Research Article

Transfusion intensity, not the cumulative red blood cell transfusion

burden, determines the prognosis of patients with myelodysplastic
syndrome on chronic transfusion support
Arturo Pereira,1* Meritxell Nomdedeu,2 Josep-Llus Aguilar,3 Mohamed Belkaid,2 Anna Carrio,4
Francesc Cobo,2 Dolors Costa,4 Mara Rozman,3 Cristina Sanz,1 and Benet Nomdedeu2
Transfusion-dependency is associated with poor prognosis in patients with MDS although the causal link
for such association is disputed. This study tests thee hypotheses on the association between transfusion
burden and prognosis in the MDS: (1) the cumulative transfusion burden is a confounder merely reecting
the time elapsed from diagnosis; (2) it is a surrogate for higher transfusion intensity, which would reect a
more severe disease; and (3) it is the total amount of transfused RBC units that inuences on prognosis.
We studied 191 transfusion-dependent patients with MDS or chronic myelomonocytic leukemia. Transfusion
intensity was calculated at the time of each transfusion as the yearly-equivalent number of RBC units. The
main outcome was acute leukemia-free survival from rst transfusion. Median transfusion burden was 30
(range: 4330) RBC units and 112 patients received 25 units after a median of 9 months from rst transfusion. In nested Cox models, having received 25 RBC units had a signicant effect on survival (P < 0.001)
that was not abrogated by including follow-up 9 months as a time-dependent covariate. Including transfusion intensity in the model had a signicant effect on leukemia-free survival (P < 0.001) and cancelled the
prognostic value of having received 25 RBC units. In conclusion, transfusion intensity, instead of the cumulative transfusion burden, is the transfusion-related variable really inuencing on the prognosis of
C 2010 Wiley-Liss, Inc.
patients with transfusion-dependent MDS. Am. J. Hematol. 86:245250, 2011. V

Introduction
The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders, mostly appearing in older people,
which are characterized by cytopenias, dysplastic hematopoiesis, and an inherent propensity to clonal evolution into
acute myeloid leukemia (AML) [1]. Most patients with MDS
have symptomatic anemia at presentation or develop it during the clinical course. Although recombinant erythropoietin
and, more recently, thalidomide and lenalidomide can ameliorate symptomatic anemia in some cases, frequent red
blood cell (RBC) transfusion remains cornerstone in the
treatment of many patients with MDS [2].
A history of heavy RBC transfusion has recently been
identied as a predictor for shorter survival, increased risk
of progression into AML, and poorer outcomes after allogeneic stem cell transplantation [36]. By extrapolating the
well known deleterious effects of transfusional hemosiderosis in patients with thalassemia major and other congenital
anemias, several authors have postulated iron overload as
the causative factor linking heavy transfusion burden to
poor outcomes in the MDS [5,79]. The association found
in several studies between high serum ferritin levels and
poor prognosis adds further weight to that purported causal
link [3,10,11], and has driven many experts to recommend
that MDS patients for whom chronic transfusion support is
likely should be started on iron chelation therapy [9,1215].
On the contrary, other authors are sceptical about that explanation and believe instead that heavy transfusion
requirements are merely a surrogate for more severe disease in patients with MDS [16,17].
Conicting hypotheses on the causal pathway between
heavy transfusion burden and prognosis in the MDS will
probably not be resolved in the short-term because of the
complexities involved in conducting the necessary clinical
studies. Meanwhile, statistical modeling of competing
hypotheses using available patient datasets can provide
some clues that may prove useful in the management of
transfusion-dependent patients with MDS.

