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REVIEW ARTICLE OPEN

Polycythemia vera: historical oversights, diagnostic details, and

therapeutic views
1✉ 2 3
Ayalew Tefferi , Alessandro M. Vannucchi and Tiziano Barbui

© The Author(s) 2021

Polycythemia vera (PV) is a relatively indolent myeloid neoplasm with median survival that exceeds 35 years in young patients, but
its natural history might be interrupted by thrombotic, fibrotic, or leukemic events, with respective 20-year rates of 26%, 16%, and
4%. Current treatment strategies in PV have not been shown to prolong survival or lessen the risk of leukemic or fibrotic
progression and instead are directed at preventing thrombotic complications. In the latter regard, two risk categories are
considered: high (age >60 years or thrombosis history) and low (absence of both risk factors). All patients require phlebotomy to
keep hematocrit below 45% and once-daily low-dose aspirin, in the absence of contraindications. Cytoreductive therapy is
recommended for high-risk or symptomatic low-risk disease; our first-line drug of choice in this regard is hydroxyurea but we
consider pegylated interferon as an alternative in certain situations, including in young women of reproductive age, in patients
manifesting intolerance or resistance to hydroxyurea therapy, and in situations where treatment is indicated for curbing
phlebotomy requirement rather than preventing thrombosis. Additional treatment options include busulfan and ruxolitinib; the
former is preferred in older patients and the latter in the presence of symptoms reminiscent of post-PV myelofibrosis or protracted
pruritus. Our drug choices reflect our appreciation for long-term track record of safety, evidence for reduction of thrombosis risk,
and broader suppression of myeloproliferation. Controlled studies are needed to clarify the added value of twice- vs once-daily
aspirin dosing and direct oral anticoagulants. In this invited review, we discuss our current approach to diagnosis, prognostication,
and treatment of PV in general, as well as during specific situations, including pregnancy and splanchnic vein thrombosis.

Leukemia (2021) 35:3339–3351; https://doi.org/10.1038/s41375-021-01401-3

HISTORICAL PRELUDE examining the pathogenetic role of JAK2 mutations are high-
Polycythemia vera (PV), “maladie de Vaquez,” was first described lighted by its origin at the stem cell level and the demonstration
by Louis Henri Vaquez (1860–1936), a French physician, in 1892 of heightened JAK-STAT activation and induction of mutant JAK2-
[1]. A few additional cases were later described and systematically driven PV phenotype in mice [5, 12, 13]. JAK2V617F is one of three
reviewed by William Osler (1849–1919) in 1903 [2]. In 1951, MPN-specific driver mutations that include CALR and MPL
William Dameshek (1900–1969) included PV in his conceptual mutations; the latter are usually not found in patients with PV
classification of myeloproliferative disorders, now referred to as but are prevalent in JAK2V617F-negative ET and PMF. It is currently
“myeloproliferative neoplasms (MPN),” along with essential assumed that the phenotypic differences between PV and the
thrombocythemia (ET) and primary myelofibrosis (PMF) [3]. other two MPN variants are in part contributed by differences in
Dameshek’s concept of MPN was genetically ratified in 2005 by the specific cytokine receptors that are activated by the
the seminal discovery, across these three clincopathologic entities, corresponding driver mutation and interactions with other co-
of a JAK2 gain of-function mutation (JAK2V617F; a G to T somatic occurring mutations and their order of acquisition [12].
mutation at nucleotide 1849, in exon 14, resulting in the The historical account of PV therapeutics spans over a century,
substitution of valine to phenylalanine at codon 617) [4–7]. In annotated by key contributions from the Polycythemia Vera Study
2007, additional JAK2 mutations in exon 12 were described in Group (PVSG), founded in 1967 [14]. The pre-PVSG era included
JAK2V617F-negative patients with PV [8]; JAK2 mutational mostly ineffective and potentially detrimental treatment modal-
frequencies, in PV, are estimated at 97% for JAK2V617F and 3% ities, save for therapeutic phlebotomy [15, 16], including skeletal
for other JAK2 mutations, including JAK2 exon 12. In other words, radiation therapy (1917) [17], acetylphenylhydrazine (1918) [18],
for all practical purposes, the presence of a JAK2 mutation is now potassium arsenite (1933) [19], radiophosphorus (P32) (1940) [20],
expected in virtually all patients with PV, a fact that has greatly lead acetate (1942) [21], nitrogen mustard (1950) [22], triethylene
complemented our morphologic-based diagnostic approach; melamine (1952) [23], pyrimethamine (1954) [24], busulfan (1958)
current literature suggests similar outcome in patients with JAK2 [25], 6-mercaptopurine (1962) [26], pipobroman (1962) [27], uracil
exon 14 vs exon 12 mutations [9–11]. Laboratory studies mustard (1964) [28], chlorambucil (1965) [29], and dapsone (1966)

1
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA. 2Department of Experimental and Clinical Medicine, CRIMM, Center Research and Innovation
of Myeloproliferative Neoplasms, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy. 3Research Foundation, Papa Giovanni XXIII Hospital, Bergamo,
Italy. ✉email: tefferi.ayalew@mayo.edu

Received: 31 May 2021 Revised: 17 August 2021 Accepted: 23 August 2021

Published online: 3 September 2021
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Fig. 1 Current diagnostic algorithm for polycythemia vera. Our approach to diagnosis of polycythemia vera (PV).

