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How to manage children and young adults with myeloproliferative

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Leukemia (2012) 26, 1452 - 1457
& 2012 Macmillan Publishers Limited All rights reserved 0887-6924/12
How to manage children and young adults with
myeloproliferative neoplasms
T Barbui
On the basis of my personal clinical and research experience and validated by the current literature, my approach to the
management of pediatric (age o18 years) and young patients (age o40 years) with classic myeloproliferative neoplasms is
presented by focusing on diagnosis, patient communication, risk stratification and therapy. The WHO-2008 diagnostic criteria
are recommended, even though in children suspected with essential thrombocythemia (ET), a specific set of diagnostic features
may be required. Patient communication includes information on natural history, genetic abnormalities and counseling in all
women of child-bearing age. The main challenge in children and young adults with ET and polycythemia vera (PV) is to avoid
recurrence of major thrombosis by selecting those patients who ultimately can benefit from cytotoxic and antithrombotic
therapy without increasing the incidence of drug-induced side effects. In asymptomatic low-risk patients no therapy is
prescribed while in high-risk low-dose aspirin, hydroxyurea and interferon-alpha are my п¬Ѓrst line drugs. My п¬Ѓrst decision when
considering treatment of a young patient with primary myelofibrosis (PMF) or post-PV or post ET-myelofibrosis, is whether
he/she qualifies for bone marrow allotransplantation. In the remaining young PMF patients palliative therapy or experimental
drugs are considered.
Leukemia (2012) 26, 1452 -- 1457; doi:10.1038/leu.2012.12
Keywords: myeloproliferative neoplasms; treatment; young people
Polycythemia vera (PV), essential thrombocythemia (ET) and
primary myelofibrosis (PMF) are currently classified among the
bcr/abl-negative, �classic’ myeloproliferative neoplasms (MPNs) and
represent a stem cell-derived clonal myeloproliferation. Hematopoietic progenitors derived from patients with MPNs are hypersensitive to the stimulation of physiological growth factors such as
thrombopoietin or erythropoietin (EPO).1 Since 2005, the pathophysiology of these diseases has advanced considerably with the
discovery of an acquired mutation of JAK2 V617F in a vast majority
of PV patients and in almost half of those with ET and PMF.2
The mutation, located within the negative regulatory pseudokinase,
or Janus homology 2 domain, causes cytokine-independent activation of several biochemical pathways implicated in EPO receptor
signaling. Subsequently, mutations in MPL were reported in B4%
of patients with ET or PMF. The significance of JAK2 and MPL
mutations for the evolution of the MPNs and their relative roles
in determining disease phenotype as well as progression to
myelofibrosis and leukemic transformation are unclear at present.
In this context, it should be underscored that most of the
information in terms of diagnosis, prognosis and therapy focuses
on the �average’ MPN patients of whom median age ranges
between 60 and 65 years. On the other hand, less consistent data
are available in the groups of MPN patients who are presenting
below this median age such as pediatric and young adults (20% of
MPN patients). This issue is now becoming more and more
important, because with the advent of automatized blood cell
counters in the past years, new cases of MPNs are diagnosed in
young patients with increasing frequency.
This article is based on my personal clinical and research
experience and is validated by the currently published literature.
I will discuss my approach to the management of pediatric
(ageo18 years) and young patients (ageo40 years) with classic
MPNs focusing on the salient points as diagnosis, patient
communication, risk stratification and therapy.
In 2007/8, the WHO investigators proposed criteria and algorithms
for MPN diagnosis.3,4 These criteria combine genetic, clinical and
pathological characteristics and emphasize the neoplastic nature
of the previously termed myeloproliferative diseases and renamed
them MPNs.
Polycythemia vera
For PV diagnosis, the WHO requires the demonstration of
increased hemoglobin/hematocrit levels with the presence of
JAK2 mutation (major criteria) and one minor criterion as well.
In the absence of the second major criterion (JAK2 or related
mutations), at least two of three minor supportive criteria should
be demonstrable that are low EPO blood level, characteristic
morphological features of bone marrow biopsies and spontaneous
erythroid colonies. Contrary to previous recommendations, red
cell mass measurement is no longer required.
