SYMPOSIUM ON NEOPLASTIC HEMATOLOGY AND MEDICAL ONCOLOGY

Myelodysplastic Syndromes: Diagnosis and

Treatment
David P. Steensma, MD

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Physicians should claim only the credit commensurate with the extent of
their participation in the activity.
Learning Objectives: On completion of this article, you should be able to (1)
diagnose myelodysplastic syndrome in a patient with unexplained cytopenias;
(2) describe the role of molecular testing in evaluation of patients with sus-
pected myelodysplastic syndromes; and (3) apply risk stratification tools to
choose appropriate initial therapy for patients with myelodysplastic syndromes.
Disclosures: As a provider accredited by ACCME, Mayo Clinic College of
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For editorial
ments discussed in their presentation. Disclosure of this information will be comment, see
published in course materials so that those participants in the activity may page 848
formulate their own judgments regarding the presentation.
In their editorial and administrative roles, William L. Lanier, Jr, MD, Terry L.
Jopke, Kimberly D. Sankey, and Nicki M. Smith, MPA, have control of the con- Dana-Farber Cancer Insti-
tent of this program but have no relevant financial relationship(s) with industry. tute and Harvard Medical
Dr Steensma is a consultant for Celgene, MEI Pharma, Astex, and H3/Eisai and School, Boston, MA.
serves on the Data Safety Monitoring Committee for Amgen and Novartis.
Only azacitidine, decitabine, and lenalidomide are FDA approved for MDS.
All other agents and uses are off label or experimental.
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Abstract

In the past few years, new biological insights into the myelodysplastic syndromes (MDS) resulting from
molecular genetic analysis have improved pathologic understanding, but treatment advances have not kept
pace. More than 40 genes are now known to be recurrently mutated in MDS. However, because most of
these genes encode spliceosome components, chromatic remodeling factors, epigenetic pattern modula-
tors, or transcription factors rather than more easily inhibited activated tyrosine kinases, there are as of yet
few narrowly targeted therapies available for MDS. Three drugsdazacitidine, decitabine, and lenalido-
midedwere approved by the US Food and Drug Administration for MDS indications a decade ago, and
these agents can improve hematopoiesis, delay disease progression, and improve survival and quality of
life for a subset of patients. However, only a few patients with MDS respond to these agents, and their
benefit is temporary. The only potentially curative therapy for MDS is allogeneic hematopoietic stem cell
transplant, but owing to the advanced age of many patients with MDS and the frequency of serious co-
morbid conditions, less than 10% of patients currently undergo stem cell transplant. This narrative review
summarizes the current understanding of MDS and treatment options for these challenging disorders.
ª 2015 Mayo Foundation for Medical Education and Research n Mayo Clin Proc. 2015;90(7):969-983

T
he myelodysplastic syndromes (MDS) myeloid neoplasms characterized by ineffective
are the most commonly diagnosed ac- clonal hematopoiesis and abnormal “dysplastic”
quired bone marrow failure syndromes cell morphology, resulting in peripheral blood
in adults.1 The umbrella term MDS is used to cytopenias and functional blood cell abnormal-
describe a heterogeneous group of chronic ities.2,3 The MDS are inherently unstable and

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may progress over time, including evolution to
acute myeloid leukemia (AML). Acute myeloid
leukemia is currently defined by the World
Health Organization (WHO) as at least 20%
blasts in the marrow or blood or the presence
of either myeloid sarcomas or certain AML-
defining karyotypes, such as t(15;17) and
t(8;21). Therefore, all patients with MDS have
less than 20% marrow blasts, by definition.4
EPIDEMIOLOGIC PROFILE
Owing to the use of ambiguous diagnostic ter-
minology, the exclusion of MDS cases from
most cancer registries, and the incomplete eval-
uation of many older patients with cytopenias,
the incidence and prevalence of MDS have
been difficult to estimate accurately.5 Data
from the US National Cancer Institute’s Surveil-
lance, Epidemiology, and End Results Program
(which has captured MDS cases since 2001) sug-
gest that 10,000 to 12,000 new cases are diag-
nosed in the United States each year (ie, w3-4
cases per 100,000 persons per year).6 However,
analysis of Medicare claims in conjunction with
Surveillance, Epidemiology, and End Results
data indicates that the actual incidence of MDS
in the United States may be closer to 30,000 to
40,000 new cases per yeardseveral times higher
than the incidence of AML.7
Aging is the most important risk factor for
the development of MDS. Owing to errors in
DNA replication and spontaneous mutations
from normal metabolic by-products (eg, conver-
sion of cytosine to thymidine by oxidative deam-
ination from reactive oxygen species), coding
mutations accumulate in hematopoietic stem
cells at a mean
SD rate of 0.13
0.02 exonic
mutations per year of life.8 When an acquired
DNA mutation or combination of mutations pro-
motes growth or generates a survival advantage
to a hematopoietic stem or progenitor cell, clonal
hematopoiesis emerges. Approximately 10% of
individuals older than 70 years have clonal mu-
tations in genes associated with myeloid
neoplasia, such as DNMT3A, TET2, and SF3B1,
and these persons have a 0.5% to 1% chance
per year of acquiring additional mutations that
lead to progression to MDS or another hemato-
logic neoplasm, similar in magnitude to the
risk of monoclonal gammopathy of undeter-
mined significance progressing to myeloma.9,10
In the United States and Western Europe, the
median age at diagnosis of MDS is approximately
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MAYO CLINIC PROCEEDINGS
70 years, and the incidence increases steadily
with age. In Eastern Europe and parts of Asia,
the median age at diagnosis is younger than in
the West, for unclear reasons. Although MDS
have a modest male predominance, a specific
MDS subtypedMDS associated with isolated
deletion of the long arm of chromosome 5, hypo-
lobated megakaryocytes, and erythroid hypopla-
sia (so-called 5qe syndrome)dis more common
in women.11
Approximately 85% to 90% of MDS cases
are idiopathic and result from aging-related he-
matopoietic stem cell injury. Secondary or
therapy-related MDS (t-MDS) represents 10%
to 15% of cases.12 Myelodysplastic syndrome
can be induced by exogenous DNA-damaging
agents, including DNA alkylating drugs (eg,
cyclophosphamide and melphalan), inhibitors
of topoisomerase II (eg, etoposide), ionizing
radiation, and volatile hydrocarbons (eg, ben-
zene). Although it can be difficult to prove a
direct link between an exposure and subsequent
MDS development, features supporting t-MDS
rather than de novo MDS include complex kar-
yotype (defined as 3 acquired chromosome
abnormalities), abnormalities of chromosomes
5 and 7, and TP53 mutation.
Pediatric MDS, which are rare, are frequently
associated with inborn disorders such as Fanconi
anemia, Down syndrome, and congenital neutro-
penia.13 Germline mutations in RUNX1 and
GATA2 transcription factors also predispose to
MDS. Germline RUNX1 mutations are associated
with a prodrome of thrombocytopenia that is
often mistaken for immune thrombocytopenia,
and GATA2 mutations may be associated with
monocytopenia, mycobacterial infections, and
lymphedema (MonoMAC syndrome).14,15
CLASSIFICATION
The fourth edition of the WHO Classification of
Tumours of Hematopoietic and Lymphoid Tissues,
published in 2008, is currently the most widely
used MDS classification (Table 1).4 The 2008
WHO MDS classification is similar to the
earliest formal MDS classification, the 1982
MDS classification of the French-American-
British Cooperative Group. In 2016, a revision
of the WHO classification will be published
that will simplify classification and formally
address the role of molecular genetic testing
in myeloid neoplasia diagnosis. The current
WHO classification has limited prognostic
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 another condition.
cussed further herein.16