[30]. Hydroxyurea (HU) and melphalan were added to the list in level above 16.5 g/dL/49% in men and 16 g/dL/48% in women or
1970 [31, 32]. Early retrospective studies in PV had suggested a red cell mass >25% above mean normal predicted value;
superior median survival with myelosuppressive therapy as consistent bone marrow morphology; and presence of a
opposed to either no treatment (median survival ∼18 months) JAK2V617F or exon 12 mutation) and one minor (subnormal
or treatment with phlebotomy alone (median survival close to 4 serum erythropoietin (Epo) level) criteria; WHO-qualified diagnosis
years) [33], while at the same time raised concerns regarding requires the presence of either all three major criteria or the first
myelosuppressive drug leukemogenecity [34, 35]. The PVSG two major criteria plus the minor criterion [50]. Our current
clinical trials, shepherded by Louis Wasserman (1912–1999), were approach to the diagnosis of PV is consistent with these
designed to clarify these issues at hand with support from NIH fundamentals, with some modifications that accommodate clinical
that lasted until 1987 and included 14 separate studies [36]. The practice scenarios, which are further elaborated below (Fig. 1). In
PVSG studies implicated both chlorambucil and P32, but not HU, general, screening for other mutations through next-generation
as being leukemogenic and detrimental to survival [37, 38], sequencing (NGS) or cytogenetic abnormalities is more useful in
although the leukemogenic hazards of HU are still being debated. terms of prognostication (discussed below in the section of
Across the Atlantic, Tiziano Barbui (1938) and fellow investigators prognosis) rather than diagnosis.
from Europe have successfully conducted a series of controlled
prospective studies that have confirmed the antithrombotic value JAK2 mutation screening
of keeping the hematocrit target below 45%, with phlebotomy ± Virtually all patients with PV harbor either JAK2V617F (exon 14;
HU/cytoreductive therapy (2013) [39], and low-dose aspirin 97% sensitivity) or JAK2 exon 12 mutation (majority of JAK2V617F-
therapy (2004) [40] in PV, and that of HU in high-risk ET (1995) negative cases) [51]. Accordingly, the first step in approaching the
[41]. The expanding therapeutic armamentarium for PV now diagnosis of PV should include JAK2 mutation screening, and we
includes pegylated interferon (peg-INF) [42] and ruxolitinib [43]. favor upfront targeting of both exons 14 and 12, in order to avoid
Over the last several years, we have been involved in the undue delay in the diagnostic process; it should also be noted that
development of both the 2008 [44] and 2016 [45] World Health peripheral blood and bone marrow samples are equally informa-
Organization (WHO) classification system for MPNs and have in tive in detecting and quantifying JAK2V617F [52]. In order to
addition fostered contemporary diagnostic and treatment algo- address issues with inconclusive test results and also provide an
rithms [46–49]. In the current review, we considered new additional layer of diagnostic comfort, we recommend concomi-
developments and also revisited with ongoing controversies in tant measurement of serum Epo level, which is expected to be
order to outline our current approach in the diagnosis, subnormal in more than 85% of patients with PV [53]. JAK2
prognostication and treatment of PV. mutation screening might also be a more sensitive diagnostic tool,
compared to bone marrow morphology, in patients presenting
with “MPN-unclassifiable (MPN-U)” phenotype or splanchnic vein
OUR CURRENT DIAGNOSTIC APPROACH IN POLYCYTHEMIA thrombosis (SVT), as discussed below [54].
VERA
PV is currently defined by an acquired increase in hemoglobin/ Is bone marrow examination mandatory for the diagnosis of
hematocrit level above 16.5 gm/dL/49% in men and 16 g/dL/48% PV
in women, in the context of a JAK2 mutation and characteristic The official WHO diagnostic criteria for PV allow bypassing bone
bone marrow morphology. The 2016 WHO classification system marrow examination, for diagnostic purposes, in JAK2-mutated
for hematopoietic tumors recognizes the almost perfect associa- cases with Hb/Hct level above >18.5 g/dL/55.5% in men and
tion between PV and a JAK2 mutation, as well as the fact that 16.5 g/dL/49.5% in women, with subnormal serum Epo. However,
JAK2V617F is also detected in 50–70% of patients with either ET or we advise the specific procedure in all patients, save for certain
PMF [45]. The formal diagnostic table lists three major (Hb/Hct clinical scenarios, not only for confirming the diagnosis but also

