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Leukemia Research 27 (2003) 95–120
Millennium review
The myelodysplastic syndrome(s): a perspective and
reviewhighlighting current controversies
David P. Steensma∗, Ayalew TefferiDivision of Hematology,
Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905,
USA
Received 21 May 2002; accepted 30 May 2002
Abstract
The myelodysplastic syndrome (MDS) includes a diverse group of
clonal and potentially malignant bone marrow disorders
characterizedby ineffective and inadequate hematopoiesis. The
presumed source of MDS is a genetically injured early marrow
progenitor cell orpluripotential hematopoietic stem cell. The blood
dyscrasias that fall under the broad diagnostic rubric of MDS
appear to be quiteheterogeneous, which has made it very difficult
to construct a coherent, universally applicable MDS classification
scheme. A recentre-classification proposal sponsored by the World
Health Organization (WHO) has engendered considerable
controversy.
Although the precise incidence of MDS is uncertain, it has
become clear that MDS is at least as common as acute myelogenous
leukemia(AML). There is considerable overlap between these two
conditions, and the former often segues into the latter; indeed,
the distinctionbetween AML and MDS can be murky, and some have
argued that the current definitions are arbitrary. Despite the
discovery of severaltantalizing pathophysiological clues, the basic
biology of MDS is incompletely understood. Treatment at present is
generally frustratingand ineffective, and except for the small
subset of patients who exhibit mild marrow dysfunction and low-risk
cytogenetic lesions, theoverall prognosis remains rather grim. In
this narrative review, we highlight recent developments and
controversies within the context ofcurrent knowledge about this
mysterious and fascinating cluster of bone marrow failure states.©
2002 Elsevier Science Ltd. All rights reserved.
Keywords:Disease classification; FAB; IPSS; Myelodysplastic
syndrome; Acute myelogenous leukemia; WHO
1. Introduction
Almost every journal article reporting research on
themyelodysplastic syndrome (MDS) or reviewing these disor-ders
includes an introductory statement similar to the fol-lowing.
The myelodysplastic syndrome(s) include(s) a heteroge-neous
group of clonal bone marrow disorders character-ized by ineffective
hematopoiesis and a variable risk oftransformation to acute
myelogenous leukemia.
This broad definition, refined and supported by ample re-ports
over several decades, is a statement with which almostall
contemporary MDS investigators can wholeheartedlyagree. But when it
comes time to debate more specificdetails, this harmony quickly
dissolves. This is because anumber of important questions about MDS
currently lackthe definitive answers that all investigators crave:
answersgrounded in unambiguous data from rigorously reviewed
∗ Corresponding author. Tel.:+1-507-284-2479;
fax:+1-507-266-4972.E-mail address:[email protected] (D.P.
Steensma).
scientific reports. As is the case in many other areas
ofmedicine and science, in the absence of convincing evi-dence to
answer the tough questions, strong and contraryopinions can
flourish and vigorous discussion results.
How should MDS be defined—what minimal criteria mustindividual
cases meet in order to be labeled “MDS”? Whatare the most useful
ways to classify the various subgroups ofpatients? There are many
reports describing potential patho-physiological clues; which
avenues of biological explorationare most likely to yield results?
Of more immediate inter-est to suffering patients: what are the
best therapeutic ap-proaches to the various subtypes of MDS, and
which patientand disease features allow the most accurate
prognosticationof future events?
Complex questions like these have no easy solutions, andmany
dedicated investigators across the globe are workingdiligently to
try to burn away the fog that enshrouds MDS.The authors of this
review certainly do not presume to havethe answers to any of these
challenging questions. Instead,we share in the excitement of those
who are fortunate enoughto be pursuing their research quarry with
increasingly so-phisticated laboratory techniques in this present
era of rapid
0145-2126/02/$ – see front matter © 2002 Elsevier Science Ltd.
All rights reserved.PII: S0145-2126(02)00098-X
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96 D.P. Steensma, A. Tefferi / Leukemia Research 27 (2003)
95–120
biomedical progress. We confidently look forward to
devel-opments in the near future that will lead to more
certaindiagnoses and better treatments.
This article is not meant to be comprehensive overviewof MDS.
More than 4800 manuscripts about “myelodys-plastic syndromes” have
been published since the NationalLibrary of Medicine began indexing
this term in 1986, and1151 articles on “preleukemia” appeared
between 1977 and1985. It would take a large volume indeed to do
justiceto each critical topic and each major area of
investiga-tion. In lieu of being all-inclusive, we hope to
highlighthere some of the most active, controversial, or
interestingareas.
2. Terminology: the power of language
Challenges with respect to MDS begin at the mostfundamental
level: the language used to define and de-scribe the condition. The
importance of accurate and un-ambiguous disease terminology extends
far beyond thedevelopment of communication tools to aid
researchersand clinicians. Writing in the neoplasia–nosology
traditionestablished by literary critic Susan Sontag, the late
Profes-sor Suzanne Fleischman, an exceptionally articulate
MDSpatient who was a scholar of French and Romance Philol-ogy at
the University of California at Berkeley, pointedout that the
language of medicine also colors the waypatients think of
themselves and their suffering and canaffect the perceptions of
their physicians[1–3]. For ex-ample, “preleukemia”, an older term
for MDS that is no
Table 1Some previous terms for the myelodysplastic syndromes,
with key references (modified from[370,371])
Anemia pseudo-aplastica 1907 Luzzatto[372]Refractory anemia 1938
Rhoades and Barker[373]Odoleucosis 1942 Chevallier[374]Preleukemic
anemia 1949 Hamilton-Paterson[375]Preleukemia 1953 Block et
al.[376]Chronic refractory anemia with sideroblasts 1956
Bjorkman[377]Refractory normoblastic anemia 1959 Dacie et
al.[378]Smoldering acute leukemia 1963 Rheingold et
al.[379]Subacute myeloid leukemia 1960s First use uncertainChronic
erythremic myelosis 1969 Dameshek[380]Refractory anemia with
partial myeloblastosis 1969 Dreyfus et al.[381]Refractory anemia
with excess myeloblasts 1970 Dreyfus et al.[382]Subacute
myelomonocytic leukemia 1972 Zittoun et al.[383]Refractory
megaloblastic anemia 1972 Lehrer et al.[384]Refractory macrocytic
anemia 1970s First use uncertainPreleukemic syndrome 1973 Saarni
and Linman[385]Chronic myelomonocytic leukemia 1974 Miescher and
Farquet[386]Hypoplastic acute myelogenous leukemia 1975 Beard et
al.[387]Hemopoietic dysplasia 1978 Linman and
Bagby[138]Dysmyelopoietic syndrome 1980 Streuli et
al.[388]Myelodysplastic syndromes 1982 Bennett et al.[78]
The most appropriate name for what are now known as the
myelodysplastic syndromes was a major topic at a 1975 symposium in
Paris; a transcriptof the debate was published in a special 1976
issue of the journalBlood Cells[5]. Terms discussed included
preleukemia, preleukemic states, myeloiddysplasia, myeloid
dysplastic disorders, myelodysplastic syndrome(s),
hematopoietic/hemopoietic dysplasia, stem cell dysplasia, and stem
cell disease.
longer widely used[4], cast a darker specter than the cur-rently
favored terms because it included the emotionallycharged word
“leukemia”. “Preleukemia” also fell into dis-favor because some
patients died of complications of thecondition even though the
dreaded full-blown leukemianever appeared, while in other instances
the “preleukemic”syndrome behaved so aggressively and evolved so
rapidlythat there was never a real distinction from overt
leukemiaanyway.
The term “myelodysplastic syndrome(s)” emerged in themid 1970s
from a long list of potential candidate descriptors(Table 1) [5]
and has become sanctified through internationalcurrency. The ideal
terminology remains elusive; althoughthe term MDS appears to have
staying power, it may bemisleading in several respects[6].
2.1. “Myelo-” may be misleading. . .
Although the prefixmyelo- accurately designates the siteof
origin of MDS in the bone marrow, the term has severalmeanings,
andmyelo- can imply narrow restriction of a dis-order to
non-lymphoid cells, i.e. those of erythroid, granu-locyte,
megakaryocyte, and monocyte/macrophage lineage.Yet in some cases of
MDS, lymphoid cells can also be shownto be part of the aberrant
clone[7–12], albeit infrequently[13–16], and rarely, cases of MDS
will transform to lym-phoblastic leukemias[17–20]. These phenomena
reflect thefact that the cell of origin in MDS can be a very early
multi-potential hematopoietic progenitor and perhaps even the
truemarrow incunabulum, the omnipotent undifferentiated stemcell
[21]. Admittedly, this terminological quibble is minor in
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97
comparison to the other problems described in the
followingsections.
2.2. “Dysplasia”: deceptive?
