The lower risk MDS patient at risk of rapid progression.

Abstract

Most patients with myelodysplastic syndrome (MDS) are classified at diagnosis as having a low/INT-I or INT-II/high risk disease, based on the classical International Prognostic Scoring System (IPSS) criteria. The low/INT-I risk patients are usually managed mildly with supportive care, including red blood cell (RBC) transfusions, erythroid stimulating agents (ESAs), other cytokines (G-CSF, platelet stimulating agents), as well as thalidomide and lenalidomide. Some patients receive immunosuppressive therapy, and iron chelation is indicated in iron overloaded patients. Aggressive approach (hypomethylating agents, chemotherapy and stem cell transplantation) is usually not applied in such patients. Occasionally, we observe a "low risk" patient with rapid progression of disease and poor outcome. Can we identify demographic, clinical, laboratory, cellular-biological and/or molecular parameters that can predict "poor prognostic features" (PPF) in "low risk" MDS patients? Clinical and laboratory parameters have been reported to be associated with poor prognosis, in addition to the known "classical" IPSS criteria. These include older age, male gender, poor performance status, co-morbidities, degree of anemia, low absolute neutrophile count (ANC) and platelet counts, RBC transfusion requirements, high serum ferritin, high LDH, bone marrow (BM) fibrosis, increased number of BM CD34+ cells and multi-lineage dysplasia. Certain immunophenotypes (low CD11b, high HLA-Dr, CD34, CD13 and CD45), clonal granulocytes, multiple chromosomal abnormalities, chromosomal instability, short telomeres and high telomerase activity were also reported as PPF. Studies of apoptosis identified Bcl-2 expression and high caspase 3 as PPF, while the reports on survivin expression have been confusing. Recent exciting data suggest that methylation of p15 INK4b and of CTNNA1 (in 5q-), high level of methylation of other genes, absence of the TET2 mutation, down regulation of the lymphoid enhancer binding factor 1 (LEF1), mutation of the polycomb-associated gene ASXL1 and a specific 6-gene signature in gene expression profiling - are all associated with poor prognosis in MDS. Do we have data suggesting a different treatment for "low risk" MDS patients displaying PPF? Two teams, the combined Nordic-Italian and the GFM groups have reported an improved survival with ESAs. The GFM has achieved prolonged survival with iron chelation. Recently, encouraging data with survival advantage in azacitidine-treated patients have been published, including a few INT-I patients. Finally, data suggest that low/INT-I MDS patients who undergo stem cell transplantation (SCT0 do better than INT-II/high risk patients). In summary, some patients, classified as "low risk MDS" carry PPF. An appropriate therapeutic approach is indicated. Future updated classifications and prospective trials may lead to a better outcome.

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Contents lists available at ScienceDirect
Leukemia Research
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Invited review
The lower risk MDS patient at risk of rapid progression
Moshe Mittelmana,∗, Howard S. Ostera, Michael Hoffmana, Drorit Neumannb
aDepartment of Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann St., Tel Aviv 64239, Israel
bDepartment of Cell and Developmental Biology, Tel Aviv Sourasky Medical Center, Tel Aviv University, Tel Aviv, Israel
a r t i c l e i n f o
Article history:
Received 17 May 2010
Received in revised form 17 May 2010
Accepted 19 May 2010
Available online xxx
Keyword:
Myelodysplastic syndrome (MDS)
a b s t r a c t
Most patients with myelodysplastic syndrome (MDS) are classified at diagnosis as having a low/INT-I
or INT-II/high risk disease, based on the classical International Prognostic Scoring System (IPSS) crite-
ria. The low/INT-I risk patients are usually managed mildly with supportive care, including red blood
cell (RBC) transfusions, erythroid stimulating agents (ESAs), other cytokines (G-CSF, platelet stimulating
agents), as well as thalidomide and lenalidomide. Some patients receive immunosuppressive therapy,
andironchelationisindicatedinironoverloadedpatients.Aggressiveapproach(hypomethylatingagents,
chemotherapy and stem cell transplantation) is usually not applied in such patients.
Occasionally, we observe a “low risk” patient with rapid progression of disease and poor outcome. Can
we identify demographic, clinical, laboratory, cellular-biological and/or molecular parameters that can
predict “poor prognostic features” (PPF) in “low risk” MDS patients?
