Achievements in Understanding and Treatment of
Myelodysplastic Syndromes
Eva Hellström-Lindberg (Chair), Cheryl Willman, A. John Barrett, and Yogen Saunthararajah
The myelodysplastic syndromes (MDS) constitute a
challenge for the biologist as well as for the treat-
ing physician. In Section I, Dr. Willman reviews the
current classifications and disease mechanisms
involved in this heterogeneous clonal hematopoi-
etic stem cell disorder. A stepwise genetic progres-
sion model is proposed in which inherited or
acquired genetic lesions promote the acquisition of
“secondary” genetic events mainly characterized
by gains and losses of specific chromosome
regions. The genetic risk to develop MDS is likely
multifactorial and dependent on various constella-
tions of risk-producing and -protecting alleles. In
Section II Dr. Barrett with Dr. Saunthararajah
addresses the immunologic factors that may act as
important secondary events in the development of
severe pancytopenia. T cells from patients with
MDS may suppress autologous erythroid and
granulocytic growth in vitro, and T cell suppression
by antithymocyte globulin or cyclosporine may
significantly improve cytopenia, especially in
refractory anemia. Recent studies have also dem-
onstrated an increased vessel density in MDS bone
marrow, and a phase II trial of thalidomide showed
responses in a subgroup of MDS patients espe-
I. BIOLOGIC AND GENETIC FEATURES OF THE
MYELODYSPLASTIC SYNDROMES
Cheryl L. Willman, M.D.*
Recent scientific advances have provided new insights
into the etiology and pathogenesis of the myelodysplastic
syndromes (MDS). Despite heterogeneous morphologic,
genetic, biologic, and clinical features, all forms of MDS
are clonal hematopoietic stem cell disorders character-
ized by ineffective hematopoiesis and peripheral cyto-
penias. Although a substantial proportion of MDS cases
evolve to acute myeloid leukemia (AML), the natural
* University of New Mexico Cancer Center, 2325 Camino de Salud
NE, Room 101, Albuquerque NM 87131
110
cially in those with low blast counts. In Section III
Dr. Hellström-Lindberg presents results of alloge-
neic and autologous stem cell transplantation
(SCT), intensive and low-dose chemotherapy. The
results of allogeneic SCT in MDS are slowly improv-
ing but are still poor for patients with unfavorable
cytogenetics and/or a high score according to the
International Prognostic Scoring System. A recently
published study of patients between 55–65 years
old showed a disease-free survival (DFS) at 3 years
of 39%. Consolidation treatment with autologous
SCT after intensive chemotherapy may result in
long-term DFS in a proportion of patients with high-
risk MDS. Low-dose treatment with 5-azacytidine
has been shown to significantly prolong the time to
leukemic transformation or death in patients with
high-risk MSA. Erythropoietin and granulocyte
colony-stimulating factor may synergistically
improve hemoglobin levels, particularly in
sideroblastic anemia. Recent therapeutic advances
have made it clear that new biological information
may lead to new treatment modalities and, in
combination with statistically developed predictive
models, help select patients for different therapeu-
tic options.
history of these syndromes ranges from more indolent
forms of disease spanning years to those with a rapid
evolution to AML. Thus, MDS is best considered a pre-
leukemic disorder in which the neoplastic clone that has
been established may or may not fully progress to acute
leukemia. Although the relationship between MDS and
de novo AML has been controversial and current disease
classification systems (Table 1) are considered unsatis-
factory, most hematologists now consider MDS and AML
as part of the same continuous disease spectrum rather
than as distinct disorders. This review will briefly high-
light current controversies in the classification of MDS
and AML, the cytogenetic and molecular genetic features
of MDS, the biologic features that characterize MDS in-
cluding abnormal apoptosis and an altered marrow mi-
American Society of Hematology
Table 1. MDS Classification Systems.1

IPSS Risk-Based
FAB Classification System2 WHO Classification System3 Classification System4

