C HAPTER 60 
MYELODYSPLASTIC SYNDROMES
Christopher J. Gibson, Benjamin L. Ebert, and David P. Steensma
Myelodysplastic syndromes (MDS) are clonal hematopoietic disor-
ders characterized by ineffective hematopoiesis and peripheral blood
cytopenias, abnormal cell morphology on blood and bone marrow
examination (Fig. 60.1) and a risk of progression to acute myeloid
leukemia (AML). It has a variable clinical course, manifesting in some
patients as indolent cytopenias necessitating occasional transfusions
and in others as aggressive diseases that rapidly evolve into treatment-
refractory leukemias, with a broad spectrum of severity in between.
Despite this phenotypic variability, individual cases of MDS share
many pathophysiologic mechanisms at the molecular and cellular
levels, and our understanding of these mechanisms has evolved
substantially in the last decade. At the same time, although MDS also
shares features with AML and other myeloid malignancies, mounting
evidence shows that it is appropriately conceived as a distinct class of
diseases, and that the older conceptualization of MDS as “preleuke-
mia” is overly simplistic.
While understanding of MDS pathophysiology is improving, the
condition remains difficult to treat, and outcomes for patients with
MDS have unfortunately not improved substantially since the last
edition of this textbook. This chapter describes our current under-
standing of the classification, pathobiology, clinical features, and
treatment approaches for this heterogeneous group of disorders.
HISTORY
Central to an understanding of how MDS is diagnosed and classified
is the concept of morphologic dysplasia, a pathologic term that was
originally introduced as a shortening of the phrase dysmorphology of
neoplasia. Although specific criteria for diagnosis of MDS as a distinct
clinical syndrome exist and are discussed subsequently, the term
myelodysplasia refers more generally to an abnormal appearance of
hematopoietic precursors during pathologic examination of bone
marrow, which may result from many different causes (e.g., drug
toxicity, nutritional deficiency, viral infection). The process by which
our understanding of MDS has evolved from that of a morphologic
oddity to that of a distinct disease process has been a century in the
making, propelled forward at several points by paradigmatic shifts in
pathologic and molecular characterization of hematologic diseases.1
In describing the history of MDS as a distinctly categorized disease
entity, it is perhaps most useful to separately describe the history of
its major conceptual components. The earliest recognized of these, not
surprisingly, was that of dysplasia itself. Although studies of peripheral
blood in anemic patients were reported in the 19th century,2 the first
real characterization of actual dysplasia was probably made by Giovanni
di Guglielmo in Pavia in 1923, when he described abnormal erythroid
forms in the marrows of patients with various types of cytopenias.3 A
second major concept, that of ineffective hematopoiesis, was developed
in the 1930s with the description of refractory anemia in patients
unresponsive to iron pills or liver extract (the precursor to vitamin B12
supplementation);4 in the 1950s, others expanded this to include
similarly refractory leukopenia and thrombocytopenia and termed the
collective disorder “refractory cytopenias.”5 Importantly, however,
ineffective hematopoiesis and marrow dysplasia were initially incom-
pletely linked, and the ineffective hematopoiesis of many early refrac-
tory anemia patients was probably rooted in other disorders, such as
anemia of inflammation caused by advanced rheumatologic disease or
nonmyeloid neoplasia.
944
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The third major component of MDS, and possibly the most
prominent, is its temporal positioning as a potential preleukemic
state. This was first conceptualized in 1942 as odo-leukemia (“odo”
from the Greek for edge or threshold) by a group from France led by
Paul Chevallier to describe a case of anemia evolving into leukemia,6
which they attributed to benzene exposure. A similar disorder was
termed preleukaemic anemia by a British hematologist, J.L. Hamilton-
Paterson, in 1949.7 This term was adopted and expanded by an
American group based in Chicago in the early 1950s,8 providing one
of the clearest descriptions of a disorder clinically defined by both
cytopenias and a risk of leukemia. Other groups in the 1950s and
1960s published similar descriptions under different terminologies.9
The 1970s saw some of the greatest strides toward our modern
conceptualization of MDS. In 1970, Dreyfus and colleagues coined
the term refractory anemia with excess blasts (RAEB, described in
French as les anémies réfractaires avec excès de myeloblasts)10 and later
attempted to further characterize components of RAEB based on
morphology and clinical characteristics.11 The term hematopoietic
dysplasia was used in the early 1970s to describe a heterogeneous
group of disorders distinct from AML, and the term was later simpli-
fied to myelodysplasia.
One of the key events in the history of myeloid disease classifica-
tion was the formation of the French-American-British (FAB)
Cooperative Group in 1976, which in that year issued a comprehen-
sive and influential categorization of AML12 based on the 1975
classification of Galton and Dacie.13 The FAB classification persisted
as the dominant descriptive system for AML until the early 2000s.
The original FAB AML formulation from 1976 included two types
of “dysmyelopoietic syndromes” that should not be confused with
AML: RAEB and chronic myelomonocytic leukemia (CMML),
which had first been described in the late 1960s.14 However, it was
not long before MDS was recognized as a separate group of diseases
and accorded a distinct classification system, described in more detail
later.
CLASSIFICATION
The currently accepted classification scheme for MDS was initially
published by the World Health Organization (WHO) in 2001 and
most recently revised in 2008 (Table 60.1), with a third revision
planned for 2016. Like the classifications of the FAB group, the
WHO classification is principally a morphologic system and classifies
disease chiefly based on the number of dysplastic lineages and the
percentage of marrow blasts, though it also includes one specific
cytogenetically defined subtype, MDS with isolated del(5q). The
other WHO 2008 subtypes include refractory cytopenia with unilin-
eage dysplasia (RCUD), which is most commonly refractory anemia
(RA); refractory cytopenia with multilineage dysplasia (RCMD);
refractory anemia with ringed sideroblasts (RARS); RAEB (subdi-
vided into RAEB-1, 5%–9% blasts, and RAEB-2, 10%–19% blasts);
and unclassifiable MDS (MDS-U) for those cases that do not clearly
fall into any other category. In addition, the WHO system classifies
cases with myeloproliferative features separately; this group includes
CMML and RARS with thrombocytosis (RARS-T).
The WHO classification was intended to replace the prior FAB
classification system, which was initially proposed in 1982 as an
MDS correlate to the FAB system for classifying AML.15 The 1982
 Chapter 60  Myelodysplastic Syndromes 945

A B C
Fig. 60.1  ELEMENTS OF MYELODYSPLASTIC SYNDROME. Myelodysplastic syndromes are generally
characterized by cytopenias (A) caused by ineffective hematopoiesis (B), which is related to multilineage
dysplasia (C). (A) This patient presented with a white blood cell count of 1500/µL, hemoglobin 8.9 g/dL,
and platelet count 47,000/µL. (B) The bone marrow was hypercellular, indicating ineffective hematopoiesis.
(C) Evidence of trilineage dysplasia was apparent on the peripheral smear. Anisocytosis with macroovalocytes
and poikilocytosis is seen in the red blood cells (C, top). The latter included the somewhat uncommon finding
of Cabot ring forms (right). A large proportion of the granulocytes were severely hypogranular (C, middle left)
compared to some normal forms still in the circulation (right). Platelets (C, bottom) were decreased in number,
and many were severely hypogranular (middle, barely visible) compared with residual normal platelets (left).

FAB system distinguished five subtypes of MDS, namely (1) RA,
(2) RARS, (3) RAEB (defined as 5%–19% blasts in the marrow),
(4) RAEB in transformation (defined as 20%–29% blasts in the
marrow), and CMML.
The WHO system thus bears some similarities to the FAB scheme,
but there are several notable changes. First, the WHO system recog-
nizes that MDS may present with isolated leukopenia or thrombo-
cytopenia, albeit uncommonly, hence the change from RA to the
broader RCUD and the addition of a second distinct class for patients
with more than one affected cell line. Second, a mounting body of
evidence suggested that MDS with proliferative features is clinically
and biologically distinct from MDS without such features and thus
warrants separate designation.16,17 Third, the unique clinical syn-
drome associated with isolated del(5q), in combination with its
particular responsiveness to treatment with lenalidomide, warranted
its designation as a specific entity.18 Finally, the cutoff for diagnosis
of AML was changed from 30% to 20% bone marrow blasts or
greater, rendering the designation of RAEB in transformation obso-
lete, although this change was not without its detractors.19
The WHO revision improved on certain aspects of the FAB
system. In particular, the FAB system required that patients display
at least 10% dysplasia in two different cell lineages to achieve even a
diagnosis of RA; this excluded patients with mild or unilineage
dysplasia, many of whom had natural histories indistinguishable from
those who met the diagnostic criteria. While the WHO guidelines
eliminated the dual-lineage requirement and allows a diagnosis of
MDS in patients with unilineage dysplasia, it nevertheless draws
arbitrary lines of distinction between subclasses of a heterogeneous
disease, and patients with minimal dysplasia are still typically excluded
from the diagnosis.20 Artificial boundaries such as the 10% dysplasia,
15% ring sideroblasts and 5%/10%/20% blast cutoffs often prove
themselves to be of variable relevance, both biologically and clinically,
because they fail to capture a number of variables important in MDS,
including age, sex, and most cytogenetic and genetic data.
Although some of the FAB and WHO subgroups imply very
rough prognostic information—for instance, patients with FAB
RAEB or WHO RAEB-2 are at higher risk of progression to AML
than subgroups without excess blasts21—other systems specifically
dedicated to estimating disease risk, such as the International Prog-
nostic Scoring System (IPSS; see later), are better suited to this task.
Future iterations of a classification system may incorporate elements
of genetic or clinical data that better group MDS patients based on
disease biology, prognosis and natural history, or anticipated respon-
siveness to treatment modalities.22 For now, however, this classifica-
tion scheme remains only one of several descriptive tools applied to
patients with MDSs.
EPIDEMIOLOGY AND ETIOLOGY
Most available data suggest that MDS is one of the most common
hematologic malignancies, although this claim has been difficult to
validate until recently because of confusing terminology and incom-
plete reporting of cases to registries.23,24 Cases of MDS were not
reported to the National Cancer Institute’s Surveillance, Epidemiol-
ogy, and End Results (SEER) until 2001, and initial reports to the
registry suggested an incidence of only about 10,000 new cases per
year.25 Subsequent comparison of these data with Medicare and
insurance claims for MDS suggested that a substantial proportion of
MDS cases went unreported to SEER, with an estimated age-
adjusted incidence of >5.3 per 100,000, compared to the SEER
estimate of 3.3.26
The reporting difference was especially stark in patients age 65
and older, where it was estimated that the actual incidence of MDS
might actually be close to fourfold higher than what was captured in
the database (75 versus 20 per 100,000). Some of the underreporting
was likely related to specific criteria for entry into the database (for
instance, myeloid malignancies could only be counted once, such that
patients presenting with a new diagnosis of secondary AML were
usually coded as AML, without mention of MDS). Much of the
underreporting, however, was likely because of the complexity of
diagnosing and classifying MDS, as described earlier. The rate of
reporting appears to have recently improved, with annual incidence
in the 2007–2011 SEER database estimated at around 20,500 and
an age-adjusted incidence of 4.9 per 100,000.27
Even the most accurate database, however, would probably under-
estimate the total global burden of MDS, which is likely present in
a substantial percentage of older patients with idiopathic cytopenias
who never undergo bone marrow analysis.28 Although some propor-
tion of this uncaptured population likely has biologically indolent

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 946 Part VII  Hematologic Malignancies

TABLE 2008 World Health Organization Classification of the TABLE Genes Recurrently Mutated in Myelodysplastic
60.1 Adult Myelodysplastic Syndromes 60.2 Syndrome
Refractory Cytopenia With Unilineage Dysplasia Gene Frequency (%) Notes
Dysplasia ≥10% of cells from a single lineage
Splicing Factors
Blasts <5% in marrow; <1% in peripheral blood; no Auer rods SF3B1 20–30 Strong association with RARS
Notes Includes refractory anemia (RA), refractory neutropenia, SRSF2 10–15 (MDS) Enriched in CMML
refractory thrombocytopenia; RA is by far the most 40 (CMML)
common subtype
U2AF1 5–12 Association with del(20q)
Refractory Anemia With Ring Sideroblasts
Epigenetic Modifiers
Dysplasia Isolated erythroid dysplasia
TET2 20–30 (MDS) Enriched in CMML
Blasts <5% in marrow; <1% in peripheral blood; no Auer rods 40–50 (CMML) Mutually exclusive with IDH
Notes ≥15% of erythroid precursors are ring sideroblasts DNMT3A 8–13
Frequently associated with SF3B1 mutations ASXL1 10–20 (MDS) Enriched in CMML
MDS With Isolated del(5q) 30–40 (CMML)
Dysplasia Normal or increased megakaryocytes with hypolobated EZH2 5–10 (MDS) Enriched in CMML
nuclei 20–30 (CMML) May be functionally involved
Blasts <20% (though usually much less) in 7q−
Notes del(5q31) must be sole chromosomal abnormality IDH1/2 <5 More frequent in AML
Refractory Cytopenia With Multilineage Dysplasia ATRX Rare Associated with acquired
Dysplasia ≥10% of cells from two or more myeloid lineages thalassemia
Blasts <5% in marrow; <1% in peripheral blood; no Auer rods Transcription Factors
Notes Peripheral monocyte count must be <1 × 109/L; ring RUNX1 10–15 Can be somatic or germline
sideroblasts may be present GATA2 Rare Mostly germline
Refractory Anemia With Excess Blasts ETV6 <5 Can be somatic or germline
Dysplasia No specific requirement
TP53 10–12 Association with complex
Blasts RAEB-1: 5%–9% in marrow, <5% in peripheral blood, AND karyotype, therapy-related
no Auer rods disease
RAEB-2: 10%–19% in marrow, 5%–19% in peripheral Kinases and Receptors
blood, OR Auer rods JAK2 <5 Enriched in RARS-T
Notes Old designation of RAEB-t (20%–30% blasts) now NRAS 5–10 Seen in progression to AML
considered AML CBL <5 Enriched in JMML
Unclassifiable MDS
PTPN11 <5 More common in JMML
Dysplasia Minimal, or not meeting criteria for another subtype
BRAF Rare Also seen in hairy cell
Blasts <5% in marrow; <1% in peripheral blood; no Auer rods
leukemia
Notes In presence of clonal cytogenetic finding considered Cohesin Complex
diagnostic of MDS STAG2 5–10 Cohesin class mutations
Note: excludes refractory cytopenias of childhood. MDS/myeloproliferative RAD21 <5 enriched in high-risk MDS
neoplasms such as chronic myelomonocytic leukemia and RARS with SMC3 <2 and secondary AML.
thrombocytosis are classified separately.
AML, Acute myeloid leukemia; MDS, myelodysplastic syndrome; RAEB, SMC1A <2
refractory anemia with excess blast. GCPR Complex
GNAS Rare Mutations recently described
GNB1 Rare in wide range of
hematologic malignancies,
including MDS.
disease that would never require therapy, more thorough cross-
sectional studies, particularly in older patients, would help clarify the AML, Acute myeloid leukemia; CMML, chronic myelomonocytic leukemia;
GCPR, G-coupled protein receptor; IDH, isocitrate dehdryogenase; JMML,
distinction between this end of the MDS spectrum and more aggres- juvenile myelomonocytic leukemia; MDS, myelodysplastic syndrome; RARS,
sive biology that brings patients to clinical attention. refractory anemia with ring sideroblasts; RARS-T, RARS with thrombocytosis.
As referenced earlier, MDS is by and large a disease of older adults
and reflects the inexorable acquisition of genetic mutations by aging
hematopoietic progenitor cells (Table 60.2). In the United States, the
median age at diagnosis is approximately 71 years,29 and in the
absence of a congenital disorder or exposure to radiation or cytotoxic anemia,36 dyskeratosis congenita and other telomeropathies, and
chemotherapy for another disease, diagnosis before the age of 50 is germline mutations in GATA2,37 RUNX1,38 and ETV6.39 In Fanconi
rare.30 Recent data suggest that a substantial proportion of older anemia and the telomeropathies,40 MDS during young adulthood
adults, perhaps as many as 10% of those over age 70, harbor hema- may be the initial presenting sign of the disease.
topoietic clones defined by the presence of mutations recurrently Most subtypes of MDS appear to be more common in men than
found in MDS and AML, and that this state of “clonal hematopoiesis women, with the most recent SEER data suggesting respective age-
of indeterminate potential” progresses to MDS at a rate of 0.5% to adjusted incidences of 6.7 versus 3.9 per 100,000.41 The one excep-
1% per year.31,32 MDS occurs in children much more rarely, at an tion to this is MDS with isolated del(5q), which most series show to
estimated annual rate of 1 per 1 million.33 Most cases are classified be more common in women.42 The reason for these sex differences
as oligoblastic myelogenous leukemia (essentially RAEB), and other is unclear; some have postulated a protective factor encoded on the
subtypes are even less common.34 Several genetic syndromes confer X chromosome, or a similar protective factor on the Y chromosome
an increased risk of MDS; these include Down syndrome,35 Fanconi (which is clonally lost in some cases of MDS). Others have suggested