The pathological termdysplasiausually refers to congen-ital,
developmental disorganization of cells; in the contextof evolving
neoplasia,dysplasiaencompasses architecturaldisruption accompanied
by cellular pleomorphism and isclassically restricted to epithelial
tissues[22]. The term“myelodysplasia” in the former sense is
actually used insome medical circles to refer to the congenital
neural tubedefects, confounding computerized searches of the
medicalliterature. Hematopoietic MDS, which arises in a mesoder-mal
tissue (marrow), usually represents a well-establishedneoplastic
clone and not “dysplasia” in the strictest senseof the
word[23].
When MDS was first proposed as a diagnostic term inthe 1970s,
the word “dysplasia” was evolving to a broaderusage that included
virtually any pre-cancerous lesion; atthat time MDS was considered
to be a preliminary stageto acute leukemia[5,24]. Although it was
widely suspectedin the 1970s that MDS/preleukemia was a clonal
disorderon the basis of the characteristic chromosomal
abnormali-ties, several years passed before more definitive proof
of theclonality of MDS arrived in the form of studies of
X-linkedgene and gene product polymorphisms[10,25–27]. More
re-cently, MDS has been shown to share some biological fea-tures
with clonal “dysplasias” in other body sites, such as thedysplasias
affecting the uterine cervix and gastroesophagealmucosa, including
increased proliferation rates, increasedapoptosis, altered telomere
dynamics, alterations in levelsof cell cycle and apoptotic
regulatory proteins, alterations inmicroenvironmental cytokine
levels, and a tendency to un-dergo genetic devolution[28]. However,
MDS differs fromthese other dysplasias in several critical
respects, such as thelack of a proven microbiologic origin and the
extreme rarityof spontaneous regression[28,29].
Some investigators have argued that the chronic myeloiddisorders
are really “myeloneoplasias”—i.e. they do notrepresent preliminary
stages of true clonal disorders butare already fully developed
clonal, malignant disordersthat tend to have an indolent nature
initially but undergoclonal evolution, analogous to the well-known
Vogelsteinmodel for the progression of colon cancer[30,31]. Thesame
considerations apply to the myeloproliferative dis-orders, which
are also (almost always) clonal entities andshare some overlapping
morphological and clinical fea-tures with MDS [32,33]. In fact, at
one time, the term“myelodysplasia” was proposed as a broad
categorical la-bel for all of the chronic myeloid disorders, and
couldhave been the heir to an older, non-specific eponym onceused
indiscriminately for marrow disorders chiefly af-fecting the
erythroid elements, “DiGuglielmo syndrome”[34,380]. However, this
terminology did not catch on,and the word myelodysplasia was
eventually applied to
the restricted set of disorders that are the subject of
thisreview.
The dysplasia versus neoplasia distinction has
importantpractical consequences. Patients diagnosed with MDS
oftenask their physicians, “Do I have a form of cancer?”— aquestion
especially relevant for patients who carry one of theincreasingly
common cancer-specific health insurance poli-cies[35]. Savvy
patients with MDS may also ask whether ahematologist or an
oncologist should direct their care. It canbe unsatisfying to
explain to such patients that their diseaseis felt to reside along
a shadowy frontier between malignantand benign disease. It can be
equally challenging to persuaderesearch funding agencies dedicated
to curing cancer thattheir money would also be well spent by
bankrolling MDSinvestigations. Improving the terminology of the
chronicmyeloid disorders might mitigate some of these problems.
2.3. “Syndrome” is suspect: should it be superseded?
The nebulous wordsyndromereflects the incomplete un-derstanding
of MDS when the disorder began to be morewidely recognized in the
early 1970s[36,37]. Although thepathogenesis and natural history of
MDS have become morecompletely understood in the last 30 years, a
great deal ofwork remains. Still, there has been enough progress
thatsome have argued that the time may now be ripe for MDSto be
considered a set of “diseases” with common biologicaland clinical
parameters[37,38].
From classical Greece until the 20th century, the term“syndrome”
referred exclusively to a cluster of three or moresigns and
symptoms often seen together, without referenceto etiology. During
the 20th century, the term “syndrome”underwent devolution and is
now used to describe virtuallyany characteristic pattern or bizarre
occurrence, includingsome in areas of life far removed from
medicine (e.g. Su-permom syndrome, Clinton syndrome)[36]. Medical
librar-ians have pointed out that MDS represents an unusual useof
the term syndrome as an all-encompassing label for acluster of
possibly related pathologic conditions[36]. Per-haps, only the
so-called 5q− syndrome[39] fits the former,stricter syndrome
definition, because it is always associatedwith hypolobated
micromegakaryocytes and isolated chro-mosome 5 deletions, while the
responsible etiologic agent—presumably a tumor suppressor
gene—remains obscure.
In truth, some conditions that currently reside under thebanner
of MDS have little apparent resemblance to one an-other. Pure
sideroblastic anemia, for example, behaves quitedifferently from
the typical case of chemotherapy-relatedrefractory anemia with
excess blasts and a complex kary-otype [40,41]. Given this
diversity, is the general categoryof MDS worth keeping at all? At
least for the moment, itseems reasonable to do so, although disease
“lumpers” and“splitters” may differ intelligently on this point.
AlthoughMDS represents a cluster of associations without the
impri-matur of a consistent genetic lesion, these conditions
retainseveral hallmarks of “real” disease entities:
pathologists
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95–120
can generally recognize the subtypes of MDS and theirdistinction
has clear clinical relevance[42].
While each patient is a unique individual, and the ad-vent of
proteomic and genomic profiling threaten to smearthe several
“primary colors” of MDS currently recognizedby marrow morphologists
into a rainbow of intermediatehues, we believe general terms for
these diseases will stillbe needed. There is power in group
identity; most patientswant to know the name of their enemy and
know that theyhave a disorder that their doctor recognizes and has
seenbefore, even if their specific case has peculiar or
idiosyn-cratic features[43]. Despite the pressure to fit patients
intoa meaningful diagnostic category, the plurality of the
blooddyscrasias that comprise MDS certainly should not be
for-gotten, and clinicians need to be prepared for
unpredictabil-ity. In light of this diversity, if the “syndrome”
designationis to be maintained for MDS, perhaps the plural
termsyn-dromesis preferable.
3. Difficult diagnostic dilemmas
All that glitters is gold, and not all bone marrow
conditionswith pathologic features similar to MDS represent a
truemonoclonal or oligoclonal neoplastic condition. The mini-mal
criteria for a diagnosis of MDS are unclear, and severalversions
have been proposed[37,44–49]. Some bone marrowmorphologists are
uncomfortable making the diagnosis ofMDS in the absence of
dysplasia in at least two cell lineages(erythroid, granulocytic, or
megakaryocytic) since isolatederythroid dysplasia has so many
potential etiologies. Therecent finding of mildly dysplastic
hematopoiesis in a largepercentage of normal subjects[48,50] argues
in favor of ahigher threshold for the morphologic diagnosis of MDS
if anaccompanying MDS-associated cytogenetic abnormality islacking.
Complicating matters is the recent finding of mon-oclonal
hematopoiesis in some apparently normal elderlywomen[51], which may
represent the myeloid counterpartof monoclonal gammopathy of
undetermined significance(MGUS), an age-related clonal process.
Whether myeloidclonality of undetermined significance has a risk
for pro-gression similar to MGUS[52] has yet to be determined.
Clinicians must be scrupulous to exclude MDS mimicssuch as
nutritional deficiency (particularly Vitamin B12 andfolate [53]),
toxin exposure (e.g. myelotoxic drugs, alcohol[54], lead, and
arsenic[55]), and infection (HIV[56] andparvovirus B19[57,58]) in
order to avoid a misdiagnosisand the potential for inappropriate
administration of toxictherapy[59]. These disorders may look
dysplastic, but theyare not clonal and they do not appear to have
associatedgenetic abnormalities.
One these non-clonal disorders are ruled out, however,the
diagnostic work is not done. Distinguishing MDS fromsimilar clonal
hematopoietic conditions can present a seri-ous challenge, as the
frontiers between subsets of chronicmyeloid disorders are nebulous
and there may be consid-
erable overlap. Hybrid
myeloproliferative–myelodysplasticsyndromes, for example, are not
uncommon[32,60–62]. Di-agnosing MDS in the presence of a
hypocellular marrow canbe particularly difficult[63], as cases of
aplastic anemia thatare otherwise unremarkable may have detectable
cytogeneticlesions, and the etiology of both disorders may be
similar[64–66]. Marrow and peripheral blood cells in MDS canhave a
paroxysmal nocturnal hemoglobinopathy (PNH) phe-notype with absence
of glycosyl-phosphatidylinositol (GPI)anchored proteins[67–69]. MDS
can also be seen in as-sociation with T-cell large granular
lymphocyte disorders(T-LGL) [70], but the simple presence of a
T-cell receptorgene rearrangement does not define a T-LGL, as such
generearrangements are not lineage specific[71].
