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Author: Guillermo Garcia-Manero, MD
Article Title: Myelodysplastic syndromes: 2011 update
on Diagnosis, Risk-stratication and Management
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2011 Wiley-Liss, Inc.
American Journal of Hematology 490 http://wileyonlinelibraray.com/cgi-bin/jhome/35105
ANNUAL CLINICAL UPDATES IN HEMATOLOGICAL MALIGNANCIES:
A CONTINUING MEDICAL EDUCATION SERIES
Myelodysplastic syndromes: 2011 update on diagnosis,
risk-stratification, and management
Guillermo Garcia-Manero*
Disease overview: The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders charac-
terized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia
(AML). MDS occurs more frequently in older male and in individuals with prior exposure to cytotoxic
therapy.
Diagnosis: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of
a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, ow
cytometry, or molecular genetics is complementary but not diagnostic.
Risk-stratication: Prognosis of patients with MDS can be calculated using a number of scoring systems.
In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the
bone marrow, and cytogenetic characteristics. The most commonly used system is the International Prog-
nostic Scoring System. This score divides patients into a lower risk subset (low and intermediate-1) and a
higher risk subset (int-2 and high). Other more modern systems have been developed that allow more pre-
cise risk calculation.
Risk-adapted therapy: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts
and more recently cytogenetic prole. Goals of therapy are different in lower risk patients than in higher
risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or
AML. In higher risk, the goal is to prolong survival. Current available therapies include growth factor sup-
port, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplanta-
tion. The use of lenalidomide has signicant clinical activity in patients with lower risk disease, anemia,
and a chromosome 5 alteration. 5-azacitidine and decitabine have activity in higher risk MDS. 5-azacitidine
has been shown to improve survival in higher risk MDS. Additional supportive care measures may include
the use of prophylactic antibiotics and iron chelation.
Management of progressive or refractory disease: At the present time, there are no approved interventions
for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options
include cytarabine-based therapy, transplantation, and participation on a clinical trial. Am. J. Hematol.
86:491498, 2011. V VC
2011 Wiley-Liss, Inc.
Disease Overview
MDS comprises a very heterogeneous group of myeloid
malignancies with very distinct natural histories. Ongoing
studies of cytogenetic, genetic, and epigenetic alterations
of this group of disorders are adding further complexity to
our understanding of MDS but also provide opportunities
for future targeted interventions [1,2].
MDS occurs in three to four individuals per 10
5
in the US
population [3]. Prevalence increases with age. For instance
in individuals age 60 and above, prevalence is 7 to 35 per
10
5
[3]. Other series have reported higher rates [4] but those
were based on Medicare reporting that is not based on histo-
pathological diagnosis. MDS affects more frequently males
than females [3]. It has been reported that MDS can have
certain degree of ethnic distribution. Exposure to prior chemo
or radiation therapy is a risk for the development of MDS.
MDS is usually suspected by the presence of cytopenia
on a routine analysis of peripheral blood. This prompts
evaluation of bone marrow cell morphology (aspirate) and
cellularity (biopsy). A manual count of bone marrow blasts
is fundamental for risk assessment. Cytogenetic analysis
helps in predicting risk and in selecting therapy. Once this
information is collected, the risk of the patient can be calcu-
lated. At the present time, the International Prognostic
Scoring System (IPSS) [5] is still the most commonly used
score. Natural history and therapeutic decisions are differ-
ent for patients with lower risk disease (low and INT-1)
versus those with higher (INT-2 and high). In lower risk dis-
ease, interventions have been traditionally developed to
improve transfusion needs; whereas higher risk options
have been modeled following therapy of AML with remis-
sion induction being the goal. This concept is being modi-
ed by the better understanding of the natural progression
of MDS and the development of new therapies. Another im-
portant concept is that a large majority of patients with
MDS die from causes intrinsic to the disease and not due
to progression to AML [6]. This has important implications
for the development of therapies in MDS.
Diagnosis
The diagnosis of MDS is suspected based on the
presence of an abnormal CBC. Diagnosis is conrmed by
Conict of interest: Nothing to report
Department of Leukemia, University of Texas MD Anderson Cancer Center,
Houston, Texas
*Correspondence to: Guillermo Garcia-Manero, Department of Leukemia,
MD Anderson Cancer Center, Box 428, 1515 Holcombe Blvd, Houston, TX
77030. E-mail: ggarciam@mdanderson.org
Received for publication 28 March 2011; Accepted 29 March 2011
Am. J. Hematol. 86:491498, 2011.
Published online in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.22047
AJH Educational Material
V V
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2011 Wiley-Liss, Inc.