Refractory Anemia (RA): Cytopenia of one Myelodysplastic Syndromes Overall IPSS Risk Score Based On:
PB lineage; normo- or hypercellular marrow with
dysplasias; < 1% PB Blasts and < 5% BM Blasts. Refractory Anemia (RA) Marrow Blast Percentage
With ringed sideroblasts (RARS) Blast % IPSS Score
Refractory Anemia with Ringed Sideroblasts Without ringed sideroblasts <5 0
(RARS): Cytopenia, dysplasia and the same % 5-10 0.5
blast involvement in BM and PB as RA. Ringed Refractory Cytopenia (MDS) with 11-20 1.5
sideroblasts account for >15% of nucleated Multilineage Dysplasia (RCMD) 21-30 2.0
cells in marrow.
Refractory Anemia with Cytogenetic Features5
Refractory Anemia with Excess Blasts Excess Blasts (RAEB) Karyotype IPSS Score
(RAEB): Cytopenia of two or more PB lineages; Good prognosis 0
dysplasia involving all 3 lineages; < 5% PB 5q- Syndrome (-Y, 5q-,20q-)
blasts and 5-20% BM Blasts. Intermediate prognosis 0.5
Myelodysplastic syndrome, Poor prognosis 1.0
Refractory Anemia with Excess Blasts in unclassifiable (abn. 7; Complex)
Transformation (RAEB-T): Hematologic features
identical to RAEB. > 5% Blasts in PB or 21-30% Myelodysplastic/Myeloproliferative Cytopenias6
Blasts in BM or the presence of Auer rods Diseases Cytopenia IPSS Score
in the blasts. None or 1 Type 0
Chronic Myelomonocytic 2 or 3 Types 0.5
Chronic Myelomonocytic Leukemia (CMML): Leukemia (CMML)
Monocytosis in PB (>1x109 per liter); < 5% blasts Overall IPSS Score and Survival
in PB and up to 20% BM blasts Atypical Chronic Myelogenous
Leukemia (aCML) Overall Score Median Survival
Low (0) 5.7 Yrs.
Juvenile Myelomonocytic Intermediate
Leukemia (JMML) 1 (0.5 or 1.0) 3.5 Yrs
2 (1.5 or 2.0) 1.2 Yrs.
High (> 2.5) 0.4 Yrs.

1 Abbreviations: PB, peripheral blood; BM, bone marrow; abn, abnormality

2 References 3-4.
3 Reference 21.
4 Reference 30.
5 IPSS Cytogenetic Classification28: Good prognosis: -Y only, normal, del(5q)
only, del(20q) only; Intermediate prognosis: +8, Single
miscellaneous abnormality, double abnormalities; Poor prognosis: Complex (i.e. > 3 abnormalities), any chromosome 7 abnormality.
6 IPSS Types of Cytopenia28: Hemoglobin <10g per deciliter; Absolute neutrophil count <1500 per cubic millimeter; Platelet count
< 100,000 per cubic millimeter.