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DIAGNOSTIC EVALUATION

Mayo Clin Proc. n July 2015;90(7):969-983

n
been developed, as described further herein.

group that includes chronic myelomonocytic leu-

tion of ATRX, a chromatin remodeling factor

exhibit both MDS and myeloproliferative features
value, so other risk stratification tools have

plete blood cell count is performed to evaluate

with MDS may seek medical attention because

are discovered to have MDS only when a com-

precursors or Auer rods are present, and, to

patients are asymptomatic at diagnosis and

of fatigue, dyspnea, poor exercise tolerance,
that alters alpha-globin expression.18 Patients
less than 100109/L or an absolute neutrophil
g/dL; 80% of patients have a platelet count
level of patients at diagnosis is 9.5 g/dL (to

cytic but rarely can be microcytic owing to

multiple cytopenias. The median hemoglobin
penia in MDS, but most patients present with
AML because outcomes in these patients are
related MDS is grouped with therapy-related
dysplastic cells, whether ring sideroblast erythroid
The 2008 WHO classification considers

toid erythroid maturation, binucleate erythroid

more than 10% of examined cells is considered
Currently, the observation of dysplastic
bruising, bleeding, or an infection, but some
patients have a hemoglobin level less than 11
convert to g/L, multiply by 10.0), and 75% of
MDS/MPN are distinct from those of MDS
and refractory anemia with ring sideroblasts

genetics, biology, and clinical approach to

and marked thrombocytosis (which requires a
such as leukocytosis and thrombocytosisda
poor regardless of the blast count. For cases that

acquired alpha-thalassemia from somatic muta-

ated with MDS is usually macrocytic or normo-
count less than 1.0109/L.17 Anemia associ-
Anemia is the most commonly observed cyto-
cation includes a separate MDS/myeloprolifera-
platelet count >450109/L)dthe WHO classifi-
a limited extent, karyotype results. Therapy-
myeloid cell lineages exhibit greater than 10% of
marrow and blood blast proportion, which

kemia (defined by >1109/L blood monocytes)

without proliferative features and are not dis-

tive neoplasm (MPN) overlap category. The

observed dysplastic features include megaloblas-

important for MDS diagnosis.19 Commonly
blood and marrow cell morphologic features in
TABLE 1. 2008 World Health Organization (WHO) Classification of Myelodysplastic Syndromes (MDS)a,b
Key features WHO-estimated
patients with
Name Abbreviation Peripheral blood Bone marrow MDS (%)
MYELODYSPLASTIC SYNDROMES: DIAGNOSIS AND TREATMENT

RCUD
Refractory anemia RA Anemia; <1% peripheral blood blasts Unilineage erythroid dysplasia (in >10% of cells); <5% blasts 10-20

http://dx.doi.org/10.1016/j.mayocp.2015.04.001
Refractory neutropenia RN Neutropenia; <1% peripheral blood blasts Unilineage granulocytic dysplasia; <5% blasts <1
Refractory thrombocytopenia RT Thrombocytopenia; <1% blasts Unilineage megakaryocytic dysplasia; <5% blasts <1
Refractory anemia with ring sideroblasts RARS Anemia; no blasts Unilineage erythroid dysplasia; 15% of erythroid precursors are
ring sideroblasts; <5% blasts 3-11
Refractory cytopenias with multilineage dysplasia RCMD Cytopenia(s); <1% blasts; no Auer rods Multilineage dysplasia
ring sideroblasts; <5% blasts; no Auer rods 30
Refractory anemia with excess blasts, type 1 RAEB-1 Cytopenia(s); <5% blasts; no Auer rods Unilineage or multilineage dysplasia; 5%-9% blasts; no Auer rods 40c
Refractory anemia with excess blasts, type 2 RAEB-2 Cytopenia(s); 5%-19% blasts;
Auer rods Unilineage or multilineage dysplasia; 10%-19% blasts;
Auer rods
MDS associated with isolated del(5q) Del(5q) Anemia; normal or high platelet count; 1% blasts Isolated 5q31 chromosome deletion; anemia, hypolobated megakaryocytes <5
Childhood MDS, including refractory
cytopenia of childhood (provisional) RCC Pancytopenia <5% marrow blasts for RCC; marrow usually hypocellular w1
MDS, unclassifiable MDS-U Cytopenias; 1% blasts Does not fit other categories; dysplasia; <5% blasts; if no dysplasia, Unknown
MDS-associated karyotype
a
RCUD ¼ refractory cytopenias with unilineage dysplasia.
b
If peripheral blood blasts are 2% to 4%, the diagnosis is RAEB-1 even if marrow blasts are less than 5%. If Auer rods are present, the WHO considers the diagnosis RAEB-2 if the blast proportion is less than 20% (even if <10%) or
acute myeloid leukemia (AML) if at least 20% blasts. Cases of RCUD, RARS, or RCMD where the peripheral blood blasts are exactly 1% should be considered MDS-U according to the WHO. For all subtypes, peripheral blood
monocyte counts must be less than 1109/L. Bicytopenia may be observed in RCUD subtypes, but pancytopenia with unilineage marrow dysplasia should be classified as MDS-U. Therapy-related MDS, whether due to alkylating
agents, topoisomerase II inhibitors, or radiation, is classified together with therapy-related AML in the WHO classification of AML and precursor lesions. The listing in this table excludes MDS/myeloproliferative neoplasm overlap
categories, such as chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, and RARS with thrombocytosis.
c
This 40% figure represents the proportion of patients with RAEB-1 or RAEB-2, collectively.
Adapted from WHO.4