Clinicalandlaboratoryparametershavebeenreportedtobeassociatedwithpoorprognosis,inaddition
to the known “classical” IPSS criteria. These include older age, male gender, poor performance status, co-
morbidities,degreeofanemia,lowabsoluteneutrophilecount(ANC)andplateletcounts,RBCtransfusion
requirements, high serum ferritin, high LDH, bone marrow (BM) fibrosis, increased number of BM CD34+
cells and multi-lineage dysplasia. Certain immunophenotypes (low CD11b, high HLA-Dr, CD34, CD13
and CD45), clonal granulocytes, multiple chromosomal abnormalities, chromosomal instability, short
telomeres and high telomerase activity were also reported as PPF. Studies of apoptosis identified Bcl-2
expression and high caspase 3 as PPF, while the reports on survivin expression have been confusing.
Recent exciting data suggest that methylation of p15 INK4b and of CTNNA1 (in 5q−), high level of
methylation of other genes, absence of the TET2 mutation, down regulation of the lymphoid enhancer
binding factor 1 (LEF1), mutation of the polycomb-associated gene ASXL1 and a specific 6-gene signature
in gene expression profiling – are all associated with poor prognosis in MDS.
Do we have data suggesting a different treatment for “low risk” MDS patients displaying PPF? Two
teams, the combined Nordic-Italian and the GFM groups have reported an improved survival with ESAs.
The GFM has achieved prolonged survival with iron chelation. Recently, encouraging data with survival
advantage in azacitidine-treated patients have been published, including a few INT-I patients. Finally,
data suggest that low/INT-I MDS patients who undergo stem cell transplantation (SCT0 do better than
INT-II/high risk patients).
Insummary,somepatients,classifiedas“lowriskMDS”carryPPF.Anappropriatetherapeuticapproach
is indicated. Future updated classifications and prospective trials may lead to a better outcome.
© 2010 Elsevier Ltd. All rights reserved.
Contents
1.
2.
Poor prognostic features (PPF) in lower risk MDS – diagnostic tools ...............................................................................
Poor prognostic features (PPF) in lower risk MDS – therapeutic options...........................................................................
Conflict of interest ...................................................................................................................................
Acknowledgement...................................................................................................................................
References ...........................................................................................................................................
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∗Corresponding author. Tel.: +972 3 697 3366; fax: +972 3 697 4855.
E-mail address: moshemt@tasmc.health.gov.il (M. Mittelman).
0145-2126/$ – see front matter © 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.leukres.2010.05.023

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Patients are usually diagnosed as having myelodysplastic syn-
drome (MDS), based on well known recognized criteria [1–7]. This
is commonly followed by prognostic staging, in order to plan the
therapeuticapproach.Thecommonlyusedprognosticsystemisthe
InternationalPrognosticScoringSystem(IPSS)[8].TheIPSSisbased
on three classical criteria, i.e. blast percentage in the bone marrow
(BM),originallyproposedbytheFABclassification[9],cytogenetics
(three types: favorable, poor, and intermediate), and the number
of affected cytopenias. Using these criteria, each patient is given
a score, according to which he is categorized as belonging to one
of the four IPSS groups, i.e. low risk (LR), intermediate-I (INT-I),
intermediate-II (INT-II) and high risk (HR) MDS.
Usually, the patients classified as LR and INT-I IPSS, are referred
to as “lower risk MDS” (LrMDS) and offered relatively mild and
conservative treatments. These include supportive care, such as
red blood cell (RBC) transfusions [1,2,4–7], erythroid stimulat-
ing agents (ESAs) [10–12] and granulocyte – macrophage colony
stimulating factors (GM-CSF) [11–13]. Recently, thrombopoietic
agents [14], thalidomide [15] and lenalidomide have been intro-
duced [16–18]. Some patients, especially those with hypocellular
BM receive immunosuppressive therapy [19] and iron chelation is
indicated in patients with iron overload [20,21]. More aggressive
therapies such as hypomethylating agents [22–24], chemotherapy
and stem cell transplantation (SCT) are usually not administered to
patients with LrMDS [25,26].
Most LrMDS patients experience a slowly progressive disease
with a long course [8,27]. However, occasionally, we encounter a
patient, who is classified as having LrMDS, yet progresses rapidly,
i.e. displays decreasing counts, complications, possible leukemic
transformation, and a short survival.