In my practice, in children with elevated hemoglobin and
hematocrit (HCT) levels the diagnostic algorithm includes a
number of steps: the п¬Ѓrst is to exclude congenital heart diseases,
then it is necessary to check the EPO levels. If EPO level turns out
to be low, primary erythrocytosis might be suspected and the
work-up is focused on the diagnosis of PV (JAK2 mutation) or
familial and congenital polycythemia (EPO receptor gene mutations),
Hematology and Research Foundation, Ospedali Riuniti di Bergamo, Bergamo, Italy. Correspondence: Professor T Barbui, Hematology and Foundation for Research, Ospedali
Riuniti di Bergamo, Largo Barozzi 1, Bergamo 24128, Italy.
Received 10 January 2012; accepted 11 January 2012; accepted article preview online 18 January 2012; advance online publication, 7 February 2012
Myeloproliferative neoplasm vs children and young adults
T Barbui
particularly in cases of JAK2 or JAK2 exon-12 negativity. If EPO
levels are normal or elevated, extrinsic influences have to be
considered such as secondary causes of increased EPO production
and other conditions including hemoglobin variants, von Hippel -Lindau gene mutations and 2,3 phosphoglycerate deficiency.
Essential thrombocythemia
Diagnosis of ET requires the meeting of four criteria: п¬Ѓrst, platelet
count of at least 450 Г‚ 109/l; second, bone marrow biopsy
specimens showing proliferation mainly of the megakaryocytic
lineage with increased numbers of enlarged, mature megakaryocytes and no significant increase or left-shift of neutrophil
granulopoiesis or erythropoiesis; third, not meeting the WHO
criteria for PV, PMF, chronic myeloid leukemia (CML), myelodysplastic syndromes (MDS) or other myeloid neoplasms; fourth,
demonstration of JAK2 or other clonal marker, or, in the absence,
no evidence for reactive thrombocytosis. My approach in children
with thrombocytosis who are negative for the JAK2 mutation
(40 -- 50%), is the exclusion of any infectious, rheumatological,
autoimmune or neoplastic conditions. Of note is that the WHO
diagnostic recommendations in children suspected with ET are
thought to be not adequate and a specific set of diagnostic criteria
is required.5,6 Contrary to adults, most of children with ET present
polyclonal, rather than monoclonal hematopoiesis, the capacity to
form spontaneous colonies is present less often and the presence
of JAK2 mutation is significantly less frequent than in the general
MPN population. Therefore, the WHO criteria cannot be used for
the diagnostic screening of these young patients. Diagnosis of ET
in children may require exclusion of hereditary manifestations
transmitted as hereditary character, involving genetic defects of
thrombopoietin receptor, thrombopoietin and MPL mutations
expressed in both somatic and germ line cells.7
Primary myelofibrosis
The proposed 2008 WHO criteria for PMF are applicable in children
and young adults. Bone marrow histology is essential to exclude
secondary causes of myelofibrosis (neoplastic and non-neoplastic)
and the prefibrotic phase of PMF that presents a different natural
history in comparison with true ET.8 It should be considered that
both the familial and idiopathic forms of PMF may be associated
with congenital anomalies and chromosomal abnormalities.9
Del(20q) or del(13q) as well as normal karyotype are associated
with a favorable prognosis, whereas most other cytogenetic
aberrations render a negative prognostic impact.10,11 Fewer than
100 cases of pediatric myelofibrosis have been reported worldwide and approximately half of published cases occurred in
children younger than 3 years. These latter patients are more likely
to have Down’s syndrome, rickets or a familial (possibly autosomal
recessive) form of myelofibrosis. Among older children, systemic
lupus erythematosus, tuberculosis and acute myeloid leukemia
(AML), which has usually a fulminant course (survival o1 year), are
the most common associations.12,13
As soon as the diagnosis is established, I explain in details the
natural history of the disease. The onset of the MPNs is often a
very slowly advancing process and both in the WHO-defined PV
and ET, disease-specific survival (loss in life expectancy) is not
substantially different from that of a control population, especially
in younger adults.14 PMF is a more serious disease with expected
median observed survival of about 6 years,15 whereas in prefibrotic
myelofibrosis median survival is about 10 years.14
Information on the genetic abnormalities most commonly
encountered in MPNs has to be explicitly discussed. The concern
regarding the possibility that MPNs can be heritable should be
addressed in this context by emphasizing that the vast majority of
& 2012 Macmillan Publishers Limited
MPN cases are sporadic and that the genetic mutation of JAK2 is
not a predisposing factor. However, familial clustering of PV, ET
and PMF has been well described and patients should know that
occasionally other members of the family may present these
In accordance with the European Leukemia Net (ELN) investigators,18 in the absence of hematological or clinical abnormalities, I do not routinely genotype for JAK2 mutations or JAK2
46/1 (GGCC) haplotype the relatives of individuals with MPNs.19
Patients should be notified that follow-up of PV, ET and to
lesser extent early/prefibrotic PMF20 is marked by thrombohemorrhagic complications, constitutional symptoms, such as
pruritus, night sweats, fatigue and a propensity to transform
into overt myelofibrosis (10 -- 25%), and acute leukemia (o5%),
however, at different incidence concerning the disease entities.
