative dose of alkylators is associated with
antiplatelet therapy, whereas high-risk patients receive AML.58
cytoreductive treatment in addition to low-dose aspirin The European LeukemiaNet recommendations33 and
(depending on the type and date of the previous throm- the subsequent European Society for Medical Oncology
botic event, oral anticoagulation may be indicated instead guidelines9 suggest interferon alfa as a first-line alternative
of low-dose aspirin).33 to hydroxyurea, although interferon alfa is not approved
The ideal target hematocrit for either phlebotomy or for the treatment of PV in any of its various presentations.
cytoreduction has long been unclear, resulting in different Interferon alfa induces a high rate of hematologic responses
approaches that largely depend on the clinician’s inclina- and can significantly reduce the JAK2 V617F allele bur-
tion. Some clinicians will aim for more stringent hema- den.59 Even though an elevated allele burden is associated
tocrit control—for example, below 45%—whereas others with more aggressive disease features, such as leukocytosis,
who are satisfied with a more “relaxed” approach will seek splenomegaly, and increased risk for thrombosis, and even
hematocrit values between 45% and 50%, or even below though a JAK2 V617F allele burden above 50% is associ-
52%. The CYTO-PV (Cytoreductive Therapy in PV) ran- ated with an increased risk for myelofibrosis evolution,8 it
domized trial has demonstrated a reduction in fatal and is still unclear whether and to what extent reduction of the
nonfatal thrombotic events in the group of patients treated mutational load translates into a clinical benefit.
to maintain hematocrit levels below 45%.52 This is there-
fore the treatment goal in all patients with PV. However, First-Line Therapy: Hydroxyurea or Interferon?
additional risk factors for thrombosis, such as leukocytosis Two prospective trials in the first-line setting were pre-
and cardiovascular risk factors, need to be considered in sented at the 2016 meeting of the American Society of
the treatment algorithm of patients with PV. A progressive Hematology.60,61
increase in the leukocyte count is considered a criterion PROUD-PV (A Randomized Controlled Phase 3
to initiate cytoreductive treatment, and actionable cardio- Trial Comparing Ropeginterferon Alfa-2b to Hydroxy-
vascular risk factors should be managed to ameliorate the urea in Polycythemia Vera Patients) is a randomized,

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controlled, parallel-group multicenter phase 3 study urea first, respectively. The efficacy of pegylated interferon
that is being conducted in patients with PV (diag- in PV has been demonstrated retrospectively.59,62,63 These
nosed according to the 2008 WHO classification) who analyses reported a reduction of the JAK2 V617F load
either are treatment-naive or have been pretreated with from baseline value in 48% of patients. Overall hema-
hydroxyurea for less than 3 years. Patients are randomly tologic response was excellent (95%), although 24%
assigned to receive ropeginterferon alfa-2b or hydroxy- of patients discontinued pegylated interferon because
urea. The study was designed as a noninferiority trial, of toxicity. Similar results were obtained in 40 patients
with complete hematologic remission at 12 months being treated after a median time of approximately 5 years from
the primary endpoint. Of the 257 patients randomized, PV diagnosis.62,63 The overall hematologic response rate
62% were treatment-naive. Both treatments have been was 80%, and abrogation of the V617F clone occurred
well tolerated, with a dropout rate of 15%. Overall, 45% in 14% of cases. However, it must be said that the (albeit
of patients have had a hematologic response, without preliminary) results of the PROUD-PV and MPD-RC
significant differences noted between the 2 treatments. 112 trials, reported in the previous section, have lowered
The MPD-RC (Myeloproliferative Disorders the expectations for interferons.
Research Consortium) 112 Global Phase III Trial is com- On the other hand, the concept of second-line ther-
paring pegylated interferon alfa-2a with hydroxyurea in apy in PV is not so clear. Criteria for hydroxyurea intol-
PV and ET. The PV group includes patients with newly erance and resistance for clinical trials (not for clinical
diagnosed PV (<5 years) and treatment-naive patients practice) have been proposed thanks to an international
at high risk for thrombosis (age >60 years, history of effort.64 Recently, a Spanish study provided the size of
thrombosis, extreme thrombocytosis, symptomatic sple- this condition: overall, the criteria for hydroxyurea intol-
nomegaly, and/or uncontrolled cardiovascular risk fac- erance or resistance were found in 15% of 890 patients
tors). Complete hematologic remission after 12 months with PV. In detail, a need for phlebotomy was reported
is the primary endpoint. A total of 168 patients have been in 3.3%, uncontrolled myeloproliferation in 1.6%, failure
enrolled, without significant differences in clinical presen- to reduce massive splenomegaly in 0.8%, cytopenia at the
tation noted between the 2 groups. Complete hemato- lowest hydroxyurea dose to achieve response in 1.7%, and
logic remission, partial hematologic remission, and overall extra-hematologic toxicity in 9%. Concerning the predic-
response have been observed in 33%, 36%, and 69% of tive role of these criteria, cytopenia affected survival, pro-
the hydroxyurea-treated patients and in 28%, 53%, and gression to myelofibrosis, and AML, and splenomegaly
81% of the patients treated with pegylated interferon, increased the occurrence of myelofibrosis.
without statistically significant differences. Among 38 Two prospective, randomized studies, RESPONSE
patients, phlebotomy was performed in none of those (Study of Efficacy and Safety in Polycythemia Vera Sub-
treated with hydroxyurea vs 20% of those treated with jects Who Are Resistant to or Intolerant of Hydroxyurea:
pegylated interferon (P=.02). No differences in terms of JAK Inhibitor INC424 Tablets Versus Best Available
MPN Symptom Assessment Form Total Symptom Score Care) and RESPONSE-2 (Ruxolitinib Efficacy and Safety
have been reported (>50% reduction in total symptom in Patients With HU Resistant or Intolerant Polycythe-
score in 32%-35% of patients). Concerning toxicity, mia Vera vs Best Available Therapy), have reported data
grade 3 adverse events have occurred in 14% of the in the last 2 years.65,66 RESPONSE included 222 patients
hydroxyurea-treated patients and in 44% of the patients with hydroxyurea intolerance/resistance, need of phle-
treated with pegylated interferon. botomy, and splenomegaly, and RESPONSE-2 included
Overall, when the 12-month results of these 2 173 patients with the same entry criteria except for
prospective studies are taken into account, hydroxyurea splenomegaly. Patients were randomly assigned to receive
remains the first-line treatment of choice in high-risk ruxolitinib (Jakafi, Incyte) or best available therapy.
patients with PV, arguably with some exceptions, such as Initial standard therapy included hydroxyurea (59% in
women of childbearing potential at high risk and young RESPONSE, 49% in RESPONSE-2); interferon (12%
patients at high risk who refuse hydroxyurea because of in RESPONSE, 13% in RESPONSE-2); or no medica-
the fear that it may favor leukemic evolution. However, tion (15% in RESPONSE, 28% in RESPONSE-2). The
the ongoing phase 3 studies will provide further results primary composite endpoint included hematocrit control
with longer follow-up. (phlebotomy independence from week 8 to week 32, with
≤1 phlebotomy after randomization) in the absence of
Second-Line Therapy phlebotomy and 35% reduction in spleen volume at week
The European LeukemiaNet recommendations list 32 (the latter absent in RESPONSE-2).
hydroxyurea or interferon as second-line cytoreductive In RESPONSE, the primary endpoint was achieved
therapy for patients who received interferon or hydroxy- in 21% of patients treated with ruxolitinib and 1% of