Often, only the evolution of a particular patient’s disorderover
time can allow clearer distinction between these severaloverlapping
entities. The National Comprehensive CancerNetwork (NCCN)
recognized this, and NCCN guidelinessuggest that if a case lacks
classic features, several monthsof observation should pass before a
diagnosis of MDS isassigned[72].
Detailed genetic profiling aided by “gene chips” andrelated
microarray technology promises eventual relieffor these difficult
diagnostic dilemmas[73]. Eventually,MDS-specific DNA and mRNA
transcript patterns may bedefined, which will set the diagnosis and
classification ofthese marrow conditions on more solid ground, as
genomicprofiling is already showing potential to do for other
dis-eases[74,75]. MDS gene and protein expression patternswill
become even more relevant when specific and effec-tive therapies
are developed based upon them. Until thesepatterns are ferreted out
and the critical genes are defined,the MDS counterparts of highly
specific therapies such asSTI-571 (imatinib mesylate, GleevecTM)
for chronic myel-ogenous leukemia[76] must remain only a distant
dream.
4. Disease classification: schemes and controversies
The appropriate classification of the many varieties ofMDS has
been a contentious topic for many years, and thedebate shows no
signs of abating. The fundamental prob-lem seems to be that it is
simply not possible to classifyincompletely understood disorders
like MDS with absolutecertainty and to the complete satisfaction of
all investiga-tors. Yet, paradoxically, further understanding of
enigmaticdisorders cannot easily be achieved in the absence of
theframework of a working classification. Each patient withMDS is
unique and presents idiosyncratic clinical problems,yet if every
patient were to be considered a “special case”because of their
peculiar constellation of clinical and patho-logical features, the
overall syndrome would suffer death bydeconstruction. Reproducible
patterns of bone marrow be-havior are clearly seen; recognition of
these can facilitatecommunication between investigators and allow
forecastingof a particular patient’s disease course.
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Table 2The 1982 French–American–British (FAB) Cooperative Group
classification of the myelodysplastic syndromes
Subtype Myeloblasts inperipheralblood (%)
Myeloblasts inbone marrow(%)
Ringedsideroblasts(%)
Absolutemonocytes inperipheral blood
Auer rodspresent in bonemarrow?
Refractory anemia (RA)
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Table 3The proposed World Health Organization (WHO)
classification of neo-plastic diseases of the hematopoietic and
lymphoid tissues[42]: categoriesrelevant to the myelodysplastic
syndromes
Myelodysplastic syndromesRefractory anemia
With ringed sideroblasts (pure sideroblastic anemia)Without
ringed sideroblasts
Refractory cytopenia with multilineage dysplasia
Refractory anemia with excess blastsWith 5–10% myeloblasts
(RAEB-1)With 11–19% myeloblasts (RAEB-2)
5q− syndromea
Myelodysplastic syndrome, unclassifiable
Myelodysplastic/myeloproliferative syndromesChronic
myelomonocytic leukemiaa
Atypical chronic myelogenous leukemiaJuvenile myelomonocytic
leukemia
Relevant acute myeloid leukemia (AML) categoriesAML with
multilineage dysplasia
With prior myelodysplastic syndromeWithout prior myelodysplastic
syndrome
AML and myelodysplastic-syndromes, therapy-relatedAlkylating
agent-relatedEpipodophyllotoxin-relatedOther types
a Like RAEB, CMML can also be subdivided based on
myeloblastcount. The 5q− syndrome is narrowly defined to include
only cases withde novo isolated del(5q) and the characteristic
morphologic findings ofhypolobated megakaryocytes and less than 5%
marrow myeloblasts[37].
count of 19%. Based on these considerations, there werecalls to
eliminate RAEB-T and to split the heterogeneousRAEB category into
multiple subgroups.
4.3. The World Health Organization (WHO) proposal
In 1997, a working group of more than 100 cliniciansand
pathologists met at Airlie House in Virginia under theauspices of
the World Health Organization (WHO) to dis-cuss a new master
classification of hematologic disorders[42]. Included in this
classification was a proposal for there-classification of MDS
(Table 3). In 2001, the final versionof the classification was
published and incorporated into the10th edition of the WHO
International Classification of Dis-eases (ICD-10), which was first
used in 1994 and is the mostcurrent ICD classification[87,88].
Clinicians and investigators with an interest in lym-phoma were
already exposed to a forerunner of the newWHO classification in the
form of the 1994 RevisedEuropean–American Lymphoma (REAL)
classification[89]and were perhaps somewhat battle-weary after many
decadesof contentious classification debate[90,91]. This group
of-fered comparatively little resistance to the new WHO
clas-sification[92]. Controversy over the subclassification of
themyeloid disorders, in contrast, contributed to delays in
thefinal publication of the classification, and several
revisions
were made between the initial and final WHO proposals.Another
comparison between myeloid and lymphoprolif-erative disorders is
revealing. Although MDS appears asclinically diverse as lymphoma,
in the original WHO pro-posal MDS was represented by only six
“pure” MDS sub-types and three myelodysplastic–myeloproliferative
overlapdisorders; the lymphoproliferative disorder
classificationcomprised more than 40 entities[42].
4.4. Single lineage versus multilineage dysplasia: doesdegree
matter?
One major change between the WHO and the FAB clas-sifications is
the recognition in the former that there is in-deed a difference
between cases of MDS with morphologicdysplasia primarily restricted
to one cell lineage (usuallyerythroid) and those with more
widespread dysplasia. Asmentioned above, the FAB originally defined
refractoryanemia and refractory anemia with ringed sideroblasts
assyndromes with dysplasia largely restricted to the
erythroidlineage, rendering cases with marked trilineage
dysplasiadifficult to classify [93]. One key caveat is that mild
dys-plasia restricted to the erythroid lineage is sometimes
notclonal [50]. Stricter definitions for MDS such as thoserequiring
at least bi-lineage dysplasia avoid inadvertentlyaffixing the label
of MDS to cases that are not monoclonal,but also risk excluding
genuine MDS cases with mini-mal dysplasia—a sacrifice of
sensitivity at the expense ofspecificity for which there is no easy
solution.
Several reports have demonstrated that multilineage dys-plasia
(e.g. “refractory cytopenia with multilineagedysplasia”) carries a
worse prognosis than simple erythroiddysplasia[41,84,94], including
cases with ringed siderob-lasts[40,95]. Whether this finding is
independent of otherknown prognostic variables for MDS remains
unclear[37].In addition, more severe dysplasia within a given
lineagemay also portend a worse prognosis[96,97], although fur-ther
studies are needed to support this claim and the samecaveat about
independent prognostic value applies. A re-port by the Vienna group
reviewing 431 MDS patients didnot validate the prognostic value of
the new category ofRCMD, but a German group reviewing 1600 patients
didsupport the WHO proposal on this point[41,98]. Several ofthe
architects of the WHO classification pointed out that theVienna
group used a different threshold (50% dysplasticcells versus 10%
for other groups) to define whether alineage exhibited dysplastic
features or not[97]. This dis-tinction may turn out to be quite
important—dysplasia isunlikely to be a “yes or no” issue—but at
present, thereare no studies that have published the effect of
changesin the value of the “dysplasia differential” on
prognosis.Most morphologists who diagnose RCMD appear to oper-ate
more by a general gestalt (i.e. is there heavy dysplasia,occasional
dysplasia, or none at all?) rather than actuallyenumerating the
dysplastic and normal red cells, white cells,and megakaryocytes.
More work is needed in this area.
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4.5. Chronic myelomonocytic leukemia (CMML): asyndrome with a
new home
The WHO classification removes CMML from MDSproper and puts it
in a myeloproliferative–myelodysplasticoverlap category, along with
two unusual disorders, atypicalchronic myelogenous leukemia and
juvenile myelomono-cytic leukemia. This distinction seems
reasonable, as CMMLwas always an awkward bedfellow in the FAB
scheme, asmentioned above (fans of the musical group “The
Beatles”might compare CMML’s uncomfortable presence along-side the
FAB 4—RA, RARS, RAEB, and RAEB-T—to theawkward coupling of Yoko Ono
with John, Paul, Ringo,and George).
Although there is universal agreement on CMML’s
het-erogeneity[79,82,99], it is unclear at present how one
mightreproducibly split the disorder into distinct
subtypes[81].Placement of CMML in a separate overlap category is a
par-tial solution to this ambiguity, and dividing CMML into
twocategories based on the blast count, as the WHO has donein their
final proposal, may have more prognostic relevancethan attempts to
divide CMML based on peripheral whitecount[97].
But other overlap MDS-myeloproliferative conditionsdo not easily
fit into one of the WHO categories[32,61],and there is currently no
appropriate default category forsuch cases. Otherwise typical cases
of MDS may have neu-trophilia, monocytosis, thrombocytosis,
splenomegaly, orother myeloproliferative features, raising
diagnostic angst:are such cases truly MDS with minor variation, or
are theyactually different enough to require re-designation as
aunique overlap syndrome?