croenvironment, and new and highly interesting insights
into the complex genetic predisposition to MDS. Excel-
lent, well-referenced reviews are also available.1,2
MDS and AML Disease Classification Systems:
Unresolved Controversies
The French-American-British (FAB) Classification, pro-
posed in 1977, provided hematologists with the first con-
sistent framework for morphologic classification of MDS
(Table 1), the myeloproliferative disorders, and the acute
leukemias.3,4 However, the separation of MDS as a dis-
tinct disorder from AML in the FAB classification scheme
has been perceived by many to have scientifically im-
peded our understanding of the full spectrum of leuke-
mic progression.1 Indeed, the initial failure to recognize
and classify MDS as a “neoplastic” pre-leukemic disor-
der and part of the same disease spectrum as AML re-
sulted in the exclusion of MDS cases from virtually all
US cancer registries and the NCI-sponsored Surveillance,
Epidemiology, and End Results (SEER) program
(www.seer.cancer.gov). This has greatly impeded stud-
ies of the true incidence, natural history, and epidemiol-
ogy of MDS in the US. Importantly, however, European
epidemiologic studies suggest that the incidence of MDS
is at least as high as that of AML, particularly AML cases
that arise in older individuals.5 In the US, the age-spe-
cific incidence rate for AML in males aged 50 years at
diagnosis is 3.5 per 100,000, increasing dramatically to
15 at age 70 and 35 at age 90. 6 (See also
www.seer.cancer.gov.) With the exponential increase in
the incidence of AML with age and the aging of our popu-
lations, the median age at diagnosis of AML in the US is
currently 63 years. Thus, the majority of AML cases, like
MDS, occur in older individuals. Further linking MDS
and AML, several studies have noted that the biologic,
morphologic, and genetic features of AML arising in older
individuals are similar to 1) primary MDS; 2) AML aris-
ing secondary to antecedent MDS; 3) AML arising sec-