971

precursor cells and other nucleation abnormal-
ities, ring sideroblasts, neutrophil hypolobulation
or hypogranulation, and small megakaryocytes
with abnormally segmented nuclei. The diag-
nostic requirement for morphologic dysplasia
may evolve with more routine use of molecular
genetic testing in diagnostic evaluation.
Dysplastic morphologic features are often
accompanied by cellular dysfunction. For
example, hypogranular neutrophils have
impaired bactericidal activity, which increases
neutropenia-associated infection risk, and
platelets in MDS often express abnormally low
levels of procoagulant cell surface markers or
lack intracellular granules, which exacerbates
bleeding from thrombocytopenia.20,21 As a
result of such functional defects, infection and
bleeding risks in MDS correlate poorly with
the circulating neutrophil and platelet count.
Although the bone marrow in MDS usually
is normocellular or hypercellular for age, 10%
to 20% of cases are accompanied by a hypocel-
lular marrow. These hypoplastic or hypocellu-
lar MDS cases may be difficult to distinguish
from aplastic anemia and may have an
increased likelihood of response to immuno-
suppressive drug therapy.22 Increased reticulin
fibrosis is frequently present in the marrow in
MDS; severe fibrosis is associated with poorer
prognosis.23 Occasionally, patients with MDS
present with immune dysregulation, paraneo-
plastic syndromes, or other clonal disorders,
such as a small B-cell clone, paroxysmal
nocturnal hemoglobinuria clone, and mono-
clonal gammopathy of undetermined signifi-
cance. The influence of paroxysmal nocturnal
hemoglobinuria clones on clinical behavior is
unpredictable, but these clones are usually
small, clinically irrelevant, and not associated
with hemolysis.24 Leukocytosis and spleno-
megaly are rare in MDS, and their presence sug-
gests the possibility of chronic myelomonocytic
leukemia or another MDS/MPN overlap syn-
drome, or an alternative diagnosis.
Diagnostic evaluation of the patient with sus-
pected MDS includes medical history and phys-
ical examination, complete blood cell count,
review of the blood smear, bone marrow aspirate
and biopsy, and laboratory tests to rule out other
disorders that mimic MDS.25 Not all that is
dysplastic is MDS, and nutritional deficiency
(iron, vitamin B12, folate, and copper), medication
effect (eg, antimetabolites, such as methotrexate
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MAYO CLINIC PROCEEDINGS
and azathioprine), alcohol abuse, human immu-
nodeficiency virus infection, and immune-
mediated cytopenias need to be excluded.
Although the blood smear may suggest MDS,
marrow aspiration is essential to establish the
diagnosis. Bone marrow core (trephine) biopsy
provides complementary information on
cellularity and architecture, megakaryocyte
morphology, and the presence of fibrosisduseful
information that may inform therapeutic
decisions.
Flow cytometric analysis is often used by
pathologists to evaluate patients suspected of
having MDS.26 Flow cytometry may detect
aberrant antigen expression by hematopoietic
cells or abnormal cell populations, such as
increased blasts, but flow cytometry is currently
a complementary assay that is best interpreted
in the context of marrow morphology. Because
flow cytometric enumeration of marrow blasts
is subject to various technical artifacts, it should
not replace a marrow aspirate manual differen-
tial count.
In contrast to flow cytometry, cytogenetic
studies of the marrow are essential in evaluation
of suspected MDS. Abnormal cytogenetic results
can provide confirmation of the diagnosis when
the morphologic profile is ambiguous. Specific
karyotypes correlate with prognosis and response
to treatment (Tables 2 and 3), such as deletion of
chromosome arm 5q and high response rate to
lenalidomide.17,27,28 Rarely, fluorescence in situ
hybridization (FISH) analysis with probes
directed toward common MDS-associated abnor-
malities reveals specific chromosomal transloca-
tions and gains or losses of large DNA segments
not detected using standard cytogenetic methods.
The yield of FISH is low if karyotyping is success-
ful, and the clinical relevance of small clones
detectable only by FISH and not by karyotyping
is unclear.29 Although the WHO classification al-
lows labeling patients with cytogenetic abnormal-
ities but bland morphologic features as having
unclassifiable MDS, certain karyotypes (trisomy
8, loss of the Y chromosome, and deletion 20q)
are not specific enough to diagnose unclassifiable
MDS.4
Almost all patients who develop t-MDS
secondary to exposure to mutagenic agents
have chromosomal abnormalities.30 Therapy-
related MDS that is associated with previous
treatment with alkylating agents or exposure
to ionizing radiation frequently demonstrates
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MYELODYSPLASTIC SYNDROMES: DIAGNOSIS AND TREATMENT

TABLE 2. The 1997 International Prognostic Scoring System (IPSS) for Myelodysplastic Syndromesa
Category scoreb
Prognostic factor 0 (best) 0.5 1.0 1.5 2.0 (worst)
Marrow blasts (%) <5 5-10 e 11-20 21-30c
Karyotype Good: normal, isolated eY, isolated Intermediate: all karyotypes Poor: abnormal chromosome e e
del(5q), or isolated del(20q) not defined as good or poor 7 or a complex karyotype
(3 anomalies)
Peripheral blood
cytopeniasd 0 or 1 2 or 3 e e e

Median survival (y) Time until 25% of

Total Patients aged Patients aged surviving patients
Risk category score All patients <60 y (n¼205) 60 y (n¼611) developed leukemia (y)
Low 0 5.7 11.8 4.8 9.4
Intermediate-1 0.5 or 1.0 3.5 5.2 2.7 3.3
Intermediate-2 1.5 or 2.0 1.2 1.8 1.1 1.1
High 2.5 0.4 0.3 0.5 0.2
a
Although replaced by the revised IPSS in 2012, numerous clinical trial protocols still use the original IPSS for determination of eligibility.
b
Scoring system: A point value from 0 to 2.0 is determined for each of the 3 prognostic factors, and the 3 values are summed to obtain the total IPSS score.
c
No longer considered myelodysplastic syndrome (redefined as acute myeloid leukemia by the World Health Organization in 2001).
d
The IPSS definition of peripheral blood cytopenias: hemoglobin level less than 10 g/dL; absolute neutrophil count less than 1.8109L; and platelet count less than 100109L.
Adapted from Blood.17