It has to be emphasized in detail that drugs are chosen to reduce
thrombosis and bleeding events and should be balanced in
consideration of the risks associated with their long-term use.
Therefore, in children and young adults, cytotoxic agents will be
prescribed to prevent severe vascular recurrences and it should be
clarified that with exception of allotransplantation, current drug
therapy is not able to eradicate the malignant clone. In my
opinion, the relevance of coexisting thrombophilic factors to
justify cytoreductive therapy in low-risk asymptomatic patients is
not yet well established. Thus, in the absence of familial recurrent
vascular events, I consider it not to be very helpful to test for
hereditary thrombophilic or acquired factors such as the
congenital deficiencies of natural anticoagulants (antithrombin,
protein C and protein S) and genetic mutations (factor V Leiden
and prothrombin G20210A).
Regarding PMF, patients should be informed about prognosis
that usually is even in the prefibrotic stages more severe
compared with PV and ET.14 The International Prognostic Scoring
System (IPSS) for classical-advanced PMF uses п¬Ѓve independent predictors of inferior survival (age 465 years, hemoglobin
o10 g/100 ml, leukocyte count 425 Г‚ 109/l, circulating blasts
41% and presence of constitutional symptoms) to stratify
patients into low, intermediate-1, intermediate-2 and high-risk
categories based on the presence of 0, 1, 2 or 43 risk factors,
respectively; the corresponding median observed survivals are
estimated at 135, 95, 48 and 27 months.15 On the other hand, it
has to be tested whether this International Prognostic Scoring
System may be also applicable on patients with early PMF that
infrequently present with constitutional symptoms.
All women of child-bearing age should adequately be counselled concerning the potential dangers and complications of the
disease during pregnancy and potential consequences for the
child.21,22 Concerning contraception, there is currently insufficient
evidence either to support or refute an association between
estrogen-based hormonal treatment and thrombosis in MPNs.23
My suggestion is to avoid the use of estrogen-based contraceptives in MPNs and to use alternative methods. In the event that
reproductive therapy is indicated, patient should be informed that
ovarian hyperstimulation may be associated with increased risk of
thrombosis and that antithrombotic prophylaxis may be indicated.
Polycythemia vera
PV in children and adolescents is very rare. The incidence before
the age of 25 years, accounts 1/10 000.000. On the contrary in
adults, with a median age at presentation of 60 years, the
incidence is around 10 -- 20 cases per 1 000 000. Owing to the rarity
of MPN in children o18 years, very few studies with limited
number of patients are available.5,24
An extensive review of the literature describing the clinical
course and treatment modalities of 35 PV cases in children was
Leukemia (2012) 1452 - 1457
Myeloproliferative neoplasm vs children and young adults
T Barbui
recently reported.25 The youngest was 7 months and the oldest
17.5 years old (median age 11 years). Budd-Chiari syndrome was
the prevalent complication and it is recommended to take this
event into account even though diagnosis may not be clinically
obvious. In fact, concurrent hypersplenism, occult gastrointestinal
bleeding or hemodilution can mask blood count abnormalities.