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for purposes of establishing a baseline and obtain prognostically bone marrow fibrosis at time of diagnosis [56, 57], and persistent
relevant cytogenetic information. Exceptional cases include older leukocytosis [64] to be associated with increased risk of fibrotic
patients and those with significant comorbidities, where the transformation. More recent studies in PV have confirmed the
additional information from bone marrow examination might not adverse and age-independent impact on survival of karyotype,
affect treatment decisions or long-term prognostication. leukocytosis, and certain non-JAK2 mutations including SRSF2 and
IDH2 [66, 67]; of note, NGS studies have revealed that over 50% of
The concept of masked polycythemia vera and MPN- patients with PV harbor DNA sequence variants/mutations other
unclassifiable than JAK2, with the most frequent being TET2 (18%), ASXL1 (15%),
There is increasing awareness of patients presenting with SVT and LNK (3%) [67, 68]; combined prevalence of adverse mutations
associated with a JAK2 mutation, but not meeting the WHO-listed (SRSF2, IDH2, RUNX1, U2AF1) for overall, leukemia-free or
criteria for PV or other MPN. The WHO classification system defines myelofibrosis-free survival in PV was estimated at 5–10% [67].
such presentation as MPN-U, which also includes cases with the These observations have led to the development of an
so-called masked PV [50]. From a biological standpoint, a integrated clinical and genetic survival risk model for PV,
documented increase in Hb/Hct from an individual’s baseline, dubbed as mutation-enhanced international prognostic
associated with a JAK2 mutation, should be approached as PV, model-PV (MIPSS-PV) [67]; prognostic variables for overall
even if Hb/Hct levels do not cross the WHO-defined diagnostic survival assigned in the MIPSS-PV model were age >67 years
thresholds; such circumstances should also be considered in (three adverse points), leukocytosis (≥15 × 109/L; two adverse
distinguishing PV from JAK2-mutated ET, where JAK2V617F allele points), abnormal karyotype (one adverse point), and SRSF2
burden might provide additional clue (i.e., expected to be higher mutation (two adverse points); accordingly three risk cate-
in the former and often <20% in the latter). Similarly, the dilutional gories were considered: low-risk (0–1 points), intermediate-risk
effect of marked splenomegaly might underestimate Hb/Hct (2–3 points), and high-risk (>3 points) with corresponding
levels in some patients. In the end, such details regarding median survivals of 24, 13.1, and 3.2 years [67]. We believe that
diagnostic accuracy might not influence specific treatment additional prognostic information from NGS and/or karyotype
strategies, as long as one errs on the side of keeping the Hct is useful when available but not mandated in routine clinical
level <45%, in equivocal cases [55]. practice; furthermore, additional studies are needed to validate
MIPSS-PV and identify prognostically specific cytogenetic
The relevance of bone marrow fibrosis in the context of PV abnormalities [58, 59]. Regarding the latter, in one study of
A subset of patients with PV displays variable degree of bone 196 cytogenetically annotated patients with PV, the presence
marrow fibrosis at time of diagnosis. Such occurrences do not alter of abnormal karyotype predicted inferior overall, leukemia-free,
the diagnostic label if the other WHO-defined formal criteria are and myelofibrosis-free survival [59]; however, the number of
met. We have in the past investigated the prevalence and informative cases with specific cytogenetic abnormalities was
prognostic relevance of bone marrow fibrosis at time of initial too small to further delineate their individual prognostic
diagnosis of PV [56, 57]; in one study [57], approximately 14% of contribution.
526 patients displayed mostly grade 1 reticulin fibrosis that was
associated with increased incidence of palpable splenomegaly Thrombosis risk stratification
and post-PV MF but lower incidence of thrombosis. Another study In general, patients with MPN, across all age groups, are at a
of 262 patients reported an even higher (48%) incidence of grade higher risk of both arterial and venous thrombosis, compared to
1 reticulin fibrosis and confirmed the association with an matched controls [69]. Treatment-relevant risk stratification in PV
increased risk of fibrotic transformation [56]. These observations is designed to estimate the likelihood of thrombotic complica-
underline the importance of bone marrow examination at time of tions, which is estimated to occur in approximately 26% of
diagnosis, which also facilitates detection of abnormal karyotype patients followed for a median of 20 years [70]. The original PVSG
that has previously been associated with inferior survival in PV studies had identified advanced age, history of thrombosis, and
[58–60]. On the other hand, diagnosis of post-PV MF requires the treatment with phlebotomy alone as the main risk factors for
presence of ≥grade 2 fibrosis, accompanied by development of thrombosis [71]. Accordingly, conventional risk stratification in PV
progressive splenomegaly, anemia, leukoerythroblastosis, or con- includes two risk categories: high-risk (age >60 years or
stitutional symptoms [61]. thrombosis history) and low-risk (absence of both risk factors).
Clinical practice in PV has since adopted cytoreductive therapy for
the management of high-risk patients and this should be
PROGNOSTICATION considered when evaluating post-PVSG era studies of risk factor
Predicting overall, leukemia-free, and myelofibrosis-free analysis [38]. In that context, a multicenter prospective European
survival Collaborative Low-dose Aspirin Polycythemia Vera (ECLAP) study
Overall survival in PV and other MPNs is inferior to that of age- and of 1638 patients with PV confirmed that age >65 years and history
sex-matched general population [60, 62]. Age remains the most of thrombosis remained as the most important risk factors for
important predictor of survival in PV; among 665 Mayo Clinic cardiovascular events in patients receiving contemporary treat-
patients with PV seen between 1967 and 2017, 79 (12%) were ment, whereas antiplatelet therapy was more effective than
ages ≤40 years, 226 (34%) ages 41–60, and 360 (54%) ages >60, cytoreduction in protection against cardiovascular events [72]. In a
with corresponding median survivals of 37, 22, and 10 years [63]. more recent rendition of the particular ECLAP study, risk factors for
In an international study of 1545 patients with PV, age- arterial thrombosis included prior arterial event and hypertension,
independent risk factors for overall survival included leukocytosis, and for venous thrombosis included previous venous event and
venous thrombosis, and abnormal karyotype [60]. The adverse age ≥65 years [73]. These observations were confirmed by a more
effect of persistent leukocytosis on disease progression was also recent study, which also identified hyperlipidemia and diabetes as
underlined in a recent study [64]. In the aforementioned risk factors for arterial events and leukocytosis and major
international PV study [60], cumulative risk for leukemic transfor- hemorrhage for venous events [74]. The detrimental effect of
mation was 2.3% at 10 years and 5.5% at 15 years; risk factors for hypertension to arterial thrombosis was underlined by another
leukemic transformation included older age, abnormal karyotype, study [75]. In patients who have already experienced a first
leukocytes ≥15 × 109/L and treatment exposure to pipobroman or thrombotic event, risk factors for recurrence included age >60
P32/chlorambucil, but not to HU or busulfan [60]. Other studies years, and, for arterial thrombosis, leukocytosis at time of first
have found JAK2V617F allele burden of >50% [65], presence of event, in patients younger than 60 years old [76, 77].

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Fig. 2 Current treatment approach in polycythemia vera. Our risk-adapted treatment algorithm in polycythemia vera (PV).