losses involving chromosomes 5 and 7 and
emerges 3 to 7 years after exposure. Patients
treated with epipodophyllotoxins may exhibit
translocations at the chromosome 11q23 locus
involving the MLL gene; the latency period be-
tween exposure and diagnosis with this form
of t-MDS/AML is typically 1 to 3 years.
Increasingly, molecular genetic profiling is
used to evaluate patients suspected of having
MDS. Molecular genetic profiling can augment
prognostic assessment and predict outcomes
after allogeneic stem cell transplant.31,32 Molec-
ular genetic profiling may also be useful diag-
nostically, especially in cases that lack another
explanation for cytopenias but do not meet
the diagnostic criteria for MDS or another dis-
order. The term idiopathic cytopenia(s) of unde-
termined significance (ICUS) has been used for
such patients, and although some individuals
with ICUS will eventually be diagnosed as hav-
ing MDS or AML, others will resolve or be
found to have a nonneoplastic diagnosis.33
Several commercial vendors offer MDS molec-
ular genetic panels, and a homegrown clinically
validated 96-gene panel that returns results in
72 hours is now routinely used for evaluating
patients with ICUS or suspected MDS in the au-
thor’s practice.34 Because more than 80% of pa-
tients with MDS have a somatic mutation in 1
of the more than 40 most commonly mutated
MDS-associated genes, the negative predictive
value of a normal result on an MDS mutation
panel is relatively high, and nonneoplastic
causes of cytopenias should be carefully
excluded when mutation results are normal.35
However, because clonal hematopoiesis is pre-
sent in more than 10% of healthy people older
than 70 years, clinicians must be cautious in
interpreting mutations in patients with a
normal karyotype and without morphologic
changes of dysplasia.
PROGNOSIS
Risk assessment in MDS is important for therapy
selection and for counseling patients. Although
the natural history of MDS includes a risk of pro-
gression to AML in 25% to 30% of patients, most
patients with MDS do not develop AML and
instead die of complications of cytopenias or of
unrelated conditions that are common in geriatric
populations, such as cardiovascular disease.36
This observation led to a change in the name of
these disorders in the 1970s from the simpler
but incomplete designation preleukemia to MDS.
Until recently, the most widely used risk strat-
ification tool for MDS was the 1997 International
Prognostic Scoring System (IPSS) (Table 2).17 The
IPSS, which is still reflected in drug labels and
used for clinical trial eligibility determination, is
based on the sum of 3 subscores: karyotype,

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 MAYO CLINIC PROCEEDINGS

TABLE 3. 2012 Revised International Prognostic Scoring System (IPSS-R)a-c

Updated cytogenetic classification for use in the IPSS-R (n¼7012)
Time until 25% of
Median patients developed Patients in
Risk group Included karyotypes survival (y) AML (y) this group (%)
Very good del(11q), -Y 5.4 Not reached 4
Good Normal, del(20q), del(5q) alone or with 1 other anomaly, del(12p) 4.8 9.4 72
Intermediate þ8, del(7q), i17q, þ19, any other single or double abnormality not 2.7 2.5 13
listed, 2 or more independent clones
Poor Abnormal 3q, -7, double abnormality include -7/del(7q), complex with 1.5 1.7 4
3 abnormalities
Very poor Complex with >3 abnormalities 0.7 0.7 7

IPSS-R
Categories and associated scores
Parameter Very good Good Intermediate Poor Very Poor
Cytogenetic risk group 0 1 2 3 4
Marrow blasts (%) <2 2-<5 5-10 >10
0 1 2 3
Hemoglobin (g/dL) 10 8-<10 <8
0 1 1.5
Absolute neutrophil count (109/L) 0.8 <0.8
0 0.5
Platelet count (109/L) >100 50-100 <50
0 0.5 1

IPSS-R (see: http://www.mds-foundation.org/ipss-r-calculator/)

% patients in this risk group Median survival, Median survival for pts Time until 25% of patients
Risk group Points (n¼7012; AML data on 6485) years under 60 years develop AML, years
Very low 0-1.5 19% 8.8 Not reached Not reached
Low 2.0-3.0 38% 5.3 8.8 10.8
Intermediate 3.5-4.5 20% 3.0 5.2 3.2
High 5.0-6.0 13% 1.5 2.1 1.4
Very high >6.0 10% 0.8 0.9 0.7
a
AML ¼ acute myeloid leukemia.
b
SI conversion factors: To convert hemoglobin values to g/L, multiply by 10.0.
c
Possible range of summed scores: 0-10.
Adapted from Blood.28

