1. science
2. medicine
3. oncology

VOLUME
29
䡠
NUMBER
29
䡠
OCTOBER
10
2011
JOURNAL OF CLINICAL ONCOLOGY
O R I G I N A L
R E P O R T
Treatment of Polycythemia Vera With Hydroxyurea and
Pipobroman: Final Results of a Randomized Trial Initiated
in 1980
Jean-Jacques Kiladjian, Sylvie Chevret, Christine Dosquet, Christine Chomienne, and Jean-Didier Rain
Jean-Jacques Kiladjian, Sylvie Chevret,
Christine Dosquet, Christine Chomienne, and Jean-Didier Rain, Hoˆpital
Saint-Louis; and Jean-Jacques Kiladjian,
Universite´ Paris 7, Paris, France.
Submitted March 22, 2011; accepted
July 14, 2011; published online ahead
of print at www.jco.org on September
12, 2011.
The content of this article, the data
interpretation, and the decision to
submit it for publication in Journal of
Clinical Oncology was made by the
authors independently.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this
article.
Corresponding author: Jean-Jacques
Kiladjian, MD, PhD, Centre d’Investigations
Cliniques, Hoˆpital Saint-Louis, AP-HP, 1
avenue Claude Vellefaux, Paris, France
75010; e-mail: jean-jacques.kiladjian@
sls.aphp.fr.
© 2011 by American Society of Clinical
Oncology
0732-183X/11/2929-3907/$20.00
A
B
S
T
R
A
C
T
Purpose
The overall impact of hydroxyurea (HU) or pipobroman treatments on the long-term outcome of
patients with polycythemia vera (PV) has not been assessed in randomized studies. We report final
analyses from the French Polycythemia Study Group (FPSG) study, which randomly assigned HU
versus pipobroman as first-line therapy in 285 patients younger than age 65 years.
Patients and Methods
The full methodology has been described previously. FPSG results were updated with a median
follow-up of 16.3 years. Statistical analysis was performed by using competing risks on the
intention-to-treat population and according to main treatment received.
Results
Median survival was 17 years for the whole cohort, 20.3 years for the HU arm, and 15.4 years for the
pipobroman arm (P ⫽ .008) and differed significantly from that in the general population. At 10, 15, and
20 years, cumulative incidence of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) was
6.6%, 16.5%, and 24% in the HU arm and 13%, 34%, and 52% in the pipobroman arm (P ⫽ .004).
Cumulative myelofibrosis incidence at 10, 15, and 20 years according to main treatment received was
15%, 24%, and 32% with HU versus 5%, 10%, and 21% with pipobroman (P ⫽ .02).
Conclusion
Data from this unique randomized trial comparing HU with another cytoreductive drug in PV showed
that (1) survival of patients with PV treated with conventional agents differed from survival in the
general population, (2) evolution to AML/MDS is the first cause of death, (3) pipobroman is
leukemogenic and is unsuitable for first-line therapy, and (4) incidence of evolution to AML/MDS with
HU is higher than previously reported, although consideration should be given to the natural evolution
of PV.