Of significant diagnostic help is the determination of JAK2 mutation,
which is found in about 45% of adult patients with Budd-Chiari
syndrome and in 34% with portal vein thrombosis. However,
it should not be overlooked that negativity of this mutational
status does not exclude MPDs. Other described complications
in children include stroke, cerebral vein thrombosis and severe
Essential thrombocythemia
ET is also rare in children o18 years and no sufficient data to
recommend treatment are available, especially as in the current
literature the WHO criteria for ET were not stringently applied.8,27
Moreover, no evidence for a risk stratification particularly useful to
guide therapeutic decisions is available and there are no indications
on how to monitor cytoreductive therapy. In adults, ELN recently
reported criteria for monitoring therapy.28 In particular, It has been
emphasized that all studies in PV and ET failed to show a clear
association between platelet count and thrombotic events. Rather,
functional and structural platelet abnormalities are of more
relevance. Paradoxically, very high platelet counts can induce a
bleeding tendency, mainly due to an acquired Von Willebrand’s
disease.29 I fully agree with ELN recommendations that cytoreductive drugs in children with PV and ET should be prescribed as a last
possibility and I suggest that, in the rare cases that need treatment,
the selection of a cytotoxic or cytoreductive agent should be done
after discussion with the child and parents. Hydroxyurea (HU) and
interferon-alpha (IFN-a) are п¬Ѓrst line therapy at any age including
children and young adults. The long-term leukemogenicity of HU
may be a special concern, although none of the pediatric patients
treated with this agent have yet undergone malignant transformation.27,30 Adverse effects of IFN-a such as flu-like syndrome,
neuropsychiatric symptoms and autoimmune phenomena can be
particularly dangerous for children. Anagrelide is not licensed as
п¬Ѓrst-line therapy for ET in Europe and the ELN group recommends
this drug as second line therapy.18 The use of aspirin (ASA) in
children less than 12 years of age should be prescribed with caution
because of the risk of Reye’s syndrome. Overall, according to ELN
experts, there are insufficient data to recommend a specific agent
in children, and the choice should be individually tailored.
Primary myelofibrosis
Natural history of PMF in children seems different from the adult
variant. Variable outcomes with either fulminant course rapidly
evolving to acute leukemia or relative indolent courses have been
described. A thorough search for an underlying disease should be
made in order to exclude secondary myelofibrosis.31 - 33 The only
effective therapy in acute leukemia phase lies in allogeneic bone
marrow transplantation. Indolent disease may respond to corticosteroid.31 - 33
The main challenge in young adults with classic MPNs is to select
those patients who ultimately can benefit from a therapy without
increasing the incidence of life threatening side effects of the long
use of cytotoxic drugs (Table 1).
Cornerstone of treatment for PV is represented by phlebotomy.
The immediate goal of this practice is to reduce hyperviscosity by
decreasing the venous HCT level to less than 45%. This strategy is
based on PV Study Group investigations that reported the best
Leukemia (2012) 1452 - 1457
Table 1.
Risk-adapted therapy in young adults with PV and ET
Risk stratification: high-risk patients are defined by previous life
threatening major thrombotic or severe hemorrhagic complication.
Low-risk patients PV: target hematocrit below 45% plus aspirin
100 mg/day by phlebotomy.
ET: aspirin 100 mg/day if microcirculatory symptoms (that is,
erythromelalgia) or concomitant cardiovascular risk factors.
High-risk patients as above, plus myelosuppressive therapy:
hydroxyurea as first choice; PEG-interferon in special situations
(that is, pregnancy); in ET patients intolerant or refractory to
hydroxyurea PEG-interferon or Anagrelide.
Abbreviations: ET, essential thrombocythemia; PV, polycythemia vera.
median observed survival of 12.6 years for this type of
treatment.34 However, some experts have cast doubts on these
п¬Ѓndings, noting that up to 50% of patients treated with
phlebotomy alone had to switch to other therapies by the п¬Ѓfth
year.35 Moreover, in the ECLAP (European Collaborative Low-dose
Aspirin in Polycythemia) Study, multivariate analysis considering
all the confounders failed to show any correlation between HCT
values in the range from 40 to 50% and incidences of thrombosis.36 This uncertainty prompted Italian investigators to activate
a prospective, multicenter, randomized clinical study (CYTO-PV)
addressing the issue of the optimal target of cytoreduction in PV
(EudraCT 2007-006694-91). While waiting for the results of this
trial, my practice is to follow ELN recommendations and to
perform phlebotomy withdrawing 250 to 500 ml of blood daily or
every other day until a HCT value between 40 and 45% is
obtained. Once normalization of the HCT has been obtained,
blood counts at regular intervals (every 4 to 8 weeks) will establish
the frequency of future phlebotomies. Supplemental iron therapy
should not be given as iron depletion may impose a constrain to
The use of low-dose ASA is considered the second mainstay for
patients with PV. This statement is based on the ECLAP double
blind placebo controlled randomised clinical trial, in which a
benefit of 100 mg ASA in reducing major thrombosis in PV was
demonstrated.37 In this trial, after a follow-up of about 3 years,
there was a statistically significant 59% reduction of major thrombosis (both arterial and venous) without a significant increase in
hemorrhagic complications in the ASA group.