number of cytopenias, and proportion of marrow
blasts. Patients younger than 60 years with a low
IPSS score have median survival of more than 5
years, and older patients with a high IPSS score
have median survival of only less than 6 months,
if treated with supportive care alone. For each
IPSS risk group, outcomes tend to be better for
younger patients than for older patients.
The 1997 IPSS had several important limita-
tions.37 It was validated only for adult patients
with de novo disease treated with supportive
care or hematopoietic growth factors. It did not
weight severity of cytopenias, included a limited
repertoire of karyotypes, did not include risk
n n
974 Mayo Clin Proc.
factors such as transfusion dependence, and did
not adequately stratify patients with MPN fea-
tures or those with t-MDS. In addition, in each
IPSS risk group there are wide variations in pa-
tient outcomes. Several newer MDS prognostic
systems have been introduced since 2007 to try
to overcome these limitations. The WHO-based
Prognostic Scoring System integrates the WHO
classification with karyotyping data, the degree
of anemia, and the presence or absence of marrow
fibrosis; it is used primarily in Europe.38 A general
risk model proposed by investigators at the MD
Anderson Cancer Center is valid across a broad
spectrum of patients with MDS, including those
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MYELODYSPLASTIC SYNDROMES: DIAGNOSIS AND TREATMENT
with t-MDS and those who previously have been
treated with a disease-modifying drug.39 A risk
model for IPSS lower-risk MDS also was devel-
oped at the MD Anderson Cancer Center.40
A revised IPSS (IPSS-R) based on analysis of
more than 7000 patients from more than 10
countries was published in 2012 (Table 3).28
The major changes in the IPSS-R from the IPSS
are that the IPSS-R includes a broader range of cy-
togenetic abnormalities than those included in the
1997 IPSS, and the IPSS-R also weights cytoge-
netic findings more heavily than other variables,
such as cytopenias, whereas the IPSS weighted
blasts most heavily. In addition, blast cutoff points
are different in the IPSS-R, which has 5 risk cate-
gories compared with 4 for the IPSS, and the de-
gree of cytopenias is considered in the IPSS-R,
whereas the IPSS considered only the number of
cytopenias. Despite these improvements, the
IPSS-R is still valid only in patients with de
novo MDS at the time of diagnosis. In addition,
other prognostically important variables, such
as the presence of comorbid conditions, kinetics
of clonal evolution, and molecular genetic find-
ings, are not accounted for by the IPSS-R or by
any of the other MDS risk stratification tools.
In the future, molecular genetic data will
be increasingly used for risk stratification.
For example, in 1 study, mutations in EZH2,
ETV6, ASXL1, RUNX1, and TP53 retained
prognostic significance independent of the
IPSS in a multivariable analysis, and the over-
all mutation burden was also prognostic, with
a higher risk of AML progression and death in
those with more detected mutations.41
BIOLOGY
A detailed discussion of MDS biology is beyond
the scope of this review. Cytogenetic and mo-
lecular genetic abnormalities indicate that
MDS are clonal disorders. The neoplastic clone
in MDS includes stem/progenitor cells and
more differentiated myeloid, erythroid, and
megakaryocytic cells; B cells are also sometimes
part of the clonal process, but T cells are rarely
involved, although T-cell clones similar to
those seen in large granular lymphocyte leuke-
mia can be detected in some patients.42 Most
marrow and blood cells in MDS are clonal,
even if blast counts are not increased.
Recurrent MDS-associated DNA mutations
cluster in genes that encode biological pathways
for messenger RNA splicing, DNA methylation,
Mayo Clin Proc. n July 2015;90(7):969-983 n http://dx.doi.org/10.1016/j.mayocp.2015.04.001
www.mayoclinicproceedings.org
and chromatin remodeling (Figure 1).35 Cell
culture studies with primary MDS samples have
found reduced growth of multilineage colony-
forming unit progenitors.43,44 Experimental
evidence also implicates inhibitory cytokines
and increased intramedullary apoptosis as con-
tributors to ineffective hematopoiesis in early
MDS.44 The role of the marrow microenviron-
ment and hematopoietic niche in MDS continues
to undergo scrutiny as stromal support of the
growth and maturation of normal hematopoietic
progenitors is impaired in MDS, and in a murine
model, mutation of a gene in osteoprogenitor cells
resulted in an MDS-like phenotype.45
TREATMENT
Other than allogeneic hematopoietic stem cell
transplant (HSCT), which is currently used in
less than 10% of patients and is successful 20%
to 50% of the time, there is no cure for MDS.46
Three medications have specific US Food and
Drug Administration (FDA) approval for
MDS-related indications: azacitidine, a DNA
methyltransferase inhibitor and nucleoside
analogue that was approved in 2004; lenalido-
mide, a modulator of cereblon and ubiquitin
ligase activity that was approved in 2005; and
decitabine, another DNA methyltransferase in-
hibitor that was approved in 2006. Several other
drugs, such as hematopoietic growth factors,
are commonly used off label in the MDS setting.
Risk stratification systems, such as the IPSS-
R, supplemented by molecular genetic testing
and clinical assessment, can aid treating physi-
cians in therapeutic decision making.47,48 The
goals of MDS therapy depend on prognostic
assessment and the individual patient profile.
For lower-risk patients, common goals of therapy
include symptom control and quality of life,
improvement of hematopoiesis, and delay of dis-
ease progression.49,50 For higher-risk patients,
extension of survival has been reported with aza-
citidine therapy.49-51 Figure 2 displays a general
treatment algorithm for MDS. Experimental com-
pounds currently undergoing testing in patients
with MDS were recently reviewed elsewhere.52
Supportive Care: Transfusions and Iron
Chelation
The proportion of patients with MDS receiving
red blood cell transfusion is approximately 40%
in lower-risk patients and 60% to 80% in
higher-risk patients.53 Patients receiving regular
975
 MAYO CLINIC PROCEEDINGS

MDS mutation landscape

IPSS independent good prognosis

No clear independent effect
Proliferation CDKN2A <1%
IPSS independent poor prognosis
CBL
2% Impaired differentiation
JAK2
BRAF <1% PTPN11 <1%
3%
RUNX1
ETV6 SETBP1
9%
GNAS <1% 3% 7%
KRAS NRAS PTEN <1%
1% 4%
STAG2
NPM1 2% and other
TP53
Epigenetic regulation cohesins -
8%
Other 5%-10%
EZH2
6% ASXL1
DNMT3A 14% SF1 Pre-mRNA splicing SF3A1
8% 1%
1%

U2AF1 PRPF40B
IDH1/2 1%
2% 8%
TET2 SF3B1
21% UTX ATRX 22%
SRSF2
1% <1% U2AF65
ZRSR2 11%
5% <1%

FIGURE 1. Recurrent somatic mutations in myelodysplastic syndromes (MDS), including approximate frequency and prognostic
significance. Some mutations influence the phenotype and are, therefore, more common in specific subtypes of MDS; for example,
SF3B1 mutations are found in more than 50% of patients with refractory anemia with ring sideroblasts, ATRX mutations are most
common in MDS associated with acquired alpha-thalassemia, and SRSF2 mutations are more common in myeloproliferative
neoplasm/MDS overlap syndromes, such as chronic myelomonocytic leukemia. The prognostic value of SF3B1 mutations is unclear,
with some series suggesting no independent value and others suggesting a more favorable outcome even when accounting for other
clinicopathologic parameters. IPSS ¼ International Prognostic Scoring System. Adapted from the American Society of Hematology.101

transfusions have inferior survival compared
with those who do not require transfusions,
either because transfusions indicate more severe
hematopoietic failure or because transfusions
themselves cause harm via iron overload,
immunomodulation, or another mechanism.54
There is controversy about the magnitude of
risk from transfusion-related hemosiderosis in
patients with MDS and the importance of hemo-
siderosis compared with other disease-associated
risks.55,56 Lower-risk patients with MDS who
have a ferritin level greater than 1000 ng/mL
(to convert to pmol/L, multiply by 2.247) have
worse survival than patients with lower ferritin
levels, and patients with ferritin levels greater
than 2500 ng/mL have inferior survival with
HSCT.54,57 However, serum ferritin is an acute
phase reactant that has only moderate correlation
with iron burden, so newer magnetic resonance
imaging techniques have been developed for
n n
976 Mayo Clin Proc.
noninvasively measuring hepatic, cardiac, and
other organ iron concentrations. Quantitative
R2*/T2* magnetic resonance imaging of the liver
or heart may be useful in determining which pa-
tients are appropriate candidates for iron chela-
tion therapy. T2* signals in the heart are
usually normal until patients have received at
least 80 to 100 U of blood.58 Measurement of
reactive oxygen species (nonetransferrin-bound
iron) suggests that these volatile species are
elevated in transfused patients with MDS and
decrease rapidly during chelation therapy, but
the clinical significance is unclear.59
Iron chelation therapy with oral deferasirox
or parenteral deferoxamine can be considered
in patients with a relatively good MDS prognosis
who have evidence of tissue iron overload. There
are currently no controlled prospective data indi-
cating benefit from iron chelation in MDS, and
chelation therapy is expensive (deferasirox), is
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MYELODYSPLASTIC SYNDROMES: DIAGNOSIS AND TREATMENT