Whoarethese“LrMDS”patientswithrapiddiseaseprogression?
Can we identify them at diagnosis upon classification or earlier?
And if so, what are the additional poor prognostic features (PPF), in
additiontotheknownclassicalIPSScriteriathatareusedtoidentify
these patients? If and when we identify these “LrMDS” patients,
who are probably not low risk, should we attempt an alternative
therapeutic approach to achieve better outcome? Do we have data
to support such an alternative treatment? This review will address
these questions.
1. Poor prognostic features (PPF) in lower risk MDS –
diagnostic tools
Studies, summarized in Table 1, have identified a list of param-
eters which are not used in the IPSS classification, but may have
prognostic relevance. Starting with the simple clinical and demo-
graphic markers, which can be applied in every practice, one
can review the original IMRAW/IPSS data. Kao et al. [28] re-
examined the data on 816 MDS patients, which served for the
original IPSS classification, and concluded that hemoglobin (Hb),
but not neutrophile or platelet counts, was a reliable predic-
tor for overall survival but not for time to leukemia conversion.
Kantarjian at al. [29] analyzed the data on 1915 MDS patients,
including 507 patients with primary MDS, treated at the MD
Anderson Cancer Center. They found that older age, poor perfor-
mance status, anemia, low platelet count and prior transfusion
need – were all predictors of poor outcome. They also proposed a
new risk model, based on these prognostic parameters. A recent
Chinese prospective analysis on 435 patients, reported that age
>60 year, ANC<1000/mmc and Hb below 9g/dl were PPF [30].
The Dusseldorf MDS registry confirmed older age, especially >
50yr, as PPF [31]. The German-Austrian MDS study group has
recently summarized data on 897 patients with primary MDS and
found in their retrospective analysis that older age (>66 year)
and male gender were associated with poor prognosis [32]. The
Table 1
Poor prognostic features (PPF) in lower risk MDS (LrMDS).
Class of markers PPF Refs.
Clinical/demographic
Older age
Gender (male)
Poor performance status
Co-morbidities
Transfusion needs
Iron overload
High serum ferritin
[29–32]
[32]
[29]
[33]
[29,34–37]
[35–37]
[37]
Lab values
Hb ↓
PLT ↓
ANC ↓
High LDH
[28–30,37]
[29]
[30]
[27]
Bone marrow (BM)
BM fibrosis
CD34+ clusters
Multi-lineage dysplasia
Normal/high cellularity
[39]
[39–41]
[35,36,39–41]
[42]
Immunophenotyping
↑ HLA-Dr
Low CD11b
↑ CD34
↑ CD13
↑ CD45
Flow score
[43]
[43]
[44]
[44]
[44]
[45]
ClonalityClonal granulocytes[41]
Cytogenetics
Additional chromosomal
abnormalities
Chromosomal instability
[8,46]
[47]
Telomeres
Short telomeres
High telomerase activity
[48–51]
[49,52–54]
Apoptosis
↑ BCl2
↑ Caspase 3
Survivin (???)
Cell senescence (PIG INKa4)
[56]
[57]
[58–60]
[61]
Genetic/epigenetic/
molecular
P15 INK4b methylation
CTNNA1
High methylation
Unmutated TET2
LEF1 down regulation
ASXL1 mutation
6-gene poor risk signature
[62,63]
[64]
[65]
[66]
[67]
[68]
[69]
Austrian group has emphasized that co-morbidity, as used by
the hematopoietic-stem cell transplantation-specific co-morbidity
index (HCT-CI) and Charlson co-morbidity index (CCI), were addi-
tional PPF [33].
Although many felt for years that MDS patients who require
regular blood transfusions represent a “poor prognostic” dis-
ease, Cazzola and Malcovati [34] demonstrated that transfusion
dependent MDS patients do worse than MDS patients who are
transfusion free. The same Pavia team later on, comparing their
data on more than 400 MDS patients with the Dusseldorf reg-
istry, reported that transfusion dependence, iron overload, and
multi-lineage (as opposed to uni-lineage) dysplasia predicted poor
outcome [35,36]. Based on transfusion requirements they pro-
posed an updated version of the IPSS system – WHO classification
– based prognostic scoring system (WPSS). A recent retrospec-
tive analysis of 137 patients from the Czeck Republic, confirmed
that transfusion dependence, Hb<8g/dl, and high serum ferritin
level (>2000mg/dl) were associated with poor prognosis [37].