Since in the transfusion-dependent patient the cumulative

transfusion burden can only increase over time (it cannot
decrease or uctuate), it behaves as a clock variable
somehow measuring the time elapsed from the start on
chronic transfusion support. It can, therefore, be spuriously
associated with the many things that can get worse over
time; namely, the increased accumulated risk of leukemic
transformation or of death from any other cause as the disease progresses and the patient gets older and sicker. On
the other hand, higher cumulative transfusion burden may
merely reect deeper transfusion dependency, with shorter
intervals between consecutive transfusions and/or more
RBC units needed at each transfusion episode, which otherwise would be a reection of more severe bone marrow
dysfunction. Alternatively, the cumulative transfusion burden
may be deleterious by itself, either because of progressive
iron overload or because of any other adverse effect purportedly mediated by RBC transfusion, e.g. transfusionrelated immunodepression.
The present study was aimed at testing the above
hypotheses in a large series of transfusion-dependent
patients with MDS or CMML. We relied on statistical modeling to control for confounding or mediating effects between
variables in order to identify those transfusion-related
Additional Supporting Information may be found in the online version of this
article.
Conict of interest: Nothing to report.
1
Service of Hemotherapy and Hemostasis, Hospital Clnic, Barcelona, Spain;
2
Service of Hematology, Hospital Clnic, Barcelona, Spain; 3Unit of Hemopathology, Hospital Clnic, Barcelona, Spain; 4Unit of Cytogenetics, Service of
Pathology, Hospital Clnic, Barcelona, Spain
*Correspondence to: Arturo Pereira, M.D., Service of Hemotherapy and
Hemostasis, Hospital Clnic, Villarroel 170, 08036 Barcelona, Spain. E-mail:
apereira@clinic.ub.es
Received for publication 30 November 2010; Accepted 2 December 2010
Am. J. Hematol. 86:245250, 2011.
Published online 14 December 2010 in Wiley Online Library (wileyonlinelibrary.
com).
DOI: 10.1002/ajh.21959

C 2010 Wiley-Liss, Inc.

V

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245

http://wileyonlinelibrary.com/cgi-bin/jhome/35105

research article
factors that are more probable to be causally related with
shorter survival.
Methods
Study population and measures. Clinical, hematologic, and followup data of patients with MDS seen at the Hospital Clnic of Barcelona
have prospectively been recorded in an electronic database from the
mid 1990s onwards. We queried this database and the Transfusion
Service database in order to identify transfusion-dependent MDS
patients. Transfusion-dependency was dened according to the WPSS
criteria [4] as requiring at least one RBC transfusion every 8 weeks
over a period of 4 months. Patients who were seen for second opinion
consultation or at irregular intervals and whose transfusion management was carried out at other hospitals were excluded, as were those
transfused only in the context of bone marrow transplantation or after
transformation into AML. Patients seen before 2003 had been diagnosed following the FAB criteria and were reclassied according to the
2001 WHO classication [18]. Patients with MDS unclassied or with
20% blast in the bone marrow were excluded so that the following
categories were considered: refractory anemia (RA), RA with ringed
sideroblasts (RARS), refractory cytopenia with multilineage dysplasia
(RCMD), RCMD with ringed sideroblasts (RCMD-RS), RA with excess
of blasts (RAEB-1 and -2), and MDS with isolate del(5q). For the purpose of this study we also considered patients diagnosed with chronic
myelomonocytic leukemia (CMML). The IPSS criteria were used to
derive the karyotype-based risk classication [19].
Clinical and hematologic variables analyzed for prognostic signicance included sex, age at the time of rst transfusion, WHO category
(RA, RARS, del(5q) vs. RCMD, RCMD-RS vs. RAEB-1, RAEB-2,
CMML), the karyotype-based risk group, and the IPSS. Transfusionrelated variables included the cumulative transfusion burden (in number
of RBC units) and the transfusion intensity, both being measured at the
time of each transfusion episode. Transfusion intensity was calculated
using the following formula:
Number of RBC units transfused at the episode
3 365 days=Number of days from the previous transfusion episode:
It represents the number of RBC units the patient would have
received over a full year had he/she kept being transfused at the current rate over a complete year. For instance, a patient who receives 2
RBC units 40 days after the previous transfusion episode has a transfusion intensity of [2 units 3 365 days/40 days] 5 18.25 RBC units per
year. If he/she is transfused with 3 RBC units 30 days later, the transfusion intensity at that time would have increased to [3 units 3 365 days/
30 days] 5 36.5 RBC units per year.
End-points and statistical analysis. The primary end-point was
AML-free survival from the time of rst transfusion. To test the
study hypotheses, we conducted several nested Cox models in
which the covariate transfusion burden 25 RBC units was successively adjusted for transfusion intensity and the median follow-up
at the time patients had received 25 RBC units, both covariates
being analyzed as time-dependent. Initial patient features signicantly inuencing on prognosis were included in every model. The
underlying assumption was that transfusion burden would be an
spurious prognostic factor (mediated or confounded by other variables) if its association with survival was abrogated by the inclusion
of any of the above covariates in the regression, and the resulting
Cox model had signicantly better specication and goodness of t
statistics [20].
We cut-off the cumulative transfusion burden at 25 RBC units
because this is the threshold for pathologic iron deposition in the liver
as measured by T2* MRI [21] and the threshold at which many practice
guidelines recommend starting on iron chelation therapy [12.14,15]. In
the multi-state model, we set an additional cut-off at 100 RBC units
because it has previously been identied as the critical threshold for
increased risk of myocardial iron overload [21,22].
To gain further insight into the prognostic signicance of transfusiondependency, we built a multi-state model representing the most relevant events of the disease course and the patient transfusion history.
Transitions from one state to each of the next states were modeled as
competing-risks, taking the occurrence of AML/death as an absorbing
state. The effect of covariates on transition hazards was analyzed by
Cox proportional hazards regression adapted to the competing-risks
framework [23].
Survival curves were drawn by the Kaplan and Meier method.
Nested Cox models were evaluated for goodness of t and specication