DOI: 10.1200/JCO.2011.36.0792
J Clin Oncol 29:3907-3913. © 2011 by American Society of Clinical Oncology
INTRODUCTION
Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that typically presents at a median
age of 60 years and is characterized by the occurrence of vascular complications.1-4 Over time, PV
may undergo hematologic evolution to myelofibrosis (MF), acute myeloid leukemia (AML), and
myelodysplastic syndrome (MDS). Although the
mechanisms behind these evolutions remain unclear, there is some evidence suggesting that PV
therapy, such as radioactive phosphorus or alkylating agents, may increase the frequency of progression.5 The incidence of such evolution in untreated
patients or patients treated only with phlebotomy
appears to be low at less than 2%.1,6-8
The aim of treatment for PV is to reduce the
risk of vascular events in the short term while mini-
mizing the risk of transformation to AML and MF
in the long-term.2 According to the recently published European LeukemiaNet (ELN) guidelines,
hydroxyurea (HU) and interferon alfa (IFN-␣) are
recommended as first-line treatment in high-risk
patients with PV.9 HU displays a good efficacy and
tolerability profile and is associated with significant
reductions in thrombotic complications.10-12 It has
been suggested that long-term HU therapy may increase the risk of leukemic evolution, with AML
incidence rates ranging from approximately 5% to
15%.10,11 However, the largest randomized trial in
PV to date, the European Collaboration on LowDose Aspirin in Polycythemia Vera (ECLAP) study,
suggested that HU therapy is not associated with an
increased risk of evolution to AML.13 It should be
noted that the prospective follow-up at time of publication was short (2.8 years), and the study design
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3907
Kiladjian et al
prevented real assessment of the total exposure time to HU. Thus, the
potential leukemic risk associated with long-term therapy with HU is
still not clearly defined. This prompted the expert panel of the ELN
to underscore that it is wise to proceed with caution when considering the use of HU in young patients or patients with cytogenetic abnormalities.9
Patients with PV may also be treated with pipobroman, a bromide derivative of piperazine. This compound has similarities to alkylating agents and mediates its effects using one of two mechanisms: by
inhibiting DNA and RNA polymerase or by reducing pyrimidine
nucleotide incorporation into DNA. Early research in the United
States showed pipobroman to be an effective agent in the treatment of
PV,14 and it is extensively used in Europe, particularly in France
and Italy.15,16
Survival rates in PV have increased dramatically since the
introduction of cytoreductive treatments1; however, the underlying association with disease progression means that long-term
comparison of compounds is essential for making informed clinical treatment decisions. The French Polycythemia Study Group
(FPSG), recently reconstituted as the French Intergroup of Myeloproliferative Neoplasms (FIM), conducted a randomized clinical study comparing HU and pipobroman in 292 patients with PV
younger than age 65 years. They reported no difference between
HU and pipobroman in terms of survival, risk of thrombosis, or
evolution to AML, MDS, or MF at the time of first analysis, and
median follow-up was 7 years.17
This article provides updated long-term data from the FPSG/
FIM study after a median follow-up of 16.3 years in patients with PV
treated with either HU or pipobroman.
PATIENTS AND METHODS
The full methodology for the FPSG study, including details of ethics
committee approval and the informed consent process, was published
previously.17 Patients younger than age 65 years received either HU 25
mg/kg/d followed by low-dose HU maintenance of 10 to 15 mg/kg/d or
pipobroman 1.25 mg/kg/d followed by low-dose pipobroman maintenance of 0.4 to 0.7 mg/kg/d. Here we report the updated results of the FPSG
trial at the reference date of April 15, 2008, with a median follow-up of
16.3 years.
To allow treatment crossovers to be taken into account, statistical analyses were performed both in the intention-to-treat (ITT) patient
population and according to the main treatment received. Estimated survival curves generated via the Kaplan-Meier method were compared by
using the log-rank test. Cumulative incidences of AML/MDS were estimated in a competing risks setting in which death precluded the occurrence of the specific event of interest and were then compared by using the
Gray test.
The expected annual mortality rates for each patient were based on
French life tables according to the patient’s sex and age during that calendar
year. The expected number of deaths for patients were calculated as the sum of
the expected rates during their survival times. The standardized mortality rate
(SMR; the ratio of the observed number of deaths to the expected number) was
computed for each group of interest. Confidence intervals for the SMRs
were computed.
All statistical tests were two-sided, with P values of ⱕ .05 denoting
statistical significance. SAS v9.2 (SAS Institute, Cary, NC) and R v2.10.1
software packages (R Foundation for Statistical Computing, Vienna, Austria)
were used for statistical analysis.