MDS initial diagnosis (using WHO 2008 diagnostic criteria,

supplemented by novel genomics approaches)

Individualized risk assessment, using Higher-risk

Clinical monitoring IPSS-R or other tools
Lower-risk
No
Is there a need for
Development of a treatment now?
need for therapy
Is the patient a
Yes transplant candidate?
No, other important
Is anemia cytopenias are also present
isolated, or the No Yes
major problem?
Azacitidine or decitabine AlloSCT, perhaps
Yes (ie, HMA) until disease with HMA or
progression, relapse, or chemotherapy as
drug intolerance bridging therapy
Is del5q No sEPO <500 No
present? U/L?
Relapse
Yes
Yes
Lenalidomide; if sEPO Optimal approach is
<500 U/L, ESA trial ESA ± G-CSF Donor lymphocyte
unclear; consider G-
before or after CSF or TPO agonist, infusion or second
Failure alloSCT, possibly after
Failure HMA, IST, clinical trial
cytoreductive therapy
Failure

Failure Failure
Optimal therapy unclear consider HMA, IST,
androgens, lenalidomide (if not already used),
or clinical trial
AlloSCT, enrollment in a clinical Enrollment in a clinical trial,
trial, or palliative/supportive care or supportive/palliative care

FIGURE 2. A general approach to myelodysplastic syndromes (MDS) therapy. All the patients should receive supportive care with
transfusions and antimicrobial agents as needed. Iron chelation therapy can be considered for selected red blood cell transfusione
requiring lower-risk patients. For lower-risk patients in whom the clinical picture is dominated by anemia, the initial therapeutic
choice depends on the karyotype and the serum erythropoietin (sEPO) level. For patients with del(5q), lenalidomide is an appropriate
first choice and is Food and Drug Administration approved for that indication. For patients without del(5q) but with sEPO levels less
than 500 U/L, the erythropoiesis-stimulating agents (ESAs) epoetin and darbepoetin are recommended. The most appropriate
therapy for lower-risk patients with anemia with sEPO levels greater than 500 U/L and without del(5q), pancytopenia, or a clinical
picture dominated by individual cytopenias other than anemia (ie, neutropenia or thrombocytopenia) is unclear. Hypomethylating
agents can be beneficial in some patients with lower-risk disease, although their effect on survival in this group is unclear, and some
reports indicate the potential for inferior survival. Patients with isolated thrombocytopenia may overlap with immune thrombocy-
topenia and may benefit from corticosteroids, romiplostim or eltrombopag, intravenous gamma globulin or other immune throm-
bocytopeniaedirected therapies. Immunosuppressive therapy, lenalidomide, supportive care alone, and hematopoietic stem cell
transplant (HSCT) are all reasonable choices in the other patient groups, depending on patient-specific factors. For higher-risk patients,
the treatment approach differs depending on whether the patient is an HSCT candidate. Higher-risk patients who are HSCT can-
didates should proceed with definitive HSCT therapy as soon as feasible. The HSCT may be preceded by a few treatment cycles of a
hypomethylating agent as a “bridging” therapy to try to cytoreduce or at least keep the disease stable until a donor is identified and
pretransplant screening tests are completed. Patients who are not HSCT candidates can be treated with a hypomethylating agent until
disease progression or intolerance. Some investigators prefer azacitidine over decitabine because of the demonstrated survival
advantage in this setting. Once initial therapy fails, no optimal second-line therapy is defined, and the choice depends on clinical
circumstances. Clinical trial enrollment is always appropriate if a well-designed study is available for which the patient is eligible.
alloSCT ¼ allogeneic stem cell transplant; G-CSF ¼ granulocyte colony-stimulating factor; HMA ¼ hypomethylating agent (azacitidine
or decitabine); IPSS-R ¼ 2012 Revised International Prognostic Scoring System; IST ¼ immunosuppressive therapy; TPO ¼
thrombopoietin; WHO ¼ World Health Organization. Partly based on European LeukemiaNet and National Comprehensive Cancer
Network guidelines; see Malcovati et al48 and http://www.nccn.org. Adapted from Blood.52

Mayo Clin Proc. n July 2015;90(7):969-983 n http://dx.doi.org/10.1016/j.mayocp.2015.04.001 977