246

TABLE I. Characteristics of 191 Transfusion-Dependent MDS Patients at

Different Time Points During Their Transfusional History
Cumulative transfusion
burden

No. of patients (% of total)

Age at that time in
years, median (range)a
Sex (male/female)
WHO category
RA/RARS/del(5q)
RCMD/RCMD-RS
RAEB-1/RAEB-2
CMML
Karyotype-based
risk categoryb
Good/intermediate
Poor
Follow-up from rst
transfusion,a median (range)
a
b

At rst
transfusion

25
RBC units

191 (100%)
74 (1699)

112 (59%)
75 (1899)

100 RBC
units
29 (15%)
73 (2886)

97 (51%)/94

63 (56%)/49

17 (59%)/12

24 (13%)
91(48%)
54 (28%)
22 (11%)

14
53
32
13

8 (28%)
15 (51%)
6 (21%)
0

141 (85%)
25 (15%)

(12%)
(47%)
(29%)
(12%)

83 (84%)
16 (16%)
9.4 (169)
months

21 (84%)
4 (16%)
29 (1262)
months

At the time the surviving patients reached the cumulative transfusion burden.
Available in 166 patients.

by the likelihood ratio test and the Akaikes information criterion (AIC)
[24]. The AIC is a measure of the goodness of t of an estimated statistical model; lower AIC indicates better likelihood. In nested Cox models, the mediation or confounding effect on the association between the
cumulative transfusion burden and survival was measured by the percentage reduction of its regression coefcient after adjustment for the
mediating or confounding covariate [25]. All the statistical analyses
were done with Stata, version 10 (www.stata.com). Cox regression
models and cumulative incidence curves were calculated within the
competing-risks framework with the stcompadj module [26]. The timespan splitting method [27] was used to t the Cox models with time-dependent covariates. By using this method, the 191 patient records were
split at the time of each transfusion episode into a total of 5,306 observations. This study was approved by the Research Ethics Committee of
the Hospital Clinic of Barcelona, Spain.

Results
Patient characteristics and survival
Among the 466 patients recorded in the MDS database
up to December 31, 2009, 191 met the eligibility criteria
and were included in this study. Their main clinical and hematologic features at the time of rst transfusion are summarized in Table I. At the study closing date, median follow-up from rst transfusion was 1.5 (0.410.5) years, 128
(67%) patients had died, 8 (4%) were lost to follow-up, and
55 (29%) remained alive. Forty-six patients had progressed
to AML after a median of 8 (range: 453) months from the
rst transfusion. Median survival after progression to AML
was 2.5 months, with 44 (95%) patients having died within
the rst year following leukemic transformation.
Overall median survival from rst transfusion was 2 years
for the 191 patients, and the median AML-free survival was
1.96 years (Fig. 1). Male sex, WHO category, and high risk
karyotype were independent predictors for overall and
AML-free survival (Table S1, Fig. S1).
Transfusion data
A total of 5,306 transfusion episodes were recorded.
They involved 10,684 RBC units, 1,022 (9.5%) of which
were transfused after the recipient had progressed to AML.
Since prognosis after leukemic transformation was nearly
invariable fatal in the short term and presumably not
affected by transfusions given once the patient had progressed to AML, further analyses of the prognostic signicance of RBC transfusion were restricted to the AML-free
phase of MDS. The median number of RBC units transfused per patient before leukemic transformation was 30

American Journal of Hematology

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Figure 1. AML-free survival from rst transfusion in 191 MDS patients with transfusion dependency.