American Journal of Hematology 491 http://wileyonlinelibrary.com/cgi-bin/jhome/35105
performing a bone marrow aspiration and biopsy. Both pro-
cedures provide different information. The bone marrow
aspirate allows for detailed evaluation of cellular morphol-
ogy and evaluation of percent of blasts. The bone marrow
biopsy allows for determination of bone marrow cellularity
and architecture. There is some controversy regarding the
utility of bone marrow biopsy. In my practice, we treat
patients with hypocellular MDS (those with bone marrow
cellularity less than 20 to 30% depending on age) with spe-
cic forms of therapies (immune based approaches) and
do not routinely use cytotoxic forms of therapy in that set-
ting. I therefore believe that is fundamental to have access
to this type of information. Diagnosis is conrmed by the
presence of dysplasia. A number of morphological classi-
cations are in place to classify patients with MDS. The
most recent one being the 2008 WHO version (Table I) [7].
A number of additional tests are needed to complete the
laboratory evaluation of a patient with MDS. These include
analysis of bone marrow cytogenetics. It is well established
that cytogenetic patterns are very heterogeneous (Table II)
[9]. As will be discussed below, cytogenetics are of impor-
tance to calculate prognosis of patients and in some sub-
sets of patients to select the most effective form therapy. A
number of other assays can be used to help in the diagno-
sis of MDS. These include the use of ow cytometry and
uorescent in situ hybridization (FISH). Flow cytometry can
help in the identication of abnormal phenotypic patterns
and can be of help in cases of minimal dysplasia. Because
the heterogeneity of cytogenetic alterations in MDS, there
is no evidence that a panel of FISH probes could replace
routine 20 metaphase cytogenetic analysis. Thus, in my
opinion, FISH and ow cytometry should not be considered
part of the standard work up evaluation procedure of the
patient with MDS and should be used in specic situations.
Diagnostic problems in MDS
Because diagnosis of MDS is based on morphological
assessment, it can be subjective particularly in patients
with early low risk disease. It is calculated that diagnostic
discrepancy can occur at the time of initial presentation in
20 to 30% of patients. At MD Anderson Cancer Center
(MDACC), we compared the nal MDACC diagnosis with
that of the referral center and found a discrepancy of close
to 20%. This discrepancy affected 50% of IPSS calcula-
tions, usually going from a lower to a higher risk score [10].
This has obvious implications for therapeutic decision mak-
ing and patient counseling. In general, diagnosis is obvious
in patients with excess blasts. The problem is in patients
without excess blasts were diagnosis is based on dyspla-
sia. This can affect one line or all of three and can be mini-
mal. Clinical assessment is therefore needed in those
patients. The presence of a cytogenetic alteration can also
aid in conrming diagnosis. In these cases, it is recom-
mended that other causes of cytopenia be excluded.
Routine test include the analysis of anemia and thrombocy-
topenia, exclude cause of blood loss and inammatory
processes. When suspected, evaluation of GI tract needs
to be considered. I recommend GI and gynecological evalu-
ation in all patients referred to our group that are not up to
date on their respective screening follow up based on
accepted guidelines.
Another subset of patients are those without evidence of
dysplasia but with presence of unexplained cytopenia and
those with evidence of abnormal karyotype without evi-
dence of dysplasia. These two situations can be encoun-
tered in the evaluation of patients with cytopenia. Once
other potential causes of cytopenia are excluded, these
patients are considered in the subset of idiopathic cytope-
nia of unknown signicance. The natural history of this
group of patients is not well known and observation is rec-
ommended at the present time.
Finally, there are two subsets of patients with overlap fea-
tures of importance. Those are patients with evidence of a
myeloproliferative component (with or without brosis) and
patients with evidence of a paroximal nocturnal hemoglo-
binuria (PNH) clone. At the present time, we do not fully
understand the natural history of patients with MDS/MPN
features. In our center, they are currently treated as MDS
but studies are ongoing to clarify this issue. Second,
although it has been reported that PNH clones can be iden-
tied in up to 30% of patients with MDS [11], in the majority
of the patients these are of no signicance [11].
Risk Stratication
The prognosis of patients with MDS is very heterogene-
ous and thus the need to develop prognostic systems that
allow risk stratication and help in the timing and choice of
therapy. Apart from the intrinsic prognostic value of mor-
phological classications [7], a number of prognostic scores
are currently in use in MDS.
The most commonly used one if the International Prog-
nostics Scoring System (IPSS) [5]. This system has been
TABLE I. WHO 2008 MDS Classication
Disease Bone marrow ndings
RCUD Dysplasia in >10% in one myeloid lineage.
Less than 5% blasts and less than
15% ring sideroblasts
RA
RN
RT
RARS 15% ring sideroblasts, less than
5% marrow blasts
RCMD Dysplasia in >10% in more than one
myeloid lineage. Less than 5% blasts.
