Can pegylated interferon improve the outcome of polycythemia vera patients?
Crisà et al. Journal of Hematology & Oncology
Can pegylated interferon improve the outcome of polycythemia vera patients?
0 Hematology Division, Università degli Studi di Torino , Via Genova 3, 10126 Turin , Italy
1 Transfusion Medicine Unit, A.O. Città della Salute e della Scienza , Turin , Italy
2 S.C. Hematology, A.O. Città della Salute e della Scienza , Turin , Italy
3 Hematology Division, Università degli Studi di Torino , Via Genova 3, 10126 Turin , Italy
4 Section of Pathology, Department of Molecular Biotechnology and Health Sciences, University of Torino , Turin , Italy
Pegylated interferon (peg-IFN) was proven by phase II trials to be effective in polycythemia vera (PV); however, it is not clear whether it could improve patient outcome compared to hydroxyurea (HU). Here, we present an observational study on 65 PV patients aged 65 years or younger, who received either peg-IFN (30) or HU (35) according to the physician choice. Median follow-up was 75 months. The two cohorts were comparable for patient and disease characteristics. Eighty-seven percent of the patients treated with peg-INF responded, with a CR rate of 70% as compared to 100 and 49% with HU, respectively. Discontinuation rate was similar in the two groups (20% in peg-IFN vs 17% in HU). JAK2 allele burden was monitored in peg-INF arm only, and a reduction was observed in 88% of the patients. No thrombotic events were observed during peg-IFN treatment compared to three on HU. Disease progression to myelofibrosis or acute myeloid leukemia occurred to a patient only in peg-INF, compared to three in HU. Overall, three second malignancies were observed during the study, two in patients who received HU only, and one in a patient largely treated HU who received also peg-IFN for 3 months. Overall survival was significantly better for peg-IFN patients compared to HU, p = 0.027. Our study, albeit limited by small patient and event number and lack of randomization, confirms the efficacy of peg-INF in PV and shows a significant survival advantage for peg-INF-treated patients. Waiting for confirming data from the ongoing phase III trials, our study can support peg-INF as a first-line treatment option for PV, at least for younger patients.
Pegylated interferon; Polycythemia vera; JAK2 allele burden; Hydroxyurea
PV . However, the studies published so far did not
address the question of whether peg-INF could reduce
disease progression rate and eventually improve
longterm survival compared to hydroxyurea (HU), the actual
gold standard treatment in PV . Here, we report our
observational study comparing peg-INF with HU in a
population of PV patients below 65 years.
Since 2010, peg-INF becomes available off-label in our
Institution. Patients diagnosed with PV according to
WHO 2008 classification, aged 65 years or younger, with
normal cardiac, renal, and liver function, and without
history of autoimmune disease were eligible for this
study. According to the physician choice, newly
diagnosed patients requiring cytoreductive treatment could
receive either peg-INFalpha-2a (Pegasys, Roche) or HU
and patients previously treated with HU could be
switched to peg-INF regardless of the response achieved.
Data were prospectively collected in the Registry of
Myeloproliferative Neoplasms of our Institution and the
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Age at diagnosis (years)
Age at treatment start
Time from diagnosis
to study entry (months)
Cardiovascular risk factors
Table 1 Patients characteristics
criteria . Treatment with peg-INF was started
subcutaneously at 90 μg weekly and increased to 135 μg
weekly if tolerated. The dose was decreased in case of
intolerance or cytopenia. HU dose could range from 500
up to 2000 mg orally per day and was modulated
according to hematological response.
Two different populations were compared: patients
who received peg-IFN vs the control group receiving
HU only. Patients’ characteristics were compared using
Fisher’s exact test for the categorical variables and the
Kruskal-Wallis test for the continuous ones. Overall
survival was estimated from the study start until death or
last follow-up by Kaplan-Meier method; any statistical
difference between curves was assessed by log-rank test.