Additional pro-thrombotic variables in PV considered over the HOW WE TREAT

last three decades include leukocytosis [64, 78–81], JAK2V617F Treatment backbone for all patients, regardless of risk
allele burden [65, 82] and intensity of phlebotomy [83, 84]. In category
regard to the latter, one retrospective study suggested an The cornerstone of treatment in PV includes scheduled phlebot-
association between intensity of phlebotomy (>3 sessions/year) omy, with a Hct target of <45%, and daily low-dose aspirin
and increased risk of thrombosis in high-risk PV patients receiving therapy, in all patients, regardless of risk category [87]. The
HU [84]; however, this observation was not supported by a more antithrombotic value of phlebotomy is supported by both
powerful analysis of the aforementioned ECLAP and cytoreductive controlled [39] and uncontrolled [33, 88] evidence and the case
therapy in PV (CYTO-PV) database [83]. Two studies are for phlebotomy in the treatment of PV was skillfully argued by
noteworthy for their evaluation of thrombosis impact from William Dameshek in a 1968 commentary [15]. In a practically
JAK2V617F allele burden in PV [65, 82]; one included 320 patients useful and elegant discussion, Barbui et al. considered the two
[65] and found no association with thrombosis risk, although the most noteworthy controlled studies that are the basis for current
authors reported an association with risk of fibrotic progression; recommendations regarding phlebotomy in PV [89, 90]; the PVSG-
the second study included 173 patients [82] and reported an 01 study [71] included 431 patients with PV who were randomized
association between JAK2V617F allele burden of >75% and to receive phlebotomy alone or phlebotomy with P32 or
cardiovascular events as well as increased need for cytoreductive chlorambucil; results of the study included respective median
therapy. survivals of 13, 11, and 9 years; increased thrombosis risk in
A recent systematic review and meta-analysis of articles patients treated with phlebotomy alone, during the first 3 years;
involving over 30,000 patients suggested the role of leukocy- and increased rates of leukemic transformation and secondary
tosis in terms of arterial, but not venous, thrombosis in both PV cancers associated with chlorambucil or P32 treatment; the more
and ET, although the association was stronger in the latter [80]. recent CYTO-PV study included 365 patients with PV who were
The methodology applied in this particular analysis was already receiving treatment with phlebotomy, HU, or both, prior to
questioned by other investigators [85], who, in a subsequent study entry, who were then randomly assigned to a target
report [64], did not find an association between persistent hematocrit goal of <45% or 45–50% [39]; after a median follow-up
leukocytosis and thrombosis in PV; however, the latter analysis of 31 months, thrombotic events or deaths from cardiovascular
did not distinguish arterial from venous thrombosis because of causes were recorded in 5 of 182 patients in the <45% hematocrit
low event rates [81]. The controversial contribution of leukocy- group (2.7%) and 18 of 183 patients in the 45–50% hematocrit
tosis, for thrombosis risk in PV, was also addressed in several group (9.8%). These two studies provide the basis for current
other studies [78, 79, 86]. practice in terms of the need for phlebotomy and the desired Hct
Based on the above outlined discussion, we consider history target in patients with PV. We are cognizant of limitations in both
of arterial and venous thromboses in PV to be the most studies, which however do not undermine their overall value [89].
important risk factors for subsequent arterial or venous We are also receptive of situations where either the patient or
vascular events, respectively. We also endorse the inclusion their physician prefers a lower Hct target level (e.g., 42%) because
of advanced age, variably defined as >60 or 65 years, as a major of a variety of reasons including a lower baseline value for an
risk factor for both arterial and venous thrombosis. Cardiovas- individual patient (e.g., women vs men; in the setting of SVT or
cular risk factors signal the need for institution and dose pregnancy) and the desire to achieve better symptom control or
optimization of aspirin therapy. At the present time, there is minimize excess residual risk of thrombosis despite standard
not adequate and reproducible evidence that allows formal therapy. In particular, a lower target Hct might be advisable during
inclusion of either leukocyte count or JAK2V617F allele burden, pregnancy since Hct levels are expected to be lower from the
as independent risk factors for thrombosis in PV. As such, we second trimester onwards
do not use these variables to modify our overall treatment The therapeutic role of aspirin in the treatment of PV has long
strategy (Fig. 2). being suspected [71] and was initially faced with some concerns

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regarding bleeding complications [91], but its formal transition consideration of the primary indication for treatment being
into routine clinical practice was facilitated by a controlled study control of symptoms or curbing the need for frequent phlebo-
from the ECLAP group [40]. The latter study enrolled 518 patients tomies, as opposed to prevention of thrombosis. Our proposed
with PV in a double-blind randomized trial to low-dose aspirin overall treatment strategy is supported by accumulating evidence
(100 mg daily) or placebo [40]. Treatment with aspirin did not of safety and treatment efficacy for peg-IFN, in the treatment of PV
increase the incidence of major bleeding and instead reduced the [103–108], its efficacy in alleviating intractable pruritus [109], and
risk of combined endpoints for “nonfatal myocardial infarction, its selective but not consistent [110, 111] effect on the malignant
nonfatal stroke, or death from cardiovascular causes” and clone [112–114]. A recent phase-2 randomized study of young
“nonfatal myocardial infarction, nonfatal stroke, pulmonary patients (ages 18–60) with PV compared treatment with peg-IFN
embolism, major venous thrombosis, or death from cardiovascular (ropeginterferon alfa-2b, 100 mg subcutaneous injection every
causes” [92]. Aspirin therapy has also been reported, in a 2 weeks) + phlebotomy + low-dose aspirin against phlebotomy +
retrospective study, to be beneficial in JAK2V617F-mutated low- low-dose aspirin [115]; 127 patients were randomized to the two
risk ET, in preventing venous thrombosis, and also in patients with treatment arms and followed for a median of 12.1 months; the
cardiovascular risk factors, in preventing arterial thrombosis [93]. peg-IFN treatment arm provided superior hematocrit control (84%
In addition to its value as an antithrombotic agent, low-dose vs 60%) without significant difference between the two treatment
aspirin therapy is also effective in alleviating microvascular arms in terms of grade 3 or higher adverse events. However, a
symptoms in both PV and ET [94]. Recent studies have suggested numerically larger study with longer follow-up is needed, to clarify
greater antiplatelet effect from twice-daily, as opposed to once- the role of cytoreductive therapy in low-risk PV; such a study will
daily dosing, not only in patients with MPN, but also in those with also address the growing debate on whether asymptomatic, low-
other diseases, where shortening of aspirin dosing interval is risk PV patients should be treated with peg-IFN, outside of a
thought to overcome time-dependent renewal of the drug target clinical trial, on account of its selective anti-clonal activity and its
[95]. In a recent meta-analysis of seven randomized clinical trials anti-inflammatory properties.
that included 379 participants [95], twice-daily vs once-daily
aspirin dosing resulted in greater diminishing of serum thrombox- Management of high-risk disease
ane B2 (TxB2) levels, regardless of underlying disease phenotype. There is currently broad consensus regarding the need for
The particular phenomenon was specifically confirmed by several cytoreductive therapy in high-risk patients with PV, in addition
studies in the setting of MPN (mostly ET) [96–98], where increased to phlebotomy and aspirin therapy [116]. There is also general
platelet turnover is thought to compromise 24-h durability of agreement on which drugs should not be used in this regard (e.g.,
aspirin inhibition of platelet cyclo-oxygenase-1; in one particularly chlorambucil [71, 117], P32 [71], pipobroman [60, 118]) because of
noteworthy study, three aspirin dosing regimens (100 mg) were their previously well-demonstrated leukemogenic and/or carcino-
investigated and twice-daily/thrice-daily dosing was more effec- genic potential. In contrast, a series of long-term prospective
tive, compared to once-daily dosing, in reducing platelet studies in PV [38, 41, 119–124] and randomized studies in ET
activation, measured by serum TxB2 level [97]. Although none of [41, 125] have confirmed the favorable safety and efficacy record
the aforementioned studies reported clinical outcome, their of HU therapy in high-risk disease. The pioneering study in this
results were consistent in showing that multiple daily aspirin regard was a non-randomized PVSG trial that showed a lower
dosing was more effective than ASA 81 mg once-daily or 325 mg incidence of early thrombosis in HU-treated patients, compared to
once-daily at suppressing serum TXB2, which is an in vivo marker a historical cohort treated with phlebotomy alone (6.6% vs 14% at
of platelet activation. Regardless, controlled prospective studies 2 years) [38]. Similarly, the incidence of AML in the first 11 years of
are needed to confirm clinical relevance and safety of applying the treatment was lower with HU, compared to historical controls
specific treatment strategy in MPN as well as other diseases; in the treated with chlorambucil or P32 (5.9 % vs 10.6% vs 8.3%) [38].
meantime, we believe it is reasonable to consider twice-daily low- Other studies have since confirmed the low incidence of AML in
dose aspirin dosing in PV, in the absence of contraindications and HU-treated PV (1–5.6%) [121, 126, 127].
presence of a higher risk for arterial thrombosis, including in In a recent reappraisal of 1042 PV patients from the ECLAP
patients with cardiovascular risk factors and leukocytosis. Aspirin database, the authors reported an advantage for HU over
therapy should be avoided in patients with bleeding symptoms phlebotomy alone, in terms of protection from fatal/nonfatal
associated with acquired von Willebrand syndrome; however, in cardiovascular events and fibrotic transformation, whereas venous
the absence of bleeding history, we are comfortable in continuing thrombosis rates were similar between the two treatment cohorts;
with once-daily low-dose aspirin therapy provided ristocetin leukemic transformation rate was very low (only three cases
cofactor activity is above 20%, consistent with our current practice including two in the phlebotomy alone treatment group) after a
in ET [99]. median follow-up of approximately 3 years [124, 128]. A recent
meta-analysis of 3236 HU-treated patients with PV [129] high-
Indications and choice of cytoreductive drugs in low-risk PV lighted follow-up duration as an important variable in determining
In general, cytoreductive therapy is not indicated for low-risk survival and fibrotic transformation and age in determining
disease and its lack of additional value was indirectly surmised thrombosis rates (the latter were 1.9%, 3.6%, and 6.8% persons/
from a controlled study in ET [100]. However, aggressive year at median ages 60, 70, and 80 years, respectively). The
phlebotomy in low-risk patients with PV might result in severe particular study [129] estimated fibrotic transformation rates of 5%
phlebotomy-induced side effects and might also not be adequate at 5 years and 34% at 10 years, while the respective mortality rates
in controlling certain disease-associated symptoms such as severe were approximately 13% and 56%; overall leukemic transforma-
pruritus [89, 101, 102]. As such, cytoreductive drugs might need to tion incidence was lower at 0.4% persons/year and remained
be considered, in addition to phlebotomy and aspirin, in such stable over time. In another ECLAP analysis of 1638 PV patients
circumstances. In this regard, because guidance from high-quality [130], which included 342 patients treated with phlebotomy alone
controlled studies is currently lacking, one must rely on available and 700 treated in addition with HU, multivariable analysis did not
experience from long-term prospective and retrospective studies disclose a significant difference in the risk of secondary
and should always take patient preference into account, in malignancies other than AML, between the two treatment
deciding when to commence such treatment and which cohorts.
cytoreductive agent to choose [89, 101, 102]. Our first-line drugs Favorable information regarding the therapeutic role of peg-
of choice in the particular scenario include peg-IFN for younger IFN, in the setting of upfront therapy, is slowly accumulating and
patients and HU for older patients; our choices reflect has now reached the point where it can be considered as an