4.6. “Secondary” MDS/AML: “secondary” to what?
The WHO classification includes a sub-category
fortherapy-related MDS and AML. This category reflects
thehistorical distinction between “secondary” and “primary”MDS; the
former applies to patients who have previouslyreceived chemotherapy
or radiotherapy for another disease.Confusing matters is the fact
that the term “secondary”AML is used to describe both patients with
prior genotoxictherapy exposures as well as patients with leukemia
arisingout of a prior chronic myeloid disorder. Although
pretreatedpatients generally do more poorly than those without
sucha history[100–102], the prognosis appears to depend pri-marily
on the cytogenetic profile (frequently abnormal and“high-risk”
[83,103]) and not the history of treatment perse [21]. Whether or
not such patients represent a distinctsubset of MDS deserving of a
separate classification isquestionable.
Someday it may become clear thatall MDS is “secon-dary”, albeit
not always iatrogenic. Although findings havebeen somewhat
inconsistent, there are already considerabledata supporting the
fact that many cases of MDS and AMLmay result from toxin exposure
in a susceptible host. Some
of these susceptible persons may be those with polymor-phisms in
genes encoding NADP(H) quinone oxidoreductase(NQO1) and
glutathioneS-transferases (especially GSTT1and GSTM1), a group of
enzymes involved in hydrocarbondetoxification[104–110]. Whether an
MDS-inciting agentis encountered in the home or workplace or was
instead dis-pensed by a pharmacist or radiotherapist may turn out
to bean unimportant distinction.
4.7. Distinguishing MDS from AML: scratchinglines in the
shifting sand
In some cases of AML, the diagnosis is obvious, whilein other
cases making a clear distinction between MDSand AML can be
extremely difficult. The FAB classifica-tion imposed an arbitrary
threshold value of 30% marrowblasts to define AML; the WHO proposal
lowers this thresh-old to 20% and thereby does away with the FAB
categoryof “refractory anemia with excess blasts in
transformation”(RAEB-T or RAEBIT). This proposed change has
engen-dered strong criticism. Some have argued that RAEB-T
isbiologically different from AML and should be retained asa
diagnostic category[37,111], while others have empha-sized the
similar prognosis for the two entities as well as theidentical
response to treatment[85,86] and certain biologi-cal features which
are indistinguishable[112]. Both propos-als suffer from the
limitation that regardless of which blastcut-off for AML is
accepted (30 or 20%), such numbers areof course fundamentally
arbitrary[37]. The effect of blastpercentage on prognosis in MDS
appears to be a continu-ous variable, as is true of most biological
systems. Reflect-ing this, the final WHO proposal separates RAEB
into twosub-categories depending on whether the marrow blast
per-centage is 5–10% or 11–19%, a distinction that has beenshown to
be prognostically important[37,83,113,114]. Thismay be the best
that can be done given the limited precisionof bone marrow
differential counts.
One proposed compromise position is to redefine AMLin terms of a
rate of progression rather than a strict blastpercentage; such an
assessment would require several mea-surements over time, with
relative stability consideredthe hallmark of MDS[37,38].
Cytogenetic features arealso important; MDS is most often
characterized by dele-tions and (less commonly) gains of
chromosomal material,while recurrent translocations are more common
in AML[101,115]. Most hematologists would consider a
marrowexhibiting a classic AML-associated genetic lesion such
ast(8;21)(q22;q22), t(15;17)(q22;q11–12), inv(16)(p13q22),or an
anomaly of 11q23 as diagnostic of AML regardless ofthe blast count,
and in fact the WHO scheme does categorizesuch cases as AML[42]. An
MDS phase is observed onlyrarely with such lesions[116,117]. Yet,
there are certainlycases of AML with a high blast count which are
character-ized more by ineffective hematopoiesis than by blast
burden[38], and there have been few calls to reclassify such cases
asMDS. In addition, in some cases of AML, the bone marrow
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demonstrates multi-lineage dysplasia but no preceding MDSwas
recognized. Although the WHO includes an AMLsub-category for such
cases, the simple presence of dysplasiain AML has not had
consistent prognostic value[118–123].
4.8. Unclassifiable MDS: a spacious prison for caseswith
disorderly conduct?
The inclusion of an “unclassifiable” MDS category inthe WHO
classification has been criticized[37]. The WHOworking group
recognized that cases are occasionally seenwhich do not easily fit
into the FAB classification andwanted to have a category for such
patients for epidemi-ologic purposes. However, the number of
unclassifiablecases is likely to be very dependent on each
individualhematologist or morphologist and the strictness of the
stan-dard to which each case is held. Among other
difficultcases[60], hypoplastic/hypocellular MDS[63,65], MDSwith
fibrosis[124], “refractory thrombocytopenia” and “re-fractory
neutropenia” without anemia[125], MDS in thepresence of a
simultaneous untreated lymphoplasmacyticclone [126,127], MDS
associated with a granulocytic sar-coma[128], clonal cytogenetic
abnormalities characteristicof MDS without clear morphologic
changes[129,130],MDS with an associated T-cell clonal gene
rearrangement[70], “paraneoplastic” MDS (of uncertain
clonality)[131],and miscellaneous MDS-myeloproliferative overlap
cases[62] could all be considered unclassifiable under the
WHOscheme. It is not clear whether these should be
considereddiscrete entities, though, because most of them are
rareenough that they have not clearly been shown to
behavedifferently from more typical MDS cases in large series.The
WHO classification has been validated in a large ret-rospective
study in which unclassifiable patients apparentlyaccounted for a
very small number of cases, but not allmorphologists are
convinced[41,98].
In addition to these criticisms, the pediatric MDS com-munity
has pointed out that their needs have not beenwell-served by either
the FAB or WHO schema[38,132].The WHO classification controversy
highlighted the factthat a robust, evidence-based pediatric MDS
classificationwas sorely needed, and a consensus system has
recentlybeen proposed[133].
4.9. Beyond the FAB 5 and the WHO: rolling towarda less rocky
classification
The ideal classification for MDS will be simple, re-producible,
and useful for treatment and prognostication.Among other virtues,
such a classification scheme will“lump” similar biologic entities
and “split” disparate ones,will minimize arbitrary distinctions,
and will be fluid andeasily alterable in the face of progressive
enlightenmentby research reports. Although the current schemes
appearto fall somewhat short of these goals, emerging data ongene
expression patterns and other biologic parameters may
clarify distinctions among subtypes of MDS and betweenAML and
MDS and move the science of classificationforward [73,134].
The WHO classification architects are to be commendedfor
successfully building on the FAB scheme with whichclinicians and
pathologists were familiar, including some cy-togenetic data, and
refining diagnostic categories in reason-able ways. But as with all
classification schemes, the WHOproposal should be considered a work
in progress, and asmore evidence accumulates about the significance
of spe-cific genetic lesions and clinical features, revisions will
benecessary.
5. Epidemiology: how trustworthy are the numbers?
Several factors have made true the incidence and preva-lence of
MDS difficult to ascertain. As one epidemiologistcomplained, “we
are put off by the fact that MDS is aheterogeneous, vaguely defined
group of conditions withseemingly ever-changing names”[135]. MDS
terminologyhas been somewhat consistent only since the 1982
FABclassification, and as discussed earlier, many MDS casesremain
unclassifiable, uncertain, or diagnostically prob-lematic.
Compounding the difficulty is the fact that casesof MDS are not
routinely reported to cancer registries[136,137], a legacy of the
benign vs. malignant murkinessdetailed earlier. Standard disease
classifications such as thestill widely used ICD-9 carry
terminology that is not evenconsistent with the FAB classification,
let alone the WHO[135,137]. Additionally, MDS can be confused with
otherconditions with similar names. It is not uncommon to finddeath
certificates, hospital summaries, and patient databaserecords in
which the terms “myeloproliferative disorder”and “myelodysplastic
syndrome” and “myeloid leukemia”have been used interchangeably.
Such muddle confoundsregistry-based work. Further, most
epidemiologic studies inMDS have been limited to data from small,
regional reg-istries[137]; large national or international studies
are rare.
5.1. How common is MDS?
In the 1970s, shortly after MDS was morphologicallydefined by
the FAB, it was estimated that there would be ap-proximately 1500
new cases of MDS per year in the UnitedStates[138]. More recent
estimates suggest that this figureis too small by at least a factor
of 10. If the annual incidencein the USA were as high as the crude
rate of 9.3–12.6 casesper 100,000 persons per year suggested by two
English stud-ies [139,140], more than 30,000 American cases of
MDSwould be diagnosed annually. In comparison, the
overallage-adjusted incidence rate of acute myeloid leukemia inthe
USA was estimated at 2.9 cases per 100,000 personsper year in 1998,
a figure that has not changed significantlysince 1973[141]. Even if
only the more conservative MDSincidence estimates are
accepted—crude incidence figures
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103
which generally range between 2 and 4 cases per 100,000persons
per year[136,142–144]—it seems probable thatMDS is at least as
common as AML. The elderly are partic-ularly vulnerable, as annual
MDS incidence rates in patientsover 70 years of age have ranged
between 15 and 50 casesper 100,000 persons per year[145].