No Auer rods
RAEB-1 5 to 9% blasts. No Auer rods
RAEB-2 10 to 19% blasts or Auer rods
MDS-U Dysplasia in less than 10% myeloid cells
but with cytogenetic abnormality
MDS associated
with isolated
del(5q)
Less than 5% blasts with normal or increased
megakaryocytes and isolated del(5q).
No Auer rods
RCUD, refractory cytopenia with unilineage dysplasia; RA, refractory anemia;
RN, refractory neutropenia; RT, refractory thrombocytopenia; RARS, refractory
anemia with ring sideroblasts; RCMD, refractory anemia with multilineage dyspla-
sia; REAB, refractory anemia with excess blasts; MDS-U, myelodysplastic syn-
drome unclassied. Adapted from Vardiman et al.7
TABLE II. Frequency of Cytogenetic Alterations in MDS8
Alteration %
5q2 15
27/7q2 11
18 8
218/18q2 4
20q2 4
25 3
2Y 3
121 2
217/17q2 2
Inv/t(3q) 2
213/13q2 2
11/11q 1
221 1
111 1
12p2 1
T(5q) 1
11q2 1
9q2 1
T(7q) 1
220 1
Adapted from Refs. 8,56.
492 American Journal of Hematology
annual clinical updates in hematological malignancies: a continuing medical education series
in place since 1997. The prognostic score includes percent
of blasts, number of cytopenias, and cytogenetics. IPSS is
of fundamental importance as it has allowed the prognosti-
cation of patients over 2 decades. This system is highly re-
producible and very simple to use. The system has several
limitations that have become evident over the years. The
most important one is that it is not a very precise predictor
of prognosis in patients with lower risk disease and that it
attributes relatively little weight to cytogenetics.
Another commonly used system is the WPSS developed
by the Pavia group [12]. This system was developed after
the realization that red cell transfusion dependency is an in-
dependent predictor of prognosis in MDS [13]. This system
was also developed as time dependent model meaning that
it can be used sequentially at any time during the course of
the disease. The main limitations of the WPSS are that it
requires WHO classication of the disease and requires
prior information of transfusion needs.
Both the IPSS and WPSS were developed in a very spe-
cic subset of patients: newly diagnosed patients at the time
of initial presentation. Patients with proliferative features and
CMML or that have received prior therapy were excluded [5].
To overcome these limitations, the global MDACC model
was developed [14]. This model is summarized in Table III.
This model has now been validated by at least one inde-
pendent group [11]. The importance of the global MDACC
model is that allows evaluation of all patients that are consid-
ered as MDS at any time during their course of their disease
without needed WHO evaluation.
It has become apparent that the natural history of
patients with lower risk disease is very heterogeneous [15].
We evaluated outcomes in a large series of patients with
low or int-1 disease by IPSS. We found that expected prog-
nosis varied signicantly in patients with lower risk MDS
and were able to develop a lower risk MDS specic prog-
nostic score (Table IV). This has signicant implications for
the development of specic interventions for patients with
lower risk disease. In the future, and if conrmed, this
model will allow identication of patients with poor progno-
sis lower risk disease that could be candidates for early
alloSCT or other therapies.
MDS occurs in older patients that suffer from comorbid-
ities more frequently. None of the systems discussed above
include impact of comorbidity to the calculation of the natu-
ral history of MDS patients. To study this issue, we used a
comprehensive comorbidity score known as ACE-27
[16,17] in a cohort of 500 patients with MDS [17] (Naqvi
et al., JCO in press). Presence of comorbidity had a signi-
cant independent impact on survival and a prognostic score
could be developed that included age, IPSS, and ACE-27
score [17]. This data indicates the need to add comorbidity
scores in MDS. The impact of comorbidity on survival of
patients with MDS is shown in Fig. 1.
Finally, a global group of MDS investigators are working
on the development of a unied revised IPSS. The data-
base thus generate includes more than 10,000 patients so
far. Initial results are expected this year.
Risk Adapted Therapy
At the present time, we still use IPSS to decide the
choice of therapy for an individual patient. Below is a
TABLE III. The Global MDACC MDS Prognostic Model14
Prognostic factor Points
PS 2 2
Age
6064 1
>64 2
Platelets 310
9
/L
<30 3
3049 2
50199 1
Hemoglobin <12 g/dL 2
BM blast %
5 to 10 1
11 to 19 2
WBC > 20 310
9
/L 2
Alteration of chromosome 7 or 3 alterations 3
Prior transfusion 1
Patients with 0 to 4 points had a median survival of 54 months and a 3-year
63% survival. Patients with 5 and 6 points had a median survival of 23 to 30
months and 3-year survival of 30 to 40%. Patients with 7 to 8 points had a median
survival of 13 months and a 3-year survival rate of 13 to 19%. Patients with 9 or
more points had a median survival of 5 to 10 months and a 2% 3-year survival.
Adapted from Ref. 14.