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alternative option in young patients, although superiority or non- patients with PV and 65 with ET, who were refractory or intolerant
inferiority to HU is yet to be demonstrated in a controlled setting to HU, received subcutaneous pegylated IFN-α (starting dose
[42, 108, 131]. In a recent randomized study that compared 45 mcg weekly and titrated to a maximum of 180 mcg) with 69%
pegylated INF (ropeginterferon alfa-2b; starting at 100 mcg overall response rate, including 60% (22% complete response) in
subcutaneously every 2 weeks) with oral HU (starting at 500 mg/ patients with PV. Statistically significant improvement in symptom
day), 257 PV patients with limited prior exposure to cytoreductive burden was also noted but countered by pegylated IFN-α
therapy were randomly assigned to one of the two treatment treatment-emergent adverse events, which were mostly tolerable;
arms [42]; 217 patients completed the first part of the study and treatment discontinuation because of adverse events was
171 patients were rolled over to the continuation part of the relatively low at 14%. As expected, pegylated IFN-α therapy
study. Complete hematological response with normal spleen size induced partial suppression of JAK2V617F in some patients [133].
was achieved in 21% of patients receiving ropeginterferon vs 28% Ruxolitinib (a JAK1/2 inhibitor) has also been shown to be effective
for HU, thus not meeting the criteria for non-inferiority. Similarly, in HU refractory/intolerant PV; in a phase-3 study (RESPONSE)
hematologic response without meeting the spleen response comparing ruxolitinib (n = 110) with best available therapy (BAT;
criterion was similar between the two arms (43% vs 46%, n = 112) [43], hematocrit/spleen control was achieved in 60%/40%
respectively), at 12 months, as was the case with molecular of patients receiving ruxolitinib vs 20%/0.9% for BAT; 80-week
response. In the extension part of the study, response rates, follow-up [134] disclosed 83% of patients remaining on ruxolitinib
including molecular response, in patients receiving ropeginter- therapy treatment, while 88% of the patients on BAT crossed over
feron gradually improved over time but with the difference not to ruxolitinib. Similar superiority in hematocrit control for
reaching statistical significance; however, at 3 years of treatment, ruxolitinib vs BAT (62% vs 19%) was shown in a subsequent
significantly more patients receiving ropeginterferon maintained randomized but not blinded study (RESPONSE-2) of PV patients
their hematological response. Treatment with ropeginterferon was without splenomegaly who need second-line therapy.
associated with a spectrum of adverse events that required dose The efficacy of oral busulfan (dosed at 2–4 mg/day) in patients
reductions in 40% of patients, dose interruption in 23%, and drug with advanced PV or ET refractory or intolerant to HU was
discontinuation because of drug-related toxicity in 8%. Common assessed in two recent studies [135, 136]; in one study of 36
side effects of treatment with ropeginterferon included fatigue, patients with treatment duration of 256 days, which included 15
liver function test abnormalities, thrombocytopenia, and leukope- patients with PV [135], complete hematological response was
nia. Treatment-emergent serious adverse events were similar reported in 83% of the patients, which was sustained in the
between the two treatment arms and follow-up was too short to majority of the patients at 2 years. Busulfan was discontinued in 18
evaluate differences in thrombosis or leukemic transformation (67%) patients because of unmaintained remission, which is a
rates. In a recent systematic review and meta-analysis of IFN (both unique feature of busulfan treatment response in patients with
peg and non-peg) treated patients with PV or ET [108], 44 studies MPN; and 33% of informative cases demonstrated partial
including 1359 patients were analyzed; complete hematologic molecular response. The particular study listed 22% hematologic
response rate in PV was reported at 49% with no difference toxicity that was more likely to occur in patients receiving >14 mg/
between peg- and non-peg-IFN preparations; annualized rates of week [135]; with a follow-up of 117 person-years from initiation of
thrombotic complications and treatment discontinuation in treatment with busulfan, six patients had died, corresponding to a
patients with PV were estimated at 0.5% and 6.5%, respectively rate of 5.8 deaths × 100 person-years; causes of death were acute
[108]. leukemia (n = 3), infection (n = 2), and unknown (n = 1). In
Taking the above-elaborated review and our own personal addition, three cases of second neoplasms were reported,
experiences into consideration, HU (starting dose 500 mg twice- including cancers of the skin, prostate, and liver. The second
daily) remains our current first-line cytoreductive drug of choice in study that included 51 informative patients with PV, a complete or
older (age >60 years) patients with high-risk PV. We consider peg- partial hematologic response rate was reported in 75% of patients
IFN (starting dose 45 mcg weekly SC injection for pegasys or [136]; the study also reported a low (15%) rate of adverse drug
100 mcg for every 2 weeks for ropeginterferon) as a reasonable effects and corresponding treatment dropouts (6%). Earlier studies
alternative in younger patients and the preferred choice for young of busulfan use in an upfront treatment setting, in both PV and ET,
women of reproductive age and where treatment indication have also reported favorable efficacy and safety profile [137, 138].
involves alleviation of symptoms (e.g., pruritus) or reducing the On the other hand, the evidence for busulfan leukemogenicity in
frequency of phlebotomies. Additional drug treatment choices the context of treatment for PV or ET remains circumspective, and
(busulfan and ruxolitinib) are discussed below in the section of not validated in larger patient cohorts that accounted for other
“treatment for HU refractory/intolerant PV.” Of note, neither risk factors of leukemic transformation including older age,
prospective nor well-designed retrospective studies, in ET or PV, leukocytosis, and disease duration [60, 127, 139]; regardless, we
implicate HU as amplifying the intrinsic vulnerability of PV or ET are acutely aware and appreciative of opposing views on the
patients for leukemic transformation [127, 132]. PV patients with subject matter and the possibility of increased risk for leukemic
venous thrombosis require systemic anticoagulation, in addition transformation, especially in patients receiving both busulfan and
to cytoreductive drug therapy; we also consider adding low-dose HU. One important confounding factor in the particular issue
aspirin in some instances in order to subvert the additional risk of might involve busulfan dose and schedule; we recommend
arterial thrombosis, especially in the presence of JAK2 mutation or starting at the lower dose of 2 mg/day with close monitoring
cardiovascular risk factors, as well as lessen the risk of recurrence and consider periodic drug holidays, especially in the context of
of venous thrombosis [77]. The therapeutic role of direct oral having achieved treatment objectives in controlling Hct and
anticoagulants (DOACs) is currently being investigated and further platelet count. Incidentally, drug-induced JAK2V617F allele burden
elaborated below in the section of “management of splanchnic reduction has also been demonstrated with busulfan use in PV
vein thrombosis.” [140].
Taking the above discussion into consideration, with emphasis
Treatment of hydroxyurea refractory/intolerant PV on long-term track record of safety [104, 135, 141] and activity
There are currently three drugs that are considered for use in beyond symptom control (i.e., suppression of clonal myeloproli-
patients who are intolerant or resistant to HU: pegylated IFN-α, feration) [113, 114, 142], in patients who are either intolerant to or
ruxolitinib, and busulfan. Our first drug of choice in such an show suboptimal response to HU, we prefer the use of peg-IFN for
instance is peg-IFN. In a recent phase-2 clinical trial from the patients younger than age 65 years and busulfan in the older age
Myeloproliferative Disorders Research Consortium [133], 50 group, although there is no controlled evidence to support or