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that the increased incidence in men overall is likely caused by differ-
ences in occupational exposures, but this has never been clearly
demonstrated. Indeed, the only toxic chemical exposure definitively
proven to cause MDS is benzene,43 which is now significantly less
prevalent in industrial workplaces than it had been in the past. Other
environmental exposures, including cigarette smoking, have been
postulated but never definitively proven to predispose to MDS.44
MDS in the United States and Western Europe is epidemiologi-
cally similar, but there are differences between these geographic
regions and other parts of the world. In Asia45 and Eastern Europe,46
for instance, the average age at MDS diagnosis is younger, and the
frequency of both severe cytopenias and risk of progression to leuke-
mia may differ.47 Some of these differences are likely caused by
variance in environmental exposures. In Japan, for example, broad
population-wide exposure to ionizing radiation from the atomic
bombings of Hiroshima and Nagasaki in the 1940s continued to
influence MDS incidence well into the 1990s.48 However, the cause
of differences in MDS subtypes, such as the low incidence of RARS
in Japan compared with the West, remain unclear.
Indeed, the two exposures most consistently associated with
subsequent development of MDS are ionizing radiation and cytotoxic
chemotherapy, and MDS arising in these settings, known as therapy-
related MDS or t-MDS, is frequently characterized by TP53 muta-
tions,49 multiple large-scale chromosomal abnormalities including
complex karyotypes (most commonly defined as ≥3 clonal chromo-
somal anomalies),50 and frequent transformation to treatment-
refractory AML.51 In the United States, radiation is most frequently
encountered as treatment for other cancers, and radiation fields that
include the hips or pelvis, the most active sites of hematopoiesis in
adults, probably pose the greatest risk.52 Less commonly, exposure to
radiation can occur as the result of occupational exposures (e.g.,
workers at nuclear reactors) or industrial accidents. Among chemo-
therapeutic agents, there is a substantial difference in the risk of
subsequent MDS. In particular, alkylating agents (e.g., cyclophospha-
mide and melphalan)53 appear to carry the greatest risk, while the risk
with nucleoside analogues is lower. Of particular note, the rapidly
progressive AML seen in association with topoisomerase inhibitors
(e.g., doxorubicin, etoposide) is not typically preceded by MDS.54
PATHOBIOLOGY
The past 10 years have witnessed significant advances in our under-
standing of the rich and complex pathobiology underlying MDSs.
MDS is now recognized to arise from interactions between acquired
genetic mutations in hematopoietic precursor cells, alterations in the
microenvironment of the bone marrow, and dysregulated immune
surveillance. Broadly speaking, the acquisition of sequential muta-
tions in precursor cells drives the development of a malignant clone,
and alterations in the microenvironment and the immune response
allow that clone’s expansion. This section details our current under-
standing of these concepts.
Myelodysplastic Syndrome Stem Cells
One of the central challenges in understanding the pathogenesis of
MDS has been isolating the cell of origin and understanding that
cell’s mechanisms of self-renewal and propagation, both of which are
necessary for the establishment of a malignant clone.55 In theory, the
exact state of hematopoietic differentiation from which a malignant
clone arises could vary between cases of MDS, but the capacity for
self-renewal implies that the origin cell was either a hematopoietic
stem cell (HSC), and thus possessed intrinsic self-renewal capabilities,
or it was a more differentiated myeloid progenitor that acquired the
ability to self-renew. Clonal expansion then occurs through the
acquisition of new mutations or epigenetic alterations that either
enhance proliferation or confer resistance to apoptosis. MDS presum-
ably becomes morphologically apparent when the dominant clone
acquires a subsequent genetic lesion that leads to dysplasia within one
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Chapter 60  Myelodysplastic Syndromes 947
or more hematopoietic compartments; this may or may not coincide
with genetic lesions that lead to ineffective hematopoiesis and cyto-
penias, at which point MDS also becomes clinically evident.56
Proving that MDS is a clonal disease was not as straightforward
a proposition as it was for AML, in which examination of the bone
marrow typically identifies sheets of abnormal, morphologically
identical blasts. In contrast, for MDS—particularly low-risk disease
in which blasts are rare and the marrow architecture is disorganized
and heterogeneous—a clonal origin was not immediately obvious
based on morphology alone. Nonetheless, the clonal nature of MDS
was established in the 1980s by studies that showed skewed inactiva-
tion of glucose-6-phosphate dehydrogenase (G6PD), an X-linked
gene, in the hematopoietic cells of female MDS patients heterozygous
for G6PD deficiency.57 More recent studies have used deep sequenc-
ing techniques to track the clonal evolution from MDS into AML
and have confirmed that in these cases, the preexisting MDS is as
highly clonal as the resulting secondary AML.58
That MDS is a disorder of stem or early progenitor cells has been
more difficult to prove.59 Some of this difficulty is a reflection of the
elusiveness of human HSCs themselves: the ability of different human
cell populations to self-propagate after xenotransplantation into
immunodeficient mice, considered the functional hallmark of “stem-
ness,” varies with the exact degree of immunodeficiency of the mice
into which the cells are transplanted.60 Moreover, xenotransplant
experiments using immunophenotypically defined hematopoietic
stem and progenitor cells (HSPCs; classically CD34+ CD38− Lin−)
from MDS patients have not shown a striking proliferative or self-
renewal advantage for the MDS cells compared to normal controls,61
and the degree to which these experiments accurately depict the
clonal dynamics of MDS in humans is unclear. Some have further
been troubled by the observation that lymphoid clonal expansion,
which should occur with near-equal frequency to myeloid clonal
expansion if MDS is indeed a disorder of very early hematopoietic
progenitors, is only rarely observed.62,63 However, more recent studies
combining immunophenotypic analysis with deep sequencing of
clonal mutations in MDS cells have shown that the mutations appear
to originate exclusively in the most primitive, stem-cell-like compart-
ment,64 and others have shown that differential expansion of specific
progenitor compartments may vary between different phenotypes
and risk profiles of MDS.65 This evidence has contributed to the
conclusion that MDS is, in fact, a disorder of transformed HSCs.66
The conceptualization of MDS as a stem cell disorder explains,
in large part, why it is so refractory to most attempts at conventional
therapy. Both normal HSCs and leukemia stem cells remain quiescent
for much of their lifetimes, and during these periods they are largely
impervious to any agents, such as most chemotherapeutic drugs, that
exert their effects during active DNA replication.67 Overcoming the
intrinsic resistance to therapy conferred by the existence of quiescent
reservoirs of disease is one of the central challenges in developing
effective treatments for MDS.68
Genetic Alterations
Like other cancers, the core hypothesis underlying MDS pathogenesis
is that the originating clone of MDS becomes increasingly abnormal,
and ultimately malignant, through the sequential accumulation of
acquired genetic or epigenetic abnormalities.69 Improvement in our
understanding of how these abnormalities are acquired, how they
interact with each other, and their impact on pathways affecting
proliferation, self-renewal, and differentiation, has been one of the
major advancements in the study of MDS over the last decade.
Several different classes of genetic abnormalities may be found in
MDS. The first to be recognized were cytogenetic abnormalities on
standard karyotyping,70 which are present in about 50% of patients.71
A second category of cryptic chromosomal aberrations, including
microdeletions and copy number-neutral loss of heterozygosity, are
too small to be detected by karyotype but may be found with fluo-
rescence in-situ hybridization (FISH)72 or single nucleotide polymor-
phism (SNP) arrays.73 The most common type of abnormality,
 948 Part VII  Hematologic Malignancies
mutations in single genes, has been increasingly well characterized,
and clinical tests for recurrent mutations are becoming increasingly
available, though as discussed later, it appears that not all mutations
have equal clinical relevance.74 Finally, epigenomic alterations—global
aberrations in histone and chromatin modification—are common in
MDS, and are often, though not always, associated with mutations
in genes involved in epigenetic regulation.75
Somatic Mutations
Of the types of genetic abnormalities found in MDS, acquired muta-
tions in individual genes are the most recently recognized; they are
also the most frequent, currently estimated to be present in around
80% of MDS patients.69 Although certain environmental exposures
increase the risk of acquiring potentially deleterious mutations, most
are acquired randomly, either spontaneously (e.g., deamination of
cytosine to uracil), during DNA replication before cell division, or
during DNA repair.
One of the central challenges of understanding the genetics of
MDS has been determining which mutations contribute to the
pathogenesis of the disease and which do not. Accumulating evidence
has shown that HSCs acquire nonsynonymous exonic mutations with
translational consequences at a rate of about one mutation per
decade.76 Since the incidence of MDS increases with age, HSPCs
from an average MDS patient should typically contain between 5–10
such mutations (though the actual number varies widely between
patients), against a background of hundreds of noncoding single
nucleotide variations. The vast majority of these mutations, both
coding and noncoding, are of no pathogenic consequence and are
thus termed passenger mutations, while a minority, the so-called driver
mutations, actually contribute to the development of the disease.77
Distinguishing driver mutations from passenger mutations is not
always trivial. Passenger mutations, without conferring clonal advan-
tage, tend not to recur with any significant frequency in cohorts of
MDS patients; however, whereas a few driver mutations are relatively
common in MDS, many have been found in only a small fraction
(<5%) of cases, suggesting novel mechanisms of disease pathogenesis.78
Similarly, whereas noncoding mutations are unlikely to contribute to
pathogenesis and can thus be ignored when analyzing MDS genomes,
the majority of coding mutations, even those present within a major-
ity of cells in the malignant clone, are also nonpathogenic and are
simply artifacts captured by an aging HSPC. Classifying a mutation
as a driver thus involves accumulating evidence that the mutation
occurs recurrently in MDS, that its putative function could plausibly
contribute to MDS pathogenesis, and, in the best-case scenario, that
this function can be recapitulated using in vitro or in vivo models.
Large-scale genomic studies of MDS cohorts have shown that many
of the recurrently mutated genes can be segregated into one of a few
functional categories,78–81 and this functional characterization has in
turned revealed insights about how an MDS clone develops over time.
Genes affecting RNA splicing (SRSF2, SF3B1, U2AF1) are the most
commonly mutated and tend to be early events in MDS pathogenesis.
Genes affecting epigenetic regulation (TET2, ASXL1, EZH2,
DNMT3A) are the next-most commonly mutated and also tend to
occur early. On the other hand, mutations in genes for growth factors
(NRAS, JAK2) tend to occur late and in subclonal populations.
These observations have contributed to an overarching model of
how sequential somatic mutations cooperate to bring about MDS.
In this model, early mutations in splicing factors and epigenetic genes
do little to affect proliferation or differentiation on their own, but
rather create a permissive environment for the acquisition of subse-
quent mutations in genes that confer proliferative advantages or
blocks in differentiation. The latter group of mutations contributes
more directly to the clinical features of MDS, but the former is
responsible for its tendency towards genomic and epigenomic insta-
bility, which in turn may contribute to the disease’s poor response to
treatment. This section is a brief summary of our current understand-
ing of some of the most important genes and pathways that are
recurrently deranged in MDS.82
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Splicing Factor Mutations
Genes encoding splicing factors, which excise introns to create mature
messenger RNA (mRNA) transcripts, are the most commonly
mutated class of genes in MDS, with between half and two-thirds of
patients harboring such a mutation.83 As opposed to most of the other
classes of mutations discussed here, which occur in other malignan-
cies with significant frequency, splicing factor mutations are rarer in
other cancers than MDS, and some have unique associations with
specific morphologic phenotypes.84 Splicing factor mutations tend to
be mutually exclusive within MDS clones, and most of the affected
genes encode proteins that comprise the E/A splice site recognition
complex that acts at the 3′ end of pre-mRNA, suggesting that the
mutations converge on a shared biologic pathway.85 Exactly how
splicing factor mutations predispose to the development of MDS,
and whether they can help predict aspects of natural history or
treatment response, remain areas of active investigation.
SF3B1
SF3B1 encodes the U2 small nuclear riboprotein complex (snRNP)
responsible for 3′ branch site recognition and is the most frequently
mutated splicing factor gene. SF3B1 mutations can be found in
about 20% to 30% of all MDS patients; there is a particularly
strong association with ring sideroblast morphology, with mutations
found in 60% to 85% of patients with RARS or RARS-T and
substantial percentages of other MDS subtypes in which ring
sideroblasts can be found.86,87 The most common mutations are
missense substitutions that change lysine to glutamate at codon
700, with other smaller hotspots in the same vicinity. These muta-
tions all occur within a cluster of 26 nonrepeating HEAT domains
that are thought to be involved in binding of SF3B1 to other
members of the U2 snRNP.88 As with other splicing factor muta-
tions, they tend to be heterozygous and imply a gain of function.
How exactly the mutations affect MDS pathogenesis is not com-
pletely clear, but they are often acquired early in disease develop-
ment, tend not to be associated with complex karyotypes, and tend
not to be associated with poor-prognosis mutations.89 SF3B1 muta-
tions are clinically associated with a distinct phenotype of isolated,
transfusion-dependent anemia with preserved white blood cell and
platelet counts relative to SF3B1-wildtypes, as well as a lower risk
of progression to AML.90 Indeed, in larger studies of MDS cohorts,
SF3B1 mutations appear to confer an improvement in relative
survival, making them somewhat unique among MDS-associated
mutations.80
SRSF2
SRSF2 encodes a member of the serine/arginine (SR)-rich family of
pre-mRNA splicing factors that interacts with the U2 and U1 com-
ponents of the spliceosome. After SF3B1, it is the second-most
commonly mutated splicing factor, with mutations present in 10%
to 15% of MDS91 and 40% of CMML.92 The overwhelming majority
of mutations are heterozygous missense substitutions for proline at
codon 95, implying a gain of function. A small minority of in-frame
insertions or deletions affects the same region. SRSF2 mutations
co-occur with several other mutations, many of which are also fre-
quently found in CMML, including TET2, ASXL1, CUX1, IDH2,
and STAG2. In contradistinction to patients with SF3B1 mutations,
patients with SRSF2 mutations tend to have more dysplasia in the
granulocytic lineage and less in the erythroid lineage, and patients
consequently tend to have a less prominent transfusion requirement,
more enrichment in the RAEB subtypes, and, at least in some studies,
a greater risk of progression to AML.93 This phenotype is more het-
erogeneous than that associated with SF3B1, but most studies have
nevertheless shown that SRSF2 mutations appear to confer an inferior
prognosis.91

U2AF1
U2AF1 encodes an auxiliary factor in the U2 spliceosome that is
responsible for recognizing the AG splice acceptor dinucleotide at the
3′ end of introns. U2AF1 mutations occur in about 12% of patients
with MDS.94 Similar to other commonly mutated splicing factor
genes, the two most common mutations are both heterozygous mis-
sense substitutions, again implying a gain of function, and both
appear to alter sequence specificity of pre-mRNA binding and splic-
ing.95 The two mutations are in separate zinc finger DNA binding
domains, one at codon 34 toward the N-terminal of the protein, and
one at codon 157 toward the C terminal. Some studies have shown
an increased tendency of MDS with U2AF1 mutations to evolve into
secondary AML,96 but given the small numbers of patients in these
studies, the strength of this effect is unclear.
Epigenetic Modifier Mutations
Epigenetic changes are biochemical modifications that affect chroma-
tin structure, and thereby gene expression, without actually altering
the DNA sequence itself. The two types of epigenetic changes most
relevant to MDS are DNA methylation and histone modification.75
DNA methylation involves the addition of a methyl group to the
cytosine residues of cytosine-guanine pairs by members of the DNA
methyltransferase (DNMT) family of enzymes. These cytosine-
guanine pairs frequently cluster together in “CpG islands,” which are
typically located just upstream of promoter regions. CpG islands tend
to be unmethylated at baseline, but their progressive methylation
leads to transcriptional silencing of the downstream genes. Studies
have shown that many MDS patients display aberrant methylation
patterns compared to healthy controls, with isolated hypermethyl-
ation in the promoters of critical tumor suppressors despite global
hypomethylation elsewhere. This phenomenon has been hypothesized
to play a role in the pathogenesis of MDS, but attempts to glean
prognostic or predictive information from specific methylation pat-
terns in MDS patients have been largely unsuccessful, and the success
of so-called hypomethylating agents such as 5-azacitidine and
decitabine (which may in fact not truly act by reducing global
methylation) has been variable.
A second type of epigenetic regulation involves the biochemical
modification of histones, the structural protein complexes that form
scaffolding for chromatin packaging. The interaction between his-
tones and chromatin represents an additional level of transcriptional
control, in which unwinding of chromatin is required for the tran-
scription machinery to physically access DNA. The dynamics of
chromatin-histone interactions are largely mediated by complex
biochemical modifications of specific histone amino acids. In MDS
and other myeloid disorders, these modifications can either be
affected directly by mutations in genes coding for histone-modifying
enzymes or indirectly by the permutation of biochemical pathways
that regulate the balance between open and closed chromatin.
TET2
TET2, which encodes a member of the Ten-Eleven Translocation
gene family, is the most commonly mutated epigenetic regulator in
MDS.97 TET2 mutations occur in 20% to 30% of all MDS and are
particularly enriched in CMML, where they can be found in 40%
to 50% of cases.98 The TET2 protein is a methylcytosine oxy-
genase responsible for converting 5-methylcytosine (5mC) into 5-
hydroxymethylcytosine (5hmC) using iron and α-ketoglutarate
(α-KG, produced by IDH1 and IDH2), and for further oxidizing
5hmC to 5-formyl- and 5-carboxycytosine.99 These reactions are
thought to contribute to active demethylation through base excision
repair back to unmodified cytosine.100 Mutations in TET2 tend to be
inactivating frameshift or nonsense mutations or specific missense
substitutions predicted to lead to abrogation of protein function, and
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Chapter 60  Myelodysplastic Syndromes 949
many patients are either compound heterozygotes or have uniparental
disomy (UPD) at chromosome 4q, leading to effective abrogation of
TET2 function.101 Indeed, patients with TET2 mutations have been
shown to have globally altered methylation profiles.102 TET2 muta-
tions often occur early in MDS pathogenesis and are thought to alter
HSC homeostasis, a theory supported by the fact that HSCs in TET2
knockout mice display enhanced self-renewal and repopulation
capacity. In humans, however, TET2 mutations do not appear to
themselves confer a specific phenotype;79 rather, they may create an
epigenomic environment permissive to the acquisition of other muta-
tions that are responsible for determining these factors. Recent evi-
dence suggests that TET2 mutations appear to predict a favorable
response to hypomethylating agents, particularly in the setting of
wildtype ASXL1.103 TET2 mutations were not previously felt to
confer prognostic information, but newer data suggest that, at least
in patients undergoing stem cell transplant, they predict an inferior
outcome.104
DNMT3A
DNMT3A is a member of the family of DNMTs, which catalyze the
addition of methyl groups to cytosine residues of CpG dinucleotides.
These dinucleotides tend to cluster in 5′ promoter regions upstream
of genes, and increased methylation of these CpG islands is associated
with decreased expression of the associated downstream gene.105 The
observation that many cancers often display aberrant methylation
relative to healthy tissue has led to the hypothesis that hypermethyl-
ation, particularly in the promoters of tumor suppressor genes, plays
a role in cancer pathogenesis. This hypothesis has been somewhat
supported by the efficacy, albeit imperfect, of so-called hypomethylat-
ing agents like decitabine and 5-azacitidine in MDS and AML (see
section on Therapy, later).
The DNMT3A gene consists of 29 exons and encodes a 908-
amino acid protein that, along with DNMT3B, is one of the two
enzymes responsible for de novo CpG methylation independent of
replication, whereas a third methyltransferase, DNMT1, is respon-
sible for maintenance of baseline hemimethylation during active
replication. Only DNMT3A mutations, however, have been found to
occur recurrently in myeloid malignancies, perhaps suggesting dif-
ferential expression in hematopoietic cells. Analysis of DNMT3A
mutations in patients with MDS has shown a preponderance of
missense single nucleotide variations predicted to alter protein func-
tion, although nonsense mutations, insertions, and deletions (indels)
have been observed as well. The mutations occur throughout the
gene, although a mutational hotspot at R882H, in the methyltrans-
ferase domain, has been described in a minority of MDS patients.106
In AML, the R882H mutant protein has been shown to inhibit
wildtype DNTM3A, suggesting a dominant negative mechanism.107
In earlier studies, DNMT3A-null HSCs transplanted into mice
displayed aberrant global methylation patterns, increased self-renewal,
and impaired differentiation capacity compared to wildtype HSCs,
but the mice themselves did not develop dysplasia or other hemato-
logic malignancies.108 In more recent studies, however, mice trans-
planted with DNMT3A-null HSCs had shortened overall survival
and developed a spectrum of hematopoietic malignancies similar to
that seen in humans, including leukemia and MDS.109 The different
outcomes in these two studies is thought to be caused in large part
by the fact that mice in the older experiments were serially trans-
planted at 18 weeks, before they had a chance to develop overt
hematologic disease, whereas mice in the later experiments were
observed for 6 months. The long latency to development of malig-
nancy in these experiments may speak to the subtlety of the epig-
enomic abnormalities initially conferred by acquisition of DNMT3A
mutations.
In humans, the significance of DNMT3A mutations in the
pathogenesis of MDS is not clear. They occur with somewhat less
frequency than the most common recurrent mutations (between 8
and 13% in most studies80,110 although some studies have quoted
much lower frequencies below 5%).111 On the other hand, clonal
 950 Part VII  Hematologic Malignancies
DNMT3A mutations have recently been shown to exist with modest
frequency in healthy older adults and are in fact significantly more
common than mutations in any other single gene,31 with an overall
frequency that is significantly higher than their aggregate representa-
tion among hematologic malignancies. This discrepancy could either
reflect the same long latency of DNMT3A-mutated hematologic
malignancy that was observed in mouse models, or it could suggest
that DNMT3A mutations have a relatively less potent pathogenic
effect than some other genes (e.g., TET2 mutations, which are less
frequent in the general population but more frequent in MDS).
DNTM3A mutations appear to be negatively correlated with
mutations in certain other genes, particularly SRSF2 and ASXL1,80
and in low-risk MDS they seem to have a positive correlation with
SF3B1 mutations.112 There is evidence that DNMT3A mutations
confer a poor prognosis in cytogenetically normal AML,106 but that
prognostic significance so far has not been convincingly shown to
apply to DNMT3A-mutated MDS.
ASXL1
ASXL1 codes for a polycomb chromatin-binding protein and is
involved in epigenetic regulation of gene expression. It acts as a
co-activator of the retinoic acid receptor and directly interacts with
chemical modifiers of histones (e.g., NCOA1, a histone acetyltrans-
ferase, and LSD1, a histone demethylase). ASXL1 mutations occur
in about 10% to 29% of total MDS and myeloproliferative neoplasm
(MPN),113 17% of AML, and 40% of CMML.114
The specific mechanisms by which ASXL1 mutations affect the
development of MDS are not clear. The first mice engineered to have
constitutive ASXL1 germline insufficiency survived to adulthood
with relatively mild lymphopenia and modest splenomegaly, and did
not develop myelodysplasia.115 Subsequently, ASXL1 mutations were
found to confer global reduction H3K27 trimethylation by disrupt-
ing normal recruitment of polycomb recessive complex 2 (PRC2),
which places the H3K27 mark in vivo.116 This was followed by a more
physiologic attempt at conditional ASXL1 knockout in murine
hematopoietic cells, which did induce abnormal myeloid differentia-
tion that was compounded by additional loss of TET2. In this study,
ASXL1-deficient cells displayed differential expression of a set of
genes largely related to hematopoietic differentiation.117
In humans, most MDS-associated ASXL1 mutations affect the
C-terminal portion of the protein, specifically the plant homeo
protein interaction domain.118 This observation has led to speculation
that the mutant protein retains DNA-binding activity and thus exerts
a dominant-negative effect on wildtype ASXL1, which may not have
been captured in the mouse experiments. In studies of MDS cohorts,
investigators have observed that ASXL1 mutations co-occur less fre-
quently with certain other recurrent genetic lesions, particularly
DNTM3A and JAK2.119 On the other hand, ASXL1 mutations have
been found to cooccur with both RUNX1 and TET2 abnormali-
ties.120 The most recent rigorous studies suggest that ASXL1 muta-
tions have a modestly poor prognosis, but tend to occur in patients
with low IPSS scores who would otherwise be felt to have indolent
disease, perhaps suggesting a more profound pathogenic effect
than might be suspected.79
EZH2
EZH2 encodes the catalytic subunit of PRC2, which promotes the
di- and trimethylation of lysine 27 on histone 3 (H3K27). Locally,
methylated H3K27 results in closed chromatin and transcriptional
repression, and global H3K27 trimethylation in particular is associ-
ated with reduced pluripotency and cellular senescence, suggesting a
role for EZH2 in regulation of cell fate.121 Recent studies have shown
that α-KG also regulates relative levels of methylation at this locus,
suggesting a possible convergence with the TET2/IDH pathway.122
EZH2 resides on the long arm of chromosome 7, and its loss has
been hypothesized to be at least part of the reason 7q− is such a
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deleterious cytogenetic occurrence in MDS,123 though not all 7q
deletions affect the EZH2 locus.124 Mutations in EZH2 itself are
found in 5% to 10% of patients with MDS80 and 20% to 30% of
patients with CMML.125 Consistent with the model of EZH2 as a
negative regulator of pluripotency and survival, mutations tend either
to be inactivating frameshift or nonsense mutations, or missense
mutations concentrated in the gene’s SET domain, which is critical
for DNA binding.126,127 EZH2 mutations confer a negative prognosis
in MDS that appears to be independent of other prognostic factors,
including the IPSS score, in part because they tend not to be associ-
ated with specific clinical characteristics that are incorporated into
these systems.79
IDH Genes
The isoforms of isocitrate dehydrogenase, encoded by IDH1 and
IDH2, are responsible for the conversion of isocitrate to α-KG, which
as above is used by TET2 in the conversion of 5mC to 5hmC.
Mutations in IDH1 and IDH2 lead to enzymes with neomorphic
activity that convert α-KG to d-2-hydroxyglutarate, which accumu-
lating data suggests is an oncometabolite that can inhibit both TET2
and other epigenetic enzymes, including prolyl hydroxylases and a
number of histone demethylases.128 Mutations in IDH1/2 and other
members of the IDH pathway (including WT1) have repeatedly been
shown to be important in AML,129 but IDH mutations are relatively
infrequent in MDS, occurring in 5% or fewer of patients.79,80 Both
IDH1 and IDH2 mutations can cooccur with most other recurrent
mutations besides TET2, with which they are essentially mutually
exclusive.
Transcription Factor Genes
Transcription factors represent a third class of genes commonly
mutated in MDS. Similar to epigenetic and splicing genes, mutated
transcription factors can have pleiotropic effects on a number of gene
targets, and these mutations are indeed also often early events in
MDS pathogenesis.
RUNX1
RUNX1 (formerly known as AML1) is the transcription factor gene
most commonly mutated in MDS, and its biology is complex. It
encodes the alpha subunit of the core binding transcription factor
and is involved in determining the lineage fate of HSCs.130 RUNX1
was initially identified as one of the genes involved in two different
common pathogenic translocations: t(8;21), found in AML, and
t(12;21), found in acute lymphoblastic leukemia.131,132 Subsequently,
germline point mutations in RUNX1 were identified in autosomal
dominant familial platelet disorder with propensity for AML,38 and
later as somatic events in both sporadic AML and MDS.133 Reflecting
the complexity of RUNX1 biology, mutations occurring throughout
the gene, can be either monoallelic or biallelic, and can be frameshift
insertions or deletions or nonsense or missense substitutions.134
However, most mutations appear to have an inactivating effect on
RUNX1 function, either by affecting the DNA-binding RUNT
domain or by disrupting the C-terminal protein interaction domain.135
Many of the remaining mutations outside these regions appear to
affect RUNX1 interactions with epigenetic regulators like MLL,
thereby affecting histone methylation.136 Both clonal and subclonal
RUNX1 mutations appear to confer a poor prognosis in MDS
patients, irrespective of other prognostic factors.78
ETV6
ETV6 encodes an ets-like transcription factor with mostly repressive
activity.137 It is situated on the short arm of chromosome 12, and its