www.mayoclinicproceedings.org

cumbersome (deferoxamine), and can have
adverse effects. In elderly patients with MDS, a
dose of deferasirox high enough to cause a nega-
tive iron balance (ie, 20-30 mg/kg per day)
often results in elevated creatinine levels or intol-
erable gastrointestinal symptoms.59,60
Bleeding is the second most common non-
AML cause of death in MDS, after infection.61
Platelet transfusions can decrease bleeding
risk, but the development of alloimmunization
is common with repeated platelet transfusions.
Hematopoietic Growth Factors
Recombinant erythropoiesis-stimulating agents
(ESAs; epoetin and darbepoetin) induce erythroid
response rates in 20% to 50% of patients.62-64
Combinations of an ESA and granulocyte
colony-stimulating factor (G-CSF) may be more
effective than an ESA alone in ameliorating ane-
mia, especially in patients with refractory anemia
with ring sideroblasts, for unclear reasons.62
Although several retrospective studies suggest
that ESAs may improve life expectancy in MDS,
no prospective studies have found increased sur-
vival. For patients with serum erythropoietin
levels less than 500 U/L, an 8- to 12-week trial
of an ESA is appropriate; patients with higher
serum erythropoietin levels rarely respond.65
The myeloid growth factors G-CSF (filgrastim
and tbo-filgrastim) and granulocyte-macrophage
CSF (sargramostim and molgramostim) increase
the neutrophil count in many patients but do
not increase survival. In one study of 102 pa-
tients, progression to AML was similar between
G-CSFetreated patients and the control group,
but survival was shorter in patients with excess
blasts who received G-CSF.66 Patients with
recurrent infections are the best candidates for
myeloid growth factors but may not be helped
by these agents if the increased circulating neu-
trophils are dysfunctional. There are reports of
spontaneous splenic rupture and leukemoid re-
actions in MDS with pegfilgrastim, so this agent
should be used only with caution.67
One of the major shifts in clinical practice in
the past few years is the increased use of throm-
bopoietin (TPO) receptor agonists in MDS.68
Although romiplostim and eltrombopag are
currently not approved for use in MDS, their la-
bel includes immune thrombocytopenia, which
some patients with MDS also have. These
agents can improve platelet counts and reduce
bleeding events, especially in patients who have
n n
978 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
an endogenous TPO level less than 500 pg/mL
and are not heavily dependent on platelet trans-
fusions.69 One important safety concern is that
blasts can have functional TPO receptors, so
patients treated with romiplostim or eltrombo-
pag may experience an increase in blood or
marrow blasts. In a placebo-controlled study
of romiplostim, AML progression was observed
in 6% of romiplostim-treated patients and in
2.4% who received placebo, and most patients
who progressed to AML had excess blasts before
therapy.70 Romiplostim combined with azaciti-
dine, decitabine, or lenalidomide has also been
used to ameliorate thrombocytopenia. The antifi-
brinolytic drug epsiloneaminocaproic acid can
decrease bleeding in thrombocytopenic patients
who have mucosal hemorrhage, but it increases
thrombosis risk when used systemically.71
Immunosuppressive and Immunomodulatory
Drugs
Autoreactive T cells, either clonal or polyclonal,
can contribute to suppressed hematopoiesis in
some patients with MDS.72 This has prompted
studies with antieT-cell immunosuppressive
treatment approaches similar to those used for
aplastic anemia, such as antithymocyte globulin
with a calcineurin inhibitor such as cyclosporine
or tacrolimus. The most difficult task is selection
of patients most likely to respond.73 Benefits are
primarily seen in younger patients (<60 years)
with lower-risk disease who are not transfusion
dependent and have either normal cytogenetics
or trisomy 8.74 In some studies, marrow hypocel-
lularity and HLA-DR15 have predicted a higher
likelihood of response to immunosuppression.
In the 1990s, thalidomide was used as an
immunomodulatory agent and as an inhibitor
of neoangiogenesis. Favorable responses were
seen in 15% to 25% of patients, but adverse
events were problematic, especially sedation,
constipation, and neuropathy.75,76 Lenalidomide
is a drug that is a minor chemical modification of
thalidomide and has an improved safety profile. It
is now known that the pleiotropic biological ef-
fects of thalidomide and lenalidomide are medi-
ated by modulation of the activity of cereblon, a
component of an E3 ubiquitin ligase complex
that targets cellular proteins for degradation.77
Lenalidomide specifically alters the degradation
rate of casein kinase 1, a serine-threonine kinase
encoded on chromosome arm 5q that modulates
Wnt/b-catenin signaling.78
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MYELODYSPLASTIC SYNDROMES: DIAGNOSIS AND TREATMENT
Lenalidomide is most effective in patients
with IPSS low-risk or intermediate-1erisk dis-
ease who have deletion of chromosome 5q31.
In this group, 67% achieve transfusion indepen-
dence, with a median time to response of 4.6
weeks, a median increase in hemoglobin level
of 5.4 g/dL, and a median duration of response
of more than 2 years.79 Cytogenetic remissions
are seen in up to one-half of patients, but
del(5q) hematopoietic stem cells are still detect-
able even in patients in remission.80 For patients
who lack del(5q), responses are less frequentd
approximately 25% become transfusion free
during lenalidomide therapydand less durable,
with a median response of 40 weeks.81 The most
common adverse effect with lenalidomide is
myelosuppression. Patients with a low platelet
count (especially <50109/L), excess blasts, or
a complex karyotype are less likely to respond
to lenalidomide therapy.
Hypomethylating Agents (DNA
Methyltransferase Inhibitors)
Epigenetic changes are those such as DNA
methylation or histone acetylation that alter
gene expression without changing the DNA
sequence. Methylated cytidine residues cluster
in CpG islands, which are located near the pro-
moter regions of many genes. DNA methylation
is a dynamic process that affects transcription
rates of adjacent genes; when CpG islands are
hypermethylated, expression of nearby genes is
silenced.82 The aza-substituted cytosine nucleo-
side analogues azacitidine and decitabine are in-
hibitors of DNA methyltransferase 1, the enzyme
that maintains cytidine methylation patterns.
Azacitidine and decitabine treatment decreases
methylation of DNA and reverses gene silencing.
These agents also induce DNA damage similar to
cytarabine and other nucleoside analogues, and
it remains unclear whether epigenetic changes
or other activities are responsible for clinical ac-
tivity.83 Patients with TET2 or DNMT3A muta-
tions have a higher likelihood of response to
DNA methyltransferase 1 inhibitor therapy.84,85
AZA-001 was a multicenter trial in which 358
patients with IPSS intermediate-2e or high-risk
MDS were randomized to receive either azaciti-
dine, 75 mg/m2 subcutaneously for 7 consecutive
days every 28 days, or conventional care (best
supportive care alone, low-dose cytarabine, or
AML-like induction chemotherapy using in-
fusional cytarabine and an anthracycline).50
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www.mayoclinicproceedings.org
Median survival was 24 months in patients
receiving azacitidine and 15 months in patients
receiving conventional care; thus, azacitidine
was the first choice. The complete response rate
in the azacitidine-treated group was less than
20%, but subsequent analysis found that a com-
plete response was not necessary for patients to
achieve a survival benefit.86 Azacitidine is FDA
approved for either intravenous administration
or subcutaneous dosing. Intravenous administra-
tion avoids injection site reactions but necessi-
tates venous access.
Decitabine is also clinically active in MDS,
but neither an American nor a European multi-
center study of decitabine reported a survival
benefit.87,88 It is unclear whether this is because
decitabine is an inferior molecule to azacitidine
or because the studies enrolled different patient
populations than AZA-001. The latter is sug-
gested by the short (<10 months) survival of
the control arms in decitabine studies. Decita-
bine is given most commonly intravenously
for 5 consecutive days every 4 to 6 weeks.89
Clinical response to hypomethylating
agents may be slow, and an adequate therapeu-
tic trial of either agent requires at least 4 treat-
ment cycles with decitabine or 6 treatment
cycles with azacitidine. The most common
adverse events associated with these drugs are
neutropenia and thrombocytopenia, which
may improve with time as the MDS clones are
suppressed and normal hematopoiesis recovers.
The optimal maintenance dosing once patients
achieve a response is unknown, but some main-
tenance therapy seems to be required to main-
tain responses.90 Thus far, no therapy has
been found to improve survival for patients
with lower-risk MDS, although azacitidine or
decitabine can reduce transfusions and improve
counts in some patients.
Deacetylase inhibitors maintain chromatin in
a transcriptionally active state by inhibiting deace-
tylation of histone tails on chromatin. In vitro,
these agents reverse transcription repression and
gene silencing and are synergistic with hypome-
thylating agents. However, although several
deacetylase inhibitors have been FDA approved
for lymphoma (panobinostat and vorinostat), in
3 randomized cooperative group trials, the com-
bination of azacitidine plus a deacetylase inhibitor
(entinostat [MS-275] in E1905, vorinostat in
S1117, and valproic acid in Aza-Plus) was not su-
perior to azacitidine monotherapy.91,92
979