Clinical Advances in Hematology & Oncology Volume 15, Issue 9 September 2017  705
MAFFIOLI ET AL

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12. Passamonti F, Rumi E, Caramella M, et al. A dynamic prognostic model to predict
Taken together, results from the RESPONSE and survival in post-polycythemia vera myelofibrosis. Blood. 2008;111(7):3383-3387.
RESPONSE-2 trials indicate that ruxolitinib is the stan- 13. Passamonti F, Brusamolino E, Lazzarino M, et al. Efficacy of pipobroman in
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previously treated with hydroxyurea. Data derived from 14. Passamonti F, Rumi E, Arcaini L, et al. Blast phase of essential thrombocythe-
the RESPONSE study showed that patients receiving mia: a single center study. Am J Hematol. 2009;84(10):641-644.
ruxolitinib (from randomization or after crossover) had 15. Gianelli U, Iurlo A, Vener C, et al. The significance of bone marrow biopsy and
JAK2V617F mutation in the differential diagnosis between the “early” prepoly-
consistent reductions in JAK2 V617F allele burden (up to cythemic phase of polycythemia vera and essential thrombocythemia. Am J Clin
40%) throughout the study.68 The relationship between Pathol. 2008;130(3):336-342.
changes in allele burden and clinical outcomes in patients 16. Johansson PL, Safai-Kutti S, Kutti J. An elevated venous haemoglobin concen-
tration cannot be used as a surrogate marker for absolute erythrocytosis: a study
with PV, however, remains unclear. of patients with polycythaemia vera and apparent polycythaemia. Br J Haematol.
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Conclusions 17. Alvarez-Larrán A, Ancochea A, Angona A, et al. Red cell mass measurement
in patients with clinically suspected diagnosis of polycythemia vera or essential
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The management of PV has changed since the discovery 18. Cassinat B, Laguillier C, Gardin C, et al; PV-Nord Group. Classification of
of the JAK2 mutation. Basically, doctors must consider myeloproliferative disorders in the JAK2 era: is there a role for red cell mass? Leu-
kemia. 2008;22(2):452-453.
the revised WHO diagnostic criteria in light of the 19. Barbui T, Thiele J, Carobbio A, et al. Discriminating between essential
new cutoffs for hemoglobin level and hematocrit. First- thrombocythemia and masked polycythemia vera in JAK2 mutated patients. Am J
line therapies are hydroxyurea and possibly interferon Hematol. 2014;89(6):588-590.
20. Barbui T, Thiele J, Gisslinger H, et al. Masked polycythemia vera (mPV):
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still to be demonstrated). In patients whose disease fails to 21. Silver RT, Chow W, Orazi A, Arles SP, Goldsmith SJ. Evaluation of WHO
respond to hydroxyurea, ruxolitinib is a safe choice. criteria for diagnosis of polycythemia vera: a prospective analysis. Blood.
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22. Sandes AF, Gonçalves MV, Chauffaille ML. Frequency of polycythemia in
Disclosures individuals with normal complete blood cell counts according to the new 2016
The authors have no financial disclosures. WHO classification of myeloid neoplasms. Int J Lab Hematol. 2017.
23. Barbui T, Thiele J, Gisslinger H, Carobbio A, Vannucchi AM, Tefferi A.
Diagnostic impact of the 2016 revised who criteria for polycythemia vera. Am J
Acknowledgments Hematol. 2017;92(5):417-419.
This work was supported by grants from the Fondazione 24. Barbui T, Thiele J, Passamonti F, et al. Initial bone marrow reticulin fibrosis in poly-
cythemia vera exerts an impact on clinical outcome. Blood. 2012;119(10):2239-2241.
Matarelli in Milan, Italy, and the Fondazione Rusconi in 25. Barraco D, Cerquozzi S, Hanson CA, et al. Prognostic impact of bone marrow
Varese, Italy. fibrosis in polycythemia vera: validation of the IWG-MRT study and additional
observations. Blood Cancer J. 2017;7(3):e538.

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