role in hematologic malignancy has been best characterized by its
involvement in recurrent translocations, including t(3;12)(q26;p13)138
and deletions of 12p.139 In MDS, however, both missense and inac-
tivating frameshift point mutations have been described as well.
There is some data that the missense mutations, which mostly cluster
in the DNA-binding ETS domain, have a dominant negative effect
on the wildtype allele.140 However, whether malignant transformation
requires ETV6 activity below a critical threshold remains unclear, as
not all frameshift mutations occur with loss of heterozygosity (and
some frameshifts can confer dominant negative function as well).
ETV6 mutations are relatively rare events in MDS, occurring in at
most 5% of cases;79 recently, familial cases of MDS and AML because
of inherited ETV6 mutations have also been described.39
GATA2
GATA2 encodes a transcription factor with pleiotropic effects in early
hematopoietic progenitor cells.141 In contrast to most other genes
described here, acquired mutations in GATA2 are quite rare, but there
are a number of clinical syndromes associated with germline GATA2
mutations, several of which involve a risk of developing MDS and
AML. These include Emberger syndrome (congenital lymphedema
and risk of AML),142 autosomal dominant monocytopenia and
mycobacterial infection syndrome,143 and dendritic cell, monocyte, B
and natural killer (NK) lymphoid deficiency syndrome.144 In addi-
tion, GATA2 mutations have also been described in kindreds with no
accessory phenotype beyond a strong history of early-onset MDS/
AML.37 Several phenotypic components appear to be dependent on
the type of mutation. For instance, nearly all patients who develop
MDS or AML have mutations in or immediately 5′ to the second
zinc finger domain, which tend to be missense substitutions predicted
to affect DNA binding.145 On the other hand, a second group of
patients with truncating frameshift mutations in the N-terminal
region of the gene tend to present at younger ages with more pro-
nounced immune deficits, but have a lower risk of MDS or AML.
Although the mechanism by which these patients develop MDS is
not completely clear, the subset of patients with GATA2 germline
mutations who develop MDS or AML has been observed to acquire
ASXL1 mutations with frequency much greater than would be
expected to occur by chance.146
TP53
TP53 mutations occur in about 10% of patients with MDS, and as
in other settings imply a poor prognosis and response to therapy.79
They are closely associated with a complex karyotype and tend not
to cooccur with other recurrent driver mutations.147,148 They fre-
quently cooccur with del(5q) and may represent a progression
pathway for patients with 5q− syndrome.149 They are also frequently
found in t-MDS and AML.49 Recently, a small series of patients with
t-AML showed that TP53 mutations present in the leukemia were
detectable in samples collected 3–6 years earlier, which in at least two
patients predated their original chemotherapy.150 This suggests that
the expansion of rare preexisting clones harboring TP53 mutations
may be the leukemogenic mechanism in at least some patients with
therapy-related disease, rather than accumulation of DNA damage
induced by the chemotherapy itself.
Tyrosine Kinases and Growth Factor Receptors
Mutations in tyrosine kinase and growth factor receptor genes are
typically associated with proproliferative signals and occur in a wide
range of myeloid malignancies, including AML (FLT3151), MPNs
(JAK2152 and MPL153), and mast cell disorders (KIT).154 While they
do occur in MDS, they are usually late, subclonal events that often
mark progression to secondary AML.155 A few of these deserve specific
mention. Activating mutations in NRAS are the most frequent
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Chapter 60  Myelodysplastic Syndromes 951
tyrosine kinase mutations found in MDS,156 but still only occur in
about 5% of cases and as mentioned earlier, tend to begin as sub-
clonal, proproliferative events that frequently drive the transition to
AML.157 Best known for its role in MPNs, JAK2 is mutated in about
3% to 5% of MDS, particularly RARS-T and CMML.158 JAK2
mutations in MDS tend not to be associated with overproduction of
mature hematopoietic cells as they are in MPNs, likely as a conse-
quence of concomitant biologic defects contributing to ineffective
hematopoiesis.159
Cohesin Complex Genes
Genes encoding members of the cohesin complex family, including
RAD21, STAG2, SMC3, and SMC1A, are each mutated in a small
minority of MDS cases, but collectively, cohesin mutations can be
found in about 10% of MDS.160 Their physiologic role is in the
maintenance of chromatid structural fidelity, particularly during
mitosis. How cohesin complex mutations affect MDS pathogenesis
is not completely understood, since they do not appear to directly
promote chromosomal instability. Clinical studies, however, have
shown that they appear to be disproportionately associated with
multilineage dysplasia, and confer inferior survival and an increased
risk of progression to AML.161
Other Genes
The genes described previously collectively account for the majority
of mutations found recurrently in MDS, but this list is certainly not
exhaustive. Even very recent, broad surveys of patients with MDS
using the most updated panels of gene mutations and high-resolution
FISH and karyotyping have shown that between 10% and 20% of
patients lack a detectable genetic abnormality.78–81 There are multiple
possible explanations for this observation. For example, some of
these patients may have other types of aberrations not captured by
sequencing or karyotyping, such as small copy number abnormali-
ties that might be detected by SNP arrays, which are not routinely
performed in clinical practice. More likely, however, many of these
patients probably have mutations in genes that are less frequently
altered in MDS pathogenesis. Some of these mutations are in path-
ways represented by other, better-known genes; for example, rare
mutations have been described in PTPN11, a tyrosine phosphatase
that acts as a downstream effector in the RAS pathway,162 and in
BRAF, better known for its association with melanoma and hairy
cell leukemia.163 Similarly, rare mutations have been described in
EED and SUZ12, other components of the PRC2 that affiliate with
EZH2 and collectively interact with ASXL1.164 Other times, MDS
can occur in the setting of mutations in genes better known for being
associated with other diseases, such mutations in CBL, a gene better
known for its association with juvenile myelomonocytic leukemia
that encodes an E3 ubiquitin ligase responsible for degrading several
tyrosine kinases.165 Finally, mutations are occasionally described in
relatively novel gene classes, including genes encoding the G-protein
subunits GNAS166 and GNB1167 and the DNA repair enzymes
hOGG1, XRCC3, and XPD.168 Some patients may have mutations
in other genes that have yet to be described. While it is unlikely
that a major, frequently mutated pathway remains undiscovered
in MDS, study of these low-frequency, “long-tail” mutations may
yield valuable further insights into the molecular pathogenesis of the
disease.
Karyotypic Abnormalities
Chromosomal abnormalities, larger-scale genetic aberrations that can
be detected on either karyotype or FISH, are also common events in
MDS.169 The most common types of abnormalities in MDS are
deletions or duplications of very large chromosomal regions; as
opposed to some other hematologic cancers, translocations and
 952 Part VII  Hematologic Malignancies
inversions are less common. Several of the most common karyotypic
abnormalities have been shown to have prognostic value, and one,
del(5q), has enough unique biologic features to be its own subclas-
sification within the WHO criteria.
del(5q)
Interstitial deletion of the long arm of chromosome 5 [del(5q)] is the
most common chromosomal abnormality in MDS,42 and del(5q) is
the only karyotypically-defined subtype recognized by the WHO.170
Although the specific region affected varies between patients, there
are two commonly deleted regions (CDRs), one on 5q31.1 and the
other at 5q32-33.3, with most patients having a deletion that includes
both CDRs.171 MDS patients in whom del(5q) is the sole karyotypic
abnormality often display the “5q-minus syndrome,” which is clini-
cally characterized by anemia, normal or elevated platelet count,
female predominance,172 lower risk of transformation to AML, and
a striking response to lenalidomide.173
Our understanding of the pathobiology underlying del(5q) MDS
has improved substantially over the past several years; a key observa-
tion was the lack of recurrent point mutations in genes located on
5q in other patients with MDS, which, coupled with the fact that
most patients with del(5q) retain one normal chromosome 5, sug-
gested that the pathobiology could be best explained by haploinsuf-
ficiency of deleted genes.174 Indeed, it now appears that different
genes lost in the CDRs are responsible for different aspects of the
5q− phenotype. For instance, haploinsufficiency of RPS14, a ribo-
somal subunit gene located at 5q31.2, leads to p53 activation in
erythroid progenitors and is responsible for the dyserythropoiesis seen
in the syndrome,175 and deletion of a key microRNA, miR-145, is
responsible for the megakaryocytic component of the phenotype.176
Separately, haploinsufficiency of CSNK1A1, which is located at 5q32
and encodes casein kinase 1-alpha, is responsible for the sensitivity
to lenalidomide, which accelerates the ubiquitination and degrada-
tion of remaining casein kinase 1-alpha through a cereblon-dependent
process.177 Other studies have suggested that additional genes on 5q,
including EGR1, APC178, HSPA9179, NPM1180, and others181 may
contribute to features of the disease via a similar mechanism of
haploinsufficiency in select cases.
These points apply only to del(5q) as a sole karyotypic abnormal-
ity in MDS. When del(5q) is found with other chromosomal
abnormalities, especially in the context of a complex karyotype (three
or more karyotypic abnormalities, a finding often associated with
TP53 mutations or 17p loss), the prognosis is poor and the response
to lenalidomide seen in 5q− syndrome usually does not exist.149
Cooccurrence of del(5q) with TP53 mutation or 17p loss, in fact,
occurs more frequently than would be expected by chance, suggesting
cooperativity of the two abnormalities. Del(5q) seen in the context
of AML, even if the sole karyotypic abnormality, is a universally poor
prognostic sign.182
Chromosome 7 Abnormalities
Deletion of one entire copy of chromosome 7 (i.e., monosomy 7)
is also characteristic of MDS and portends a poor prognosis.183 The
pathogenesis of chromosome 7 abnormalities is incompletely under-
stood. Several genes recurrently mutated in MDS, including
EZH2,123 MLL3,124 and CUX1,184 lie on 7q, and it has been hypoth-
esized that loss of some or all of chromosome 7 contributes to MDS
pathogenesis via a haploinsufficiency mechanism similar to that seen
in del(5q). If such a mechanism exists, however, the evidence sup-
porting it has not yet been produced. Part of the difficulty in
proving its existence lies in the fact that unlike del(5q), there is no
common deleted region on chromosome 7 in which to focus efforts
at driver gene discovery.185 It is important to note that in the revised
IPSS (IPSS-R), del(7q) is considered to be an intermediate-prognosis
abnormality distinct from monosomy 7, which is classified as poor
prognosis.186
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Trisomy 8
Trisomy 8 is present in about 5% of MDS patients and can be found
in a wide range of other myeloid disorders, including AML, MPNs,
and aplastic anemia. In MDS, it can often be seen as a late, subclonal
event.187 Although its contribution to pathogenesis is incompletely
understood, MDS patients with trisomy 8 appear to upregulate WT1,
an oncogene that can be mutated in AML (but very rarely in MDS),
which may behave as a neoantigen that stimulates the expansion of
oligoclonal CD4+ and CD8+ T cells.188 Some evidence suggests that
these populations may contribute to impairment of hematopoiesis in
MDS patients with trisomy 8,189 which may explain why some patients
with isolated trisomy 8 can have substantial responses to immune
suppression with antithymocyte globulin (ATG).190 Trisomy 8 has also
been associated with the development of paraneoplastic autoimmune
phenomena, such as Behçet disease,191 again reflective of the immune
dysregulation characteristic of this cytogenetic abnormality.
del(20q)
del(20q) is an infrequent chromosomal aberration in MDS, occurring
in about 2% of patients.192 Patients with del(20q) frequently have
prominent thrombocytopenia, may have concomitant mutations of
U2AF1, and appear to have an intermediate prognosis,193 although
20q loss can also be a late event that indicates clonal progression of
disease.194 The best candidate driver gene lying within the common
deleted region is a tumor suppressor gene known as MYBL2,195 but
recent studies suggest that in myeloid models, a reduction in MYBL2
levels below what would be predicted for classic haploinsufficiency is
required to drive clonal expansion.196 Although ASXL1 resides on
20q, it sits outside the CDR,197 and most patients with 20q abnor-
malities do not have concomitant ASXL1 mutations.
17p Deletions
Chromosome 17 abnormalities occur most often in MDS in associa-
tion with complex karyotypes, which is most likely related to the fact
that TP53 resides within the common deleted region on 17p.147 In
MDS, many patients with loss of 17p will have an inactivating
mutation of their remaining copy of TP53, implying that haploinsuf-
ficiency is not in and of itself enough to drive pathogenesis.198 At the
same time, patients almost never lose both copies of 17p as part of a
larger chromosomal event, suggesting that some other gene or genes
in this region may be essential for hematopoietic cell survival. As with
TP53 point mutations, loss of 17p is an exceedingly poor prognostic
factor in MDS, is frequently seen in cases of therapy-related disease,53
and often presages the development of treatment-refractory AML.199
Complex and Monosomal Karyotypes
Complex karyotypes, meaning those with three or more cytogenetic
abnormalities, are one of the more common abnormalities in MDS.169
About half are associated with TP53 mutations; conversely, many, but
not all, patients with TP53 mutations have complex karyotypes.147 As
opposed to 17p abnormalities, which are reflective of the TP53 loss
itself, complex karyotypes are instead downstream effects of p53 loss
and represent the type of structural DNA damage that would have
triggered p53-mediated apoptosis in normal cells. The exceedingly
poor prognosis associated with complex karyotypes is in fact probably
a proxy for p53 loss; the half of patients with complex karyotypes who
have intact p53 function appear to have prognoses similar to patients
with normal cytogenetics. Monosomal karyotypes, defined as complete
loss of at least two entire chromosomes or one monosomy plus one
other abnormality, are also common and also tend to confer a poor
prognosis, particularly when associated with monosomy 7 or mono-
somy 5.200 When monosomal and complex karyotypes occur together,