(range: 4330). One hundred and twelve patients received

25 RBC units, and 29 received 100 RBC units. The
characteristics of these heavily transfused patients are
summarized in Table I. Transfusion dependency started at
the time of diagnosis in 70 (37%) patients, and within the
rst year after diagnosis in 70 (37%) additional cases. In
total, 171 (90%) patients had started on regular RBC transfusion by the 3rd year after the diagnosis of MDS.
During the AML-free survival period, transfusion intensity
ranged from 0.7 to 746 (median: 32) yearly-equivalent RBC
units, with 90% of observations within the range of 7.7 to
78. Since rare but extremely high or low values might have
a disproportionate inuential or leverage effect on the
results of regressions, transfusion intensity was categorized
by quintiles in further analyses.
To test whether transfusion intensity behaved as a clock
variable, we plotted it against the patient follow-up time
from rst transfusion. As it can be seen in Fig. 2a, there
was no denite correlation between transfusion intensity
and the time elapsed from rst transfusion. Additionally,
transfusion intensity did not show any clear-cut trend from
year 1997 to 2009, which would have presumably happened if the transfusion trigger had changed during the
study period (Fig. 2b). Transfusion intensity was slightly
correlated with the cumulative transfusion burden (Fig. 2c).
Effect of transfusion burden on AML-free survival
Table II summarizes the results from the nested Cox
models in which the prognostic effect of cumulative transfusion burden 25 RBC units was successively adjusted for
transfusion intensity and the median follow-up (9 months,
see Table I) when patients had received 25 RBC units,
with both covariates evaluated as time-dependent. As
shown in the table, having received 25 RBC units was
signicantly associated with shorter AML-free survival after
adjustment for sex, WHO category, and the karyotype risk
group (model A). Follow-up time 9 months from rst
transfusion was associated with shorter AML-free survival
but had little effect of the prognostic signicance of transfusion burden (model B). When transfusion intensity was
entered into the model, it showed a signicant association
with shorter AML-free survival and abrogated the prognostic signicance of transfusion burden (model C). By comparing the regression coefcients of the covariate transfusion burden 25 RBC units in model A with coefcients
in models B and C, it can be estimated that 17% of its
prognostic strength in model A was mediated by the time
lapsed until patients gets 25 RBC units, and that 60%
can be explained by transfusion intensity. Moreover, when

American Journal of Hematology

Figure 2. Transfusion intensity during the AML-free survival in 191 MDS patients
with transfusion dependency. According to follow-up from rst transfusion (A), year of
transfusion (median, quartiles, and 95% CI (B), and cumulative transfusion burden (C).

these two latter covariates were simultaneously included in

the Cox regression (model D), the models specication
and goodness of t increased signicantly as shown by the
likelihood ratio test and the Alaikes information criterion
(Table II). Exclusion of the covariate transfusion burden
25 RBC units from model D had no effect on the specication and goodness of t statistics (log-likelihood 5 2404;
Chi-square 5 1.6, P 5 0.2).
Multi-state modeling
The multi-state model representing the more relevant
events occurring over the patient transfusion history and
disease progression is shown in Fig. 3. Table III summarizes the effect of covariates on the hazard for state transi-

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tions. The WHO category and high-risk karyotype had its
main prognostic impact on the transition from state 0 (rst
transfusion) or state 3 (25 RBC units) to state 1 (AML or
TABLE II. Nested Cox Models Showing the Prognostic Signicance of
Transfusion Burden 25 RBC Units After Adjustment for Selected Covariates
Covariate

HR

Model A

AIC 5 842

Male sex
WHO type
Poor prognosis karyotype
Transfusion burden 25 RBC units
Model B
Male sex
WHO type
Poor prognosis karyotype
Transfusion burden 25 RBC units
Time from rst transfusion >9 months
Model C
Male sex
WHO type
Poor prognosis karyotype
Transfusion burden 25 RBC units
Transfusion intensity
Model D
Male sex
WHO type
Poor prognosis karyotype
Transfusion burden 25 RBC units
Time from rst transfusion 9 months
Transfusion intensity