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 A. Tefferi et al.
3345
refute such a strategy. Busulfan is started at 2–4 mg/day, withheld concomitant hypercoagulable state, higher risk of venous
in the presence of platelets <200 × 109/L or WBC < 3 × 109/L, and thrombosis, and bleeding, in MPN-SVT, compared to their MPN
the dose reduced to 2 mg/day when treatment is resumed after counterparts without SVT [152, 153]. A more recent, similarly
withholding. Ruxolitinib, on the other hand, is preferred in the retrospective report looked into risk factors for adverse outcome
presence of symptoms reminiscent of post-PV myelofibrosis and in 80 patients with MPN-SVT (mostly PV) [154]; at a median follow-
in patients suffering from drug-refractory pruritus or symptoma- up of 11 years, 13% of the patients experienced an adverse
tically enlarged spleen [43]. Whether or not ruxolitinib, peg-IFN, or outcome and were enriched for cases with ≥50% JAK2V617F allele
busulfan provide protection from thrombosis, in addition to their burden, and additional mutations (spliceosome or TP53); MPN-SVT
salutary effect on hematocrit and other disease features, in patients with at least one of the latter two risk factors displayed
resistant/intolerant PV, remains uncertain [143]. inferior event-free (81% vs 100%) and overall (89% vs 100%)
survival at 10 years.
Management during pregnancy Taking the above observations and those of other studies into
Reports of pregnancies in women with MPN are less common in account [153, 155], it is reasonable to state that survival in MPN-
PV than they are in ET, because, unlike the case with ET, PV has a SVT is primarily influenced by that of the underlying MPN, rather
male preponderance with only 15% of patients diagnosed before than the SVT event itself, which would be consistent with the
age 40 years [63]. Four relatively large studies reporting on observation regarding shortened survival in patients with
pregnancies in PV included 8–48 patients with 5–121 pregnancies; abnormal karyotype [155] or certain high-risk mutations [154].
live birth rates ranged from 61 to 88%, miscarriages from 13 to Currently, there are not reliable predictors of first-event or
29%, and maternal complications from 6 to 17% for thrombosis recurrent SVT in MPN, including PV. The therapeutic value of
and 2 to 25% for bleeding [144–147]. Management included systemic anticoagulation (and the choice between VKA and
observation alone or treatment with aspirin, low molecular weight DOAC) [151] or cytoreduction (and the choice between HU and
heparin (LMWH) or IFNα, alone or in combination; considering the IFN) [156, 157] requires further validation, in a controlled setting.
retrospective nature of these studies, it is difficult to discern the In a small study of ruxolitinib, therapy in patients with MPN-SVT
specific circumstances or treatments that might have influenced did not indicate salutary effect on esophageal varices or
outcome. Regardless, we highly recommend preconceptual mesenteric circulation [158], which is consistent with lack of
counseling regarding risk of fetal loss and other complications, evidence for its value in reducing thrombosis risk [143]. In general,
especially in patients with prior pregnancy loss or history of in patients with PV/MPN-associated SVT, we recommend an
thrombosis. Along with strict control of Hct < 45% (preferably aggressive treatment approach that includes, at a minimum,
below 42%), treatment with low-dose aspirin is recommended in systemic anticoagulation [156, 157]; in the latter regard, we
all PV patients planning to be pregnant, based on favorable consider patient preference and convenience regarding the
observations extrapolated from the experience in ET, regarding choice between VKA and DOACs, since we are not yet convinced
protection from first trimester fetal losses [148]. We recommend that one is better than the other; regardless, we prefer LMWH
cytoreductive therapy with peg-IFN in patients with prior vascular therapy in the acute setting followed by VKA therapy, especially if
events and consider adding LMWH, in case of venous thrombosis there is concern regarding intestinal edema or variceal bleeding
history; we do not advise the use of HU or warfarin because of associated with portal hypertension; we believe DOAC therapy is a
their teratogenic potential. The value of LMWH during pregnancy reasonable alternative, otherwise.
or post-partum, in the absence of venous thrombosis history, is
uncertain. Perioperative management
It is important to consider the possibility of increased risk of
Management of splanchnic vein thrombosis thrombosis or hemorrhage in PV patients undergoing surgery, in
Although it is well known that SVT frequents patients with MPN, lieu of their underlying JAK2-mutated MPN as well as the generally
including MPN-U, its optimal management remains obscure. As a expected post-surgical risk of thrombosis and bleeding. There are
background on SVT in general, in one population-based study of currently limited data for guidance regarding optimal pre- and
1915 patients [149], the affected veins were portal in 78%, hepatic perioperative management of patients with PV or ET. In a 1963
in 11%, and mesenteric in 11%; risk was similar between the two report by Wasserman and Gilbert [159], 62 major surgical
sexes and the respective incidence rates were 21, 3, and 3/100,000 operations in patients with PV were analyzed and revealed fatal
persons per year. In the study [149], comorbidities included recent and nonfatal complication rates of 83% vs 21%, in hematologically
surgery (40%), liver cirrhosis (11%), pancreatitis (11%), gastro- uncontrolled vs controlled disease, respectively. More recent
intestinal cancer (9%), extraintestinal cancer (10%), and MPN studies have suggested more favorable outcome. In one such
(1.2%). The incidence of MPN as a comorbid condition was higher study [160], 255 patients with PV or ET were analyzed for a total of
in another study (8%) [150]. In a recent retrospective study, 518 311 surgical interventions, including 25 emergency procedures.
patients with MPN-SVT were compared to 1628 otherwise Antithrombotic prophylaxis included subcutaneous heparin in
unselected MPN cases [151]; the former were more likely to be 54% and antiplatelet therapy in 15% of the patients. In addition,
younger, females, and JAK2V617F mutated (90%). The study 74% of patients were on cytoreductive therapy before surgery.
included 192 (37%) patients with PV (median age 45 years; 53% Three-month post-operative course was uneventful in more than
females) and 178 (34%) with ET (median age 39 years; 71% 80% of the cases, whereas arterial or venous events were
females; 85% JAK2 mutated) and affected veins included portal documented in 12 patients, each, with the former being more
(67%), hepatic (25%), splenic (29%), and mesenteric (24%) [151]. A frequent in ET and the latter in PV; major bleeding complications
concomitant hypercoagulable disorder was documented in 39% occurred in 23 cases and deaths in 5; platelet count and
of the cases. SVT recurrence rate was 1.6 per 100 patient-years and hematocrit level at time of surgery were not predictive of vascular
significantly improved by treatment with vitamin K-antagonists events and the value of pre-procedure prophylactic therapy was
(VKA) but not cytoreductive therapy. Bleeding complications did not apparent. Regardless, our current practice is based more on
not appear to be influenced by VKA therapy but were more likely intuition rather than evidence and includes keeping hematocrit
to occur in patients with esophageal varices. Overall survival of PV level below 45% and platelet count below 450 × 109/L, before and
patients in the study [151] was not affected by SVT; furthermore, after surgery; platelet count control in low-risk patients might
there was little evidence of disease progression in patients with require a short course of treatment with HU; in addition to
MPN-U with SVT (n = 55). Other studies have confirmed lower cytoreductive therapy, careful use of LMWH is advised in high-risk
JAK2V617F allele burden, lower blood counts higher likelihood of patients.