Germing et al. [27], reported that high serum LDH can also serve as
PPF.
Regardingmorecomplexparameters,thePaviateamretrospec-
tively reviewed the BM samples of 301 patients and concluded
that BM fibrosis, the presence of CD34+ cell clusters (a reminder
of the old “Abnormal Localization of Immature Progenitors, ALIP,
as suggested by Tricot et al. [38]), and multi-lineage (as opposed to
uni-lineage) dysplasia were associated with poor prognosis [39].

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This was confirmed by others [40,41]. Yue et al. [42] reported that
hypocellular BM correlated with a favorable outcome, compared
with normal or hypercellular BM.
Immunophenotyping, both for diagnosis and for predicting
prognosis of MDS patients, has attracted several groups. We found
that high expression of HLA-Dr, and low CD11b expression pre-
dicted early leukemic transformation [43]. More recently, high
expression of CD34, CD13, and CD45 was reported as PPF [44]. Van
deLoosdrechtetal.[45]studiedtheimmunophenotypingofCD34+
BM cells from 50 MDS patients. They found high degree of aberra-
tion of myelomonocytic antigens to which they gave a flow score,
correlated with prognosis. Clonal granulocytes were also reported
to predict poor outcome [41].
Cytogenetics has always been a field for investigation in these
diseases, for diagnosis, staging and for predicting prognosis. In the
original IPSS classification multiple chromosomal abnormalities
were considered as PPF [8]. This has recently been confirmed by
the MD Anderson experience with 2743 patients [46]. Chromoso-
malinstability,ascouldbeexpected,mayalsopredictrapiddisease
progression [47].
Several studies have focused on telomeres. In summary, short
telomeres, resulting in genetic instability [48–51], coupled with
high telomerase activity (associated with a high proliferation rate)
[49,52–54], both correlate with poor prognosis.
Apoptosis was found to be increased in early MDS, and
decreased in later phases of the disease [55]. Several groups
have studied apoptosis-associated markers as predictors of disease
course. High expression of the anti-apoptotic protein BCL-2 [56],
and of caspase 3 [57], predicted poor prognosis. The current data
on the apoptosis inhibitor survivin are inconclusive [58–60]. Cell
senescence, determined by P16 INKa4 expression, was also found
to be PPF [61].
Recent epigenetic studies have generated exciting molecular
data. Methylation of p15 INK4b was found to predict poor outcome
[62,63]. In MDS patients with the 5q− abnormality, methylation of
the promoter of CTNNA1 correlated with poor prognosis [64].
Shen et al. [65], have recently screened 24 MDS patients for
promoter CpG methylation of 24 genes and identified aberrant
hypermethylation at 10 genes. They then performed quantitative
methylation analysis by bisulfite pyrosequencing of the identi-
fied genes in 317 patient samples and assessed relations between
methylation and clinical outcome. While methylation frequencies
of individualized genes ranged from 7 to 70%, by applying an indi-
vidual methylation z score based on all genes for each patient, they
found that higher methylation correlated with a shorter median
survival (12.3 vs 17.5m) and a shorter progression free survival
(6.4 vs 14.9m).
TheTET2mutationhasrecentlygainedattention.Kosmideretal.
[66], have found that not only this genetic abnormality is common
in MDS (23%), but also 5-year overall survival and 3-year leukemia-
free survival were significantly shorter in patients carrying non-
mutated TET2 compared with patients carrying the mutated gene:
18 vs 77, and 64 vs 89%, respectively.
Pellagatti et al. [67], studied the granulopoiesis regulator lym-
phoid enhancer binding factor 1, LEF1, and found that its down
regulation was associated with poor prognosis. This group has also
reported that ASXL1 mutation could serve as a molecular marker
for disease progression [68].
Finally, the Stanford team has performed detailed molecular
analysis with gene expression profile in CD34+ BM cells from MDS
patients [69]. Studying 40,000 CDNAs chip arrays, they detected
1175genesthatweredifferentiallyexpressed.Moreover,theyiden-
tified six genes (RPL23, RPS4x, RPS25, RPS19, KLK3 and TPP2), four
ribosomal and two enzymes, all over expressed in patients who
later on progressed and transformed to acute leukemia, thus pro-
viding a “6-gene-poor-risk-signature”.