however, the monosomy does not appear to confer an additional poor
prognosis beyond that of the complex karyotype.201
Other Karyotypic Abnormalities
A number of other cytogenetic abnormalities have been repeatedly
described in MDS, including –Y,202 del(13q),203 del(11q),139 del(12p)
or t(12p),204 del(9q),192 idic(X)(q13),192 t(11;16)(q23;p13.3),205 t(3;21)
(q26.2;q22.1),206 t(1;3)(p36.3;q21),207 t(2;11)(p21;q23),205 inv(3)
(q21q26.2)207 and t(6;9)(p23;q34).208 Most of these do not have spe-
cific phenotypes or associated with them, but some do confer prognostic
information and are included in the IPSS-R. In particular, –Y and
del(11q) are designated “very good” prognosis; del(12p), del(20q),
isolated del(5q), and normal karyotypes are considered “good’ ” trisomy
8, del(7q), isochrome 17(q), trisomy 19, and trisomy 21 are considered
“intermediate;” monosomy 7, double deleted (7q), derivative (3q), and
complex karyotype with exactly three abnormalities are considered
“poor,” and complex karyotypes with more than three abnormalities
are considered “very poor.” In addition, finding any of these in the
appropriate clinical context, regardless of whether they are known to
carry prognostic information, is typically enough to warrant a diagnosis
of MDS, even in the absence of clear morphologic dysplasia.
The Microenvironment in Myelodysplastic Syndrome
The malignant transformation of hematopoietic progenitors in MDS
occurs not in isolation, but within the rich microenvironment of the
bone marrow stroma, which has come to be known as the “hemato-
poietic niche.”209 Evidence has shown that under normal circum-
stances, hematopoiesis is in part regulated by paracrine signals released
from nonhematopoietic mesenchymal cells,210 and evolving data
suggest that some of these processes are dysregulated in MDS. Early
circumstantial clues came from findings that patients with MDS and
other hematologic malignancies have abnormal circulating levels of
cytokines known to affect hematopoiesis, including monocyte-colony
stimulating factor, interleukin (IL) 1a, and granulocyte-monocyte
colony stimulating factor (GM-CSF),211 and other studies have
shown that hematopoietic cells from MDS patients respond abnor-
mally to these cytokines compared to cells from healthy controls.212
More recent studies have shown that hematopoietic progenitor cells
transplanted into older mice display a narrower range of clonal expan-
sion than identical cells transplanted into younger mice, suggesting
that an aging niche might exert selective pressure on dominant
hematopoietic progenitor cell clones.213 Furthermore, it has been
discovered that conditional deletion of the gene encoding dicer1, a
microRNA processing enzyme, in osteoprogenitor cells can induce
myelodysplasia and secondary AML in mice;214 concurrently, other
studies have shown altered expression of DICER and DROSHA,
another microRNA-processing enzyme, in mesenchymal cells of
MDS patients.215 Even more intriguing, it has recently been shown
that introduction of an activating B-catenin mutation in mouse
osteoblasts can induce the development of AML through induction
of the Notch ligand jagged1, which leads to Notch activation in
HSCs.216 As tantalizing as these findings are, the extent of their
pervasiveness across all MDS patients, and how microenvironmental
alterations interact with the well-validated recurrent mutations found
in hematopoietic cells, has yet to be determined. It is worth noting
that HSC transplantation, which involves only the transplantation of
hematopoietic elements and not stroma, can be curative for some
patients with MDS, implying that at least in these patients, the niche
is not sufficient to sustain disease.
Immune Dysregulation
In normal human tissues, both the innate and adaptive immune
systems play important roles in identifying, isolating, and destroying
early clones with malignant potential before they are able to transform
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Chapter 60  Myelodysplastic Syndromes 953
into clinically evident cancers. Perturbation of this immune response
presumably allows the persistence and propagation of abnormal
clones in MDS, but the extent to which this is pathogenically impor-
tant is not clear.217
Several aspects of innate immunity have been shown to be abnormal
in MDS patients.218 Some toll-like receptors, including TLR4, are
overexpressed on MDS progenitor cells,219 and increased TLR signaling
has been associated with higher degrees of apoptosis and the develop-
ment of cytopenias. In patients with del(5q), loss of miRs 145 and 146a
from the common deleted region has been shown to upregulate tumor
necrosis factor (TNF) receptor–associated factor 6, a TLR adaptor
E3 ubiquitin ligase, as well as Toll IL-1 receptor domain-containing
adaptor protein (TIRAP), two important downstream effectors of
TLR4.220 del(5q) may also lead to the upregulation of CD14 on granu-
locytes via heterozygous loss of mDia1, a scaffolding protein involved
in actin polymerization, which appears to confer abnormalities of the
innate immune response.221 More recently, myeloid-derived suppressor
cells have been shown to be significantly expanded in some patients
with MDS, and increased signaling in these cells via interaction with
S100A9, an important inflammatory mediator, has been shown to
similarly stimulate inappropriate apoptosis in hematopoietic precursor
cells.222 Coincident with these findings, population-level data have
suggested that patients with chronic inflammatory stimulation appear
to be at increased risk of developing MDS and AML.223
Abnormalities in the adaptive immune system also exist in MDS.
These have been particularly well described in hypoplastic variants,
which have similarities to aplastic anemia at both the cellular and
genetic level, and both can respond to immune suppression.224 More
broadly, oligoclonal T-cell receptor gene rearrangements can be found
in MDS patients of all subtypes,225 and clinically detectable abnor-
malities of NK-cell, B-cell, and T-cell number and function can be
detected in a subset of patients as well.226–228
Abnormal Apoptosis
Although MDS is typically characterized by normal or increased
marrow cellularity, abnormalities of apoptosis are frequently described,
particularly in low-risk variants, where increased apoptosis has been
hypothesized to contribute to the development of ineffective hema-
topoiesis.229 There are two major mammalian apoptosis pathways.
The death receptor pathway, also known as the external pathway, is
triggered by ligation of TNF family members, which leads to the
recruitment and activation of caspases at the cell surface.230 There is
ample evidence of abnormalities in this pathway in MDS; for
instance, TNF-α levels have been shown to be increased in all MDS
subtypes,231 and other proapoptotic cytokines, including IL-8, trans-
forming growth factor β, interferon-γ, and Fas ligand, have been
shown to be elevated as well.232 The other major apoptotic pathway,
known as the BCL-2 or intrinsic pathway, involves a complex balance
between proapoptotic (BAX, BAK, BAD, PUMA, and others) and
antiapoptotic molecules (BCL-2, BCL-XL, MCL-1, and others),233
and has also been shown to be abnormal in MDS. For example, ratios
of proapoptotic (Bax/Bad) to antiapoptotic (Bcl-2/Bcl-XL) molecules
are elevated in patients with lower-risk subtypes of MDS (RA and
RARS), but the ratio reverses in RAEB and secondary AML, primar-
ily driven by increased BCL-2 expression.234 Coordinate with this
observation, but somewhat paradoxically, inhibition of apoptosis by
BCL-2 appears to prevent leukemic transformation in murine models
of MDS.235 Preclinical studies further suggest that inhibition of
BCL-2 and other antiapoptotic molecules may delay progression of
disease236 and may sensitize MDS cells to hypomethylating agents
such as azacitidine, but clinical trials combining these approaches
have not yet been performed.237
Transformation to Acute Leukemia
Although MDS and AML are often uttered in the same breath and
conceptualized as two facets of a similar disease process, this is an
 954 Part VII  Hematologic Malignancies
overly simplistic view that ignores the complexity and heterogeneity
of each disease on its own.82 Although MDS can and often does
transform into secondary AML, other types of de novo AML are
biologically quite distinct from MDS, and conversely, some low-risk
forms of MDS are biologically distinct from secondary AML. At the
same time, however, there is a continuum between the two diseases
that is only now starting to become fully understood. Recently, for
instance, it has been shown that cases of AML harboring mutations
in any of eight genes (SF3B1, SRSF2, U2AF1, ZRSR2, ASXL1,
EZH2, BCOR, or STAG2) are highly likely to have evolved out of
MDS, even when no antecedent stage of MDS was clinically
evident.148 The converse, that AML with driver mutations in other
genes must have arisen de novo, is not necessarily true; NPM1 muta-
tions appear to be restricted to de novo AML, but mutations in
DNMT3A, TET2, and IDH1/2 can occur in both secondary and de
novo AML and thus do not appear to be ontogeny-specific. In this
study, TP53-mutated AML comprised its own category and was
associated with prior chemotherapy and complex karyotypes, consis-
tent with prior studies.
Understanding this shared genetic basis of MDS and secondary
AML has also shed light on the transition from one to the other.
Although the eight genes defining secondary ontogeny (i.e., disease
arising from antecedent MDS) have different functions, they all tend
to have broad, pleiotropic effects and for the most part have in mouse
models been shown to be insufficient for leukemogenesis when they
occur in isolation. The fact that they occur infrequently in de novo
AML may imply that they have effects strong enough to commit cells
to an MDS phenotype, with increased self-renewal and inhibitory
effects on differentiation and hematopoiesis, whereas TET2 and
DNMT3A mutations may have more subtle effects that increase
self-renewal but do not in and of themselves predispose to a specific
phenotype in the absence of specific secondary mutations.
In most cases, progression of MDS to AML involves the acquisi-
tion of proproliferative mutations, which tend to be late, subclonal
events.238 These mutations frequently occur in tyrosine kinase genes
like FLT3,155 NRAS,239 or KIT,240 or in certain transcription factor
genes such as CEBPA,241 and lead to constitutively activated growth
and proliferative pathways. As discussed elsewhere, patients who
develop secondary AML from an antecedent MDS tend to have a
poorer prognosis, with both a lower rate of complete remission and
a poorer overall survival, independent of remission, than patients with
de novo AML.242 In unselected populations, some of this difference
in outcome can be explained by proximate characteristics of the
secondary AML cohorts, which tend to be older and have more
comorbidities, mirroring the demographics of the MDS population.
However, patients with secondary AML have inferior outcomes even
compared to age-matched controls with de novo AML,235 which has
remained the case when redefining ontogeny based on the genetic
stratification outlined earlier.243 This inferior outcome has been pre-
sumed to reflect the intrinsic refractory nature of the antecedent
MDS, and this presumption is now being proven true by sequencing
bone marrow samples from secondary AML patients who morpho-
logically appear to be in remission—in fact, the proliferative muta-
tions are often eliminated but the preexisting driver mutations
remain, suggesting that chemotherapy simply reverted the marrow to
the preexisting clonal state.58,148 Overcoming the intrinsic resistance
to therapy that appears to be common to most patients with MDS
remains one of the central challenges of treating the disease.
Integrating the Pathobiology of   of classic neurologic symptoms, B12 and folate levels should be
Myelodysplastic Syndrome
With the continuous, deepening accumulation of data describing the
pathogenesis underlying MDS, one of the central future challenges
will be integrating these data into coherent models that correctly
reflect fundamental aspects of the disease. The need for integration
is twofold. First, there is a need to integrate disparate components of
the biology itself, including somatic mutations, changes in gene
expression, epigenetic disruption, and cell-cell interactions within the
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marrow microenvironment and beyond. Second, it will also be neces-
sary to integrate these biologic storylines with clinical information,
in the hope that a fuller understanding of MDS biology may uncover
new treatment approaches and better predictive and prognostic
models than do single biologic features alone. Such work is already
beginning; for instance, a recent report suggested that an algorithm
integrating sequencing for common driver mutations with principal
component analysis of gene expression better predicts some clinical
features of MDS than sequencing or expression data considered in
isolation, and the algorithm outperformed the IPSS in predicting
overall survival (76% versus 64% accuracy).244 Thus far, however,
these types of integrative studies remain in relative infancy. Making
significant gains in this type of deep understanding will be a substan-
tial undertaking, requiring large, well-coordinated clinical trials with
rigorous banking of serial blood and marrow samples, careful annota-
tion of clinical features and outcomes, and intensive collaboration
between academics, industry, and clinicians in devising strategies for
rationally targeting key elements of MDS biology.
CLINICAL FEATURES OF MYELODYSPLASTIC SYNDROME
Compared to other hematologic disorders, the clinical features of
MDS are often underemphasized relative to laboratory aspects of the
disease. This is in part because of the fact that the major common
physiologic defect, ineffective hematopoiesis, usually leads to some-
what vague signs or symptoms. Nevertheless, it is important to
understand these features within the context of the disease’s pathogen-
esis and management. Some patients with MDS have distinct clinical
phenotypes that are largely related to genetics or specific pathologic
features. MDS can also coexist with other hematologic malignancies,
including multiple myeloma (even in previously untreated patients)245,
hairy cell leukemia,246 chronic lymphocytic leukemia (CLL),247 non-
Hodgkin lymphoma,248 and large granular lymphocyte leukemia
(LGL).249 Parsing the components of presentation that could be caused
by a coexisting process (e.g., in a patient with both MDS and CLL,
which is the primary contributor to the patient’s cytopenias?) is an
important task for clinicians and pathologists.
Differential Diagnosis
In the absence of clonal markers or excess blasts, MDS is a diagnosis
of exclusion, requiring that other potential contributors to cytopenias
and myelodysplastic morphology be ruled out to the greatest extent
possible.250 Since cytopenias are the most common presenting clinical
feature, the differential diagnosis is in theory broad and includes
numerous other entities covered in more detail elsewhere in this
book. In practice, however, all patients suspected of having MDS
should undergo a bone marrow aspirate and biopsy, since the diag-
nostic criteria are almost entirely pathologic and marrow findings are
critical for risk stratification and treatment planning.
Several nutritional deficiencies can cause cytopenias and morphol-
ogy similar to MDS. Folate deficiency can cause macrocytosis and,
in extreme cases, megaloblastic morphology in the marrow.251 Vitamin
B12 (cobalamin) deficiency is a more classic cause of megaloblastic
changes, and patients with severe B12 deficiency can have bizarre
morphology with an abundance of early forms that can occasionally
be confused with evolving AML, especially erythroleukemia.252 Since
the hematologic changes of B12 deficiency can occur in the absence
checked on all patients in whom a potential diagnosis of MDS is
being entertained, and methylmalonic acid and homocysteine levels
may help clarify whether deficiency is truly present in cases with
borderline levels.253
Copper deficiency is less common than B12/folate deficiency, but
can also be mistaken for MDS. It classically arises in patients who
have had gastrectomies or certain forms of gastric bypass surgery,
particularly biliopancreatic diversion,254 and can also develop in
patients taking high doses of zinc, which competes with copper for

absorption in the small bowel255 (it is important to note that newer
forms of gastric bypass, including gastric sleeve procedures and newer
iterations of the roux-en-y, maintain small bowel absorption such that
patients do not typically develop copper deficiency). Clinically,
patients with copper deficiency develop an anemia that can be nor-
mocytic or macrocytic and can occasionally be profound. Mild
neutropenia can also be seen, while clinically significant thrombocy-
topenia is rare.256 Such patients can also develop neurologic symptoms
similar to those seen in vitamin B12 deficiency, including peripheral
neuropathy, myelopathy, demyelination, and rarely optic neuritis.257
In the marrow, copper deficiency is classically associated with ring
sideroblasts and erythroid and neutrophil vacuolization.258 In the
right clinical setting, negative testing for somatic SF3B1 mutations
in the presence of definite ring sideroblasts should elevate the degree
of suspicion.
Alcohol is a common cause of hematologic abnormalities, espe-
cially macrocytic anemia, even in the absence of folate or vitamin B12
deficiency.259 Bone marrow examination often reveals sideroblastic
changes, and sometimes megaloblastic morphology, but frank dyspla-
sia is uncommon.260 Patients with borderline marrow findings who
are suspected of significant alcohol intake should be advised to
completely abstain from drinking (such advice is occasionally heeded),
with a repeat marrow examination in 2–3 months.
Other drugs and toxins have also been associated with dysplastic
changes in the marrow. Well-described offenders include valproic
acid,261 mycophenolate mofetil,262 ganciclovir,263 alemtuzumab,264
nucleoside analogues such as fludarabine265 and cytarabine, and the
antimetabolites mercaptopurine and methotrexate.266 These tend to
cause macrocytic anemias and can also cause neutropenia and throm-
bocytopenia. On the other hand, isoniazid267 and chloramphenicol,268
and to a lesser extent cycloserine269 and pyrazinamide,270 have been
associated with modest sideroblastic anemia. The anemia associated
with isoniazid, in particular, can often be reversed with high doses of
vitamin B6 (pyridoxine).271 Chloramphenicol can separately cause an
idiosyncratic pancytopenia that is particularly distinguished by
prominent vacuolization of erythroid precursors.272
Among infectious agents, HIV infection has specifically been
associated with dysplastic changes in the marrow. Patients typically
have hypercellular marrows with evidence of trilineage dysplasia most
predominant in the erythroid line.273 The erythroid hematopoiesis
almost always is megaloblastic, and reticulated fibrosis is often seen
in bone marrow biopsies. The marrows also often have polyclonal
plasma cell expansion, lymphoid aggregates, and granulomas are
often seen. The differential diagnosis of erythrodysplasia in patients
with HIV infection includes the influence of medications, opportu-
nistic infections, or a direct effect of HIV on the hematopoietic
progenitor cells.274 Since the US Preventive Services Task Force now
recommends a one-time HIV test for all adults,275 essentially all
patients in whom MDS is being considered should be tested to rule
out HIV.
Other primary hematologic disorders are also on the differential
diagnosis with MDS. Hypoplastic MDS, for example, can be difficult
to distinguish from aplastic anemia and in the absence of character-
istic cytogenetic or genetic abnormalities.276 Similarly, some patients
with MDS may have a significant degree of co-existing fibrosis, which
can complicate the distinction from a myeloproliferative disorder.277
Again, genetic analysis may help make this distinction clearer.278
Signs and Symptoms
Signs and symptoms of MDS are typically vague. Although some
patients profess to being asymptomatic, fatigue is extremely common,
as is a sense of general malaise.279 Rarely, patients may complain of
diffuse arthralgias that can lead to suspicion for an underlying rheu-
matologic disorder like systemic lupus erythematosus.
Smaller proportions of patients may present with severe or recur-
rent infections as a result of immune defects,280 most commonly
neutropenia. Bleeding or easy bruising as a result of thrombocytope-
nia or qualitative platelet defects also bring some patients with MDS
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Chapter 60  Myelodysplastic Syndromes 955
to medical attention.281 When present, fever is most commonly a sign
of infection, though a small number of patients may run low-grade
fevers in the absence of a discernible infection. Splenomegaly or
hepatomegaly are rare and should prompt consideration of either an
alternate diagnosis or an MDS/MPN overlap syndrome.
Dermatologic Manifestations
Although dermatologic manifestations of MDS are uncommon,282 a
few deserve specific mention. Neutrophilic dermatosis (Sweet syn-
drome) is characterized by painful plaques on the face, neck, or
extremities, often in association with fever and diffuse arthralgias.283
While neutrophilic dermatosis can be seen in any subclass of MDS,
it is classically associated with an impending transformation to AML.
It frequently responds to steroids or dapsone therapy, but may recur
as steroids are tapered.284 Recently, Sweet syndrome in MDS patients
has been associated with heterozygous mutations in MEFV, a gene
linked to Mediterranean fever.285
Pyoderma gangrenosum (PG) is an ulcerative, necrotic lesion that
most frequently develops on the extremities.286 Histologically it is also
characterized by neutrophilic infiltrates; clinically, it may be associ-
ated with pathergy and frequently develops at the site of recent minor
trauma, such as intravenous (IV) catheter insertion sites. PG can be
associated with a wide range of underlying conditions other than
MDS. A high index of suspicion is necessary to distinguish it from
necrotizing infections, since treatment of PG involves systemic ste-
roids, and surgical debridement is contraindicated.
Other dermatologic manifestations of MDS include monocytic
infiltrates, classically of the gingiva and other mucosal surfaces, a
process most frequently seen in CMML;287 the development of a
chloroma or granulocytic sarcoma, which by definition implies pro-
gression to AML; and petechial lesions, which most frequently develop
on the lower extremities and imply severe thrombocytopenia.
Autoimmune Manifestations
A percentage of patients with MDS may have overlapping immuno-
logic or rheumatologic features to their disease, which may in part
arise from the immune dysregulation that occurs during disease
pathogenesis.288 In a few patients, these may be the presenting
complaint. Such manifestations can include episodes of seronegative
oligoarthritis or polyarthritis,289 cutaneous vasculitis,290 polymyosi-
tis,291 or autoimmune peripheral neuropathies. Rare patients can
present with a lupus-like syndrome that can include fever, polyar-
thralgias, polychondritis, pleuritis, pericarditis, and cytopenias
(including hemolytic anemias). Other autoimmune phenomena have
also been reported, including mucocutaneous ulcerations, iritis,
polymyositis, inflammatory bowel disease, and erythrocyte aplasia.
Many of these, which are essentially paraneoplastic syndromes,
respond to the initiation of immunosuppressive agents such as
corticosteroids.292
Some reports have additionally documented cases of patients who
were diagnosed with rheumatologic conditions only weeks or months
before they were found to have MDS, including relapsing polychon-
dritis,293 polymyalgia rheumatica or temporal arteritis,294 Raynaud
phenomenon, Sjögren syndrome, and autoimmune glomerulone-
phritis.295 However, since some of these conditions are relatively
common themselves, particularly in older populations, whether they
represent a true association with MDS or are merely coincidental
occurrences is not entirely clear.
Objective Findings: Erythroid Lineage
The majority of patients with MDS present with some degree of
anemia, which contributes significantly to fatigue and lethargy, the
most common presenting complaint.296,297 The anemia is often
macrocytic, and the peripheral blood smears of MDS patients
 956 Part VII  Hematologic Malignancies