Once hypomethylating agents fail the patient,
the prognosis is grim, with median survival of less
than 6 months.93,94 Switching from one failed
hypomethylating agent to the other agent or add-
ing lenalidomide or a deacetylase inhibitor is
rarely helpful. Responses are seen in some pa-
tients with clofarabine use, AML-type induction
chemotherapy, or low-dose cytarabine therapy,
but patients in whom hypomethylating agents
are failing should instead be referred for HSCT
or enrolled in clinical trials if possible.
Allogeneic HSCT
Treatment of choice for children and young adults
with MDS is HSCT. Younger patients (ie, 40
years) without excess blasts at the time of trans-
plant may have long-term disease-free survival
exceeding 50% after an HLA-matched HSCT. Un-
less the patient has t-MDS, it is imperative to
perform a chromosome breakage assay to exclude
Fanconi anemia before transplant in a child or
young adult because patients with Fanconi ane-
mia cannot tolerate conventional conditioning
regimens. Although most patients with Fanconi
anemia have short stature, radial ray anomalies,
or other dysmorphic features, many do not.
Advanced age, the presence of comorbidities,
clinical inertia, and lack of a suitable donor limit
the availability of allogeneic HSCT, but the
growing use of reduced-intensity conditioning
approaches and alternative stem cell sources
such as cord blood and mismatched donors
(including haploidentical donors) are expanding
the roster of potentially transplant-eligible pa-
tients.46 Therefore, patients with MDS who are
potentially candidates for transplant should be
evaluated early in the disease course by a physi-
cian with expertise in stem cell transplant. In
many centers, reduced-intensity stem cell trans-
plant is routinely performed for patients aged
up to the early 70s. Patients with high IPSS scores
or treatment-resistant disease (including persis-
tence of excess blasts despite a hypomethylating
agent) have lower survival rates after HSCT. Pa-
tients with a complex monosomal karyotype,
defined as 2 or more autosomal monosomies or
1 monosomy plus additional structural chromo-
somal abnormalities, have especially poor out-
comes, as do those with t-MDS; when patients
with complex karyotype also have a TP53 muta-
tion, survival with HSCT is less than 10%.32,95,96
The optimal time to refer patients for trans-
plant is unclear, but mathematical modeling
n n
980 Mayo Clin Proc.
MAYO CLINIC PROCEEDINGS
suggests that the best strategy is to perform trans-
plant early in the disease course in patients with
higher-risk disease and to defer transplant in pa-
tients with lower-risk disease (ie, IPSS low and
intermediate-1 risk or IPSS-R very low and low
risk) until the time of progression.97,98 It is unclear
what the best strategy is with IPSS-R intermediate-
risk patients, and this is a group where molecular
genetic typing may assist in treatment selection.
No clear benefit has been found for the
administration of 1 or more courses of cyto-
toxic chemotherapy or hypomethylating agent
therapy before HSCT, although pretransplant
therapy may be useful to reduce the burden
of marrow blasts and clonal cells before
HSCT.99 Most patients with higher-risk disease
relapse after HSCT, and a variety of strategies to
reduce relapse rates are being studied.100
CONCLUSION
The MDS are among the most common and
serious hematologic disorders diagnosed in
older adults. Treatment options are limited,
but HSCT offers the possibility of cure, and
hematopoietic growth factors, azacitidine,
lenalidomide, decitabine, and supportive care
can provide palliative benefit. New insights
into pathogenesis will, hopefully, lead to novel
therapies and improved patient outcomes.
Abbreviations and Acronyms: alloSCT = allogeneic stem
cell transplant; AML = acute myeloid leukemia; ESA =
erythropoiesis-stimulating agent; FDA = Food and Drug
Administration; FISH = fluorescence in situ hybridization;
G-CSF = granulocyte colony stimulating factor; HSCT =
hematopoietic stem cell transplant; ICUS = idiopathic cyto-
penia(s) of undetermined significance; IPSS = International
Prognostic Scoring System; IPSS-R = revised International
Prognostic Scoring System; MDS = myelodysplastic syn-
drome; MPN = myeloproliferative neoplasm; RCUD =
refractory cytopenias with unilineage dysplasia; t-MDS =
therapy-related myelodysplastic syndrome; TPO = throm-
bopoietin; WHO = World Health Organization
Potential Competing Interests: Dr Steensma is a consultant
for Celgene, MEI Pharma, Astex, and H3/Eisai and serves on the
Data Safety Monitoring Committee for Amgen and Novartis.
Statement About Off-label Drug Use: Only azacitidine, deci-
tabine, and lenalidomide are FDA approved for MDS. All other
agents and uses are off label or experimental.
Correspondence: Address to David P. Steensma, MD,
Adult Leukemia Program, Division of Hematological Malig-
nancies, Department of Medical Oncology, Dana-Farber Can-
cer Institute, Brigham and Women’s Hospital, 450 Brookline
Ave, D2037, Boston, MA 02215 (David_Steensma@DFCI.
July 2015;90(7):969-983 http://dx.doi.org/10.1016/j.mayocp.2015.04.001
www.mayoclinicproceedings.org
MYELODYSPLASTIC SYNDROMES: DIAGNOSIS AND TREATMENT
harvard.edu). Individual reprints of this article and a bound
reprint of the entire Symposium on Neoplastic Hematology
and Medical Oncology will be available for purchase from
our website www.mayoclinicproceedings.org.
The Symposium on Neoplastic Hematology and Medical
Oncology will continue in an upcoming issue.
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