Contrary to PV, there are many uncertainties to indicate ASA as
primary prophylaxis in low-risk ET. A recent publication questions
the benefit of low-dose ASA in this group of patients.38 These
investigators concluded that antiplatelet therapy may be associated with a reduction of the incidence of venous thrombosis in
JAK2-positive patients and that ASA may decrease the frequency
of arterial thrombotic events in patients with associated cardiovascular risk factors. In the remaining low-risk patients (JAK2
negative and no risk factors), the net benefit of ASA in terms of
reduction of thrombosis associated with no increase in bleeding
was not favorable. Interestingly, the bleeding risk of ASA has
been reported significantly higher in thrombocythemic patients
presenting with a bone marrow morphology of early PMF (12% of
bleeders) as opposed to those with bone marrow pictures typical
of true ET (6% of bleeders). In this series of more than 1000 strictly
the WHO-defined patients, the crucial role of leukocytosis, in
addition to thrombocytosis, has been demonstrated by correcting
with meaningful confounders.39
In my daily routine I prescribe low-dose ASA (75 -- 100 mg) in
low-risk patients with erythromelalgia and limit the long-term use
of this drug in young ET asymptomatic cases in which serious
hemorrhagic problems can occur at any age including children.26
Thus, I carefully assess the individual thrombotic and hemorrhagic risk by looking in particular, at previous conditions with a
high bleeding risk (that is, gastric ulcers or esophageal varices
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Myeloproliferative neoplasm vs children and young adults
T Barbui
secondary to splanchnic vein thrombosis and portal hypertension),
and in patients with extreme thrombocytosis I require that
ristocetin cofactor activity should be 430%. In asymptomatic
ET and PV young patients a safer alternative is an aggressive
management of modifiable thrombotic risk factors, such as
diabetes, hypertension, obesity and metabolic syndrome, and in
particular, patients should be requested to stop smoking. In line
with other clinicians, in otherwise low-risk patients carrying
well-controlled cardiovascular risk factors, I do not use cytotoreductive drugs.40
More recently, JAK2 mutation and leukocytosis have been
recognized as independent predictors of major thrombosis,
particularly in low-risk ET patients.41 However, these novel
biomarkers might be incorporated in the risk classification,
possibly allowing better definition of the low-risk group, once
they have been eventually validated in prospective studies.
Although it is generally recognized that young age identifies
patients at lower thrombotic risk, the actuarial rate of major
thrombosis is higher than in general population of the same age.
Therefore, a proportion of PV and ET patients with age o40 years
needs to receive cytoreductive drugs. Limited information is
available regarding results of therapy that varies enormously. In
the reported series of young adults with PV and ET, the most used
drugs were ASA, phlebotomy, HU, IFN-a, and also alkylating
agents as pipobroman, busulfan, melphalan. In one study the
standardized mortality ratio in 70 PV patients younger than 50
years was 5.3%, indicating a life expectancy markedly lower than
the control population.42 Causes of death in this study were
mainly owing to an excess of hematological transformation in
AML or post-PV myelofibrosis. These latter events occurred after 9
years of follow-up and were likely due to long-term exposure of
cytotoxic drugs that were pipobroman in 73% and HU in 9%. Only
18% of this young people received phlebotomy as the sole
therapy. In contrast, in a cohort of 36 PV patients, median age of
37 years (range 19 -- 45 years), treated exclusively with phlebotomy, ASA and HU, no secondary leukemia or cancer were
observed during a follow-up of 14 years and the incidence of
thrombosis was comparable to other series.43
The largest prospective evaluation of risk factors for survival,
incidence of thrombosis and hematological transformation is the
ECLAP observational cohort study.44 Patients younger than 65
years in the ECLAP Study had the lowest rate of thrombosis
(2.5% patients per year), while with age older than 65 years and
a positive history of thrombosis, the corresponding rate ranged
from 6 to 10% patients per year. Of note were a consistent
association between age 465 years and risk of leukemia and
between duration of disease with risk of overt myelofibrosis.