5.2. Rumors of the coming plague: is the incidenceof MDS really
increasing?
Many hematologists from a variety of locations aroundthe world
believe that the incidence of MDS is increasing[44,146–149]. It
remains unclear whether this is actuallytrue or whether such
observed trends are simply a matterof increasing recognition of the
syndromes. Changes in de-mographics such as the overall aging of
the population inindustrialized nations can also be
misleading[145].
Several investigators have found no evidence for an in-crease in
the incidence of MDS over time[136,143]. Sinceslight macrocytosis,
for example, is not easily recognizableon a peripheral blood smear
and since a high red cell meancorpuscular volume (MCV) may be one
of earliest signsof MDS [150], it is probable that routine use of
automatedhematology counters has highlighted certain milder
casesthat might previously have been overlooked[140]. Otherfactors
such as the increasing use of remission-inducing orcurative
therapies for other disorders that are associated witha subsequent
risk of MDS[151,152]may also be making asmall contribution to
changes in MDS epidemiology[137].A widely held perception that the
general environment is be-coming more “toxic” has been suspected of
fanning fears ofa looming epidemic of exposure-related diseases
like MDSand asthma[153].
What will it take to obtain reliable incidence data forMDS?
Uniform syndrome definitions, clear and comprehen-sive
record-keeping, and multinational collaboration over aprolonged
period of time represent challenging but poten-tially achievable
goals that will greatly clarify the epidemi-ology of MDS.
6. The mysterious biology of MDS
Among the chief challenges in studying MDS are thepaucity of
adequate cell lines and the lack of an appropri-ate animal model of
the disease. Most mechanistic stud-ies have been carried out on
fresh human tissue, of whichthere is necessarily a limited supply.
The current collec-tion of MDS-related cell lines was recently
reviewed[154].Most of the 10 MDS-specific (i.e. not secondary-AML)
celllines that have been described are not currently availablefrom
major cell banks, and several of these are lymphoidlines (of less
interest for myeloid mechanistic work) and arepoorly
validated[154]. The myelomonocytoid P39/Tsuganecell line, an
MDS/AML cell line that has been the object ofseveral mechanistic
studies of myeloid differentiation, has
recently been reported by the Japanese Collection of Re-search
Bioresources (JCRB) Cell Bank to be cross-contami-nated by HL60
cells[155–158]. Additional well-validatedMDS cell lines are clearly
needed.
A detailed discussion of the mechanisms that initiate andsustain
MDS is beyond the scope of this paper, and only afew insights can
be mentioned here.
6.1. MDS causation: the prime mover remains unknown
Oncogenesis is thought to be a multi-step process in
whichseveral critical genetic lesions accumulate, eventually
re-sulting in overt cancer. The development and progression ofMDS
from its earliest stages through more advanced diseaseand its
eventual transformation to AML appear to mesh withthis
concept[106,137]. Multiple genetic pathways can beinvolved, and
sometimes several distinct clones are presentin the same
patient[101,110,159–161].
Loss of genetic material from chromosomes 5, 7, 13,17, and 20 or
a sex chromosome and (less commonly) ge-netic gains such as trisomy
8 are well described in MDS[162]. Several hundred other
MDS-associated karyotypeshave been described[163], some of which
are rare but re-current, yet the critical genes lost or grained in
most ofthese lesions remain a mystery[164]. The region of
chromo-some 5 often deleted in MDS, for example, contains
multiplehematopoietic growth factors, but attempts to define
whichgenes are the sine qua non of the classic 5q− syndromehave
thus far been unrevealing[165,166]. Large cytogeneticlesions
detectable by conventional karyotypic analysis arelikely to be late
developments in the pathogenesis of MDS.Several patients have been
described in whom clonality (asassessed by analysis of various
X-linked genes) precededthe development of an overt cytogenetic
lesion by severalyears[167].
Almost half of de novo MDS cases have normalmetaphase
cytogenetic findings. Sorting out the relevantaltered gene pathways
in such cases remains an active areaof investigation. “FISHing
expeditions” with multiplex-fluorescent in situ hybridization
(M-FISH) and spectral kary-otyping techniques in cytogenetically
normal MDS caseshave been generally unrevealing, although these
proceduresmay be useful in clarifying the karyotype in complex
cases,which at present is not often clinically
relevant[168–170].Panel FISH techniques, in which a group of FISH
probesare used to search for cryptic expression of common
MDSgenetic abnormalities, are also of limited value[171].
Two recent microarray studies of gene expression inMDS have
shown increased expression of a gene encod-ing the delta-like (dlk)
protein in low-risk MDS patientscompared with high-risk MDS, AML,
CML, and normalcontrols[73,134]. The function of this gene is
uncertain, butthere is new evidence that it may have a role in the
cellulargrowth and differentiation programs, including
differentia-tion of hematopoietic cells. In mice, forced
overexpressionof dlk was a negative regulator of adipocyte
differentiation,
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and a soluble dlk-IgG Fc chimeric protein was shown tocompletely
inhibit formation of lineage-marker negative(Lin−) bone marrow cell
colonies by colony stimulatingfactors in the presence of stem cell
factor (SCF)[172,173].These microarray experiments represent a
proof of concept,and it can be expected that global genomic work
will yieldother interesting candidate genes whose
pathophysiologicalrelevance in MDS can then be studied in more
detail.
Several MDS investigators have probed specific genesknown to be
mutated in other forms of cancer andpre-cancerous lesions.
Mutations ofras, fms, andp53 haveall been described in MDS,
although the exact prevalenceremains uncertain[174–177]. In
contrast, other genes of-ten mutated in AML such asAML1 do not
appear to beabnormal in the majority of patients with
MDS[178,179].
The root cause of the underlying genetic lesions in MDSis often
not known, although various epidemiologic asso-ciations support the
importance of exposure to a genotoxicagent in a susceptible host.
Patients treated with alkylatingagents, epipodophyllotoxins, and
ionizing radiation are atincreased risk for MDS. MDS is more common
in men,in persons with agricultural or industrial occupations
orregular exposure to petroleum products, in smokers, and inpersons
who use hair dyes[142,180–184]. MDS has alsobeen described after
exposure to atomic radiation. A numberof cases have appeared in the
Chernobyl nuclear accidentdecontamination workers[185], and
although MDS was notyet recognized in the years following the
atomic bomb blastsin Hiroshima and Nagasaki, re-review of the
marrow speci-mens from those patients who developed AML revealed
dys-plastic changes[186]. Atomic bomb survivors were recentlyfound
to have a dose-dependent increase in the risk of MDSeven many years
after exposure, lending yet more supportfor a multi-step
pathogenesis of MDS[187]. The “naturalexperiments” of familial
MDS[188–190]and MDS arisingin patients with congenital deletion of
a tumor suppressorgene (e.g. neurofibromatosis type 1[191]) or a
DNA repairdefect (e.g. Fanconi syndrome[192] and Bloom
syndrome[193,194]) underscore the importance of host
suscepti-bility.
6.2. Too much apoptosis?
In the late 1980s, apoptosis-associated morphologicchanges such
as chromatin condensation and cytoplasmicblebbing were observed in
hematopoietic progenitor cellsin bone marrow from patients with
MDS[195]. Thesefindings suggested a resolution to one of the
paradoxes ofMDS: the presence of peripheral blood cytopenias
despitea typically hypercellular bone marrow[196,197]. Numer-ous
subsequent studies have supported the hypothesis thatexcessive
programmed cell death is a contributing factor tothe ineffective
hematopoiesis in MDS. The marrow failureis usually not a result of
decreased progenitor synthesis, asmarrow kinetic studies have
determined increased prolifer-ation [198].
Various techniques can be used to measure typical apop-totic
changes in MDS marrow, including in situ end-labeling(ISEL) and
nick-end labeling (TUNEL) of DNA strandbreaks[199–204], detection
of phosphatidylserine migra-tion to the outer portion of the
cellular phospholipid bilayerusing the annexin V binding
protein[205,206], and quantifi-cation of sub-diploid (sub-G1 phase)
DNA[207]. Althoughthere continues to be significant disagreement
among in-vestigators regarding the degree and extent of apoptosis
inMDS marrow and the culpability of stromal cells, severalclear
trends have emerged.
Multiple studies have demonstrated that there is an in-crease in
the apoptotic index in the marrow of patients withearly MDS
compared with normal controls. However, theapoptotic index
represents a numerator (the number of apop-totic cells detected)
over a denominator (the total number ofcells counted), and changes
in the apoptotic index can re-sult from changes in either number.