3908
© 2011 by American Society of Clinical Oncology
Patients with
polycythemia vera
(n = 285)
Random
assignment
Pipobroman
(n = 149)
Hydroxyurea
(n = 136)
Follow-up
Hydroxyurea
only
(n = 94)
Switch to
pipobroman
(n = 42)
Pipobroman
only
(n = 130)
Switch to
hydroxyurea
(n = 19)
Fig 1. CONSORT diagram.
RESULTS
Patient Characteristics
The ITT population consisted of 285 patients randomly assigned
to 136 (48%) in the HU treatment arm and 149 (52%) in the pipobroman treatment arm. At follow-up, 94 patients (33%) had received
only HU and 130 (46%) only pipobroman. Sixty-one patients (21%)
had received both drugs, including 42 patients who had switched from
HU to pipobroman and 19 patients who had switched from pipobroman to HU during the complete follow-up period. Seven patients
were excluded from the final analysis because of incomplete follow-up
data (Fig 1). The median age at study enrollment was 55 years (range,
19 to 80 years) and 125 patients (54%) were male. Of note, 27 patients
older than age 65 years were enrolled onto the trial (protocol deviations) and were randomly allocated to either HU (n ⫽ 16) or pipobroman (n ⫽ 11). Because of the ITT principle, these patients were
analyzed in the arm they were randomly assigned to. Importantly, this
older subgroup of patients did not affect the overall outcome, and no
evidence of treatment by age interaction was found (Gail and Simon
heterogeneity test P ⫽ .17). Complete baseline characteristics of patients were previously reported in the interim analysis of this study17
(original data available in Appendix Table A1, online only). There was
no significant difference between patients randomly assigned to the
HU and pipobroman treatment arms in terms of clinical and hematologic characteristics or cardiovascular risk factors.
Primary End Point
Median overall survival (OS) in the total patient cohort was 17
years (95% CI, 15.4 to 19.4 years; Table 1; Fig 2A). Compared with the
age- and sex-matched general French population, the mortality rates
were increased significantly with an SMR of 1.84 (95% CI, 1.50
to 2.23).
Moreover, median OS significantly differed according to the arm
of treatment received. In the ITT population, patients in the HU
treatment arm had a median OS of 20.3 years (95% CI, 16.4 to 25.0
years) compared with 15.4 years (95% CI, 13.4 to 17.0 years) in the
pipobroman treatment arm (P ⫽ .008; Fig 2B). A similar difference in
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Long-Term Follow-Up From the FPSG Trial
Table 1. Summary of Outcome Hematologic Events in ITT and Main Treatment Received Analyses
Outcome
Median overall survival, years
Cumulative incidence of
AML/MDS
Analysis
ITT
ITT
Main treatment
Cumulative incidence of MF
Follow-Up
(years)
ITT
Main treatment
10
15
20
10
15
20
10
15
20
10
15
20
Hydroxyurea Arm
Pipobroman Arm
Total Cohort
%
95% CI
%
95% CI
P
%
95% CI
20.3
16.4 to 25.0
15.4
13.4 to 17.0
.008
17
15.4 to 19.4
.004
9.8
23.6
33.9
—
6.6
16.5
24.2
7.5
14.3
21.9
12.6
19.4
26.9
15.4
24.3
31.6
13.1
34.1
52.1
12.2
37.5
55.9
7.8
15.7
26.9
5.1
9.8
21.3
.008
.07
.02
10.2
17.7
26.1
—
Abbreviations: AML, acute myeloid leukemia; ITT, intention to treat; MDS, myelodysplastic syndrome; MF, myelofibrosis.
median OS was found between the two arms when follow-up data
were analyzed according to the main treatment received (P ⫽ .026;
Fig 2C).
Since 21% of patients received both drugs during follow-up, we
also analyzed the influence of switching with a time-dependent covariate introduced into a Cox model. In patients randomly allocated to
HU treatment, switching to pipobroman during follow-up significantly increased the risk of death (hazard ratio, 2.06; 95% CI, 1.09 to
3.87; P ⫽ .026) following the switch compared with patients who
remained on HU. In patients randomly assigned to pipobroman therapy, switching to HU during follow-up did not modify the risk of
death (hazard ratio, 1.37; 95% CI, 0.61 to 3.08; P ⫽ .45).