Fig. 60.2  ERYTHROID DYSPLASIA. Examples of dysplastic erythroid precursors (bottom) compared to
those with normal morphology in the sequence of erythroid maturation (top). The dysplastic forms include
(left to right) abnormal immature forms with multinucleation; maturing forms with multinucleation and
nuclear-to-cytoplasmic dyssynchrony; and more mature forms with megaloblastoid change, nuclear budding,
cloverleaf forms, cytoplasmic vacuolization, and cytoplasmic stippling. Ringed sideroblasts (far right) also are
evidence of erythroid dysplasia. Photomicrographs are from patients with refractory cytopenia with multilin-
eage dysplasia and ringed sideroblasts.

frequently show a variety of abnormal forms, including oval macro-
cytes, and less commonly dacrocytes, elliptocytes, or acanthocytes.
Anemia in MDS is usually caused by ineffective hematopoiesis.
Consequently, the erythropoietin (EPO) level is typically normal or
modestly elevated, though in many elderly patients it is still lower
than would be expected for the degree of anemia, in some cases
because of subclinical renal insufficiency.298 The ineffective hema-
topoiesis causes abnormal iron utilization in a substantial number
of patients, many of whom have evidence of iron overload based
on ferritin or transferrin saturation.299 Studies have shown other
abnormalities of erythrocytes as well, including increased levels of
fetal hemoglobin,300 aberrant surface antigens,301 increased osmotic
fragility, and low levels of pyruvate kinase,302 although none of
these are routinely checked in clinical practice. Hemolysis is not
routinely observed in MDS patients, but may occur in those with
some of these latter abnormalities or with concomitant autoimmune
disorders.
Morphologic changes in the erythroid lineage on bone marrow
examination can vary widely from patient to patient. Many patients
have megaloblastoid erythroid precursors that contain multiple nuclei
or asynchronous maturation of the nucleus and cytoplasm (Fig.
60.2). It is this asynchrony, with continued membrane synthesis in
the absence of normal nuclear maturation, which is thought to give
rise to the macrocytosis displayed by most patients. Ring sideroblasts,
erythroid precursors containing iron-laden mitochondria, are another
relatively common finding.303 They are defined by the presence of at
least five granules that are positive with the Prussian blue reaction
and line at least one-third of the circumference of the cell nucleus.
Ring sideroblasts are not in and of themselves diagnostic of MDS
and can be seen in a number of other disorders (including congenital
sideroblastic anemias and nutritional deficiencies), but their presence
in association with other dysplastic changes is highly specific for
MDS and, as described earlier, is tightly linked to acquired SF3B1
mutations.88 Ring sideroblasts may be seen in all subtypes of MDS;
the specific designation of RARS is made when ring sideroblasts
comprise at least 15% of the cellularity, blasts are not increased, and
dysplasia in other lineages is minimal.
In a normal bone marrow, myeloid precursors typically outnumber
erythroid precursors by a ratio of 2–4 to 1. A special case arises in
cases of MDS in which this normal ratio is significantly skewed
towards the erythroid lineage, that is, 50% or more of the total cellular-
ity is erythroid. If in this case 30% or more of the remaining cellularity
is comprised of myeloblasts, the case may be diagnosed as erythroleu-
kemia (WHO AML, not otherwise specified, subtype acute erythroid
leukemia, erythroid/myeloid type; formerly FAB-M6A).15,170
Acquired hemoglobin H disease is a rare but well-described
development in MDS that has been associated with acquired muta-
tions of ATRX,304 a gene encoding a chromatin-remodeling protein;
when mutated in the germline, ATRX has been associated with
X-linked alpha thalassemia/mental retardation (ATR-X) syndrome.
The pathogenesis of the syndrome is related to severe reduction in
synthesis of alpha globin chains, and indeed, patients with acquired
ATRX mutations have clinical features resembling alpha thalassemia,
including microcytosis, anisocytosis, poikilocytosis, target cells,
schistocytes, dacrocytes, and beta-chain tetramers on crystal violet
staining.305 As opposed to the macrocytosis seen in most MDS
patients, those with acquired ATRX mutations are typically pro-
foundly microcytic, again similar to thalassemia.
Myeloid Lineage
About one-half of patients with MDS are neutropenic at the time of
diagnosis.306 Many also have defective neutrophil function irrespec-
tive of the absolute neutrophil count (ANC), and patients with MDS
have been shown to have inadequate inflammatory responses to
infections. Many have diminished production of hematopoietic
growth factors like granulocyte colony-stimulating factor (G-CSF)
and GM-CSF, and their neutrophils often have reduced phagocytic,
chemotactic, or bactericidal capabilities.307–309 In place of neutrophils,
the proportion of monocytes is often elevated, which can sometimes
be shown to have been the case for months or even years before
diagnosis. Such a history can be observed patients with pure MDS,
not just those with MDS/MPN overlaps like CMML.
The granulocytes of MDS patients also display frequent morpho-
logic abnormalities (Fig. 60.3). In the marrow, either myeloid
hyperplasia or hypoplasia can occur, and there is often a prominent
left shift towards immature forms. Myeloid precursors often display
asynchronous maturation of the nucleus and cytoplasm. In promy-
elocytes this can manifest as an early hypergranulation coupled with
reticulated nuclei and a prominent Golgi apparatus, but more mature
myeloid forms are usually hypogranulated and hypolobated. The
myeloid series may also be abnormally localized: rather than differ-
entiating in an organized fashion inwards from the endosteum,
immature cells often cluster centrally in a morphologic process
known as abnormal localization of immature precursors (ALIP).
Morphologic characterization of the myeloid series is particularly
important with regard to the blast count, since ≥20% myeloblasts is
characterized as AML using the WHO classification, and ≥5% quali-
fies as RAEB. Even patients with lower blast percentages, however,

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 Chapter 60  Myelodysplastic Syndromes 957

Fig. 60.3  GRANULOCYTIC DYSPLASIA. Granulocytic dysplasia is most evident in mature neutrophils
and can be contrasted to features of normal forms (far left, top), which are usually still present as a subpopula-
tion of the total cells in most cases. Granulocytic dysplasia is characterized by (left to right, starting at second
column) reduced cytoplasmic granulation, nuclear hypolobation (resulting in the binuclear or single-lobed
pseudo–Pelger-Huët forms), hypersegmentation, ringed forms (“rodent cells”), cells with nuclear twinning,
and cells with excessive nuclear excrescences. Photomicrographs are from a number of cases of refractory
cytopenia with multilineage dysplasia and refractory anemia with excess blasts.

Fig. 60.4  MEGAKARYOCYTIC DYSPLASIA. Dysmegakaryopoiesis is most obvious with the presence of
micromegakaryocytes and abnormal larger forms (panels 2–5). These are compared with a normal megakaryo-
cyte at same magnification (panel 1, far left). Micromegakaryocytes have single, two, or four small nuclei,
which indicate a low-ploidy level. Normal low-ploidy megakaryocytes can be seen in the bone marrow, but
these are immature forms and do not have mature granular cytoplasm with platelet material, as do the
micromegakaryocytes. Larger dysplastic megakaryocytes have multiple, small, widely spaced nuclei. Photomi-
crographs are from a number of cases of refractory anemia with excess blasts and refractory cytopenia with
multilineage dysplasia.

still have an increased risk of developing AML, and some have pro-
posed designating any MDS patient with more than 2% marrow
blasts as having “oligoblastic leukemia.”310 ALIP has been shown to
occur in most cases of RAEB and in about a third of cases in which
the blast percentage is less than 5%.311 In these latter cases ALIP has
been shown to be an independent risk factor for subsequent develop-
ment of AML.312
In the peripheral blood, visible morphologic abnormalities include
so-called pseudo Pelger-Huët cells, which have condensed chromatin
and bilobed nuclei resembling an old-fashioned pince-nez (true Pelger-
Huët cells are a benign congenital abnormality seen in children).
Granulocytes may display other nuclear abnormalities as well, includ-
ing hypersegmentation reminiscent of vitamin B12 deficiency, and
aberrant ring shapes. The hypogranulation visible in the marrow
typically persists in the peripheral blood, and the left shift typical of
MDS marrows is often, though not always, present to some degree
in the blood as well.
Despite these quantitative and qualitative defects in leukocytes,
only a minority of MDS patients have problems with recurrent
infections.313 When infections do occur, they tend to be bacterial and
often arise from the lower respiratory tract, skin, and mucous mem-
branes. Patients without absolute neutropenia may still develop
recurrent infections as a consequence of abnormal neutrophil func-
tion. Even though only some patients have recurrent infections, an
infection is the most common cause of MDS-associated death.
Megakaryocytic Lineage
Thrombocytopenia is present in 25% to 50% of MDS patients at
the time of presentation,296,306 and some patients with normal platelet
counts can have functional platelet defects.314 Laboratory abnormali-
ties include prolonged bleeding times, defective granulation, and
abnormal platelet aggregation indices mediated by hypofunctional
platelet glycoprotein IIb/IIIa, leading to what is known as a
Glanzmann-type defect.315,316 These defects can occasionally manifest
as spontaneous bleeding, or can be unmasked after trauma or surgery.
Thrombocytosis, by contrast, is relatively unusual in patients with
MDS, except in those with MDS/MPN overlap syndromes, 5q−
syndrome, or RARS-T.317 JAK2 mutations, in particular, are associ-
ated with thrombocytosis. Thrombocytosis can occasionally be subtle,
especially in patients with advanced disease, in whom a normal
platelet count may in fact represent a relative thrombocytosis coun-
teracted by dwindling megakaryocytic reserves.
In the marrow, megakaryocytes are most commonly present in
normal or increased numbers. A number of morphologic abnormali-
ties can be observed, including abnormally small forms (micromega-
karyocytes), hypersegmentation, and nuclear hypolobation (Fig.
60.4).318,319 Megakaryocytes may also be abnormally distributed in
clusters scattered throughout the marrow in MDS, rather than their
normal parasinusoidal positioning.

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 958 Part VII  Hematologic Malignancies
Lymphoid Lineage
A number of abnormalities in the lymphoid lineage have been
described in subsets of patients with MDS. Some patients have been
shown to have global decreases in NK cells,226,320 some have deficient
receptor localization on B cells,228 and some have abnormal T-cell
responses to mitogenic stimuli.227 Certain types of immune functions,
however, appear to be preserved, such as antibody-dependent cellular
cytotoxicity.321
The mechanism by which these abnormalities develop in MDS is
unclear. One hypothesis proposes that they could be indirectly reflec-
tive of shared somatic defects in a multipotent progenitor. Although
this has not been directly proven, it is theoretically possible given data
showing that most driver mutations in MDS patients are present in
the long-term hematopoietic stem cells (LT-HSC) compartment and
could therefore be passed both to myeloid and lymphoid cells.64
Alternatively, a number of immune functions, including both B-cell
and T-cell diversity, diminish as a function of normal aging,322,323 and
in this context, deficiencies of immune function could develop as a
consequence of lymphoid cells arising from and interacting with an
abnormally aged hematopoietic niche.
Other Objective Findings
Patients with MDS may have a variety of other laboratory abnormali-
ties as a consequence of their disease. Ineffective erythropoiesis may
lead to inappropriate iron deposition, resulting in abnormally elevated
ferritin and transferrin saturation.324 Nonspecific markers of cellular
turnover, such as elevations in lactate dehydrogenase,325 uric acid,
and phosphate, may also be seen. Reflective of underlying immune
dysregulation, some patients may have abnormalities of immuno-
globulins (Igs), including hypogammaglobulinemia, polyclonal
hypergammaglobulinemia, and even monoclonal gammopathies.326,327
Whether this latter phenomenon is directly related to MDS or to an
unrelated, early plasma cell dyscrasia has not been definitively estab-
lished, and the answer may indeed be different in different patients.
DIAGNOSTIC SYSTEMS AND CLINICAL SYNDROMES
As discussed throughout this chapter, MDS is heterogeneous in both
morphology and clinical course, a characteristic that requires diag-
nostic criteria sufficiently broad to capture the entire spectrum of
disease, and diagnostic criteria are typically left purposefully vague to
allow for inclusion of patients in whom a high suspicion of MDS
exists but who do not specifically meet these formal criteria (Table
60.3). Patients with MDS typically have at least one persistent,
otherwise unexplained cytopenia (hemoglobin less than 11 g/dL,
ANC <1,500/mm3, or platelet count less than 100,000/mm3), plus
one of the following: (1) ≥5% blasts in the bone marrow, (2) any of
several chromosomal abnormalities that are found recurrently in
MDS; (3) a meaningful degree of dysplasia, usually 10% or more,
detectable in at least one cell lineage on bone marrow examination,
or (4) other evidence of clonal hematopoiesis.170 In the past this latter
category has usually comprised either karyotype or FISH results
demonstrating chromosomal abnormalities missed by conventional
karyotype, but evidence of clonal hematopoiesis based on detection
of recurrent somatic mutations may need to be considered as well.
However, given that at least 10% of the population aged 70 or older
harbor point mutations in genes associated with myeloid malignan-
cies,31,32 detection of such a mutation in the absence of other diag-
nostic criteria cannot be considered equivalent to MDS.
As described elsewhere, the 2008 WHO criteria divide adult MDS
into six general categories: RCUD (including RA, RARS, refractory
neutropenia, and refractory thrombocytopenia), RCMD, RAEB-1,
RAEB-2, MDS with isolated del(5q), and MDS-U. Despite the detail
of the criteria, they still have a number of limitations, a fact that is
probably inescapable when attempting to categorize a disease with so
many disparate manifestations. The most obvious limitation is the
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TABLE
Diagnostic Criteria for Myelodysplastic Syndrome
60.3
A.  Presence of at Least One Unexplained Cytopenia for at Least 6
Monthsa
Hemoglobin <11 g/dL, or
Absolute neutrophil count <1.5 × 109/L, or
Platelet count <100 × 109/L
plus B.  Presence of One or More MDS-Qualifying Criteria:
>10% dysplasia in one or more hematopoietic lineage, or
5%–19% blasts in bone marrow, or
MDS-defining cytogenetic abnormality, such as:
t(1;3)(p36.3;q21.1) t(2;11)(p21;q23) inv(3)(q21;q26.2)
t(3;21)(q26.2;q22.1) −5 or del(5q) t(6;9)(p23;q34)
−7 or del(7q) del(9q)
del(11q) t(11;16)(q23;p13.3) del(12p) or t(12p)
−13 or del(13q) i(17q) or del(17p) idic(X)(q13)
plus C.  Exclusion of Alternative Diagnoses
AML (i.e., <20% blasts, and no t(8;21), inv(16), t(16;16), t(15;17),
or erythroleukemia) or ALL
Other hematologic diseases (aplastic anemia, PNH, LGL, lymphoma,
myelofibrosis and other MPN)
Viral infections (HIV, EBV, parvovirus)
Nutritional deficiencies (iron, copper, B12, folate)
Medications (methotrexate, azathioprine, isoniazid, cytotoxic
chemotherapy)
Alcohol or other toxins
Autoimmune diseases (SLE, Felty syndrome, ITP, autoimmune
hemolytic anemia)
Congenital disorders (Diamond-Blackfan anemia, Shwachman-
Diamond syndrome, Fanconi anemia, and others)
a
Diagnosis can be made earlier than 6 months if no other cause is apparent for
cytopenias, or there are excess blasts or an MDS-defining cytogenetic
abnormality
ALL, Acute lymphoblastic leukemia; AML, acute myeloid leukemia;
EBV, Epstein-Barr virus; HIV, human immunodeficiency virus; ITP, immune
thrombocytopenic purpura; LGL, large granular lymphocyte leukemia;
MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm;
PNH, paroxysmal nocturnal hemoglobinuria; SLE, systemic lupus
erythematosus.
complexity of the criteria themselves, which can make them cumber-
some for clinicians to use. Second, as described previously, there are
a number of conditions that can mimic aspects of MDS, and the
diagnostic criteria assume these diagnostic possibilities have been
eliminated. Third, morphologic criteria are still based around strict,
arbitrary percentages of dysplasia and blasts, which can be interpreted
differently by different pathologists or may be vulnerable to sampling
variations.328,329 Finally, although WHO criteria incorporate cytoge-
netics to a limited extent, the criteria have not yet been updated to
include types of newer genetic results that have been shown to have
diagnostic value, and it is likely that incorporating some of these
features will improve diagnostic clarity. A 2016 revision of the WHO
criteria eliminated the term “refractory anemia” so that, for example,
RAEB-1 is now known as “MDS with excess blasts” (MDS-EB). This
revision also noted that MDS with ring sideroblasts (MDS-RS) can
be diagnosed with 5% to 14% ring sideroblasts if a somatic SF3B1
mutation is present; if SF3B1 is wild-type, at least 15% ring sidero-
blasts are needed.
IPSS and IPSS-R
Although the WHO classification system (and the FAB system before
it) is the accepted standard for diagnosing MDS, it does not confer
 Chapter 60  Myelodysplastic Syndromes 959

TABLE 1997 International Prognostic Scoring System for TABLE 2012 Revised International Prognostic Scoring
60.4 Myelodysplastic Syndromes (IPSS) 60.6 System for Myelodysplastic Syndrome (IPSS-R)
Score Cytogenetic Included Karyotypic Abnormalities
Risk
Variable 0 0.5 1 1.5 Very good del(11q), −Y
Marrow blasts (%) <5 5–10 – 11–20 Good Normal, del(20q), del(5q) alone or +1 other
Karyotype Good Intermediate Poor – abnormality, del(12p)
Cytopenias 0–1 2–3 – – Intermediate +8, del(7q), i(17q), +19, +21
Any other single or double abnormality
Two or more independent clones
Poor der(3q), −7, double with del(7q), complex with
TABLE Survival Based on International Prognostic Scoring exactly 3 abnormalities
60.5 System for Myelodysplastic Syndromes (Percent)
Very poor Complex with >3 abnormalities
IPSS Risk Group # Patients 2 Years 5 Years 10 Years 15 Years Scoring Table
Low 267 (33%) 85 55 28 20 Parameter Category/Score
Cytogenetic Very good Good Intermediate Poor Very poor
Intermediate-1 314 (38% 70 35 17 12
risk 0 1 2 3 4
Intermediate-2 179 (22%) 30 8 0 –
Marrow blasts ≤2 3–4 5–10 >10
High 56 (7%) 5 0 – – (%) 0 1 2 3
Hemoglobin ≥10 8–9.9 <8
(g/dL) 0 1 1.5

much specific prognostic information, and other systems have been Platelet count ≥100 50–99 <50
developed expressly for this purpose. The most widely used has been (× 109/L) 0 0.5 1
the IPSS330 and its newer revised iteration, the IPSS-R.331 The original Neutrophil ≥0.8 <0.8
IPSS was first published in 1997 and was derived by analyzing count (× 0 0.5
baseline characteristics in over 800 newly diagnosed MDS patients 109/L)
from all diagnostic categories. Patients were scored based on three IPSS-R Risk Total % of Median 25% With
characteristics: the percentage of blasts in the marrow, the presence Group Score Patients Survival AML (Years)
of specific cytogenetic abnormalities, and the number of cytopenias (Years)
in the blood. They were then stratified based on total score into four Very low ≤1.5 19 8.8 NR
risk groups (low, intermediate-1, intermediate-2, and high) that were Low 2–3 38 5.3 10.8
shown to have prognostic value, both in estimating the chance of
progressing to AML and in estimating the duration of overall survival. Intermediate 3.5–4.5 20 3 3.2
This is shown in Table 60.4 and Table 60.5. The original IPSS High 5–6 13 1.6 1.4
excluded patients with t-MDS, patients with proliferative CMML, Very high >6 10 0.8 0.73
and patients who ultimately underwent allogeneic stem cell trans-
AML, Acute myeloid leukemia; NR, not reached.
plantation or other disease-modifying therapy.
The original IPSS had several limitations that ultimately neces-
sitated its revision. First, it was formulated 4 years before the adoption
of the first iteration of WHO classification criteria, and some of
changes in those criteria (for instance, changing the cutoff for AML and the serum ferritin, that have been shown to have independent
from 30% blasts to 20% blasts) effectively invalidated certain aspects prognostic value in dedicated studies. It does not capture the kinetics
of the IPSS. Furthermore, broad application of the criteria to larger of disease or comorbid conditions. In addition, similar to the WHO
populations of MDS patients began to reveal that the original IPSS classification criteria, IPSS-R does not include any molecular data
gave insufficient weight to some important clinical features, particu- other than cytogenetics.
larly the presence of severe cytopenias. The IPSS was only validated
in de novo disease, not t-MDS, and only in patients treated with
supportive care alone. In response to some of these evident limita- Other Risk Stratification Systems
tions, several alternative prognostic systems have been proposed over
the last decade, but none of them have been widely adopted.332–334 The limitations of the IPSS prompted attempts at more refined risk
The IPSS-R (Table 60.6), which was introduced in 2012, revised stratification using alternative models. Few of these have gained much
the MDS blast cutoff to 20% and assigned a point for each individual traction in clinical practice but retain value for use in clinical trials
cytopenia present at the time of diagnosis, stratifying on the basis of and retrospective studies. For instance, a need for better stratification
severity. Furthermore, it incorporated a broader range of cytogenetic of lower-risk patients (i.e., IPSS-low or Int-1) led to the creation of
abnormalities than the original IPSS, and stratified patients into five the Lower-Risk Prognostic Scoring System (LR-PSS) by the MD
risk categories instead of four. The resulting system thus incorporates Anderson group.332 The LR-PSS uses criteria similar to the IPSS but
more informative biology and offers better refinement of prognosis sets lower thresholds for point assignment (e.g., 2 points for a platelet
than its predecessor.335,336 count <50 × 109/L and 1 point for bone marrow blasts ≥4%). Sub-
The median survival times estimated by the IPSS and IPSS-R are sequent studies have confirmed the ability of LR-PSS to risk-stratify
largely reflective of natural history since they were originally derived patients, with those in the highest risk group having the greatest risk
in patients who did not receive any therapy for their MDS (Table of developing AML, and the poorest overall survival,339 and addition
60.5). However, IPSS-R stratifications have been shown to retain of genetic sequencing has shown that in these low-risk patients,
relevance when applied to treated populations, including risk strati- EZH2 mutations, though rare, portend a poor prognosis.112 Other
fication of patients receiving hypomethylating agents337 and those attempts to improve prognostic systems have included attempts to
who undergo allogeneic stem cell transplantation.338 incorporate formal measures of comorbidity into the IPSS,340 and an
Nevertheless, the IPSS-R still has prognostic limitations. It does attempt to combine the WHO classification system with the IPSS
not incorporate laboratory findings, such as lactate dehydrogenase that has been dubbed the WPSS.341 This latter system was formulated