If the denominator wereCD34-positive cells, for instance, as has
been the case inmost studies measuring the apoptotic index,
alterations inthe pool of early hematopoietic progenitor cells
might givemisleading results. Apoptotic phenomena are also time
de-pendent, and not all studies have described the freshness
ofstudied samples[208].
The increased apoptotic index in MDS is associated withan
increased proliferative fraction (as measured by Ki-67monoclonal
antibody staining[206] or bromodeoxyuri-dine/iododeoxyuridine
labeling indices[198,199,202,209])and signal antonymy[209]. In
contrast, apoptotic indicesappear to be decreased in late MDS
(refractory anemiawith excess blasts and refractory anemia with
excess blastsin transformation) and in AML arising from a
pre-existingMDS when compared with early MDS. The percentage
ofapoptotic cells in early MDS also appears to decrease
sig-nificantly after treatment with erythropoietin and/or
G-CSF,suggesting one possible mechanism for the salutary increasein
peripheral blood counts in patients treated with
theseagents[201].
Several investigators (including groups at Stanford Uni-versity,
Rush Medical College, the University of Arizona,King’s in London,
and others) have studied the mechanisticchanges contributing to
excessive apoptosis in MDS, andmuch progress is being made. There
is evidence for involve-ment of members of the Bcl-2 family, for
example. In earlyMDS, the pro-apoptotic members of the Bcl-2 family
(Bad,Bax) are overexpressed relative to the anti-apoptotic mem-bers
(Bcl-2), but this ratio drops in late MDS and secondaryAML
[206,210]. The ratio of c-myc(pro-apoptotic) to
Bcl-2(anti-apoptotic) is elevated in cases of early MDS comparedto
normal controls[207]. Vascular endothelial growth factor(VEGF)
appears to be an important cytokine for leukemiccell proliferation
and contributes to the morphologic phe-nomenon of abnormal
localization of immature myeloidprecursors within the marrow
microenvironment[211]. Theexpression of tumor necrosis factor
(TNF), a pro-apoptoticcytokine, also appears to be increased in
MDS[212–214],
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105
and this elevation correlates with increased activity of akey
biochemical effector of apoptosis, caspase 3[215]. Inaddition,
increased expression of another death-inducingprotein, Fas/CD95,
has been noted in MDS and correlateswith ineffective
erythropoiesis[216,217]. The degree of ex-pression of this
receptor’s partner, Fas ligand, in MDS hasbeen correlated with FAB
subtype, degree of anemia, andoverall survival[218]. In contrast,
in one study granulocytesand CD34+ cells from MDS patients were
resistant to Fas,TNF-�, and interferon-induced apoptosis[219]. Not
to beoutdone, several of the receptors for the other known mem-ber
of the death ligand/receptor family, TRAIL, have alsobeen shown to
be overexpressed in MDS marrow comparedto normal controls, and
treatment with exogenous TRAILinhibits myeloid progenitor
proliferation[220,221].
The underlying genetic lesions contributing to thesechanges
remain obscure. It is also unclear whether increasedapoptosis is a
desperate cellular reaction to a rapidly prolif-erating and
genetically disturbed clone, or whether excessiveapoptosis is
instead an integral part of the pathophysiologyof the syndrome.
6.3. The enigma of ringed sideroblasts
Ringed sideroblasts are abnormal erythroid precursors inwhich
iron-stuffed mitochondria encircle the nucleus; thisiron is
unavailable for incorporation into heme, resulting inanemia. The
finding of ringed sideroblasts can be associ-ated with a number of
congenital syndromes that cause de-fects in heme synthesis—usually
via decreased activity of5-aminolevulinate (5-ALA) synthase, an
X-linked enzymewhich has been found to be mutated in a subset of
patientswith sideroblastic anemia[222]. Treatment with pyridoxine,a
precursor for the cofactor of 5-ALA synthase, can improvethe anemia
in some cases of MDS with ringed sideroblasts.Several polyclonal
acquired ringed sideroblastic states alsoexist, such as lead
intoxication and alcohol abuse, whichmay present a diagnostic
challenge[223].
Monoclonal acquired sideroblastic anemia is considereda
myelodysplastic syndrome[78]. As mentioned above,“pure” acquired
sideroblastic anemia carries a much morebenign prognosis than
sideroblastic anemia associated withmulti-lineage dysplasia; the
latter is also much more fre-quently associated with clonal
cytogenetic anomalies[40].
The genetic lesions responsible for most cases of
acquiredsideroblastic anemia remain uncertain; mitochondrial
DNAlesions may play an important role[224–226]. In one smallstudy,
substitutional, deletional, and insertional mutationsin cytochromec
oxidase subunit genes were detected in 13of 20 MDS patients but
only 2 of 10 normal individuals; thesignificance is uncertain at
present but mitochondrial cis-ternae morphologic abnormalities have
also been observed[226,227]. Autosomal defects too small to be
detected byconventional karyotypic analysis are also possible
contrib-utors to sideroblastic anemia. The recent cloning of
ABC7,an X-linked gene coding for an iron transporter which
local-
izes to the mitochondrial membrane, is of particular
interestbecause the Xq13 locus where this gene is located has
oc-casionally been associated with acquired myeloid
disordersincluding some cases with ringed
sideroblasts[228–230].
7. Treatments: too few and often too futile
Effective treatments for MDS are limited, but the longlitany of
potential treatments to which a few patients will re-spond also
makes therapeutic nihilism untenable. It is oftenstated that the
only potentially curative treatment for mostpatients is also the
riskiest, allogeneic stem cell transplanta-tion, but in fact a few
patients (especially younger patientswith a normal karyotype) will
achieve a prolonged poly-clonal remission after high-dose
chemotherapy even withouttransplantation and may turn out to be
“cured”[231]. Still,given the older age of most patients, gentle,
supportive careremains the treatment standard[232].
A number of conventional and experimental treatmentsfor MDS are
briefly reviewed below. Although the list ofpotential treatments is
long, very few are effective in a largenumber of patients. A major
challenge lies in predictingwhich patient is most likely to respond
to which treatment.Since the detailed mechanism of action for many
agents isunknown, some of the agents listed later in one
categorymay actually have activity that would make them equally
athome in a different category (e.g. the interferons, which
havegrowth, differentiation, cytotoxic, and
immunomodulatoryeffects—or thalidomide, which has many poorly
understoodbiological effects).
7.1. The importance of response criteria: whatconstitutes
success?
For chronic disorders such as MDS, treatment success isalmost
never a simple question of “yes” or “no”. Treatedpatients often
exhibit gradations of clinical change in multi-ple organ
systems—some insignificant and others of majorimportance, some
salutary and others detrimental. Definingarbitrary criteria for
therapeutic success or failure that allinvestigators can agree upon
in the face of this biologicalcontinuum represents a major problem.
When clinical tri-als in MDS are submitted to medical journals,
disagreementover response criteria may be a cause of manuscript
rejec-tion [233].
Recently, an International Working Group (IWG) labor-ing under
the auspices of the National Cancer Institute inBethesda, MD
proposed a set of standardized response cri-teria for clinical
trials in MDS[234]. Although such stan-dardized criteria are
desperately needed, the IWG proposalhas been criticized by some.
Several of these response crite-ria have been perceived as
clinically irrelevant or difficult toapply consistently[233,235].
Using the IWG criteria, for ex-ample, independent groups reviewing
raw data from clinicaltrials may come to different conclusions
about the number
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95–120
of patients responding to treatment[233]. Less
meaningfulhematologic changes could qualify as a treatment
responseunder the current IWG criteria, while in other situations
anovert cure would not technically qualify as a complete
re-sponse[235]. For now, the IWG criteria may provide a
usefulcommunication tool for reporting clinical trials, but
minormodifications might help investigators use them with
moreconfidence.
7.2. Flogging a recalcitrant marrow: the role ofgrowth factors
in MDS
Recombinant human hematopoietic growth factors canbe an
effective palliative tool in MDS, but they do notseem to prolong
survival. The detailed studies of theScandinavian group have shown
that erythropoietin (EPO)ameliorates anemia in about 20% of MDS
patients witha serum EPO level of less than 200 U/l, but only
rarelyworks in patients with RARS or those with higher endoge-nous
EPO levels[236]. Very high doses of rHuEPO (upto 240,000 units per
week) have been tolerated well byMDS patients, but using very high
doses does not seem toimprove the response rate over the more
typical dose of40,000–60,000 units per week[237]. In some patients
whodo not respond to EPO, the addition of low doses of gran-ulocyte
colony stimulating factor (G-CSF) (0.3–3.0 mcg/kgper day) or
granulocyte-macrophage colony stimulating fac-tor (GM-CSF) may help
recruit erythroid progenitors andthereby improve anemia as well as
neutropenia[238–242].Both G-CSF and GM-CSF can increase neutrophil
countand reduce infections in MDS[243–245], but no
survivaladvantage has been demonstrated and there is still
concernabout a small risk of accelerating transformation to
acuteleukemia[21]. Results from trials of modified,
longer-actinggrowth factors in MDS (e.g. darbepoeitin and
pegylatedfilgrastim) have not yet been reported.