In ET patients younger than 40 years, thrombosis varies from 10
to 16% at 10 years and the development of leukemia or overt
myelofibrosis is rarely reported.45,46
Antithrombotic drugs and the use of cytoreductive therapy to
control the myeloproliferative process are the mainstay of
secondary prophylaxis.
Concerning prophylaxis with antithrombotic drugs, I suggest to
define whether the thrombotic event has been provoked by some
triggers or has occurred without demonstrable possible causes.
In patients with unprovoked vein thrombosis including splanchnic
vein thrombosis and Budd-Chiari syndrome, I prescribe long-term
use of oral anticoagulants. This is supported by a large series of
patients showing a 68% risk reduction of recurrent thrombosis.47
In contrast, in provoked leg vein thrombosis, warfarin prophylaxis,
along with cytoreductive drugs, may last 1 year. Antiplatelet
agents given as maintenance showed to lead to a 58% risk
reduction of recurrence.47 In patients with coronary syndromes or
any other peripheral arterial thrombotic event, ASA alone or in
& 2012 Macmillan Publishers Limited
combination with clopidogrel antiplatelet drugs are used according to current guideline.
In regard to cytoreductive drugs, HU is my п¬Ѓrst choice when a
young patient with PV or ET has experienced a life-threatening
major thrombotic event (stroke, myocardial infarction, peripheral
arterial thrombosis, deep-vein thrombosis, including cerebral
thrombosis and Budd-Chiari syndrome). The latter applies also
to patients with poor tolerance to, or high need for phlebotomy,
symptomatic or progressive splenomegaly and severe disease
related symptoms, platelet counts greater than 1.5 Г‚ 109/l or
progressive leukocytosis. The starting dose of HU is 15 -- 20 mg/kg/
day until response is obtained. To keep the response, a
maintenance dose is administered without reducing white blood
cell count values below 2500 Г‚ 109/l and supplemental phlebotomy
should be performed if needed in PV patients. My practice is to
control the complete hemogram in every 2 weeks during the
п¬Ѓrst 2 months, then every month, and, in steady state responding
patients, every 3 months. It is unclear if ELN criteria for response
are valuable in daily routine of these patients. In a recent paper
the rate of thrombosis was reported to be significantly reduced by
HU, independently on the achievement of complete or partial
response.48 Some patients may be reluctant to use HU because of
fear regarding its possible leukemogenicity, but they should be
informed that to date, no robust data supporting such hypothesis
in either ET or PV is available. In a nationwide cohort of 11 039
MPN patients, a nested case -- control study including 162 AML
patients and 242 matched controls showed that the risk of AML
was similar to that of controls and not significantly increased by
HU given as sole therapy.49 Remarkably, 25% of patients who
developed leukemia were never exposed to cytotoxic therapy
supporting the notion of a major role for intrinsic MPN-related
factors in overall leukemogenesis. However, in a recent long-term
analysis of a randomized clinical trial comparing HU with
pipobroman in 292 PV patients (median follow-up 16.3 years),
median survival was 20.3 years in the HU arm and 15.4% in
pipobroman arm. Cumulative incidence of AML/MDS at 10, 15 and
20 years was 6.6%, 16.5% and 24% in the HU and 13%, 34% and
52% in the pipobroman arm, respectively, (P Вј 0.004).50 Importantly,
HU-associated leukemia could be a relatively frequent event when
given before or after alkylating agents or radiophosphorus.51
Major side effects of HU include neutropenia, macrocytic anemia
and muco-cutaneuos toxicity, most frequently presenting as oral
and leg ulcers and skin lesions. In a recent survey the rate of these
events was less than 5%.52
As suggested by the ELN, an alternative option as п¬Ѓrst line
therapy in high-risk PV and ET is IFN-a.18 This drug is known to be
non-leukemogenic, but it is associated with side effects leading to
withdrawn in about 20% of patients. Pegylated forms of IFN-a
allow weekly administration, potentially improving compliance
and possibly providing more effective therapy. In PV complete
responses according to ELN criteria both in PV and ET were
reached in a great proportion of cases and no thrombohemorrhagic complications were registered during follow-up.