PS, performance status; BM, bone marrow; WBC, white blood cell count.
TABLE IV. MDACC MDS Lower Risk Prognostic Model15
Characteristics Points
Unfavorable cytogenetics 1
Age 60 years 2
Hemoglobin < 10 (g/dL) 1
Platelets
<50 3 10
9
/L 2
50200 3 10
9
/L 1
Bone marrow blasts 4% 1
Score Median survival 4-year OS (%)
0 NR 78
1 83 82
2 51 51
3 36 40
4 22 27
5 14 9
6 16 7
7 9 N/A
Characteristics were selected from multivariate analysis model in patients with
lower risk MDS. Each characteristic is associated with a number of points. Score
is calculated by adding all points. Each score allows calculation of median survival
(in months) and probability of survival at 4 years. Adapted from Ref. 15.
Figure 1. Effect of comorbidity on survival of MDS patients. Each line represents
survival according to ACE-27 comorbidity score. Patients with no comorbidity
(ACE-27 score 5 0; solid line) have the longest survival while those with severe
comorbidity (ACE-27 score 5 3; dotted line) have the shortest survival (Naqvi
et al., JCO in press).
American Journal of Hematology 493
annual clinical updates in hematological malignancies: a continuing medical education series
summary of options and recommendations for specic sub-
sets of patients [2]. A treatment algorithm is shown in Fig. 2.
Options for newly diagnosed patients with lower risk
MDS
Therapy in this subset of patients is based on the trans-
fusion needs of the patients. Patients that are transfusion
independent are usually observed until they become trans-
fusion dependent. Below is a list of agents currently avail-
able for patients with lower risk MDS.
Erythroid growth factor support. The use of erythroid
stimulating agents (ESA) is common practice in the com-
munity [18]. It should be noted that no randomized study
has ever proven than this intervention positively affects the
natural history of patients with MDS. A number of ESAs
are available. Reported response rates range from 30 to
60% depending on study [19]. Data from the Swedish
group has indicated that addition of G-CSF to erythropoie-
tin increases responses rates and in a retrospective obser-
vational study that early introduction of this combination in
patients with low risk disease and minimally transfusion de-
pendent patients may have an impact of survival [20]. This
group has also developed an algorithm to predict response
to ESA [21] (Table V). The French group has also eval-
uated the impact of ESA on survival in a retrospective
study of 284 patients and compared it to the group of
patients that formed the IPSS cohort [22]. In this study,
patients exposed to ESA had a better survival (HR for
death was 0.43, 95% CI 0.250.72) [22]. Recent questions
on potential tumorigenic effect of these drugs have resulted
in increase scrutiny of their use. G-CSF is not approved by
the FDA for patients with anemia of MDS.
Recommendations. I believe that a course of ESA with or
without G-CSF is not contraindicated in most patients with
low risk MDS and signicant anemia without other cytope-
nia. Data indicates that early incorporation of these agents
is more effective than in patients with heavy transfusion
burdens. I maintain therapy for at least 3 months to judge
efcacy. In responding patients, I continue therapy until
transfusion effect is lost.
There is no data available with new TPO agonists and
recommendations cannot be made at the present time.
Lenalidomide. Lenalidomide is approved in the US for
patients with lower risk MDS, anemia, and alteration of chro-
mosome 5 [23]. It should be noted that this compound is not
approved in Europe due to concerns of increase transforma-
tion to AML in patients treated with this compound. Initial
phase I study of lenalidomide indicated that a potential group
of patients, described above, benetted signicantly from
therapy [24]. This was conrmed in a subsequent phase II
study of lenalidomide in patients with anemia and alteration
of chromosome 5 [24]. In that study, 148 patients received 10
mg of lenalidomide for 21 days every 4 weeks or daily. Of
those, 112 had decrease need for transfusions (76%; 95%
CI 6882) and 99 patients (67%; 95% CI, 5974) became
transfusion independent. Response was fast: median time
4.6 weeks. The median rise of hemoglobin was 5.4 g/dL. Of
interest, cytogenetic responses were observed in close to
50% informative patients. Predictors of response included
presence of a platelet count of 100 3 10
9
/L and less than 4
prior units of red cells transfused. It should be noted that in
this study patients with a platelet count of less than 50 3 10
9
/
L were excluded.
In a parallel study, lenalidomide was investigated in
patients without chromosome 5 alterations [25]. In this
study, 214 patients received 10 mg oral lenalidomide daily
or 10 mg on days 1 to 21 of a 28-day cycle. Fifty six (26%)
patients achieved transfusion independence after a median
of 4.8 weeks of therapy. Median response duration was
41.0 weeks. Lenalidomide is not approved for this indication
at the present time.