Options are more limited for growth factor-based treat-ment of
thrombocytopenia. Recombinant interleukin-11is a megakaryocyte
growth factor recently FDA approvedfor the prevention of severe
thrombocytopenia and todecrease platelet transfusion needs after
myelosuppres-sive chemotherapy. It appears to have mild efficacy
inMDS [246]. Side effects such as atrial arrhythmias andfluid
retention are common and troublesome with thisagent in standard
doses (50 mcg/kg per day), but maybe seen less often when very low
doses (10 mcg/kg perday) are used[246]. Thrombopoietin (TPO)
dynamics inMDS are complex[247,248], and no data are availableyet
on the therapeutic use of recombinant TPO in thiscondition.
Other agents with growth factor activity that have un-dergone or
are undergoing clinical evaluation in MDS in-clude interleukin-6,
interferon alpha and gamma (which alsohave differentiation
properties in vitro), and interleukin-3.Each has had rather limited
efficacy and substantial toxicity[249–260].
Several growth factors have been tried in combinationwith other
biologic agents such as amifostine, with varyingbut generally
unimpressive results[261–264]. The use of allof the hematopoietic
growth factors is currently limited bytheir high cost and the need
for parenteral administration.
7.3. The peril and promise of high dose chemotherapy
High-risk MDS has very little distinguishing it fromAML, and
therefore, AML-like therapy is a reasonableconsideration for
patients with aggressive MDS such asthose with a high blast count.
Although elderly patients tol-erate AML-type chemotherapy poorly,
the median age forMDS patients is not markedly different from that
for AML.Studies of patients with high-risk MDS reveal a
40–50%remission rate with high dose AML induction therapy,
butpatients in trials of such regimens are usually a select
groupyounger and healthier than the typical patient with
aggres-sive MDS. Almost all patients achieving a remission viasuch
therapy will relapse promptly[85,265,266]. In onestudy, only 5% of
patients receiving high-dose therapy werealive at 3 years[231].
Growth factor support following ag-gressive therapy is tolerated
but of uncertain benefit[267].
Several high dose regimens such as the combination
ofmitoxantrone and intermediate-dose cytosine arabinoside(ARA-C)
have shown excessive toxicity with little redeem-ing
characteristics[268]. In an attempt to move beyondthese
limitations, the MD Anderson group is currently pi-oneering several
combination programs containing neweragents such as topotecan, a
topoisomerase inhibitor thathas been demonstrated to be useful in a
number of solidtumors, and fludarabine, a nucleoside analog
designed totreat lymphoproliferative disorders[231,269–272].
Thesedrugs appear to be somewhat toxic but effective in MDSwhen
used in combination with ARA-C and anthracy-clines, and the optimal
dosing and schedule has yet to bedetermined.
7.4. Low dose chemotherapy: gentleness rebuffed
For older and sicker patients with MDS in whom high
dosecytotoxic therapy is deemed to be too dangerous, it wouldbe
beneficial to have a useful low dose chemotherapeuticregimen that
might assist in palliation. Unfortunately, nolow dose program has
been particularly successful, althoughoccasional patients will have
salutary results. In CMML,etoposide has been used palliatively with
conflicting resultsthat may be schedule dependent[273–275]. Low
dose oralmelphalan may also have brief palliative benefit in
MDS[276], but all patients described in the original
encouragingtrial have since relapsed and several developed a new
17pdeletion[277]. Low dose ARA-C looked promising whenfirst
attempted in the 1980s, but an intergroup trial showedlittle
efficacy and made this agent appear less exciting
asmonotherapy[278]. Today, there is little enthusiasm for lowdose,
non-specific cytotoxic agents.
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D.P. Steensma, A. Tefferi / Leukemia Research 27 (2003) 95–120
107
7.5. Differentiation therapy has yet to make a difference
One of the hallmarks of MDS is that the neoplastic cloneexhibits
a maturation block, a fixed stage of differentiationbeyond which
the abnormal cells apparently cannot progress.Since the 1980s,
multiple attempts have been made to in-duce maturation of these
“stalled” cells. The resoundingsuccess with differentiation therapy
with all-trans-retinoicacid in acute promyelocytic leukemia (AML
M3) greatlyencouraged investigators with such aspirations[279].
Thusfar, there has not been a resounding success; the litany
ofunsuccessful or marginally promising MDS trials with
dif-ferentiation agents was recently reviewed[263].
In addition to the interferons described earlier,
otherdifferentiating agents that have been tried in MDS in-clude
hexamethylene bisacetamide and its derivatives (thepolar–planar
compounds[280,281]), homoharringtonine (aplant-derived alkaloid
used in traditional Chinese medicine[282]), 5-azacytidine and
5-aza-2′-deoxycytidine (nucleo-side analogs which may also be
cytotoxic and can modifygene methylation status), butyrates such as
butyric acidand sodium phenylbutyrate (histone deacetylase
inhibitorswhich may alleviate histone deacetylase-mediated
tran-scriptional repression[283]), amifostine (an inorganic
thio-phosphate originally designed to be a radioprotective agentbut
subsequently found to stimulate hematopoiesis), hemearginate (a
promoter of heme biosynthesis[284–286]),bryostatin (a macrocyclic
lactone isolated from a micro-scopic sea creature[287]), retinoids
such as Vitamin A andits analogs (stimulants of normal erythroid
and myeloidprogenitor proliferation[262,264,288–292]), and VitaminD
and its analogs (which bind to transcription factors thatcan induce
terminal monocytic differentiation). With a fewexceptions, these
agents have shown little real benefit, orhave been excessively
toxic, or have induced only transientimprovements in
hematopoiesis[263]. Amifostine, a rela-tively well-tolerated agent,
showed considerable promise inan early trial, but subsequent
studies have engendered pes-simism about the drug’s use in
unselected cohorts of MDSpatients[293–295].
Advocates of “biological”, differentiation-style therapyrecently
received a boost when the Cancer and LeukemiaGroup B (CALGB)
reported the results of a 191-patientrandomized trial of
azacytidine versus supportive care inMDS [296]. In this study,
statistically significant benefits inquality of life (i.e. less
fatigue and dyspnea with improvedmood and overall performance
status), rate of leukemictransformation and overall survival were
observed whenazacytidine was administered subcutaneously at a
dailydose of 75 mg/m2 for 7 days every 4 weeks, especiallyamong
those patients who completed at least four cyclesof the drug[296].
Whether these results will translate intobroad usefulness in
general clinical practice and whether5-aza-2′-deoxycitabine
(decitabine) will prove even moreefficacious than its demethylating
cousin remains to beseen[297]. Despite the many disappointments,
the concept
of differentiation therapy is so appealing that considerablework
continues in this area, and one can only hope for moresuccesses in
the near future.
7.6. Anti-apoptosis therapy: suicide prevention
Since excessive apoptosis seems to contribute to ineffec-tive
hematopoiesis in MDS, it seems logical that prevent-ing programmed
cell death might improve peripheral bloodcounts. Whether
detrimental cell death can actually be pre-vented without
inadvertently immortalizing a frankly neo-plastic clone remains to
be seen. Since tumor necrosis factor(TNF) can induce apoptosis, and
since some studies havesuggested that MDS marrow has higher than
normal TNFlevels, anti-TNF therapy with etanercept (a soluble
TNF-�receptor) and infliximab (a chimeric anti-TNF
monoclonalantibody) is currently being attempted and has shown
someinitial promise[298,299]. In one small study, ciprofloxacinand
pentoxifylline down-regulated TNF expression but therewas no
hematologic effect[300]. Combination therapy withamifostine,
pentoxifylline, ciprofloxacin, and dexametha-sone is currently in
vogue, but the trial introducing this regi-men appears somewhat
less encouraging when patients whohad a neutrophil increment after
receiving dexamethasoneare excluded from the tally of responders
(see later for a dis-cussion of the effects of corticosteroids on
neutrophil count)[301]. Inhibitors of the caspases, a family of
enzymes thatrepresent the final common pathway in effecting
apoptosis,have shown inconsistent results in improving
hematopoiesisin vitro and have not yet been tried in
vivo[302–304].Anti-apoptosis therapy has many obstacles to overcome
be-fore it becomes reality.
7.7. Immunologic manipulation: suppressing theoppressors
Some patients with MDS may respond to immunesuppression directed
at potentially auto-reactive T-cells.Because of the success of
immune modulating therapyin aplastic anemia, patients with
hypoplastic MDS havebeen assumed to be particularly good candidates
for suchtherapy[21,305]. Agents including antithymocyte globulinand
antilymphocyte globulin have shown responses in ap-proximately
10–20% of patients, but because these agentsare derived from
horses, goats, or other animals, serumsickness and other toxicities
can be problematic[306,307].Cyclosporin has also been used with
some success[308,309]. To the best of our knowledge, there are no
dataon the use of other immunosuppressive agents such astacrolimus
(FK506) or rapamycin in MDS.