At the time of evaluation, 95 patients (33%) had died, with the
three main causes of death attributed to evolution to AML/MDS in 51
patients (54%), vascular events in 14 patients (15%), and solid tumor
development in 11 patients (12%). Of the 51 patients who developed
AML/MDS, 10 patients developed MDS, including three that displayed MF at transformation. Forty-one patients developed AML,
including five patients for whom AML was preceded by an
MDS phase.
Evolution to AML/MDS and MF
The cumulative incidence of AML/MDS for the total cohort of
patients was 9.8%, 23.6%, and 33.9% at 10, 15, and 20 years, respectively (Table 1). Within the ITT population, the cumulative incidence
of AML/MDS in the HU treatment arm was 6.6%, 16.5%, and 24.2%
at 10, 15, and 20 years, respectively. The corresponding values in the
pipobroman treatment arm were 13.1%, 34.1%, and 52.1%, respectively (P ⫽ .004; Fig 3A).
Patients receiving HU treatment had a significantly longer median duration of treatment (12 years) than those receiving pipobroman treatment (9.5 years; P ⬍ .001; Fig 4). This may be attributed to a
shortage in pipobroman delivery in France between 1983 and 1984.
Therefore, analyses were also performed according to the main treatment actually received by patients. These analyses demonstrated a
cumulative incidence of AML/MDS transformation of 7.5%, 14.3%,
and 21.9% with HU and 12.2%, 37.5%, and 55.9% with pipobroman
www.jco.org
at 10, 15, and 20 years, respectively (P ⫽ .008; Fig 3B). These findings
confirmed the results obtained in the ITT analyses. Results from
patients who received only one treatment during the entire follow-up
period (HU alone in 94 patients or pipobroman alone in 130 patients)
showed a cumulative incidence of AML/MDS transformation at 10,
15, and 20 years of 7.3%, 10.7%, and 16.6%, respectively in the HU
treatment arm compared with 14.6%, 34%, and 49.4%, respectively,
in the pipobroman treatment arm (P ⫽ .002; Fig 3C). In the ITT
population analysis, the cumulative incidence of MF at 10, 15, and 20
years for patients in the HU treatment arm was 12.6%, 19.4%, and
26.9%, respectively. This was comparable to the pipobroman arm at
7.8%, 15.7%, and 27%, respectively (P ⫽ .07; Fig 5A). However,
analysis according to main treatment received showed a significantly
higher incidence of MF in patients who had received HU. The
incidence rate for patients treated with HU at 10, 15, and 20 years
was 15.4%, 24.3%, and 31.6% compared with 5.1%, 9.8%, and
21.3%, respectively, in patients whose main treatment was pipobroman (P ⫽ .02; Fig 5B).
Vascular Events
A total of 85 patients experienced vascular complications, including thrombosis (n ⫽ 80) and hemorrhage (n ⫽ 5) or both (n ⫽ 5).
Cumulative incidence of such events according to treatment arms, in
both the ITT population and according to main treatment received,
are displayed in Figure 6. Across all conducted comparisons, no difference in vascular events was seen between the two treatment arms
(P ⫽ .61 and P ⫽ .32 in ITT and according to main treatment received
analysis, respectively), showing that both drugs were equally active
with respect to vascular event reduction.