1.6
2.5
3.4
2.7
AIC 5 824
1.6
3.1
3.7
2.3
10.8
AIC 5 831
1.4
2.6
2.5
1.5
1.4
AIC 5 819
1.4
2.9
2.9
1.5
8.4
1.3

95% CI

Log-likelyhood:
2417
1.12.4
1.83.5
2.05.9
1.74.3

0.011
<0.001
<0.001
<0.001

Log-likelyhood:
2407
1.12.4
2.24.4
2.16.5
1.43.7
2.546

0.02
<0.001
<0.001
<0.001
0.001

Log-likelyhood:
2410
0.92.1
1.83.6
1.44.5
0.82.6
1.21.7

0.10
<0.001
0.001
0.17
<0.001

Log-likelyhood:
2403
0.92.1
2.14.2
1.65.2
0.82.6
1.936
1.11.5

0.08
<0.001
<0.001
0.20
0.004
0.008

Likelyhood ratio tests: B versus A (chi-square 5 20; P < 0.0001); C versus A

(chi-square 5 12.5; P 5 0.0004); D versus A (Chi-square 5 27; P < 0.0001). AIC,
Akaikes information criterion.

death), which is consistent with the short survival for these

two variables shown in Fig. S1. As can be seen in Table III,
transfusion intensity at the beginning of transfusion dependency was a good predictor for reaching a cumulative transfusion burden 25 RBC units. However, once the patient
has reached that transfusion burden, continuing on high
transfusion intensity had a quite similar inuence on any of
the two competing transitions (i.e. AML or death vs. reaching 100 RBC units).
Among the 24 patients with low-risk WHO categories
[RA, RARS, del(5q)], 14 died during the period under study,
all of them from AML-unrelated causes. Nine (64%) out of
the 14 deaths occurred before the patient had reached 100
RBC units, and 6 (43%) before reaching 25 RBC units.
Discussion
Our results show that the prognostic signicance associated with high cumulative transfusion burden in the MDS is
actually confounded by transfusion intensity and, to a
lesser extent, by the time elapsed from the start on chronic
transfusion support. High transfusion intensity can be
regarded as a surrogate for severe anemia, with this
reecting a deeper bone marrow dysfunction and exposing
the patient to the increased risk of cardiac-related mortality
associated with protracted low hemoglobin levels [28,29]. It
can therefore be inferred that high cumulative transfusion
burden would inuence on prognosis through these two
causal pathways instead of being intrinsically deleterious by
itself.
Since in the transfusion-dependent patient the cumulative
number of transfused RBC units can only increase over
time (Fig. S2), transfusion burden behaves as a clock variable in some way measuring the time elapsed from the
rst transfusion. High cumulative transfusion burden can
therefore be spuriously associated with shorter survival
merely because the patient has already consumed a part
of his/her life-expectancy at the time he/she reaches a
given transfusion burden. Our results show that this kind of
time-dependent bias does actually take place but that it

Figure 3. Multi-state model representing the disease progression and transfusion history in 191 MDS patients with transfusion dependency. Panel A shows the outline
of the model. Risks of transition from state S0 or state S2 are shown in panels B and C, respectively. Panel D represents the risk of transition from state S3.

248

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TABLE III. Factors Associated With Progression Along the Multi-State Model
From cumulative burden 25 RBC units to

From rst transfusion to

25 RB units

AML or death
Covariate

HR (95% CI)

Male sex
WHO categorya
High risk karyotypeb
Transfusion intensity

1.1
2.8
3.6
1.5

a
b

(0.61.9)
(1.65.1)
(1.58.7)
(1.12.1)

P
0.13
<0.001
0.005
0.026

HR (95% CI)
1.0
1.1
2.4
3.5

(0.71.5)
(0.81.5)
(1.34.5)
(2.84.5)

100 RBC units

AML or death
P

HR (95% CI)

HR (95% CI)

0.9
0.4
0.005
<0.001

1.9 (1.043.6)
2.1 (1.33.6)
2.9 (1.46.2)
1.8 (1.22.5)

0.04
0.004
0.005
0.001

2.7 (1.017.3)
0.6 (0.31.4)
4.4 (0.922)
2.3 (1.33.9)

0.05
0.23
0.07
0.002

Categorization: RA, RAS, del(q5) 5 0; RCMD, RCMD-RS 5 1; RAEB, CMML 5 2.