It should be noted that two large randomized phase III
clinical trials are currently being conducted in MDS. One
known as AZA-004 has completed accrual and studied two
different doses of lenalidomide (5 and 10 mg orally daily)
versus placebo. This study was also designed to clarify the
issue of transformation to AML. This study was reported at
ASH 2009 and indicated that a dose of 10 mg daily was
superior [26]. A nal report is expected this year. Another
phase III is studying the role of lenalidomide in patients
with lower risk disease without an alteration of chromosome
5. This study is ongoing.
Recommendations. Despite lack of survival data with
lenalidomide, the degree of response in patients with lower
risk MDS, anemia, good platelets, and del5q makes stand-
ard of care in my opinion. I do not consider this agent in
patients with thrombocytopenia. No recommendation can
be made for patients without an alteration of chromosome
5 at the present time. It is likely that a subset of patients
with anemia, low risk disease, and diploid cytogenetics
could also benet from this compound. This is being tested
in a large phase III trial mention above.
Azanucleosides. Two azanuclesoides are approved for
MDS: 5-azacitidine [27] and 5-aza-2
0
-deoxycitidine (decita-
bine) [28]. 5-azacitidine is approved for all subsets of MDS,
whereas decitabine for those with INT-1 disease and above.
Figure 2. Proposed treatment algorithm of patients with MDS. Once diagnosis is
conrmed, patients are divided into a lower and a higher risk category. Options for
patients with lower risk disease include growth factors, lenalidomide, and azanu-
cleosides. Treatment in general is sequential: patients that do not respond to
growth factors can be treated with lenalidomide or azanuclesoides, if appropriate.
Patients that fail lenalidomide can subsequently be treated with azanucleosides.
There is little experience in terms of outcomes with this approach. Patients that fail
all three therapies should be considered for alloSCT and/or clinical trial. For
patients with higher risk MDS options are alloSCT, AML-like therapy, or azanucleo-
side. Prognosis of patients that fail any of these approaches is poor, particularly
for those exposed to azanucleosides. In this setting, alloSCT and clinical trial
should be strongly considered.
TABLE V. Prediction Model of Response to ESA21
Characteristic Points
Serum EPO level <100 u Add 2 points
Serum EPO level 100 to 500 u Add 1 point
Serum EPO level >500 u Subtract 3 points
<2 RBC units per month Add 2 points
2 RBC units per month Subtract 2 points
Patients with more than 1 point have a high response (74%) likelihood to ESA;
patients with 21 to 11 points have an intermediate response (23%) and patients
with less than 21 point have a low response rate (7%). Adapted from Ref. 21.
EPO, erythropoietin; RBC, red blood cell transfusion.
494 American Journal of Hematology
annual clinical updates in hematological malignancies: a continuing medical education series
There is very little data in the use of these compounds in
lower risk MDS. None of them have been shown to modify
the natural history of patients with lower risk disease.
Different schedules of 5-azacitidine have been explored
in MDS. In a community study, a 5-day schedule was com-
pared with a 7 day 5-2-2 schedule (weekend off) or a 5-2-5
schedule of 10 days [29]. Fifty patients were assigned to
each arm (except 5-2-2 was 51 patients). Most patients
had lower risk disease. Hematologic improvement was
achieved by 44 to 56% of patients in each arm. Transfusion
independency was documented in 50 to 64% of patients.
There was a trend for better response rates and less toxic-
ity with the 5-day schedule of 5-azacitidine.
Therefore, it is reasonable to use a shorter (5 day sched-
ule) of 5-azacitidine in lower risk MDS.
There is very little data with decitabine in patients with
lower risk disease. In the initial randomized trial of decita-
bine [28], 31 patients with INT-1 disease were treated. Four
of 28 patients achieved some type of response. A random-
ized phase II trial has been conducted exploring a 3-day
subcutaneous schedule versus a weekly 3 3 monthly
schedules. Doses were 20 mg/m
2
. The nal results of this
study are expected this year [30].
Recommendations. Both 5-azacitidine and decitabine are
used in patients with lower risk disease that are transfusion
dependent. Most patients treated with these agents have
failed or were not candidates for growth factor support or
lenalidomide. Further studies of these agents in lower risk
MDS are needed. An oral formulation of 5-azacitidine is
being studied for patients with lower risk MDS (Garcia-Man-
ero et al., JCO in press) [31].
Immune therapy. This is an area of controversy. It is
accepted that a subset of patients with MDS are character-
ized by deregulation of immunity [11,32]. This could explain
that features of bone marrow failure that are present in a
signicant fraction of patients. Based on this, it will be logi-
cal that the use if immmunemodulatory agents could have
therapeutic benet in MDS. The group at the NIH has pio-
neered these approaches. Agents studied include antithy-
mocyte globulin (ATG), cyclosporine, and steroids. These
therapies have been modeled after therapy of aplastic ane-
mia [11]. The group at the NIH has also developed an algo-
rithm to predict response to these classes of agents [33].