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3346
Management of pruritus thrombotic complications and such treatment is often more than
Pruritus is a particularly vexing symptom associated with PV and is adequate to control the hematocrit as well; second, in low-risk
often exacerbated by contact with water [161–163]. In a large patients, hematocrit control is easily achieved with drug-free
cohort of 441 German patients with PV [163], patient-directed phlebotomy and if an alternative to phlebotomy is needed, for
questionnaire revealed that 68% of the patients were affected by one reason or another, peg-IFN offers a more attractive option
aquagenic pruritus, in the majority occurring before formal since it also controls thrombocytosis, leukocytosis, splenomegaly,
diagnosis of PV; pruritus manifested in different forms including and certain symptoms such as aquagenic pruritus. Also, peg-IFN
itching, tickling, stinging, or burning sensations and its severity has a much longer track record of safety.
was labeled unbearable in 15% of the cases. In a review of the
literature spanning the period 1965–2009 [162], application of a Idasanutlin (MDM2 antagonist)
variety of treatment modalities, including antihistamines, anti- Idasanutlin is an orally administered (150 mg once-daily × 5
depressants, IFN-α, phlebotomy, phototherapy, iron supplements, repeated every month) Mouse Double Minute 2 (MDM2)
and myelosuppressive medications, was documented with mixed antagonist whose mechanism of action includes stabilization of
efficacy results. In the low-risk disease setting, we first consider TP53 activity by blocking its binding to MDM2. In a phase-2 trial of
non-drug measures, such as avoidance of precipitating conditions, 27 phlebotomy-dependent patients with PV who were resistant or
dry skin, and temperature control of one’s environment and water intolerant to HU therapy, patients were treated for a median of
used for bathing. In general, treatment responses to antihista- 257 days; hematocrit control was achieved in 9 (56%) patients,
mines have been both unpredictable and variable [161]. More complete hematologic response in 8 (50%), spleen volume
favorable responses have been reported with use of selective response in 7 (33%), and symptoms response in 6 (43%) [179].
serotonin reuptake inhibitors [164] and narrow-band ultraviolet B In addition, 76% of patients who were evaluable at week 32 of
phototherapy [165]. In high-risk disease setting, both JAK2 treatment experienced reduction in JAK2 mutant allele burden.
inhibitors [166, 167] and IFN-a [168] have shown therapeutic Unfortunately, most patients experienced significant gastrointest-
activity, which is not shared by HU. inal toxicity including nausea, vomiting, and diarrhea, which
contributed to the need for dose modifications, documented in
Management of post-PV myelofibrosis 63% of patients. These concerns are further compounded by the
In the absence of genetic information other than JAK2, it is current possibility of treatment-emergent expansion of mutant TP53
practice to stratify patients with post-PV MF in a similar fashion to clones [180], making it unlikely for the drug to garner continued
those with PMF, based on a previously published demonstration interest in the treatment of PV.
of similar applicability for risk models used for the latter, including
IPSS, DIPSS, and DIPSS-plus [169]. The suboptimal performance of Givinostat (HDAC inhibitor)
these clinical models has been addressed by more contemporary Givinostat is a histone-deacetylase (HDAC) inhibitor that selec-
mutation-enhanced prognostic models [170, 171]. For example, tively targets JAK2-mutated clones. In a series of early phase
MYSEC-PM (Myelofibrosis Secondary to PV and ET-Prognostic studies, givinostat was administered orally (50–100 mg BID) in 50
Model) [171] considers constitutional symptoms, anemia, circulat- patients with PV, either alone or in combination with HU (n = 15)
ing blasts, thrombocytopenia, advanced age, circulating blasts, [181]. At the time of the most recent analysis on long-term
and absence of CALR mutations as risk variables. One can also outcome, median drug exposure was 2.8 years and 62% of the
consider other mutation-enhanced models derived in the setting patients remained on active therapy. Treatment-emergent adverse
of PMF, including MIPSS70 [172] and MIPSSv2 [173, 174], which in effects (26% considered serious) of givinostat included QTc
addition consider karyotype and high-risk mutations, including prolongation, thrombocytopenia, diarrhea, dysgeusia, and head-
ASXL1, SRSF2, EZH2, IDH1/IDH2, and U2AF1Q157 [171, 173–176]. ache. Givinostat-treated PV patients benefitted the most in terms
From a practical standpoint, we believe that both MIPSS/MIPSSv2 of alleviation of pruritus and control of blood counts, including
and MYSEC adequately serve their main purpose in identifying hematocrit, while the drug had limited activity in reducing spleen
high-risk patients with post-PV MF who should be referred for size; in some instances, clinical response was accompanied by
allogeneic hematopoietic stem cell transplant sooner rather than reduction in JAK2 mutant allele burden [181]. Results from a
later. Non-transplant therapies for post-PV MF are like those for planned phase-3 trial are awaited, in order to position givinostat in
PMF and mostly palliative [177]. either upfront or second-line therapy in PV.