DISCUSSION
The aim of this FPSG/FIM study was to compare HU with pipobroman as first-line treatment for patients with PV and, to the best of our
knowledge, this is the only randomized trial to compare HU with
another cytoreductive drug in this setting after more than 16 years of
© 2011 by American Society of Clinical Oncology
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3909
Kiladjian et al
1.0
A
Observed
Expected
Cumulative Incidence
of AML/MDS (probability)
Overall Survival (probability)
A
0.8
0.6
0.4
0.2
0
5
10
15
20
25
30
35
1.0
Hydroxyurea
Pipobroman
0.8
P = .004
0.6
0.4
0.2
0
5
10
15
Time (years)
1.0
B
Hydroxyurea
Pipobroman
0.8
Cumulative Incidence
of AML/MDS (probability)
Overall Survival (probability)
B
P = .008
0.6
0.4
0.2
0
5
10
15
20
25
30
35
P = .026
0.6
0.4
0.2
0
5
10
15
20
25
30
35
Time (years)
Fig 2. Median overall survival (A) in the total patient cohort and compared with
a general French population, (B) in the intention-to-treat population receiving
hydroxyurea or pipobroman, and (C) according to main treatment received,
hydroxyurea or pipobroman.
follow-up. Previous data concerning the impact of HU therapy on PV
outcome consist of a small number of prospective trials, including the
nonrandomized Polycythemia Vera Study Group PVSG-08 study18
and the large ECLAP study, the primary objective of the latter being to
assess the role of aspirin in reducing thrombotic complications.19
Furthermore, the FPSG/FIM trial is the first to provide data over a
median follow-up of more than 12 years, thus allowing effective assessment of life expectancy and outcomes for the long term in newly
diagnosed patients with PV. When analyzed and published in 1997,
the study17showed that after a median follow-up of less than 10 years,
no difference in OS, vascular events, or transformation to AML/MDS
was observed between the two treatment arms. In the final analysis,
longer follow-up demonstrated important differences in results re3910
© 2011 by American Society of Clinical Oncology
35
P = .008
0.6
0.4
0.2
5
10
15
20
25
30
35
Time (years)
C
Hydroxyurea
Pipobroman
0.8
30
Hydroxyurea
Pipobroman
0.8
0
Cumulative incidence
of AML/MDS (probability)
Overall Survival (probability)
1.0
25
1.0
Time (years)
C
20
Time (years)
1.0
Hydroxyurea alone
Pipobroman alone
0.8
P = .002
0.6
0.4
0.2
0
5
10
15
20
25
30
Time (years)
Fig 3. Transformation to acute myeloid leukemia/myelodysplastic syndrome
(AML/MDS). Cumulative incidence of AML/MDS according to (A) the intentionto-treat population receiving hydroxyurea or pipobroman, (B) the main treatment received (hydroxyurea or pipobroman), and (C) patients who received
only one treatment.
garding the long-term outcome of patients with PV as well as the
impact of HU and pipobroman therapies (summarized in Table 1).
The median OS of the entire cohort was 17 years. Overall, we
found that life expectancy of patients with PV was significantly altered
compared with that of the age- and sex-matched general population,
with an SMR of 1.84. Similar results have been previously reported in
retrospective studies.20 Furthermore, in the ITT population analysis,
the median OS was significantly longer in patients treated with HU
(20.3 years) compared with those who received pipobroman
(15.4 years).
Of note, the main cause of death in patients with PV who were
younger than 65 years of age at diagnosis was evolution to AML/MDS
(54%), with vascular events responsible for cause of death in 15% of
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Long-Term Follow-Up From the FPSG Trial
0.8
A
Hydroxyurea stopped
Pipobroman stopped
Death prior to hydroxyurea discontinuation
Death prior to pipobroman discontinuation
P = .002
0.6
0.4
0.2
0
5
10
15
20
25
30
Cumulative Incidence of
VE/Hemorrhages (probability)
Cumulative Incidence
(probability)
1.0
1.0
Hydroxyurea arm
Pipobroman arm
0.8
0.6
0.4
0.2
0
5
10
Time (years)
patients. These results are similar to those reported in a phase II study
of pipobroman involving 164 patients with PV21 in whom evolution
to AML/MDS was responsible for 29% of deaths in the entire patient
cohort and 51% of deaths in patients younger than age 60 years at time
of inclusion. The combined results of these two long-term, prospective trials indicate that in younger patients with accurately managed
PV and minimized vascular risk, evolution to AML/MDS is the most
important long-term concern.