These include younger age, HLA-DR15, and shorter dura-
tion of transfusion dependency. Using this algorithm, the
NIH group has recently reported that alemtuzumab, an anti-
body against CD52, has signicant activity in patients with
MDS predicted to response to immune suppressive therapy
[34]. Recently, the group at Moftt Cancer Center has sug-
gested that a CD4/CD8 ratio could be used to predict
response [35].
Our group has not been capable to reproduce the data
discussed above. Response rates with ATG observed at
MDACC are signicantly lower than those of the NIH. The
most important predictor for response has been the pres-
ence of marrow hypocellularity [36]. This is in line of the
results of Mufti et al. in London [37].
Also recently, the impact of this interventions on survival
has been questioned. Data from a Swiss study comparing
ATG versus supportive care indicated a higher response
rate but no survival benet [38]. In this study, patients were
randomized to a combination of horse ATG with cyclospo-
rine versus best supportive care (BSC). Forty ve patients
received ATG1CSA and 43 patients received BSC. By
month 6, 13 of 45 patients on ATG1CSA had a hemato-
logic response compared with four of 43 patients on BSC
(P 5 0.0156). Despite higher response rates no signicant
effect on survival or transformation was observed.
Recommendations. This is a particular difcult group of
patients. Outcomes in older individuals are not affected by
the use of ATG and most patients are treated with some
form of supportive care that could include cyclosporine,
growth factors, and steroids. Most older patients cannot tol-
erate this type of approach. The impact of it is not known
either. In younger patients with severe hypoplastic MDS,
allogeneic stem cell transplantation (alloSCT) should be
considered as soon as possible. For those that are not can-
didates, a combination with equine ATG is recommended. I
cannot recommend the use of alemtuzumab at the present
time until more data from other clinical trials is reported.
Allogeneic stem cell transplantation. AlloSCT is usu-
ally not recommended in patients with lower risk disease
even if they are young. This is based on data from Cutler
et al. using a Markov model [39]. The explanation for this
effect is based on the expected long survival of this subset
of patients. The anticipated early mortality with alloSCT
cannot be overcome by the potential benecial survival
effect in relation to survival expectation without therapy.
Recommendations. I generally do not recommend alloSCT
in patients with lower risk disease at initial presentation. That
said because of time required for donor identication, I refer
all potential candidate patients for a transplant consult in
anticipation of future needs. Patients that are candidates for
alloSCT and that had been exposed to multiple therapies
(growth factors, lenalidomide, azanuclesoides, etc.) should
be considered for transplantation. These patients are also
candidates for clinical trials. Patients with hypoplastic MDS
that are young should be considered for alloSCT up front.
Supportive care measures in MDS. A number of inter-
ventions can be used in patients with MDS. These include
the use of prophylactic antibiotics and iron chelation. No
randomized data exists to make formal recommendation for
any of these interventions. In my experience patients with
isolated neutropenia and MDS are not at signicantly
increased risk of infection to support recommendation of
prophylactic antibiotics.
The role of iron chelation in MDS is more complicated.
Data from thallasemias indicates that iron chelation has an
important role in this setting. Iron accumulation is frequent in
MDS. The consequences of this are not fully understood in
MDS. I do not see in my practice patients with liver cirrhosis
or cardiomyopathy as reported by other groups [40]. Iron
accumulation could have a role in transformation to AML [41]
and increased infectious complications. The NCCN guidelines
recommend the use of chelation therapy in patients with ferri-
tin levels above 2500 ng/mL [42]. A large phase III study is
evaluating the role of iron chelation in MDS.
Recommendations. I do not routinely recommend antibi-
otics in patients with isolated neutropenia and MDS that
are not receiving some form of cytotoxic or immunosup-
pressive therapy. I use iron chelation in patients with ferritin
levels in excess of 2500 ng/mL but I consider all these
patients for a clinical trial of iron chelation.
Options for newly diagnosed patients with higher risk
MDS
Options for patients with higher risk MDS have evolved
signicantly over the last decade. Before that period most
patients were treated with some of cytarabine-based ther-
apy modeled after AML. The used of azanucleosides has
modied this practice [2].