NEW DRUGS IN THE HORIZON CONCLUDING REMARKS

PTG-300 (hepcidin mimetic) Although we are comforted with the relatively indolent clinical
PTG-300 (Rusfertide) is a hepcidin mimetic whose mechanism of course of patients with PV [63, 70], we are acutely aware of
action includes restriction of iron availability (i.e., negative iron outstanding issues including residual risk of thrombosis despite
regulation) for red blood cell production. In other words, it “optimal” current therapy, impaired quality of life from frequent
recapitulates iron deficiency at the cellular level, without depleting phlebotomy needs or non-thrombotic symptoms in some
iron stores. The drug is administered by weekly subcutaneous patients, and the apparently inevitable risk of premature death
injection at escalating doses of 10, 20, 40, 60, and 80 mg, adjusted and/or disease transformation into AML or post-PV MF. Regarding
to maintain hematocrit <45%. The most recent (2020) EHA the latter, currently available therapy has not been shown to
presentation abstract included 35 patients including 16 with modify the natural history of the disease and clinical trials
low-risk disease [178]. PTG-300 therapy resulted in significant addressing the issue are challenged by the need for a controlled
reduction of phlebotomy need; among 13 patients treated for at setting and long-term follow-up. We acknowledge the possibility
least 28 weeks, 10 remained phlebotomy free and concomitant of drug-induced suppression of JAK2V617F allele burden, seen in
iron deficiency was reversed in most instances, associated with some patients treated with peg-IFN [103] or busulfan [140], but
improvement in symptoms. Reported side effects of PTG-300 question its translation into longer survival or decreased risk of
included transient low-grade injection site reactions. Of note, PTG- disease transformation; furthermore, there appears to be limited
300 did not appear to affect leukocyte or platelet count [178]. We correlation between molecular and hematologic response [142].
are not certain about the prospect of PTG-300 within the On the other hand, we believe that there is feasibility for
therapeutic program for PV for a number of reasons; first, high- productive clinical trials directed at maximizing thrombosis
risk patients require broader myelosuppression to prevent protection and improving quality of life, as long as such studies

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3347
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