Sixty-five patients were included, with a median
follow-up of 75 months (range 14–80 months). Thirty
patients were treated with peg-INF and 35 with HU
only. The two cohorts were comparable for gender, age
at diagnosis, age at treatment start, time from diagnosis
to study entry, previous thrombotic events and
cardiovascular risk factors (see Table 1). In the peg-INF group,
19 patients (63%) had previously received HU for a
median time of 50 months (range 2–120 months) and were
in hematological response. There was not any significant
difference in terms of age, gender, and disease
characteristics between patients treated front line with peg-INF
and those who previously received HU.
study received Ethic Committee approval. All patients
signed an informed consent in accordance with the
Declaration of Helsinki. JAK2 quantitative level was
monitored every 6 months in the peg-IFN arm only. CR was
defined according to European LeukemiaNet 2009
Fig. 1 Overall survival from study start by intention to treat principle. peg-INF group (continuous line) vs HU group (dashed line)
Globally, 87% of the patients treated with peg-INF
responded (26/30), with a CR rate of 70% (21/30). Median
time to CR was 6 months and median peg-INF dose at CR
was 90 μg weekly. The four patients who did not respond
had to early discontinue treatment due to intolerance.
Most patients (87%) experienced some adverse events:
hematologic toxicity (43%, grade 3–4 7%), flu-like
symptoms (30%), and liver test elevation (23%, grade 3–4 7%).
Overall discontinuation rate was 20%. JAK2 allele burden
reduction was observed in 88% of the patients (21/24
evaluable ones). Median JAK2 allele burden at diagnosis
was 40.5% (range 1.5–91%), and it decreased to 17%
(range 0.3–81%) and 15.8% (range 0–77%) at 12 and
24 months after treatment start, respectively.
All patients in the HU group responded, with a CR
rate of 49%, and discontinuation rate was 17%. In the
peg-INF group, only one patient, who already had grade
1 bone marrow fibrosis, progressed to overt post-PV MF
compared to three in the HU group, of whom two
subsequently transformed to AML. Three second
malignancies were observed overall, two in the HU group, and
one in a patient treated with HU for 48 months and with
peg-INF for 3 months only. No thrombotic events were
observed during peg-IFN treatment compared to three on
HU. The landmark analysis from study start showed a
significantly better survival for peg-IFN patients, p = 0.027
(Fig. 1), with no death observed compared to three in the
HU group. No other variables such as sex, age,
cardiovascular risk factors, and previous thrombosis had a
significant impact on survival.
HU is widely considered the first-line cytoreductive
therapy for PV . As a matter of fact, data supporting
peg-INF use come from phase II studies only, while
phase III trials comparing peg-INF to HU are ongoing.
However, these data will be completely available only in
several years. Therefore, some experts are now considering
the possibility of using peg-INF front-line in younger PV
patients given its ability to reduce JAK2 allele burden,
which could impact on the natural history of the disease
and its long-term safety . Our experience confirms the
efficacy and tolerability of peg-INF, with few grade 3 or 4
adverse events and a discontinuation rate comparable to
that of HU. Moreover, no thrombosis was observed during
peg-INF treatment, suggesting the non-inferiority of this
drug to HU in preventing thrombotic events even in
patients at high thrombotic risk. Furthermore, we
observed no AML progression, and one case only of
evolution to MF in the peg-INF group, together with a
reduction in JAK2 allele burden in the majority of patients.
While alkylating agents have been shown to increase
AML progression risk, HU has never been proven to be
leukemogenic . However, concerns about long-term
exposure to this drug in young patients do exist .
Besides, a recent report showed an increased incidence
of second malignancies in patients treated with HU
compared to INF .
Our study, which has a substantial follow-up duration
but which is limited by small patient and event number
and lack of randomization, shows a significant survival
advantage for peg-INF-treated patients, a data that could
be explained by the absence of thrombotic events, the
modest but important reduction in MF and AML
progression and, possibly, the decreased risk of second
malignancies in the peg-INF group. Indeed, our data require
confirmation, but until the ongoing phase III trials give
conclusive answers, they could support peg-INF as a
firstline treatment option for PV, at least for younger patients.
AML: Acute myeloid leukemia; CR: Complete response; HU: Hydroxyurea;
MF: Myelofibrosis; peg-INF: Pegylated interferon; PV: Polycythemia vera
EC and MC equally contributed to the work. EC and MC followed the
patients, collected and analysed data, and wrote the paper. DF followed the
patients, designed the study and wrote the paper. EB, GL, PM, GB, and AB
followed the patients and collected data. LR performed molecular analysis.
MB supervised the research and provided funds. All the authors reviewed
the manuscript and approved it.
Ethics approval and consent to participate
All patients signed an informed consent in accordance with the Declaration of
Helsinki, and data were prospectively collected in the registry of myeloproliferative
neoplasms of our Institutions. The study was approved by the Ethic Committee of
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