High risk 5 1; low or intermediate 5 0.

accounts for only a small share of the association between

cumulative transfusion burden and survival, the largest
share being explained by transfusion intensity.
Previous authors have tried to segregate the prognostic
effect of transfusion intensity from that of the cumulative
transfusion burden in the MDS. Malcovati et al. [3,30] calculated the average number of RBC transfused per month
and found it to be inversely correlated with survival.
Although averaging the total RBC burden by the time the
patient was on chronic transfusion support can adjust for
differences in follow-up, it does not take into account the
changes in transfusion requirements that may happen
along the disease course. Transfusion intensity, as herein
dened, was also independent of the length of patient follow-up and proved not to behave as a clock variable, that
is, not to systematically increase or decrease over time.
Moreover, by analyzing it as a time-varying covariate, we
were able to capture the prognostic inuence of changes in
transfusion requirements that may happen over the course
of the disease. Transfusion intensity increased substantially
after progression into AML (data not show) but this was not
taken into account in the present analysis, whose main
end-point was AML-free survival.
We did not investigate the prognostic signicance of
transfusional hemosiderosis because reliable measures of
the parenchymal iron load, collected at regular intervals
over the clinical course, would have been necessary for
such kind of study. Though we have serum ferritin levels
determined in many patients, measures were not done
according to preestablished time schedules so that a selection bias could not be ruled out. Nevertheless, our ndings
are not consistent with the prognostic signicance ascribed
to transfusion-induced iron overload by previous authors
[5,79]. First, the cumulative transfusion burden, which is
the main determinant of the transfusion-induced iron overload, lost its prognostic signicance after adjustment for
transfusion intensity. Second, most patients progressed into
AML or died from AML-unrelated causes before attaining
the cumulative transfusion burden required to develop signicant iron overload in the heart, which has been estimated at about 100 RBC units [21,22]. Even among
patients classied within the low-risk WHO categories,
most of those who died did so before reaching a signicant
cumulative transfusion burden, a nding which is consistent
with that reported by Chee et al. [31] in patients with
RARS.
With regard to the purported consequences of heavy
transfusion burden, most attention has been paid to
patients with RA, RARS, or del(5q) because of their
expected longer survival and lower risk of leukemic transformation. However, our results show that the proportion of
patients accumulating 25 RBC units is quite similar
across WHO categories and karyotype-risk groups (Table
I), and that a signicant proportion of patients with RCMD
or RCMD-RS end up receiving more than 100 RBC units.
In addition, both transfusion burden thresholds are attained

American Journal of Hematology

relatively soon in surviving patients, since they were

reached after a median of 9 and 29 months, respectively,
from the start o chronic transfusion, though there was a
large variability across patients.
As shown by the multi-state model, once the patient
starts on chronic transfusion the probability of accumulating 25 RBC units nearly doubles the competing risk of
dying or progressing into AML but the contrary happens
once the patient has received 25 RBC units. After
reaching this latter threshold, the risk of dying or progressing into AML predominates over the probability of
attaining 100 RBC units.
In addition to be a surrogate for severe anemia and
contributing to iron overload, RBC transfusion may inuence on the prognosis of MDS patients by ways that
have not yet been paid much attention. Indeed, transfusion-related immunomodulation (TRIM) and the effect of
banked blood on the microcirculation hemodynamics and
tissue oxygenation have been associated with poor outcomes in several clinical scenarios [32,33]. It is conceivable therefore that these mechanisms may also operate in
the MDS, at least in those patients with comorbidities.
Since only a few RBC transfusions are enough for the
TRIM and the microcirculation effects to take place, their
deleterious consequences would not necessarily correlate
with the cumulative transfusion burden but they would
presumably be more frequent in those MDS patients with
higher transfusion intensity.
There are potential sources of bias in our analysis that
are inherent to the retrospective nature of the study and
the necessity of having the whole transfusional history of
patients available. Patients in the low risk WHO categories
who received most of their transfusion support outside our
center were excluded from the analysis, with this possibly
leading to an overrepresentation of the higher risk categories. Though the composition of our series was comparable
to the transfusion-dependent patients from whom the WHO
classication-based prognostic scoring system was derived
[4], a referral bias can not be excluded. It is therefore conceivable that a series more populated with patients in the
low-risk WHO categories would have allowed to capture a
prognostic signicance for the cumulative transfusion burden that may have been missed in the present study. It
should be noted, however, that, when measured from the
start on chronic transfusion support, patients in the low-risk
WHO categories (RA, RARS, and del(5q)) did not survived
much longer than those diagnosed with RCMD or RCMDRS (median: 3.4 and 3.1 years, respectively; see Fig. S1)
nor they were more probable to achieve the 25 RBC units
burden threshold.
In summary, this study shows that transfusion intensity is
the transfusion-related variable actually inuencing on the
prognosis of transfusion-dependent MDS patients. This
nding strongly suggests that heavy transfusion burden is a
surrogate for disease severity instead of bearing an intrinsic
prognostic signicance by itself.

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