Azanucleosides. Decitabine was studied in an initial
randomized comparing it to BSC [28]. In this study, the
dose of decitabine was 15 mg/m
2
IV infused over 3 hr ev-
American Journal of Hematology 495
annual clinical updates in hematological malignancies: a continuing medical education series
ery 8 hr for 3 days (at a dose of 135 mg/m
2
per course)
and repeated every 6 weeks. Although there was no clear
benet in terms of survival in this study, the use of decita-
bine was associated with a complete response rate of 9%
and overall response rate of 17%. These results led to the
approval of decitabine in the US. Based on the results of a
phase I trial of decitabine performed at MDACC, a Bayes-
ian randomized phase II trial of three different doses and
schedules of decitabine was conducted [43]. In this study, a
5-day schedule of decitabine administered daily at a dose
of 20 mg/m
2
was shown to be superior to a 10-day or sub-
cutaneous schedule. A multicenter phase II trial of decita-
bine (ADOPT) using the 5-day schedule conrmed the
safety of this schedule although response rates were signif-
icantly lower than those reported by the MDACC [44]. In
the ADOPT study, the median number of courses adminis-
tered was 5, the CR rate was 17%, and the median survival
was 19.4 months. No randomized survival study of a 5-day
schedule of decitabine has been conducted in MDS. In par-
allel with this work, European investigators developed a
randomized study of decitabine using the initial 3-day
schedule. The major objective of the study was survival.
Although this study has not yet been published, results pre-
sented at ASH in 2008 indicated that decitabine when used
following the 3-day schedule did not impact survival of
patients with higher risk MDS. Despite all this data, the nal
dose and schedule of decitabine is not fully understood.
Recently, Blum et al. have indicated that a 10-day schedule
of decitabine has signicant activity in AML [45].
5-azacitidine has been studied in higher-risk MDS in two
major randomized multicenter trials: CALGB 9221 [46] and
AZA-001 [27]. In the CALGB 9221 [46] study, 191 patients
with MDS were randomized between 5-azacitidine (75 mg/
m
2
/day for 7 consecutive days every 28 days) and best
supportive care (BSC). Median age was 68 years. Sixty
percent of the patients in the 5-azacitidine group, compared
with 5% of control arm patients, responded to treatment (P
< 0.0001). The median time to leukemic transformation or
death was 21 months in patients treated with 5-azacitidine
versus 12 months in the BSC arm (P 5 0.007). No signi-
cant difference in survival was observed. A landmark analy-
sis suggested a survival advantage for patients initially on
5-azacitidine or who had crossed-over to 5-azacitidine
within 6 months of inclusion on study (P 5 0.03). A signi-
cant improvement in quality of life was documented in
patients treated with 5-azacitidine compared with BSC [47].
AZA-001 was a randomized study designed to test the con-
cept that treatment with 5-azacitidine resulted in improved
survival compared with a menu of standard of care options
[27]. These included BSC, low dose cytarabine (ara-C), or
AML-like therapy. In AZA-001, 358 patients with higher-risk
MDS were randomized to either 5-azacitidine (as per
CALGB9221 schedule) or to standard of care. Median age
of patients was 69 years. Median survival was signicantly
better in patients treated with 5-azacitidine versus standard
of care options: 24.5 months versus 15 months (P 5
0.0001). Progression to AML was signicantly delayed, and
RBC transfusion requirements and rate of infections were
also signicantly improved with 5-azacitidine. The survival
advantage with 5-azacitidine was irrespective of age
(including patients older than 75 years), percent of marrow
blasts (including patients with 20 to 30% blasts, now classi-
ed as AML using WHO criteria) or karyotype. This effect
was signicant when compared with BSC and low dose
ara-C. The number of patients treated with AML-like ther-
apy was too small to allow comparison with 5-azacitidine.
Biomarkers of response to azanucleosides. An area
of active research is the identication of biomarkers predic-
tive of response to azanucleosides. Due to their capacity to
induce DNA hypomethylation, a number of groups have
focused in the identication of methylation patterns that
would predict for response. At the present time, no such
prole exists. Two candidate biomarkers and a clinical
model have been recently proposed. Levels of miR29b [45]
and mutations on TET2 [48] have been reported to be
associated with response to decitabine and azacitidine,
respectively. miR29b regulates expression levels of DNMT1
[45]. TET2 is a protein involved in the conversion of 5mC
to 5OHmC and could therefore result in passive induction
of DNA methylation [49]. None of these two biomarkers
have been conrmed in other larger studies. Our group
was not able to correlate miRNA29b levels with response
[50]. Recently, the French group reported that previous low
dose ara-C, bone marrow blasts more than 15% and abnor-
mal karyotype predicted for lower response rate to 5-azaci-
tidine [51]. Poor performance status, intermediate and poor
risk cytogenetics, circulating blasts, and more than 4 units
of red blood cells transfuse every 8 weeks were associated
with worse survival [51]. In the near future, a combination
of genetic and clinical markers could be used to dene who
may benet from this type of therapy.
Recommendations. The azanucleosides are the standard
of care for most patients with higher risk disease. No study
has compared 5-azacitidine versus decitabine. Although
response rates appear to be similar, only 5-azacitidine has
been associated with improvement of survival in a random-
ized trial. On the basis of this, I consider 5-azacitidine
standard therapy for front line treatment in higher risk MDS.
AML-like chemotherapy. AML-like protocols in higher
risk MDS have generally used classical anthracycline-araC
combinations similar to those used in de novo AML [52,53].