2. Poor prognostic features (PPF) in lower risk MDS –
therapeutic options
Once, a patient with LrMDS but with a predicted poor survival
is identified, should he be treated differently? Do we have data to
suggest an alternative approach?
Although phase III controlled trials have not been pub-
lished, we do have little evidence suggesting that an active
approach in some LrMDS patients may attenuate the course of
disease.
Erythroid stimulating agents (ESAs) have been a pivotal anti-
anemic treatment for LrMDS patients. We [70–73], as well as
others, have suggested that ESAs confer immunomodulatory anti-
neoplastic effect(s) as well. Several trials have suggested that
ESAs-treated cancer [74] and MDS [75] patients benefit from pro-
longed survival compared with patients who do not receive ESAs.
Recently, the Nordic group has compared the outcome of their
121 MDS patients treated with recombinant erythropoietin (EPO)
and G-CSF, with the outcome of 237 untreated MDS patients from
the Pavia Cohort [13]. Increased overall survival was observed in
EPO+G-CSF treated LrMDS patients (p=0.033), but not in patients
with higher risk MDS. The GFM data are similar [76].
Iron overload, aggravated by repeated blood transfusions, has
been associated with organ damage, suggesting poor prognosis
[20,21]. But, has iron chelation therapy (ICT) resulted in a better
prognosis? No prospective comparative data are available; how-
ever, two reports summarizing retrospective cohort data have
suggested a survival benefit with ICT. The GFM analysis reported
a positive survival impact of ICT in regularly transfused patients
with MDS: the median survival of the whole MDS group was 63
months,with115monthsurvivalfortheICT-treatedpatients,com-
pared with only 51 months (p<0.0001) for MDS patients with
no ICT [77]. A Canadian cohort series observed similar results
[78].
As mentioned, hypomethylating agents such as decitabine and
5-azacitidine are usually offered to higher risk MDS patients
[22,23]. The recently published AZA-001 trial reported survival
advantagein179azacitidine-treatedMDSpatients,comparedwith
the control group, treated with conventional therapy (chemother-
apy, low dose cytarabine, or supportive treatment). The overall
survival was 24.5 months for the azacitidine group but only 15.0
months for the conventional group (p=0.0001) [24]. While most
patientsintheAZA-001trialwerehigherriskMDSpatients,analyz-
ing the data reveals that 18 patients (5%) were in fact, MDS patients
classified as INT-I. Although no subset analysis has been available
onthatsubgroup,itistemptingtohypothesizethattheyalsomight
benefit from such treatment.
Finally, can stem cell transplantation (SCT) improve survival in
LrMDS with PPF? Again, no prospective trial comparing SCT with
less aggressive approach in this patient subpopulation has been
published. But, the recently published Italian – GITMO experience
with SCT outcome (1990–2006) in MDS patients, reports on 5-year
overall survival of 80%, 5-year probability of relapse of only 9%
and 5 year transplant-related mortality of only 14% for refractory
anemia (RA) patients, and 57, 22 and 39% respectively, for refrac-
tory cytopenia (RC or RCMD) patients. These results are better than
thoseobtainedwithotherpatients(RAEB-1,RAEB-2,andAMLpost-
MDS) [79]. This does not mean that SCT is recommended to all
LrMDS patients with or without PPF. But it suggests, that if a more
aggressive than the usually applied approach is considered – it
mightberelativelynon-toxic,andsometimessuccessful[25,26,79].
In summary, some MDS patients, although classified as “lower
risk MDS” (LrMDS), and probably offered a mild therapeutic
approach – are not really “lower risk”. Such patients, despite being
grouped as LrMDS experience a rapid complicated progressive
coursewithorwithoutleukemictransformationandadismalprog-

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nosis. A list of poor prognostic features (PPF) described in this
review, including clinical and laboratory values, others such as
BM parameters, and more recently established molecular mark-
ers – can identify those LrMDS patients, and predict rapid course
and poor outcome. Although, no prospective convincing data are
available, emerging information suggests that a more aggressive
approach might improve the outcome. Obviously, future prospec-
tive comparative trials will have to test this hypothesis, and will
probablyleadbothtoarevisedupdatedclassificationandtoamore
individualized treatment.
Conflict of interest
All authors have no conflict of interest to declare.
Acknowledgement
None.
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