Importantly, compared with the first analysis,17 the number of
transformations to AML/MDS increased from 13 to 51, establishing a
cumulative incidence of AML/MDS of 23.6% at 15 years. This is
Cumulative Incidence
(probability)
1.0
0.8
Myelofibrosis, hydroxyurea treatment
Myelofibrosis, pipobroman treatment
Death prior to myelofibrosis, hydroxyurea treatment
Death prior to myelofibrosis, pipobroman treatment
P = .07
0.6
0.4
0.2
0
5
10
15
20
25
30
35
Time (years)
Cumulative Incidence
(probability)
B
1.0
0.8
Myelofibrosis, hydroxyurea treatment
Myelofibrosis, pipobroman treatment
Death prior to myelofibrosis, hydroxyurea treatment
Death prior to myelofibrosis, pipobroman treatment
P = .02
0.6
0.4
0.2
0
5
10
15
20
25
30
35
Time (years)
Fig 5. Cumulative incidence of myelofibrosis (A) according to treatment
randomization and (B) according to main treatment received (hydroxyurea
or pipobroman).
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Cumulative Incidence of
VE/Hemorrhages (probability)
B
Fig 4. Treatment duration after random assignment.
A
15
20
25
30
35
Time (years)
1.0
Hydroxyurea arm
Pipobroman arm
0.8
0.6
0.4
0.2
0
5
10
15
20
25
30
35
Time (years)
Fig 6. Cumulative incidence of vascular events (VEs) according to treatment
arm: (A) intention-to-treat population; (B) per protocol analysis.
clearly higher than previously reported incidence rates, which have
been reported to range from approximately 5% to 16%.10,11 In addition, a significant difference in favor of HU arose. The higher incidence of leukemic evolution in patients treated with pipobroman,
along with the shorter median OS, clearly indicates that this drug
should no longer be used as first-line therapy but may be reserved for
use as second-line treatment in patients with a short life expectancy. Of
note, this increased risk observed with pipobroman was not dependent on treatment duration (Grambsch and Therneau proportional
hazard test P ⫽ .75), suggesting that its indication should not be based
solely on the age of the patient. These findings are particularly important in countries such as France and Italy where pipobroman is still
used as first-line treatment for PV.
The data presented here provide further evidence for the debate
on the leukemogenicity of HU. Evolution to AML is part of the natural
history of PV, but data on the impact of HU on this evolution are not
established. Early comparisons of HU and phlebotomy showed no
significant difference between incidences of leukemic transformation.18 Indeed, such evolution has been reported in untreated patients
and in those treated with phlebotomies only.1,7 On the basis of the
available evidence, the main short-term risk associated with PV is
assumed to be the occurrence of vascular events. Therefore, management has been based on cytoreduction aimed at increasing the patient’s life expectancy by lowering the risk of fatal thrombosis. In this
study, we confirm that HU and pipobroman are both equally active in
efficiently reducing the risk of thrombosis in PV.
However, PV is a chronic disorder requiring ongoing treatment,
and little is known from prospective studies about the risk of AML in
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3911
Kiladjian et al
patients receiving HU over the long term. To date, evidence suggests
that HU may have an impact on cytogenetic abnormalities and biologic features of PV and may slightly enhance the risk of transformation to leukemia.6 Follow-up data from PVSG-08 have allowed the
long-term leukemogenic potential of HU in PV to be assessed.7 As
previously mentioned, early data (378 weeks of treatment) from the
same study18 suggested that HU was not associated with an increased
risk of leukemic conversion. However, at a median follow-up of 8.6
years (maximum, 795 weeks), 5.9% of patients receiving HU developed AML compared with 1.5% receiving phlebotomies.7 The increased cumulative incidence of AML/MDS seen with HU in this
study may be due to patients living longer as a result of more effective
therapeutic options. A longer survival period potentially provides a
greater time frame for leukemic evolution because patients spend
longer with PV and also receive cytotoxic treatment for a longer
period. Thus, it is currently unclear whether the observed incidence of
AML/MDS should be attributed to the natural long-term evolution of
PV, which is unaffected by palliative HU therapy, or cumulative HU
therapy per se. More information on prospective long-term follow-up
is still required to help establish any clear patterns between HU treatment and AML incidence. Studies started more than 10 years ago are
expected to show interesting data, but follow-up across a time frame
similar to the one in this study has not yet been reported.