7.8. The disappointing and the untested: miscellaneousstandard
and novel therapies
There are several novel agents and therapeutic agents
ofhistorical importance in MDS that do not clearly fit into one
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108 D.P. Steensma, A. Tefferi / Leukemia Research 27 (2003)
95–120
of the other categories in this section. Since occasional
pa-tients with sideroblastic anemia will respond to
pyridoxine(Vitamin B6), a brief trial of this agent can be
worthwhilein patients who appear to have RARS. Supplementation
ofMDS patients with other vitamins is not usually
worthwhile,including folate supplementation, as this group
generally hasadequate folate stores[310,311]. Androgen therapy is
gener-ally ineffective in MDS[312–314]. Danazol, a synthetic
an-drogen, improved thrombocytopenia in occasional patientsin some
studies but had no effect in other trials[315–317].
Corticosteroids reliably increase the peripheral blood
neu-trophil count, but this phenomenon is due to not to
increasedneutrophil synthesis but rather to neutrophil release
fromblood vessel walls and egress of a storage pool from
bonemarrow[318]. Such increases are not associated with a
de-creased risk of infection; trials of corticosteroids in MDShave
been ineffective and associated with increased infec-tions
[319].
Iron chelation therapy with deferoxamine has been advo-cated for
red cell transfusion-dependent patients, in orderto prevent iron
overload and secondary hemochromato-sis [320]. Such therapy is
cumbersome, however, sincedeferoxamine requires prolonged
parenteral infusion bya pump. Sadly, most transfusion-dependent
patients withMDS will not live long enough to be concerned about
ironoverload, making such treatment perhaps not worthwhile.The use
of chelation therapy may be justifiable especiallyin low-risk
patients such as those with classic 5q− syn-drome. More recent data
suggesting that iron overload maycontribute to ineffective
hematopoiesis argues in support ofa wider role for chelation
therapy[320]. Oral iron chelatorsare greatly needed, but progress
has been slow. Deferiponeis a moderately effective oral iron
chelator that is currentlyavailable, but there is controversy about
its ability to preventiron-related hepatotoxicity[321].
Novel agents currently undergoing clinical trials in MDSinclude
farnesyltransferase inhibitors (which interfere withprocessing of
theras oncogene, mutated in 10–40% ofMDS cases [175,177,322]—one
farnesyltransferase in-hibitor has shown activity in relapsed
AML[323]), gem-tuzamab ozogamicin (a monoclonal antibody against
theCD33 epitope conjugated to a toxin; the CD33 epitope ispresent
on early myeloid progenitors, and this agent hasbeen approved for
acute myelogenous leukemia), variousputative anti-angiogenesis
agents including matrix metal-loproteinase inhibitors, arsenic
trioxide (an ingredient ina traditional Chinese remedy that has
shown efficacy inacute promyelocytic leukemia[324,325]), inhibitors
of theMDR-1 “drug-resistance” glycoprotein, troxicitabine (anovel
nucleoside analog[326]), leucovorin (folinic acid,used because the
dihydrofolate reductase gene maps to thelong arm of chromosome 5
and may be deleted in 5q−syndrome[327]), STI571 (a targeted
tyrosine kinase in-hibitor custom-made for chronic myelogenous
leukemia[76,328]), flavopiridol (a cyclin-dependent kinase
in-hibitor), and others. Some clinical trials of novel agents
designed for refractory AML are also open to high-riskMDS
patients, expanding their options for clinical trialenrollment.
7.9. Thalidomide: a ray of hope from a dark remedy?
Thalidomide, the tragic teratogen that in 1961 catapultedthe
Food and Drug Administration (FDA) into the modernera, was recently
approved by the FDA for the rare clini-cal situation of
leprosy-associated erythema nodosum[329].The drug is now enjoying
extensive “off-label” use in hema-tologic diseases use because of
its proven success in refrac-tory multiple myeloma[330], and it is
currently being testedin a wide range of other disorders. Its
biologic mechanismremains mysterious, as it has both
immunomodulatory andanti-angiogenic actions, and dozens of
associated cytokinechanges have been described[329,331].
Several reports have described responses to thalidomidein MDS
[332–335]. Many institutions are currently studyingthe drug alone
and in combination with other agents, whichshould more clearly
define its role in MDS[301,336]. Unfor-tunately, the drug can be
difficult to tolerate, especially forthe older age group typical of
MDS, because of its commonside effects such as drowsiness, rash,
postural hypotension,peripheral neuropathy, bradycardia,
constipation, and erec-tile dysfunction. Thalidomide embryopathy
still occurs inleprosy-plagued areas of South America[337], and
carefulsafeguards have been introduced in North America to limitthe
possibility of the drug falling into the hands of anyonewho might
become pregnant[336].
7.10. Flavors of stem cell transplantation: auto, allo,mini,
cord
The role of stem cell transplantation in MDS has recentlybeen
reviewed[338,339]. Overall, approximately 30–40%of MDS patients can
be cured with allogeneic transplan-tation, but many of those will
suffer scars such as chronicgraft-versus-host disease, which can be
so disabling thatsome “successfully” transplanted patients have
committedsuicide [340]. The best outlook with transplant is for
pa-tients with early MDS who receive stem cells from fullyHLA
matched donors; in this subgroup more than 75% willbe long-term
disease free survivors. The major limitationto allogeneic
transplantation is the older age of MDS pa-tients, whose median age
is approximately 65 years[144].Older patients tolerate allogeneic
transplantation poorly(although some success was recently achieved
in a cohortof 55–66-year-old MDS patients, with a 3-year disease
freesurvival of 33–53%, depending on disease subtype[341])and have
a higher risk of disease relapse after the proce-dure [342].
Registry data have shown that patients whoreceive stem cells from
an unrelated donor have a 2-yeardisease-free survival of only 29%
and a treatment-relatedmortality of 54%[343]. No superior marrow
ablation reg-imen has been defined[344], and the appropriate
timing
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D.P. Steensma, A. Tefferi / Leukemia Research 27 (2003) 95–120
109
of transplant in MDS remains unclear[345]. Some havesuggested
that patients transplanted early in their diseasecourse may do
better long-term[346].
Autologous stem cell transplantation for MDS at firstblush would
seem a futile proposition—why transplantmarrow that potentially
contains corrupt stem cells? Thesuccess of this endeavor hinges on
the ability to selec-tively harvest and transplant polyclonal stem
cells that arenot part of the neoplastic process, which can be
accom-plished in some cases[347,348]. Some patients with MDSretain
significant polyclonal hematopoiesis[349,350], andothers who
receive high-dose chemotherapy can achievea remission with
restoration of polyclonal hematopoiesis[351,352]. Stem cell
collection is occasionally successfulin such patients[353]. The
European Group for Blood andMarrow Transplantation has led the way
in this area[346].Although autologous transplant was well tolerated
in thesmall trials that have been reported[354,355], it is stilltoo
early to know just what role autologous transplantationwill have in
MDS, and the results of randomized trials areawaited.
Novel transplantation methods include
non-myeloablative(“mini-allogeneic”) transplantation, in which an
attempt ismade to harness the immunologic activity of donor cellsto
purge the recipient’s malignant clone and re-establishhealthy
hematopoiesis[356,357]. This treatment modality atpresent is
attempted primarily in patients felt to be too old ortoo sick to
proceed with standard allogeneic transplantation,or in those whose
disease has returned after conventionalallogeneic transplant.
Allogeneic transplantation using umbilical cord blood of-fers
distinct advantages such as a decrease in graft-versus-host
disease[358]. Although cord blood transplantationcan be successful
in adults[359], fetal blood often doesnot contain enough stem cells
to re-establish hematopoiesisin a large adult. Efforts to expand
the stem cell pop-ulation in cord blood in order to allow more
frequenttransplantation options for larger individuals are
ongoing[360].
Table 4International Prognostic Scoring System for
myelodysplastic syndromes[83]
Score
0 0.5 1 1.5 2
Marrow myeloblast percentage
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110 D.P. Steensma, A. Tefferi / Leukemia Research 27 (2003)
95–120
9. Conclusion
Much has been accomplished in the last 10 years, butmany
challenges remain in understanding the myelodysplas-tic syndromes.
As the biology of these disparate disordersbecomes better
understood, more appropriate classifica-tion schemes and more
accurate prognostic indices will beachieved. Hopefully, improved
treatments will also becomeavailable to brighten the outlook for
patients with what atpresent can only be described as dismal
diseases. Clinicaltrials of carefully selected novel therapeutic
agents deservewidespread and enthusiastic support. Even as new
agents be-come available, excellent supportive care by
conscientiousphysicians will remain the best that medicine has to
offer.
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