CLINICAL NEWS
in a Different Vein
Research from ASH’s online peer-reviewed
journal, Blood Advances
Phlebotomy and Hydroxyurea Are Underused
in Patients With Polycythemia Vera
Treatment with phlebotomy or hy-
droxyurea was associated with lower
mortality among older patients with
polycythemia vera (PV) who were
considered at high thrombotic risk,
compared with patients who received
neither treatment, according to results
from a population-based cohort study
published in Blood Advances. Each
treatment also lowered risks of throm-
bosis but, despite these benefits, the
authors, led by Nikolai A. Podoltsev,
MD, PhD, from Yale University School
of Medicine, found that these treat-
ments were underused in the popula-
tion of older patients with PV.
“These findings suggest that
patients in our study cohort were
undertreated according to European
LeukemiaNet and National Compre-
hensive Cancer Network guidelines,”
which recommend hydroxyurea as the
first-line cytoreductive treatment in the
high-risk PV setting, the researchers
explained. “Improved dissemination
and implementation of the guide-
lines may translate to better patient
outcomes.”
To evaluate the effectiveness of
phlebotomy and hydroxyurea on a
population basis, the authors con-
ducted a retrospective study of 3,173
adults at least 65 years old who were
diagnosed with PV between 2007 and
2013, using the linked Surveillance,
Epidemiology, and End Results (SEER)
Medicare database. People who died
within 30 days of PV diagnosis were
excluded (n=12), as were those who
had noncontinuous Medicare part
D coverage (n=811), noncontinuous
Medicare part A/B coverage (n=216),
health maintenance organization insur-
ance (n=840), or a diagnosis of PV
only on a death certificate or autopsy
report (n=474). In total, 74.1 percent of
identified patients were excluded.
A total of 820 patients (median age
= 77 years; interquartile range = 71-83
years) were included in the analysis
and followed through December 31,
2014 or death – whichever occurred
first.
During the study period, 336
patients (41.1%) received both
phlebotomy and hydroxyurea, either
concurrently or sequentially, while
189 (23%) underwent phlebotomy
only, 161 (19.6%) received hydroxy-
urea only, and 134 (16.3%) received
neither.
Those who underwent phlebotomy
had a median of seven phlebotomies
(range = 3-12) from diagnosis to the
end of follow-up, with a median of
2.3 phlebotomies per year (range =
1.1-4.1).
Among people prescribed hy-
droxyurea, adherence was calculated
as the percentage of days from diag-
nosis to the end of follow-up covered
by a hydroxyurea prescription, or
proportion of days covered (PDC).
The median PDC by hydroxy-
urea was 61.6 percent (range =
35.2-80.1%). Other cytoreductive
treatments were used infrequently
but included ruxolitinib (n=17; 2%)
and interferons (n=11; 1.3%).
During a median follow-up of 2.75
years (range = 1.58-4.67 years), evolu-
tion to myelofibrosis, acute myeloid
leukemia (AML), or either myelofi-
brosis or AML occurred in 19 (2.3%),
18 (2.2%), and 36 patients (4.3%),
respectively. There was no association
between disease progression and use
of hydroxyurea or phlebotomy.
A total of 305 patients (37.2%)
died during follow-up. Overall,
median survival was longer for people
who received either treatment, alone
or in combination, than for those who
did not undergo treatment:
• phlebotomy users vs. nonusers:
6.29 years vs. 4.5 years (p<0.01)
• hydroxyurea users vs. nonusers:
6.02 years vs. 5.25 years (p<0.01)
received treatment were less likely to
experience a thrombotic event:
• phlebotomy users vs. nonusers:
142 (29.3%) vs. 154 (46.0%;
p<0.01)
• hydroxyurea users vs. nonusers:
118 (27.6%) vs.178 (45.4%;
p<0.01)
Hazard Ratio 95% CI p Value Hazard Ratio 95% CI p Value Phlebotomy 0.65 0.51-0.81 <0.01 0.52 0.42-0.66 <0.01 Hydroxyurea PDC, every 10% 0.92 0.89-0.95 <0.01 0.92 0.89-0.96 <0.01 Age 1.08 1.07-1.10 <0.01 1.01 0.99-1.02 0.55 Both phlebotomy intensity and PDC
of hydroxyurea were associated with
lower thrombotic risks. Comorbidity
burden and low-income subsidy were
the only factors associated with an
increased thrombotic risk ( TABLE 1 ).
In sensitivity analyses, there were
no significant differences between
overall survival or thrombosis
between those who received either
hydroxyurea or phlebotomy (p=0.52
and p=0.28, respectively).
This observational study was
limited by the inability to capture data
about therapies such as aspirin that
were not covered by Medicare and not
mentioned in Medicare claims. Also,
because ruxolitinib was approved by
the U.S. Food and Drug Administra-
tion as a secondline treatment for
patients with PV that is refractory to
or intolerant of hydroxyurea only in
December 2014, after the conclusion
of the study period, its use could not
be adequately evaluated in this study.
“In addition, the SEER Medicare
database did not contain information
on the results of laboratory tests, such
as hematocrit level and leukocyte
count, so we could not incorporate
these important clinical parameters
into the analysis,” the authors added.
Study results also may not be gen-
eralizable to people with previously
treated PV or younger or lower-risk
patients.
The authors report financial relation-
ships with Alexion, Pfizer, Boehringer
Ingelheim, Astellas, Daiichi Sankyo,
Sunesis, Celator, Pfizer, Astex Pharma-
ceuticals, CTI BioPharma, Celgene,
Genentech, and LAM Therapeutics.
Male sex 1.36 1.06-1.73 0.01 0.94 0.74-1.20 0.61 REFERENCE
Comorbidity score ≥2 1.46 1.10-1.94 0.01 1.37 1.01-1.86 0.05 Podoltsev NA, Zhu M, Zeidan AM, et al. The impact of
phlebotomy and hydroxyurea on survival and risk of thrombosis
among older patients with polycythemia vera. Blood Advances.
2018;2:2681-90.
TABLE 1.
The authors then performed multivari-
able Cox hazard models that accounted
for patient age at diagnosis, sex, race,
disability status, receipt of low-income
subsidy, influenza vaccination in the
12 months prior to PV diagnosis,
comorbidity burden, and history of
thrombosis.
They reported that phlebotomy
was associated with a lower risk of
death (hazard ratio [HR] = 0.65; 95%
CI 0.51-0.81; p<0.01). As phlebotomy
intensity (defined as number of phle-
botomies per year) increased, risk of
death appeared to decrease (HR=0.71;
95% CI 0.65-0.79; p<0.01).
A similar relationship also was
observed for hydroxyurea users: Every
10-percent increase of hydroxyurea
PDC was associated with a 9-percent
lower risk of death ( TABLE 1 ).
Other factors associated with a
higher mortality risk included: older
age, male sex, comorbidities, and
potential underuse of the health-care
system (measured by no receipt of flu
vaccination in the year prior to PV
diagnosis).
Thrombotic events were recorded
in 296 patients (36.1%) and, as with
the survival analysis, those who
Factors Associated With Risks of Overall Survival or Thrombosis
Overall Survival
Thrombosis
Low-income subsidy 1.23 0.94-1.60 .13 1.48 1.10-1.99 0.01
Influenza vaccination 0.78 0.62-0.99 0.04 0.99 0.78-1.26 0.96
PDC = proportion of days covered
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