It has been shown that treatment with more than one agent in
succession adversely affects the outcome of patients.13 In this study, we
found that a switch from HU to pipobroman was clearly associated
with an increased risk of death. However, this result should be interpreted cautiously, because the need for changing therapy may simply
reflect a more aggressive disease.
Hematologic evolution to MF was found to be higher in patients
treated predominantly with HU (32% at 20 years) compared with
those treated with pipobroman. This is in line with results seen in the
previous analysis.17 Silverstein et al22 previously reported that patients
with PV who developed MF appeared to have a higher rate of leukemia
transformation compared with those who did not. A similar trend has
been seen in essential thrombocythemia; results from a study in 231
patients suggested that prior MF was a risk factor for subsequent
leukemia transformation (P ⫽ .008).23 The number of patients in this
study who developed AML/MDS after MF was small, and there are
insufficient data to determine whether MF may be an intermediate
stage in the progression to AML in patients with PV.
In conclusion, the data from this study show that the most important long-term concern in patients with PV younger than age 65
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Therapeutic recommendations in polycythemia vera
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Guidelines for the diagnosis, investigation and
management of polycythaemia/erythrocytosis. Br J
Haematol 130:174-195, 2005
3. Michiels JJ, Berneman ZN, Schroyens W, et al:
Pathophysiology and treatment of platelet-mediated
microvascular disturbances, major thrombosis and
bleeding complications in essential thrombocythaemia and polycythaemia vera. Platelets 15:67-84,
2004
3912
© 2011 by American Society of Clinical Oncology
years should be the evolution to AML/MDS, which was the primary
cause of death in these patients. Although pipobroman clearly appears
leukemogenic even when used as a single agent, long-term follow-up
of this prospective, randomized study also found a risk of evolution to
AML with HU higher than that previously reported. However, there is
no conclusive evidence for a leukemogenic risk associated with HU,
particularly given that the development of AML is part of the natural
history of PV. Nevertheless, our analysis highlights the importance of
evaluating the long-term leukemogenic risk of conventional treatments such as HU versus supposed nonleukemogenic agents such as
IFN-␣.24,25 A large randomized trial is currently being performed
jointly in the United States and Europe to compare HU and IFN-␣ in
the first-line treatment of high-risk patients with PV (Myeloproliferative Disorders Research Consortium Clinical Trial 112). This trial
may provide data for resolving the question of associated leukemogenic risk of each treatment. In addition, current development of new
drugs targeting Janus kinase may provide new agents without anticipated leukemogenic potential to treat patients with PV.26
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
OF INTEREST
Although all authors completed the disclosure declaration, the following
author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a “U” are those for which no compensation was received; those
relationships marked with a “C” were compensated. For a detailed
description of the disclosure categories, or for more information about
ASCO’s conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: None Stock Ownership: None Honoraria: Jean-Jacques Kiladjian,
Novartis, Celgene, YM BioSciences, Shire, AOP Orphan Pharmaceuticals
Research Funding: None Expert Testimony: None Other
Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Jean-Didier Rain
Collection and assembly of data: Jean-Jacques Kiladjian, Sylvie Chevret,
Christine Chomienne, Jean-Didier Rain
Data analysis and interpretation: All authors
Manuscript writing: All authors
Final approval of manuscript: All authors
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Long-Term Follow-Up From the FPSG Trial
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