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 960 Part VII  Hematologic Malignancies

before the introduction of the IPSS-R, but subsequent studies have
suggested that the WPSS and the IPSS-R are about equal in their
accuracy of predicting prognosis.342
Specific Clinical Syndromes
Although MDS is a heterogeneous disorder, it contains a number of
specific entities, either defined by cytogenetics, pathologic findings,
or clinical features, which possess distinctive clinical features or bio-
logic behaviors. Some of these are discussed in more detail later.
The 5q− Syndrome
Patients with isolated loss of the long arm of chromosome 5 [so-called
del(5q) or 5q minus syndrome] are a unique group whose biology is
described in more detail earlier. Clinically, 5q− syndrome is character-
ized by a predominant anemia with preservation or even elevation of
platelet counts, striking pathologic feature is the presence of mono-
nuclear micromegakaryocytes identified in the bone marrow biopsy
(Fig. 60.5A–C) and an indolent course with progression to AML in
fewer than 25% of cases.343,344 For unclear reasons, it is more common
in women, who comprise 60% to 70% of cases. The anemia in lower
risk del5q MDS is usually very responsive to the initiation of lenalido-
mide,173 which is discussed in more detail in the subsequent section
on Treatment. Those patients who become refractory to lenalidomide
typically remain transfusion dependent, and management of iron
overload then becomes increasingly important.
The designation of 5q− syndrome applies only to patients in
whom loss of 5q is the only cytogenetic abnormality. Patients in
whom 5q− is only one of several cytogenetic aberrations in fact tend
to have a worse prognosis than average, with a more rapid progression
to AML. As referenced previously, loss of 5q often occurs in tandem
with TP53 mutations (or loss of 17p), another poor-prognosis
combination.149
Hypocellular Syndromes
Most patients with MDS have hypercellular or normocellular
marrows. Hypocellular marrows, in contrast, are found in fewer
than 15% of patients, and delineate the entity of hypoplastic MDS
(Fig. 60.5D–E).224 These patients have substantial overlap, both
morphologically and clinically, with other hypoplastic syndromes,
including aplastic anemia,345 paroxysmal nocturnal hemoglobinuria
(PNH),346 and T-cell LGL.249,347 In fact, distinction between these
entities can sometimes be difficult, as patients with MDS may
occasionally have PNH or LGL clones detectable by flow cytometry,
though these are usual small and transient. Some of the resemblance
may in fact reflect a shared pathogenesis; for instance, studies have
shown that a sizable minority of aplastic anemia cases harbor clonal
somatic mutations in genes recurrently mutated in MDS, including
ASXL1 and DNMT3A,348 and that these patients have an inferior

A B C

D E F G
Fig. 60.5  SPECIFIC MYELODYSPLASTIC SYNDROMES. The 5q− syndrome (A–C); hypocellular
myelodysplastic syndrome (D and E), and myelodysplastic syndrome with fibrosis (F and G). The 5q− syn-
drome has specific morphologic correlates. There is a macrocytic anemia (A) and a cellular bone marrow
characterized by increased small monolobated megakaryocytes (B and C). The megakaryocyte nuclei have little
segmentation and are fairly round. Although some true micromegakaryocytes may be present (C, inset, same
magnification), the typical monolobated forms are not as tiny as the micromegakaryocytes. Hypocellular
myelodysplastic syndrome (D and E) can present a diagnostic problem and can be difficult to differentiate
from aplastic anemia. Dysplasia may be difficult to evaluate if the smears are paucicellular. The finding of
dysplastic megakaryocytes (note small widely separated nuclei, E) on the biopsy sample can be helpful.
Myelodysplastic syndrome with fibrosis (F) can be difficult to differentiate from myeloproliferative neoplasms
(MPNs). However, the lack of large megakaryocytes, which typically are see in the MPNs along with presence
of dysplasia in the circulating neutrophils (G) are useful clues to the correct diagnosis.

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prognosis compared to patients with mutations in PIGA and BCOR.349
It is therefore possible that these studies are defining distinct disease
processes within a homogeneous-appearing morphology, with ASXL1
and DNMT3A mutations defining disease more similar to MDS, and
BCOR and PIGA mutations defining disease more akin to true,
immune-mediated aplasia. At the same time, finding somatic muta-
tions characteristic of the alternative diagnoses (for instance, members
of the telomerase family in aplastic anemia,40 or STAT3 mutations in
LGL350) may clarify the picture as well.
Myelodysplastic Syndrome/Myeloproliferative
Neoplasm Overlap Syndromes
Although previously included as a subtype of MDS, disorders with
overlapping features of both MDS and MPN are no longer included
in the WHO classification system and are now considered an entity
unto themselves; they are discussed in more detail elsewhere.
Myelodysplastic Syndrome With Fibrosis
Marked fibrosis rarely occurs in cases of MDS (Fig. 60.5F–G) without
myeloproliferative features, but when it does occur, it can be difficult
to distinguish these cases from MPN.351 Evaluation for somatic muta-
tions may be helpful, since finding a JAK2, CALR, or MPL mutations
is more common in pure MPNs than in MDS,352 while certain other
mutations, including TET2 and SRSF2, are somewhat enriched in
MDS-MPN overlap syndromes.101,353 On the other hand, extensive
dysplasia is more suggestive of MDS. In addition, a few genetic
lesions appear to be more specific for pure MDS syndromes, includ-
ing SF3B1 mutations and complex cytogenetics.
Patients with overlapping MDS and fibrosis often have severe,
progressive cytopenias with evidence of myelophthisis on peripheral
smear, but the splenomegaly associated with myelofibrosis in an
MPN background is less common. Nevertheless, the prognosis for
these patients appears to be relatively poor.
Therapy-Related Myelodysplastic Syndrome
t-MDS is a well-recognized and feared consequence of cytotoxic
chemotherapy for other cancers, but the overall incidence is difficult
to estimate.243,354 This is partly because of the fact that it is not usually
reported as a distinct entity, and in part because it can be difficult to
establish causality in all patients who develop MDS following treat-
ment for a prior cancer. t-MDS has been best characterized in patients
with a prior history of breast cancer,52,355,356 lymphoma,357,358 and
myeloma,359 where the overall incidence is usually reported at around
1%. On the other hand, t-MDS is rare following treatment for other
types of tumors, such as gastrointestinal and genitourinary cancers.
This difference is largely attributed to differences in the types and
intensities of chemotherapeutic agents used to treat different tumor
types. In particular, high doses of alkylating agents, such as cyclo-
phosphamide, ifosfamide, melphalan, and busulfan, have been associ-
ated with classic t-MDS,360 as has extensive radiation therapy.361 A
distinct, well-characterized class of therapy-related myeloid malignan-
cies occur after treatment with topoisomerase inhibitors but largely
consists of AML without an antecedent MDS phase.54,205,362
t-MDS has a relatively distinct clinical behavior. It is typically
characterized by a latency of years and recurrent large-scale chromo-
somal abnormalities, especially of chromosomes 5 and 7 or 11q23.
Complex karyotypes are also common.363 These karyotypic abnor-
malities, which occur in only about 10% to 15% of patients with de
novo MDS, have a frequency of around 50% to 70% in t-MDS.
They tend to have a more aggressive clinical course than patients with
de novo disease, with more frequent progression to acute leukemia.
They also tend to respond poorly to all classes of treatment, and even
for those patients who undergo allogeneic stem cell transplantation,
relapse is not infrequent.364
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Chapter 60  Myelodysplastic Syndromes 961
As discussed elsewhere in this chapter, the mechanism of patho-
genesis for t-MDS has long been thought to involve the acquisition
of severe, large-scale chromosomal damage, a theory that is circum-
stantially supported by the mechanism of alkylators (which induce
double-stranded DNA breaks) and the fact that many patients with
t-MDS have complex karyotypes. On the other hand, it has previ-
ously been observed that some patients with t-MDS have point
mutations in TP53, which would not be expected to directly arise
from alkylator-induced damage,360 but which can lead to the acquisi-
tion of chromosomal rearrangements even in the absence of chemo-
therapy. Recent deep studies of a small group of patients with
therapy-related AML harboring TP53 mutations have shown that
clones harboring the mutations preceded the development of leuke-
mia by years, and in some cases could be detected before the original
initiation of chemotherapy.150 This recapitulates older data showing
that cytogenetic abnormalities present in the bone marrow of patients
who developed therapy-related leukemia after autologous transplant
for lymphoma could be found in the stimulated autologous speci-
mens, which had been banked years before the development of
t-AML.365 These findings suggest an alternate method of t-MDS
pathogenesis, in which rare clones harbor preexisting mutations that
either confer a selective growth advantage during marrow reconstitu-
tion, tolerance of DNA damage that would otherwise trigger apop-
tosis, or both, thus promoting clonal selection and expansion upon
exposure to chemotherapy.
Refractory Anemia With Ringed
Sideroblasts and Thrombocytosis
Although thrombocytopenia is the most common platelet abnormal-
ity in MDS, rare patients present with marked thrombocytosis.317
This most frequently occurs in the setting of RARS, and in the second
iteration of the WHO criteria, these patients are classified as having
RARS-T.366 On bone marrow examination, there are often features
of both MDS, such as frequent ringed sideroblasts, and MPNs,
such as megakaryocytic hyperplasia. Molecularly, patients often have
concomitant SF3B1 mutations, which drive the ring sideroblast
morphology,366 and JAK2 mutations, which drive the thrombocytosis
and are otherwise uncommon in MDS.367 Patients meeting criteria
for RARS-T are relatively uncommon and prognostic information
is thus limited, but one small series of patients had better 5-year
survival than matched patients with RARS, perhaps because the
proliferative drive of the JAK2 mutation helps preserve blood cell
counts.368
TREATMENT OF PATIENTS WITH  
MYELODYSPLASTIC SYNDROMES
Treating patients with MDS presents a number of challenges. First,
MDS patients are often elderly and thus frequently have serious
comorbid conditions and poor performance status. Second, the
protean nature of MDS, which is particularly heterogeneous even
compared with other cancers, means that treatments appropriate for
some patients may be unhelpful for others. Third, a number of
biologic factors, most importantly the disease’s origin in a quiescent
stem cell, make MDS highly refractory to most conventional treat-
ments like intensive cytotoxic chemotherapy (which many MDS
patients are not healthy enough to receive anyway).
In addition, although the biology of MDS is increasingly well
understood, most of the common derangements, like mutations in
splicing factors and epigenetic regulators, have wide-ranging, pleio-
tropic effects that render narrowly targeted therapies infeasible. While
some agents like hypomethylators and histone deacetylase inhibitors
are matched to biologic processes that are frequently deranged in
MDS, their usual clinical impact is modest at best. Allogeneic stem
cell transplantation remains the only curative therapy for MDS, but
is unavailable to many because of age and comorbidities, and even
for those who undergo it, relapse is not uncommon.
 962 Part VII  Hematologic Malignancies
Despite these challenges, all patients with MDS should be offered
some form of therapy. For elderly patients or those with serious
comorbid conditions who are too unwell to undergo active treatment,
this may consist primarily of supportive care and possibly hospice or
palliative care service referral. Other patients with lower-risk disease
may benefit from a period of observation, or judicious use of transfu-
sion and growth factor support, balanced in carefully selected cases
with chelation therapy to prevent or relieve iron overload. Patients
with higher-risk disease may derive benefit from treatment with
hypomethylating agents or other conventional therapies, and those
patients with high-risk disease who meet other selection criteria
should be referred for consideration of hematopoietic stem cell
transplantation (HSCT). Finally, patients should whenever possible
be encouraged to participate in clinical trials to the extent that this
remains consistent with their personal goals of care.
Once the decision to pursue active treatment has been made, there
are at least three major points to consider. One is the choice of initial
treatment modality, which is guided in large part by risk stratification.
This should typically start by computation of the IPSS-R, but IPSS-R
score should not be the sole consideration in choosing therapy; for
instance, a very young patient with otherwise lower-risk MDS that
has evolved quickly may still warrant consideration of a stem cell
transplant, and an elderly patient with very high risk disease may
nevertheless opt not to pursue treatment with a hypomethylating
agent after a thorough discussion of the risks and potential benefits.
Second, there are a number of special cases for which there is no clear
consensus about the single best treatment strategy; these include
patients with lower-risk disease who have a dominant cytopenia other
than anemia, anemic patients with lower-risk disease who lack del(5q)
but also have an elevated serum EPO, and patients with high-risk
disease who have progressed on a hypomethylating agent but are not
candidates for transplant.
Finally, since therapies other than allogeneic HSCT are rarely if
ever curative, defining what constitutes a meaningful response can be
a nontrivial endeavor. Objective criteria for response were proposed
by an International Working Group (IWG) in 2000 and revised in
2006, and include hemoglobin, number of metaphases with abnormal
karyotypes, and percentage of the marrow involved by blasts.369
However, improvements in these objective variables may not always
coincide with the ways patients perceive changes in their quality of
life370,371 or MDS-related symptoms,279 and these perceptions may be
more likely to impact patients’ decisions to continue or discontinue
active therapy for their disease.
Lower-Risk Disease
Many patients with lower-risk MDS do not require active treatment
directed at the underlying disease process, but this does not mean
they require no treatment at all. In fact, providing appropriate sup-
portive care is an important undertaking that can at times be complex
and time-consuming, and requires a detailed understanding of the
evidence behind the available supportive measures.372
Management of Anemia
Because most MDS patients become anemic at some point during
their disease, appropriate management of their anemia is of critical
importance.373 Management can be broken down into two main
components: transfusion support and use of erythropoiesis-stimulating
agents (ESAs).
Transfusion Support
Many, if not most, patients with MDS will require packed red blood
cell (PRBC) transfusion during the course of their disease. To mini-
mize the risks associated with repetitive transfusion, it is usually
appropriate to reserve transfusion until the hemoglobin is below
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8–9 mg/dL or the patient has symptoms referable to anemia. More
restrictive transfusion strategies, such as those suggested by studies in
inpatient or critical care settings,374,375 may be appropriate in younger,
healthy patients, while some older patients, particularly those with
significant comorbid cardiac disease, may benefit from more liberal
strategies targeting a hemoglobin of 9–10 mg/dL.376,377 Unless the
patient is an HSCT candidate (in which case irradiated blood is
essential), there is no consensus about leukocyte depletion or irradia-
tion of the product.378 Since many patients with MDS will receive
hundreds of units of PRBCs over the course of their disease, preven-
tion and appropriate management of iron overload is also of substan-
tial importance.379,380
Erythropoiesis-Stimulating Agents
Transfusion dependency is a negative predictor of outcome in
MDS.381 While transfusion requirement may to some extent may be
a marker of more severe hematopoietic insufficiency and worse
disease not captured by other prognostic markers, the poor outcomes
may also be a reflection of the adverse effects of repetitive transfusion,
including accumulation of toxic iron species, immune modulation,
and a risk of infection.382 Given these facts, the administration of
ESAs has been heavily investigated in MDS in an attempt to spare
patients from unnecessary transfusions.
More than 20 studies of ESAs have been conducted in MDS,
and 20% to 50% of patients experience meaningful, sustained
improvements in their hemoglobin level in response to ESA
supplementation.383–388 Predictors of response include lower pretreat-
ment serum EPO levels (<500 U/L, but especially <100 U/L),389
lower IPSS scores,390 normal blast counts, normal or low-risk cytoge-
netics,391 and lower serum and marrow levels of inflammatory cyto-
kines.392 The serum EPO level should be evaluated in the context of
the degree of anemia; a trial of an ESA is usually reasonable in patients
with EPO levels up to 200–300 U/L, which, while technically elevated
on most laboratory reference scales, is still lower than would be
predicted for most MDS patients’ degree of anemia. Patients with
EPO levels over 500 U/L, on the other hand, are unlikely to respond
to any dose or duration of ESA.
There are two major formulations of ESA available in the United
States. Epoetin alfa, the shorter-acting of the two, can either be given
at a dose of 150–300 U/kg three times weekly, or in a fixed dose of
40,000 to 60,000 units once weekly.388 Higher doses above 60,000 U/
weekly have not proven to be more effective.393 Darbepoetin alfa is
longer acting and is typically given in doses of 500 µg once every
3 weeks.394 Retrospective comparisons of the two agents have not
shown a significant difference in efficacy.395 Other ESA formulations
are available outside the Unites States, such as epoetin zeta and bio-
equivalent ESAs. Although there is some increase in response with
longer duration of therapy,396 in practical terms, a trial of 12 weeks
is reasonable. Before starting therapy, other causes of anemia should
be ruled out. In particular, response can be suboptimal if patients are
absolutely or even relatively iron deficient, and oral or parenteral iron
supplementation may be reasonable in patients with ferritin levels at
the lower end of the normal range.
One limitation of the numerous studies of ESAs in MDS patients
is the lack of a consistent definition of response, since most studies
predated uniform IWG criteria. Some studies define this based on a
hemoglobin increase (usually improvement by 1–2 g/dL),397,398 while
others have defined response by transfusion reduction or quality of
life metrics.399 In practice, any of these improvements could be a
reasonable criterion for continuation of therapy. Of particular inter-
est, supplementation with ESA has not been shown to increase the
rate of progression to acute leukemia, and one comparative trial
showed a nonsignificant trend toward a decreased risk of leukemia,
although the biologic basis for this is not clear.400 In addition, several
studies have shown an improvement in response in patients supple-
mented with a combination of ESA and G-CSF, especially in RARS,
likely caused by pleiotropic effects of both growth factors on hema-
topoietic progenitors.399,401