When used in MDS or AML post-MDS, AML-like therapy
results in lower CR rates (4060%), shorter CR duration
(median duration of 1012 months), and tend to be associ-
ated with more prolonged periods of aplasia. In addition,
the feasibility of AML-like therapy is also reduced by the
advanced median age of patients with MDS. The most im-
portant prognostic factor of response to AML-like therapy is
karyotype: patients with unfavorable karyotype (27/del 7q
or complex karyotype) have a low CR rate and short dura-
tion of response. This is of importance as, at least in the
AZA-001 study [27], patients with alterations of chromo-
some 7 had a signicant benet with 5-azacitidine versus
other therapies. Currently, AML-like therapy is only recom-
mended for relatively younger patients with favorable karyo-
type that are candidates for alloSCT.
Recommendations. The randomized AZA-001 study was
not powered to demonstrate the superiority of 5-azacitidine
versus AML-like therapy. The reason for this being that most
investigators did not consider their patients candidates for
such therapy. Therefore, the question is who may be a can-
didate for AML therapy. In our practice, this is restricted to
younger patients with a high likelihood of response to the
therapy, such as diploid patients. I rarely use AML therapy in
older patients or in those with poor risk cytogenetics.
AlloSCT. AlloSCT is reported to be the only curative
treatment of higher-risk MDS. Results from selected studies
report prolonged DFS in about 30 to 50% of the patients
[54]. However, its use is mainly restricted to younger
patients with an appropriate donor. Different transplant
modalities of different intensities and donor sources are
now in use. Most of them remain investigational and there-
fore in my opinion all patients should be transplanted in the
setting of a clinical trial. Current advances in transplant
technology are allowing the consideration of older patients
496 American Journal of Hematology
annual clinical updates in hematological malignancies: a continuing medical education series
and alternative donors. This should result in greater num-
ber of older patients benetting from this potentially curative
treatment modality. There are several relevant practical
questions regarding alloSCT in MDS. This includes timing
of transplant; and what to do with patients that achieved a
complete response to hypomethylating agent prior to
alloSCT. A study from the IBMTR indicated that early trans-
plantation in higher-risk MDS was associated with longer
life expectancy [39]. This study was performed before the
mature use of hypomethylating agents. A retrospective
study of the IBMTR is comparing azanucleosides use with
transplant in MDS. In terms of what to do in responding
patients, no recommendation can be given at this time.
Other questions include whether or not alloSCT should be
preceded by a cytoreductive regimen (with chemotherapy
or perhaps hypomethylating agents). Many authors con-
sider that when marrow blasts >10% at the time of trans-
plant, because of the very high relapse risk post transplant,
pretransplant therapy is required. A recent report from the
EBMTR has indicated that long-term survival of patients
with monosomy 7 is very poor with alloSCT [55]. Although
this data needs to be validated in more recent series, these
results have signicant implications for the use of alloSCT
in MDS, as this suggests that the current practice of
reserving transplant for poor prognostic features may not
be indicated.
Recommendations. All patients potential candidates for
alloSCT should be counseled regarding the possibilities of
undergoing alloSCT. Optimally patients will be enrolled in
an MDS specic clinical trial of alloSCT.
Options for patients with relapsed or refractory lower
risk MDS
Treatment of patients with relapsed or refractory lower
risk MDS is sequential. A common practice is to start
growth factor support and then consider lenalidomide or an
azanucleoside. Patients that fail either lenalidomide or aza-
nucleoside are candidates for clinical trials or alloSCT. A
list of clinical trials for patients with MDS is shown in Table
VI.
Options for patients with relapsed or refractory higher
risk MDS
At the present time, there is no therapy approved for
patients with higher risk MDS that fail hypomethylating
agents or relapsed after AML-like therapy or alloSCT. The
group of patients that failed hypomethylating agents has
particularly poor prognosis. In a study from MDACC in
patients that had received and responded to decitabine,
median survival was 4 months [56]. In general, outcomes
were very poor and patients become refractory to alternate
azanucleoside. Only patients that received alloSCT had a
meaningful outcome. This is an area of active research that
is complicated by lack of understanding of what are the
mechanisms of resistance to azanucleoside agent. A list of
potential agents is shown in Table VI.
Recommendations. All patients with higher risk disease
that have relapsed or refractory disease should be consid-
ered for alloSCT and for clinical trial.
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TABLE VI. A List of Investigational Clinical Trials in MDS
Agent Mechanism of action Phase Indication
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Oral azacitidine31 Hypomethylating agent II Lower risk
Arry-614 P38MAPK inhibitor I Lower risk
Deferasirox57 Iron chelation III Lower risk
Clofarabine58 Nucleoside analogue II Int and higher risk
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ON1910 Unknown III Hypomethylating failure
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