Interestingly, the malignant clone tested in PV, as quantitated
by the percentage of the mutated JAK2V617F, was reduced.53,54
However, whether this drug is more efficacious than HU in
reducing the rate of thrombosis remains to be demonstrated. The
evidence to indicate IFN-a as the drug of choice in any ET and PV
patient younger than 60 years and in hypercellular/early PMF55 is
not yet supported by clinical trials. There is great expectation from
an ongoing clinical trial that compares head to head HU (standard
treatment) and IFN-a (experimental drug). My current practice is to
prescribe IFN-a in very selected young patients resistant or
intolerant to HU56 and in special situations such as pregnancy.
In regard to anagrelide, the UK-PT1 Study has compared the
drug with HU.57 Patients in the anagrelide arm showed an
increased rate of arterial thrombosis, major bleeding and
myelofibrotic transformation, but a decreased incidence of venous
Leukemia (2012) 1452 - 1457
Myeloproliferative neoplasm vs children and young adults
T Barbui
Table 2.
PMF or post-PV/ET myelofibrosis in young patients
Risk stratification:
In low risk and intermediate I, I suggest palliative therapy
to correct cytopenias, symptomatic splenomegaly and
constitutional symptoms.
In intermediate II or high risk, as well as in those with either
red blood cell transfusion need or unfavorable cytogenetic
abnormalities, I indicate allogeneic stem-cell bone marrow
The efficacy of novel JAK2 inhibitors seems promising,63,64 so that
I encourage PMF and PV/ET patients with symptomatic refractory
splenomegaly and severe constitutional symptoms to participate
in clinical trials. However, I underscore that there is no evidence
that these novel drugs can eradicate or modify the natural history
of disease. I believe that widespread use of JAK inhibitors in PV or
ET should be limited to selected cases as safety of their long-term
use remains uncertain.
Abbreviations: ET, essential thrombocythemia; PMF, primary myelofibrosis;
PV, polycythemia vera.
The author declares no conflict of interest.
thrombosis compared with HU. In addition, anagrelide was more
poorly tolerated than HU and presented significantly greater
rates of cardiovascular, gastrointestinal, neurological and constitutional side effects. Transformation to AML was comparable
between the two arms (four patients in the anagrelide versus six in
the HU arm), although the small number of transformations and
short follow-up prevent any valid conclusions about leukemogenicity. Anagrelide appears to provide partial protection from
thrombosis, particularly in JAK2 V617F-negative ET patients, and
may therefore be suitable as second line therapy for patients in
whom HU is inadequate or not tolerated, according with the
criteria described above.
Therapy with anagrelide, but not with HU, was also associated
with progressive anemia and an increase in bone marrow
п¬Ѓbrosis.58 Therefore, follow-up trephine biopsies are recommended for patients receiving this agent, perhaps every 2 -- 3
years. However, it should be noted that the diagnosis of ET in the
UK-PT1 trial was made according to the PV Study Group
classification59 and it remains questionable if the UK-PT1 study
results can be applied to ET patients diagnosed according to the
WHO-classification.60 In this connection, useful information is
expected from the Anahydret Trial.61
My п¬Ѓrst decision when considering treatment of a young patient
with PMF or post-PV or post ET-myelofibrosis, is whether he/she
qualifies for bone marrow allotransplantation, which can be
potentially curative (Table 2). I select patients according to the
International Prognostic Scoring System score and indicate the
procedure in cases with intermediate 2 (median survival 48
months) or high risk (median survival 27 months) as well as those
with either need for red blood cell transfusion (median survival
B20 months) or unfavorable cytogenetic abnormalities (median
survival B40 months). The estimated 1 year treatment-related
mortality associated with conventional intensity conditioning
regimens averages about 30% and overall survival 50%.62 Therefore, I favor the risk-benefit ratio of allogeneic transplantation in
high-risk young patients with PMF. Given that no other therapy
has been proved to render a survival advantage, the remaining
patients must be treated in palliative manner or in experimental
clinical trials. In anemic patients, treatment with red blood cell
transfusions is the mainstay of palliative treatment. Corticosteroids, androgens, EPO and immunomodulators might be considered and in cases of del(5q), lenalidomide is preferred.2 Long-term
periodic transfusions can be complicated by hemosiderosis and
may require the use of chelating agents. However, according to
ELN,18 iron-chelating therapy is not indicated except in allotransplantation. Unfortunately, results of any treatment for patients
with blast phase of MPNs (median survival 6 months) are
extremely poor. In selected candidates aggressive induction
chemotherapy followed by consolidation with allogeneic stem
cell transplantation may be considered.
Leukemia (2012) 1452 - 1457
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