ESAs are no longer routinely used for management of anemia in
solid tumor patients, where studies have shown them to be associated
with an increased risk of poor outcomes.402 Similar findings have also
been noted in patients without cancer receiving ESAs for anemia
associated with renal failure.403 Such a risk has not consistently been
shown in MDS, although most studies published to date have not
had long follow-up periods. The risk of thromboembolism has largely
been correlated with the degree of improvement in hemoglobin, with
patients targeted to hemoglobins over 12 mg/dL at greatest risk.
Given this, the consensus recommendation in MDS is to initiate an
ESA at hemoglobin <10 g/dL and target a level between 11–12 g/
dL.404
Management of Neutropenia and Infections
As referenced previously, patients with MDS often become neutro-
penic but also appear to have other qualitative immune defects that
are not accurately represented by the ANC,392,393 and infection is the
leading cause of death in MDS.280 Despite this, supplementation
with either G-CSF (filgrastim, tbo-filgrastim and others) or GM-CSF
(sargramostim) has not consistently been shown to improve outcomes
in MDS patients.405–407 Nevertheless, it is reasonable to consider a
trial of growth factor (usually G-CSF, because of less frequent adverse
effects) in lower-risk IPSS patients with significant neutropenia, typi-
cally defined as an ANC <1000/mm3. Supplementation in higher-risk
patients, particularly those with any degree of excess blasts, is not
usually recommended in the absence of chemotherapy, because of
lingering concerns about promoting expansion of leukemic clones.408
Other therapeutic strategies for immune supplementation, including
granulocyte transfusion and cytokine administration, have not been
shown to be helpful.409
A thorough understanding of appropriate antibiotic use is an
important component in the care of MDS patients. Patients should
be counseled to seek medical attention for any fever greater than
100.4°F/38.4°C, and those who are neutropenic should be hospital-
ized and started on antibiotics while an appropriate search for infec-
tion is undertaken. A thorough discussion of treating febrile
neutropenia can be found elsewhere in the text, but should begin
with an antibiotic that covers a broad spectrum of gram-negative
organisms including Pseudomonas species.410 Although prophylactic
antibiotics should not be started routinely, they may be appropriate
for selected patients who demonstrate a pattern of recurrent infec-
tions.411,412 There is less consensus about prophylactic antivirals or
antifungal medications, and the efficacy of the latter depends on local
microbiologic isolates and epidemiologic patterns.
Management of Thrombocytopenia and Bleeding
Modest thrombocytopenia is common across many subtypes of MDS,
while severe depression of platelet counts is more frequently seen in
patients with higher-risk IPSS scores or those undergoing active
treatment with hypomethylating agents or chemotherapy. Overall,
bleeding is the second most common cause of nonleukemic death in
MDS patients.413 Conventional wisdom and observational studies
indicate that the risk of bleeding with trauma begins to increase at a
platelet count near 50 × 109 cells/L and that of spontaneous hemor-
rhage does not increase significantly until the count is below 10–20
× 109 cells/L. However, these cutoffs may underestimate the bleeding
risk in MDS patients, many of whom have qualitative defects in
platelet function that are not captured by the platelet count. A number
of retrospective studies have evaluated the significance of thrombo-
cytopenia in MDS, all of which have found that thrombocytopenia
confers a poor prognosis caused by both the risk of bleeding and, in
some cases, an elevated risk of transformation to AML.330,413–415
As with red blood cells, management of thrombocytopenia can
either involve transfusions or use of growth factors. Many institutions
use a standard transfusion threshold of 10 × 109 cells/L,416 but as
discussed earlier, a higher goal may be appropriate in selected patients
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Chapter 60  Myelodysplastic Syndromes 963
who show a predilection for bleeding. In general, patients should be
transfused prophylactically rather than waiting for bleeding to occur.
Although there are few large studies comparing transfusion strategies
specifically for MDS patients, a recent study of patients with other
hematologic malignancies showed that for most patients (including
those with AML), a prophylactic strategy using a trigger of 10 × 109
cells/L led to fewer significant hemorrhages than a therapeutic strategy
in which patients were transfused only when bleeding.417
Thrombopoietin (TPO) analogs, which are standard therapeutic
options for refractory chronic idiopathic thrombocytopenia purpura
(ITP),418 are not yet approved by any regulatory agencies for use in
MDS. The two major formulations approved in ITP are romiplostim,
a “peptibody” consisting of 14 amino acid peptides that bind the
extracytoplasmic domain of the TPO receptor fused to an IgG1 heavy
chain, and eltrombopag, a small molecule without TPO homology
that nevertheless binds and activates the TPO receptor.419 Romiplos-
tim is administered as intermittent subcutaneous injections, whereas
eltrombopag is an oral formulation that is taken daily.
Both agents have shown efficacy in terms of reducing platelet
transfusions and clinically significant bleeding events and increasing
platelet counts in early-phase trials in MDS.420–424 In patients with
IPSS low or intermediate-1 risk MDS who had platelet counts less
than 50 × 109/L, romiplostim consistently led to significant improve-
ments in platelet count, which were durable in about half of
patients.421 A similarly designed phase I/II trial of eltrombopag is
ongoing.
However, concerns have been raised about the safety of TPO
agonists in patients with MDS. First, a number of studies in ITP
have shown an increase in marrow reticulin fibrosis in subsets of
patients.425 While the absolute risk of fibrosis has not been deter-
mined, and fibrosis has been moderate in most patients, some have
speculated that the process could be accelerated within the abnormal
marrow microenvironment of MDS patients.426 Second, there is
concern about increased blast proliferation in the presence of TPO
agonists, since some blasts have functional TPO receptors. A random-
ized controlled trial of romiplostim versus placebo (the only phase
III study of either agent in MDS to date) was stopped early by the
study’s safety monitoring committee because of interim analysis sug-
gesting a higher rate of progression to AML in the romiplostim
arm.427 At the time the study was stopped, 10 of 167 patients in the
romiplostim group had progressed to AML, compared to two of 83
in the placebo group. Since the study was far from completion of
accrual at the time it was stopped, the risk of disease progression
could not be definitively assessed and the AML progression rate
eventually nearly equalized; nevertheless, the manufacturer has now
added a warning of risk of MDS progression to romiplostim’s label.
Until there is more conclusive evidence evaluating the link between
TPO analogs and the risk of disease progression, neither romiplostim
or eltrombopag can be recommended for routine treatment of MDS-
associated thrombocytopenia outside a clinical trial, although patients
with refractory bleeding who fail to respond to platelet transfusions
could consider trying one of these agents palliatively.
Management of Iron Overload  
(Transfusional Hemosiderosis)
Although it is clear that MDS patients who undergo repeated blood
transfusions carry an increased risk of developing iron overload,381
the importance of this relative to other disease-related risks, and how
to assess and respond to it, remains a matter of some debate.382 MDS
is distinct from pediatric illnesses associated with iron overload,
in which the benefit of chelation has been well established,428 in
that many MDS patients will not live long enough for the clinical
impact of end-organ iron deposition to be realized. Registry data
suggest that patients with higher transfusion requirements have a
greater risk of complications,429,430 but registry data cannot prove the
direction of the relationship—that is, whether the transfusions lead
to complications or whether the need for transfusion is simply a
marker of more severe disease or underlying comorbidities. Other
 964 Part VII  Hematologic Malignancies
retrospective studies have provided circumstantial evidence for delete-
rious effects of iron overload. For instance, one study has shown a
higher rate of death from heart failure among MDS patients,431 and
another has shown increased rates of heart and liver failure among
MDS patients with high lifetime numbers of transfusions,432 but
these observations again cannot prove causality.
There are two major formulations of chelating agent available in
the United States, deferoxamine and deferasirox (a third agent,
deferiprone/L1, is available only for thalassemia patients via a
restricted distribution program). Deferoxamine is administered as a
continuous subcutaneous or IV infusion, a cumbersome mechanism
that has limited its applicability in widespread practice. Deferasirox,
an oral formulation, is more convenient so is much more widely used,
but is quite costly.
Deferasirox is typically started at 20 mg/kg (14 mg/kg for the new
tablet form of deferasirox FDA approved in 2015) once daily and
escalated to 30–40 mg/kg/day (28 mg/kg for the new tablet form of
deferasirox FDA approved in 2015), depending on iron kinetics and
patient tolerance. Although deferasirox has been shown to rapidly
mobilize stored iron and reduce labile plasma iron species, it is fre-
quently discontinued either as a result of disease progression or caused
by side effects, which include gastrointestinal distress, renal impair-
ment, and rash.
To date, there have been no randomized controlled trials to
definitively evaluate the impact of iron chelation on outcomes in
MDS. The largest prospective trial to date, a single-arm cohort study
of 1744 patients treated with deferasirox, included a prespecified
MDS subgroup of 341 patients. Over the study’s single year, median
ferritin levels decreased significantly compared to baseline regardless
of whether patients were chelation naive or not, as did the median
alanine aminotransferase, which was tracked as a marker of hepatic
toxicity from iron overload. On the other hand, 48.7% of the MDS
patients discontinued treatment because of side effects. Since there
was no control arm and the study period was short, no conclusions
could be drawn about the impact of chelation on more meaningful
clinical outcomes. Other studies have shown improvements in
hematopoiesis in patients started on chelation therapy,433,434 but these
observations were not tied to longer-term outcomes either.
There are data from retrospective studies showing better out-
comes for patients who undergo iron chelation, but all of these
are subject to patient selection bias. In one, a Canadian study of
178 patients, only 18 received chelation therapy, suggesting that
these patients were carefully selected and destined to have a better
outcome anyway.435 In another, a French study of 97 patients in
whom 46% received chelation, the regimen and duration of chelation
therapy varied considerably, and no baseline assessment of iron stores
was performed.436 A recent metaanalysis of iron chelation studies
in MDS found that use of chelation therapy was associated with
an increase in length of survival (overall 61.2 months longer for
patients receiving chelation),437 but since the analysis included only
retrospective studies, it is very possible that these numbers are again
largely reflective of selection bias, with healthier or younger patients
more likely to receive chelation therapy than those who were older or
sicker.
Despite the limitations of the available data, there are several
published consensus opinion guidelines regarding the use of chelation
therapy in MDS.324,438 Although they differ with respect to their
specific recommendations, most operate on similar principles that the
patients best suited to iron chelation therapy are either those with
lower-risk disease and significant anemia who presumably face a long
period of transfusion dependency, or those who could potentially be
eligible for stem cell transplantation, since in the transplant setting
numerous studies have shown that a high ferritin is associated with
inferior outcomes.439 A third category of patients comprises those
with suspected end-organ damage as a result of iron overload.
Some of the guidelines recommend waiting to start chelation
therapy until the ferritin is greater than 1000 µg/L or the patient has
had more than 20–30 lifetime transfusions, but they also note that
neither of these criteria is supported by high-level evidence. Serum
ferritin is problematic since it is subject to variability based on
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inflammatory state, and is an imperfect marker of total body iron
burden. For quantitative assessment of hepatic iron overload, T2*-
weighted magnetic resonance imaging of the liver has supplanted
biopsy as the preferred method of validation.440
Other Therapies for Lower-Risk Disease
The literature is replete with attempts to treat lower-risk MDS with
a variety of different drugs, especially so-called differentiating agents
such as retinoic acid or arsenic trioxide (ATO). With the exception
of lenalidomide for 5q− syndrome, most of these have been incon-
sistently effective at best.
Lenalidomide
As described previously, lenalidomide is a derivative of thalidomide
that is uniquely effective in reversing the severe anemia associated
with isolated del(5q). This was previously thought to be related to
poorly characterized immunomodulatory effects (as implied by
“Imid,” the name given to the class of thalidomide derivatives).441
However, more recent work has shown that lenalidomide actually
exerts its effect in 5q− syndrome by mediating the binding of the E3
ubiquitin ligase cereblon to casein kinase 1α, thus triggering casein
kinase’s proteasomal degradation.442 Casein kinase 1α is an essential
kinase whose gene, CSNK1A1, lies within the minimally deleted
region on 5q.177 In normal cells, treatment with lenalidomide is
insufficient to deplete casein kinase 1α to lethal levels, but the hap-
loinsufficiency of CSNK1A1 induced by loss of 5q renders 5q− cells
sensitive to the drug through a p53-dependent mechanism and allows
for repopulation of the marrow by wildtype hematopoietic progeni-
tors. This activity appears to be unique to lenalidomide and is not
shared, for instance, by thalidomide. Unfortunately, the effect is not
permanent and resistance eventually develops in most cases, often
through inactivating mutations in TP53.443 Hopefully, however, these
new insights will enable further studies of how these resistance
mechanisms arise.
Lenalidomide’s efficacy was first observed in MDS-001, a phase I
study of 32 patients with symptomatic anemia who had not responded
to ESAs.444 Twenty of the 32 patients became independent of transfu-
sion for some period of time, including 10 of 12 patents with del(5q).
Of the responders, those with del(5q) had a significantly longer
duration of response. This prompted further study of lenalidomide
specifically in del(5q) patients in MDS-003, a phase II study in which
76% of 148 enrolled patients had an improvement in anemia and
67% achieved transfusion independence, with a median improve-
ment in hemoglobin near 5 mg/dL. A second phase II trial, MDS-
002, showed that lenalidomide was also effective in a substantially
smaller subset of patients without del(5q), with an overall response
rate of 43% and a transfusion independence rate of 26%. The factors
that determine lenalidomide responsiveness in non-del(5q) MDS
have not been determined.
The most conclusive evidence of lenalidomide’s efficacy in del(5q)
comes from the phase III MDS-004 trial,173 a randomized, double-
blinded study in which patients were randomized 1 : 1:1 to receive
lenalidomide 10 mg/day on days 1–21 of a 28-day-cycle, lenalido-
mide 5 mg/day on days 1–28, or placebo on days 1–28. Those
without an erythroid response at 16 weeks were unblinded and
became eligible for open-label treatment. At the conclusion of the
study, significantly more patients in both lenalidomide groups had
achieved transfusion independence for at least 26 weeks than those
in the placebo group (56% in the 10-mg group versus 43% in the
5-mg group versus 5.9% in the placebo group), with those in the
10-mg group having a longer median duration of response (82.9
weeks) than those in the 5-mg group (41.3 weeks). Intriguingly,
treatment with lenalidomide also appeared to lower the risk of
transformation to AML; at a median follow up of around 3 years,
36.4% of patients who had received placebo only and 30.4% who
had started with placebo and crossed over to lenalidomide had

developed AML, compared to 23.2% in the 5-mg group and 21.7%
in the 10-mg group, though the crossover model prevented an assess-
ment of statistical significance.
Given recent progress in understanding of lenalidomide’s mecha-
nism of action, it is perhaps unsurprising that it demonstrates con-
siderably lower efficacy in MDS patients who do not have del(5q).
In these patients, studies have consistently shown an overall response
rate of about 25%, which on average lasts less than a year.445,446 It is
not known whether the patients who respond have abnormalities of
casein kinase 1α, or whether their sensitivity to lenalidomide occurs
via a different mechanism.
Lenalidomide is generally well tolerated, especially compared to
thalidomide. The most common side effects are neutropenia and
thrombocytopenia, which are most common in the first month of
treatment and which have some correlation to treatment response.447
Pretreatment thrombocytopenia, a feature atypical of pure del(5q),
appears to negatively correlate with response and perhaps serves as a
phenotypic proxy for cooperating genetic events that blunt the
molecular sensitivity to the drug.149 Significant thromboembolism
has been observed in studies of patients with myeloma who receive
lenalidomide, an effect that largely seems to be confined to
co-administration of lenalidomide and dexamethasone;448 the manu-
facturer thus recommends thromboprophylaxis in del(5q) patients as
well, though it is not clear that the thrombotic risk is the same in
these populations, and thrombocytopenia may limit the safety of this
approach.
Low-Dose Cytarabine
Cytarabine, also known as cytosine arabinoside or Ara-c, is a pyrimi-
dine analog that is widely used in the treatment of a number of
hematologic malignancies. In MDS, its use dates to the 1980s.449,450
The typical dosing schedule is 5–20 mg/m2 per day via subcutaneous
injection (daily or twice daily) or continuous IV infusion. Although
10% to 20% of patients with MDS have some degree of pathologic
response during Ara-c therapy, these tend to last only a few months,
and treatment has not been shown to improve survival or reduce the
rate of transformation to AML.
One of the drawbacks to treatment with cytarabine or any other
conventional chemotherapeutic agent is that they cause cytopenias as
a primary side effect, and since cytopenias are a central problem in
most MDS patients, the agents rapidly become limited in utility.451
The worsening of cytopenias is likely one of the primary reasons for
the lack of survival benefit for cytarabine in MDS.
Antitumor Necrosis Factor Therapy
The observation that MDS patients often have elevated levels of
inflammatory cytokines and increased rates of apoptosis led to the
postulate that blockade of these pathways might ameliorate the inef-
fective hematopoiesis found in many patients with MDS. Etanercept,
a soluble TNF-α inhibitor, has been analyzed in two small pilot
studies of MDS patients, with mixed results: cytopenias improved in
one trial,452 whereas no effect was seen in the other.453 The drug has
also been combined with both ATG454 and azacitidine,454 but in
neither case was it clear that the addition made a difference. A separate
case report described sustained erythroid responses in two patients
treated with infliximab, a monoclonal anti-TNF antibody.455 TNF-α
and other inflammatory mediators may play a greater role in some
subsets of MDS than others,456 and better delineation of these groups
may make future study of anti-TNF therapy reasonable in selected
patients.
Immunosuppressive Therapy
Corticosteroid therapy was once a mainstay of treatment for MDS,
but despite reported response rates in the range of 10% to 20%,457
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Chapter 60  Myelodysplastic Syndromes 965
the complications of long-term steroid use in this population came
to outweigh the benefits. Nevertheless, immunosuppressive therapy
may be reasonable for certain subsets of MDS patients in whom
autoreactive T-lymphocytes contribute to the inhibition of effective
hematopoiesis. Patients with hypoplastic MDS, in particular, have
been shown to have similarities to aplastic anemia, and may respond
to treatment with ATG.458 Other studies have shown that patients
with underlying PNH clones, which can be assessed by flow cytom-
etry for PIG-anchored glycoproteins CD55 and CD59, may also
respond to ATG, as may patients with a human leukocyte antigen
(HLA) DR15 phenotype.459
Retrospective analysis of data from the International Myelodys-
plasia Risk Assessment Workshop showed that treatment with
immunosuppression was associated with an improvement in overall
survival (8.1 vs. 5.2 years, p < .001) and a lower risk of leukemic
transformation, but these results could have been subject to selection
bias since fewer patients with higher-risk disease are treated upfront
with immunosuppression.460 On the other hand, a randomized study
comparing ATG plus cyclosporine to best supportive care suggested
a slight improvement in hematologic response in the ATG + cyclo-
sporine A group, but there was no difference in disease-free or overall
survival.461 Subgroup analysis suggested that patients with hypocel-
lular marrows were more likely to respond to immunosuppression,
again hinting at biologic similarities to aplastic anemia. In studies
making careful distinction between MDS and aplastic anemia,
however, mortality with ATG treatment was higher in MDS than in
aplastic anemia.345
Alemtuzumab, a monoclonal antibody against anti-CD52, has
activity in highly selected subsets of MDS patients. In particular, one
small phase I/II study of patients yielded a 77% overall response rate
among patients with IPSS intermediate-1 disease.462 Some patients
with cytogenetic abnormalities normalized their karyotype, and the
rate of complete response appeared to increase with time in those
patients who were not lost to follow up. However, alemtuzumab is
severely immunosuppressive and the study was hampered by a high
rate of attrition and careful selection of patients, and the results have
not yet been repeated. The biologic basis for the high response rate
in this single study remains unclear.
Manipulating the Microenvironment: Vascular
Endothelial Growth Factor and Other Targets
Observations of increased microvessel density in the bone marrow of
MDS463 patients have led to some enthusiasm for targeting vascular
growth factors and other molecules associated with the marrow
microenvironment, but results so far have been somewhat disappoint-
ing. For instance, a phase II trial of bevacizumab, a monoclonal
antibody directed against vascular endothelial growth factor (VEGF),
showed a decrease in VEGF levels and a significant reduction in
microvascular density, but only one of 21 patients had any type of
hematologic response.464 Similarly, a phase II study of vatalanib, an
oral VEGF receptor inhibitor, showed hematologic responses in only
5% of patients, though many patients had to withdraw from the
study because of side effects.465
Other therapies directed at the microenvironment have similarly
shown responses in only a minority of patients. For instance, the
combination of pentoxifylline, a phosphodiesterase inhibitor, with
dexamethasone and ciprofloxacin (PCD) has been shown to induce
hematologic responses in some patients, but most of these are
transient and probably represent neutrophil demargination from the
corticosteroid.231 A more recent study combining PCD with ami-
fostine, an antiangiogenic agent usually used as a chemoprotectant,
showed a hematologic response rate of 66%, but long-term results
have not been reported.466 Lenalidomide and thalidomide were both
previously thought to act via effects on the microenvironment,467 but
with the discovery of lenalidomide’s role as a catalyst for cereblon-
mediated ubiquitination, as described earlier, the extent to which it
also affects the microenvironment is unclear.
 966 Part VII  Hematologic Malignancies
Signal Transduction Inhibitors
Activating mutations in receptor tyrosine kinases like NRAS and
FLT3 are relatively uncommon in MDS, not because they never occur
in this population, but because they usually act as catalysts for pro-
gression to secondary AML.238 The consideration for use of FLT3
inhibitors in MDS is similar to those in s-AML, and data are limited.
A more thorough discussion of these agents may be found in Chapter
59 (AML).
Other Agents
A number of other agents have been used in MDS and reported either
in anecdotes or small, nonrandomized series of patients. Historically,
many patients with RARS were started on vitamin B6 because of its
efficacy in familial sideroblastic anemia, but it has shown little efficacy
in adults.468 Other dietary supplements, include retinoids (vitamin A
analogues), vitamin D,469 and vitamin K2,470 have all been tried
because of favorable effects on differentiation in vitro, but have not
been effective in humans. A number of other drugs have also been
trialed in humans based on similar observations of prodifferentiation
effects in preclinical experiments, all without comparable efficacy in
human patients. These include amifostine as a single agent,471 the
solvent hexamethyl bisacetamide,472 and alpha and gamma interferon.
Interferon, in particular, has recently been shown to cause normal
HSCs to exit quiescence in mouse models,473,474 but whether it can
be used for similar purposes to “prime” MDS stem cells for subse-
quent treatment with cytotoxic therapy has not yet been explored.
Given their efficacy in promyelocytic leukemia, both all-trans reti-
noic acid (ATRA) and ATO have been trialed in small numbers of
MDS patients in a similar attempt to induce differentiation. ATO
has shown responses in up to 20% of MDS patients in several small
series,475–478 but the molecular basis for this action and how to predict
who will respond are unclear. ATRA by itself has largely been inef-
fective, likely caused by the absence of the PML-RARA fusion protein
that is the basis for its efficacy in acute promyelocytic leukemia
(APML).479,480 In vitro data suggest that in some AML models,
downstream targets of the retinoic acid receptor may be epigenetically
silenced by abnormal induction of histone demethylases such as
LSD1, which can be inhibited by tranylcypromine, a monoamine
oxidase inhibitor (MAOI) approved in Europe to treat depression.481
In vitro, the combination of ATRA with tranylcypromine in non-
APML leukemia derepresses targets of the retinoic acid receptor and
significantly impairs the ability of leukemia stem cells to engraft in
immunodeficient mice. Whether this pathway can be similarly
reactivated in MDS, and whether this is a viable therapeutic combi-
nation in patients, also remain as yet unexplored.
A number of other novel agents remain in clinical trials for lower-
risk MDS at the time of this writing.482 These include inhibitors of
the transforming growth factor-beta receptor,483 inhibitors of toll-like
receptors, chimeric antibodies to activin, mitochondrial modulators,
RAS pathway inhibitors, and anti-CD33 molecules. In addition,
there are ongoing trials evaluating combinations of existing therapies,
including hypomethylating agents, histone deacetylase (HDAC)
inhibitors, lenalidomide, and hematopoietic growth factors. While
some of these trials may identify novel therapies or combinations with
efficacy for subsets of MDS patients, whether any of them will have
substantial impact on the treatment landscape for low-risk MDS
remains to be seen.
Higher-Risk Disease
Hypomethylating Agents
MDS genomes frequently display aberrant methylation patterns rela-
tive to normal hematopoietic cells. This observation was initially
made in the 1990s, when investigators noted hypermethylation in
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the promoters of numerous tumor suppressor genes, including
CDKN2A, CDKN2B,484 FHIT,485 SOCS1,486 CTNNA1,487 and others.
Later, with the advent of genome-wide methylation profiling, it was
further observed that this aberrant methylation is often a global
phenomenon in MDS and that global hypermethylation, in particu-
lar, appears to confer a poor prognosis.488
This characterization of aberrant methylation in MDS soon led
to the identification of hypomethylating agents (HMA) as a candidate
class of MDS drugs. The prototypical hypomethylator, 5-azacytidine
(azacitidine), was synthesized in the 1960s and its hypomethylating
activity first clearly characterized in 1980.489 It is an azo-substituted
pyrimidine analogue that incorporates into RNA and is from there
converted to a deoxynucleotide and incorporated into DNA, where
it binds and irreversibly inhibits DNMT1. The in vitro result is a
global decrease in cytosine methylation, which leads to differentiation
in some leukemia cell lines. Of note, azacitidine also appears to have
nonepigenetic mechanisms of action, including some degree of direct
cytotoxicity and immune stimulation.490 Both azacitidine and the
related compound decitabine (5-aza-2’-deoxycytidine) are now fre-
quently administered in both MDS and AML.
Standard dosing of azacitidine is 75 mg/m2 administered subcu-
taneously once per day for 7 consecutive days each month.491 This
was the dosing schedule used in the first major study of hypometh-
ylating agents in MDS, CALGB 9221, in which azacitidine was
found to be superior to best supportive care both in terms of quality
of life and risk of progression to AML.492 In this study, about 60%
of patients had some degree of response to azacitidine, although
consensus response criteria were not used. Most of these responses
were minor hematologic improvement, but about 15% of patients
had a pathologic complete response. Most of those who responded
did so within 6 months. There was a nonsignificant trend toward an
improvement in overall survival with azacitidine, and side effects
tended to be mild, including nausea and vomiting and transient
myelosuppression.
Based on these data and a large increase in requests for compas-
sionate use of the drug after CALGB 9221 was first presented in
2002, the Food and Drugs Administration (FDA) granted approval
to azacitidine for MDS in 2004. A subsequent study, AZA-001
comparing azacitidine 1 : 1 to the patient and doctor choice of either
standard induction, low-dose cytarabine, and best supportive care in
358 patients with higher-risk MDS or CMML showed a median
9-month improvement in overall survival for those treated with
azacitidine (24 versus 15 months).493 This represents the only major
study to date in which a survival benefit has been shown for a drug
in MDS. Other studies have shown that a more convenient 5-day
azacitidine dosing schedule appears to be effective, but this has not
been directly compared to the 7-day schedule, which remains the
standard. One recent study suggested an improvement in response
from prolonged administration of azacitidine, though all patients in
this study had higher rates of hematologic normalization compared
to historical controls, for unclear reasons.494
The other major hypomethylating agent, decitabine (5-aza-2′-
deoxycytidine), is also FDA-approved for treatment in all subclasses
of MDS. Although structurally similar to azacitidine, decitabine has
a deoxyribose backbone that permits it to be directly incorporated
into DNA. At higher doses it introduces DNA cross-linking and
cell-cycle arrest, a mechanism more akin to a cytotoxic agent, but at
lower doses it appears to primarily act as a hypomethylating agent.495
Similar to azacitidine, decitabine has been shown to improve
outcomes for patients with MDS, including a reduced transfusion
requirement and slower transformation to AML. It may induce
responses more quickly than azacitidine; for instance, in the multi-
center ADOPT (alternative dosing of decitabine for outpatient
therapy) study, 90% of patients responded after four cycles, rather
than the six cycles seen in the largest azacitidine trials.496
In contrast to azacitidine, however, decitabine has never been shown
to confer an overall survival benefit. Some of the difference in out-
comes may be explained by difficulties establishing the optimal dose
and schedule; in the earliest trials it was administered at a dose of
15 mg/m2 given IV every 8 hours for 3 days,497 but subsequent

studies showed better hypomethylation and an improved overall
response rate when it was given at a dose of 20 mg/m2 once daily for
5 consecutive days,498 the dosing strategy used in ADOPT. Some
recent small studies have suggested an even different dosing strategy,
using frequent administration of low doses of decitabine (0.1–0.2 mg/
kg/day) in an attempt to minimize the cytotoxic effects of the drug
while catching more cells in S phase, when the demethylating activity
of the drug would be most effective.499
Despite the widespread use of hypomethylating agents in MDS,
a number of key questions persist. Although studies have shown that
each can demethylate the promoters of specific tumor suppressors
(e.g., P15INK4B500 for decitabine and PLCB1501 for azacitidine), it is
not clear that this is the dominant in vivo mechanism. Some studies
have shown increased demethylation in patients who respond to
hypomethylating agents,502 but this has not been a universal observa-
tion, and neither pretreatment methylation levels (either global or at
specific promoters) nor the net change in methylation with treatment
have been consistently predictive of treatment responsiveness.488,503
Recent studies have also interrogated the impact of somatic mutations
on hypomethylating agent sensitivity, and TET2 mutations in
particular have been shown to increase the likelihood of HMA
response,103 but the overall impact of these findings in the long term
remains unclear.
“Histone” Deacetylase Inhibitors
The observation that MDS frequently involves epigenomic abnor-
malities has provoked interest in other modalities beyond the hypo-
methylating agents. To date, the next most-studied class of agent is
the histone deacetylase inhibitors, which as their name implies block
the deacetylation of histone residues as well as deacetylation of other
cellular protein. In vitro, application of these drugs leads to large-scale
epigenetic modifications, but in vivo, the drugs have so far not proven
as effective as hypomethylating agents, at least when used alone.504
Several agents, however, remain in trials, including valproic acid,505
vorinostat,506 panobinostat,507 and belinostat.508 Many of these trials
combine the HDAC inhibitor with some other therapy. One coop-
erative trial of azacitidine with or without entinostat, E1905, showed
no improvement in hematologic response in the entinostat arm,
which in fact displayed less demethylation than azacitidine alone,
perhaps suggesting some degree of pharmacologic antagonism.494
However, in vitro data have also shown significant pharmacologic
differences between the different HDAC inhibitors, suggesting that
results for one drug may not be generalizable to the class as a whole.
Similar negative results were recently reported in the U.S./Canadian
Intergroup S1117, a large three-arm trial comparing azacitidine alone
to azacitidine plus vorinostat to azacitidine plus lenalidomide, as well
as a study of azacitidine with or without pracinostat.509
Induction Chemotherapy
AML-like induction regimens (e.g., cytarabine plus an anthracycline)
are not effective for most patients with MDS, with available studies
suggesting a remission rate of less than 20%. Hematologic recovery
is often incomplete, and in many cases the chemotherapy mainly
serves to select for the malignant clone. In fact, a randomized trial
comparing azacitidine to daunorubicin plus cytarabine in elderly
patients with higher-risk MDS showed that the patients treated with
azacitidine had better outcomes, although only small numbers of
patients were treated with induction.493
Induction chemotherapy, however, may be reasonable in selected
younger patients; some studies have suggested remission rates of up
to 50% in patients younger than 60, though these may have contained
some patients with de novo AML,510 and the studies were performed
before the widespread availability of deep sequencing techniques that
might have shown persistence of clonal mutations even in the ablated
marrows.148 Adding other agents, such as liposomal doxorubicin,511
topotecan,512 and thalidomide, do not seem to improve the rates of
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Chapter 60  Myelodysplastic Syndromes 967
remission. Conventional chemotherapy alone is rarely curative in
MDS, and even those younger patients who achieve a complete
remission will need further consolidation, usually with an allogeneic
stem cell transplant.
Allogeneic Stem Cell Transplantation
Allogeneic HSCT is the only known curative therapy for MDS.513
This is thought to arise from the fact that MDS progenitor cells,
being transformed stem cells, are mostly quiescent and are thus rela-
tively resistant to most chemotherapy. Allogeneic HSCT, on the other
hand, leverages both the chemotherapy of the conditioning regimen
and the antitumor effect of the newly transplanted stem cells to
eliminate all vestiges of the prior hematopoietic system. This is, of
course, a simplified description of the best-case outcome for HSCT.
The reality for most MDS patients is significantly more complicated,
although outcomes have steadily improved in recent years as centers
have gained more experience in transplanting older patients using
unrelated and even unmatched donors.514
An exhaustive review of stem cell transplantation is beyond the
scope of this chapter, but a few points specific to MDS bear mention.
Identification of patients for whom transplant might be a reasonable
option is an important first step. This group typically includes
patients younger than 60 years, who are often in otherwise good
health and would otherwise be predicted to have a long life expec-
tancy. Older patients who are in otherwise excellent health may be
considered for transplantation as well, usually with a reduced-intensity
conditioning regimen. Although there is no official upper age limit
to eligibility, most centers are hesitant to transplant patients older
than 75.515
The stage of disease is also important: in older patients, transplant
is usually reserved for those with excess blasts or other forms of
higher-risk disease, but it is important to proceed to transplant before
the disease has evolved into acute leukemia. On the other hand, some
centers occasionally offer transplantation to younger patients with
lower-risk categories of disease given that they have a longer latency
period in which their disease could progress or evolve into leukemia.
This decision, however, is not completely uniform, and some data
suggest that delayed stem cell transplantation is associated with better
overall survival in patients with low and intermediate-1 IPSS scores
regardless of age.516
Once a decision has been made to proceed to transplant, other
decisions must follow. The first involves the source of the stem cells.
If a healthy, HLA-matched sibling is available, this is often prefera-
ble;517 however, reflective of the average age of MDS patients, most
siblings are older and often have comorbidities, such as cancer or
other illnesses, that preclude them from consideration as donors. If
a related donor is unavailable, the next best option is a search of the
national donor registry for an HLA-matched unrelated donor.518
Compared to related donors, transplant from unrelated donors carries
a higher rate of graft-versus-host disease as a consequence of minor
antigen mismatch. If a matched unrelated donor cannot be found,
options then include an unrelated donor transplant mismatched at
one (or occasionally more) HLA loci, or an “alternative donor source,”
which includes umbilical cord blood519 and haploidentical donors.520
In the case of MDS patients, this latter type of transplant is often
obtained from one of the patient’s children.
The specific choice of conditioning regimen is likely less important
in MDS than in other hematologic diseases given the disease’s intrin-
sic chemoresistance, as described earlier. Options include fludarabine
plus busulfan, fludarabine plus melphalan, busulfan plus cyclophos-
phamide, or cyclophosphamide plus irradiation. Many older patients
with MDS are unlikely to tolerate myeloablative doses of condition-
ing agents and are instead given reduced doses of conditioning agents.
These “reduced intensity conditioning” transplants rely more heavily
on the graft-versus-tumor effect of the transplant to eliminate the
malignant clone.521,522 Given the intrinsic chemoresistance of MDS
stem cells, however, this is usually a reasonable tradeoff. Following
transplant, patients must remain on immunosuppressive medications
 968 Part VII  Hematologic Malignancies
to prevent the emergence of graft-versus-host disease. A full discus-
sion of posttransplant considerations is outside the scope of this
chapter, but most aspects of this area are less specific to MDS than
those discussed previously.
As mentioned, despite being potentially curative therapy, trans-
plant in MDS is associated with significant morbidity and mortality.
One study has suggested that 50% to 60% of lower-risk patients and
20% to 40% with higher-risk disease can expect long-term disease-
free survival following transplant,523 but the alternative view of these
data is that a substantial proportion of patients (40%–50% of low
risk and 60%–80% of high risk) either relapse or die of nonrelapse
complications of transplant.
Numerous studies have attempted to dissect patient and disease
attributes that may predict outcomes following transplant. Poor-risk
cytogenetics, including monosomy 7 and complex karyotypes,524
have been shown to predict a high rate of relapse, and recent data
suggest that pathogenic TP53, DNMT3A, and TET2 mutations are
predictors of poor outcomes following transplantation as well.104 So
far, no cytogenetic or genetic profiles have been clearly associated with
a favorable response to transplant. Preexisting neutropenia has been
shown to predict an increased risk of serious infections in the post-
transplant setting.525 On the other hand, a low blast count (fewer
than 5%) is associated with better outcomes, and other data show
that patients who achieved a remission or significant response to
pretransplant chemotherapy have better outcomes as well.526
Other Therapies for Higher-Risk Disease
Autologous Stem Cell Infusion
Though rarely used in current practice, infusion of autologous stem
cells has been attempted in the past, primarily for patients with oli-
goblastic disease.527,528 There are a number of reasons why this
approach is suboptimal for MDS patients. The most obvious draw-
back is that MDS is by definition a disorder of stem cells, such that
any autologous infusion will ultimately lead to repopulation of the
marrow with the original malignant clone, but without the graft-
versus-leukemia effect imparted by an allogeneic transplant. Moreover,
autologous stem cell infusion is really meant to serve as a rescue after
high-dose chemotherapy, and is thus most successful when given for
a chemotherapy-sensitive disease, which MDS is not. Finally, given
the ineffective hematopoiesis many patients experience before treat-
ment, hematopoietic recovery following high-dose chemotherapy is
often poor. Since most patients who would be candidates for autolo-
gous stem cell rescue would also be eligible for other, more effective
modalities of therapy, there are usually few reasons to pursue this
avenue.
Other Drugs
Most drugs known to have activity in AML have been tried for MDS
as well, usually with suboptimal results. These include etoposide,529
irinotecan, gemcitabine,530 low-dose melphalan,531 idarubicin,510 and
clofarabine.532 Both hydroxyurea and low-dose oral etoposide can be
used to control proliferation in patients with excess blasts, but they
do not target the underlying disease. Clofarabine is sometimes effec-
tive as a bridge to transplant therapy in patients with excess blasts
despite hypomethylating agent therapy, but renal and hepatic toxicity
and severe skin rash are limiting.533
As with lower-risk disease, there are a number of ongoing trials
for patients with high-risk MDS as of this writing. Reflective of the
poorer prognosis of these patients compared to those with lower-risk
disease, many of these trials either examine different combinations
of high-dose chemotherapy or modification of protocols for alloge-
neic stem cell transplant, and are often open to both MDS and
AML patients. However, there are a number of novel or repurposed
agents in trials as well, including immunotherapies (ipilimumab,534
adoptive T-cell transfer,535 and NK cell therapy536), small molecules
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(PIM kinase inhibitors, B-catenin degraders537), and radioisotope-
conjugated monoclonal antibodies. As mentioned earlier, whether
any of these drugs will significantly change the landscape of MDS
therapy is unclear.
FUTURE DIRECTIONS
While the last ten years have witnessed substantial improvements in
our understanding of the molecular pathophysiology underlying
MDS, similar strides have not been made in its treatment: at the time
of this writing, it has been almost 10 years since the FDA last
approved a new drug for treatment of MDS (decitabine in 2006).
There are few therapies in clinical trials that offer hope of broad or
deep efficacy, and much of the ongoing clinical effort is directed at
incremental changes to current practice, such as adjusting dosing
schedules of currently approved therapies or using modestly effective
drugs in combination. The lack of progress is to a great extent caused
by unfortunate facts of MDS biology, including its origin in quiescent
stem cells, a paucity of targetable activating mutations, and enrich-
ment for poorly targetable mutations with much more subtle effects
on growth and differentiation. Efforts are further complicated by the
heterogeneity of biology both between and within individual patients,
as well as the advanced age and poor overall health of many patients
with MDS.
Despite these significant challenges, there is nevertheless great
opportunity for improvements in care. Advances in stem cell trans-
plant techniques, including the availability of alternative donor
sources, refinements of posttransplant immunosuppression, and
augmentation of the graft-versus-tumor effect, should continue to
improve the outcomes for MDS patients able to undergo transplant.
An equally difficult challenge lies in treatment of those patients ineli-
gible for transplant, and it is in these patients that effective unification
of our improving biologic understanding of MDS with clinical care
is most essential.
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 Chapter 60  Myelodysplastic Syndromes 969.e13

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