Hematology 2000 111

ondary to prior therapy, particularly alkylating agent ex-
posure; and 4) AML cases that arise from documented
environmental or occupational exposures to agents such
as benzene, petroleum, organic solvents, and arsenical
pesticides.7-13
In the FAB Classification (Table 1), the two primary
distinguishing features between the various MDS sub-
types, chronic myelomonocytic leukemia (CMML) and
AML, are blast cell percentage and the presence of dys-
plastic features. CMML is now considered a myelopro-
liferative/leukemic-like disorder and frequently associ-
ated with t(5;12)(q33;p13),1,14 and AML is defined as >
30% marrow blasts with the various MDS subtypes rang-
ing from < 5% to < 30% blasts. However, the previous
distinction between MDS and AML has become blurred
with the recognition of several common features of the
two diseases: 1) MDS is now recognized to be a clonal
pre-leukemic hematopoietic stem cell disorder frequently
associated with specific recurrent cytogenetic abnormali-
ties15-18; 2) multi-lineage dysplasia is now recognized to
occur in the majority of AML cases presenting clinically
as “de novo” disease in older individuals7,19-21; 3) AML
arising in older individuals and primary, secondary, or
therapy-induced MDS are now known to share strikingly
similar biologic and genetic features7-13; 4) de novo AML
cases such as those with t(8;21) and inv(16) may present
clinically with less than 30% marrow blasts and may have
dysplastic features21; and 5) transgenic and “knock-in”
murine models of leukemia made with fusion genes from
translocations associated primarily with de novo AML
[t(15;17), t(8;21), inv(16)] are often characterized by
hematopoietic dysplasia or an MDS-like disease ante-
cedent to the development of AML.22-25 These more re-
cent clinical and biologic studies indicate that disorders
previously classified as MDS are part of the same dis-
ease continuum as AML and that MDS is best consid-
ered a pre-leukemic disorder with variable frequencies
and rates of progression to AML.
As we now recognize that MDS and AML are part
of the same continuous biologic and genetic spectrum of
disease, the use of arbitrary “thresholds” for the distinc-
tion of AML from MDS for the purposes of disease clas-
sification and therapeutic decision making has become
particularly problematic. At what blast cell percentage
should a clinician institute AML-based therapies in an
MDS patient progressing to RAEB-T and from RAEB-T
to AML? Should AML-based therapies be instituted in a
patient whose marrow has dysplastic morphologic fea-
tures, a blast cell percentage < 20%, and a t(8;21)-con-
taining clonal population of cells? While the threshold
of 30% blasts used by the FAB Classification to distin-
guish AML from MDS (Table 1) is clearly arbitrary, a
reduction in this threshold to 20% blasts and the result-
ant elimination of RAEB-T as a distinct clinical stage in
112
the evolution of MDS to AML as proposed in the new
WHO Classification21 (Table 1) has been perceived by
many hematologists to be even more problematic.26,27
While RAEB-T and AML arising clinically as “de novo”
disease in older patients share highly similar cytogenetic
features,13,26 they have differing clinical and biologic fea-
tures and therapeutic responsiveness.26-28 Although not
directly tested in a randomized fashion, in several, if not
all, studies RAEB-T patients appear to have a worse re-
sponse to intensive chemotherapy when compared his-
torically to AML cases with similar biologic and cytoge-
netic features.28,29 Thus, it will be particularly important
to retain the distinct RAEB-T MDS subtype in order to
compare future therapeutic advances in AML/MDS to
historical controls. Additional concerns that have arisen
with the proposed WHO Classification (Table 1) include29:
1) the proposal that a diagnosis of RA and RARS be re-
stricted to patients who have abnormalities solely involv-
ing the erythroid lineage, even though a diagnosis of MDS
requires dysplasia in at least two hematopoietic lineages;
2) the creation of vague new MDS diagnostic categories
(“refractory cytopenias with multilineage dysplasia
(RCMD)” and “MDS, unclassifiable”) which have no
biologic, clinical, or genetic basis; and 3) the general lack
of clinical and prognostic relevance in the proposed WHO
classification scheme. Unfortunately for clinicians and
diagnosticians alike, these controversies will likely con-
tinue until our knowledge has increased to the degree
that disease classification systems can be developed on
clinical features, genetics/genomics, and functional biol-
ogy. And as our knowledge continues to evolve, classifica-
tion systems will necessarily require constant revision.
Taking an alternative approach, others have worked
to develop risk-based classification systems for MDS in
order to facilitate clinical decision-making.30 The Inter-
national Scoring System for Evaluating Prognosis (IPSS)
in MDS assigns IPSS scores to varying degrees of those
clinical and biologic features that today provide the most
prognostic significance in MDS: marrow blast cell per-
centage, karyotype, and degree of cytopenia (Table 1).29
An overall IPSS score developed using these variables
has a strong correlation with predicted median survival.29
The IPSS system has proven to be a highly useful method
for evaluating prognosis in MDS patients, has achieved
international acceptance, and is being used to design clini-
cal trials.
Genetic Features of MDS: Models for Genetic
Progression and Clues to Etiology
MDS is a clonal hematopoietic stem cell disorder
characterized by step-wise genetic progression
Initially demonstrated by studies of expression of the vari-
ous isoforms of the X-linked gene G6PD and more re-
American Society of Hematology
cently by molecular methods that detect non-random pat-
terns of X-inactivation, evidence for clonality has been
found in all forms of MDS, even in their very earliest
stages.17,18 Interestingly, cytogenetic and molecular data
provide evidence, in some MDS patients, for the exist-
ence of a clonal phase of disease prior to the acquisition
of the characteristic cytogenetic abnormalities associated
with MDS.18 Similarly, MDS patients who evolve to acute
leukemia may after therapy revert to a cytogenetically
normal but persistently clonal remission. Such findings
have led to the hypothesis that the recurrent cytogenetic
abnormalities associated with MDS, previously consid-
ered the “primary” cause of disease, are actually “sec-
ondary” cytogenetic abnormalities that arise due to cyto-
genetically undetectable initiating lesions in a clonal he-
matopoietic stem cell population.30 Such initiating events
are likely to be heterogeneous and could either be inher-
ited or result from acquired somatic DNA damage, ge-
nomic instability, defective DNA repair, or perturbations
in cell signal transduction pathways that give rise to stem
cell clones that have a growth or survival advantage. In
contrast to the de novo acute leukemias that occur pri-
marily in younger patients (particularly those associated
with balanced translocations and inversions such as
t(8;21), t(15;17), inv(16), t(9;11), etc. lacking dysplastic
features), MDS and AML arising in older individuals
appear to have a different model of genetic progression
(Figure 1).31-32 In this proposed model, initiating genetic
lesions (which may be inherited or acquired) promote
the acquisition of “secondary” genetic events that are
Figure 1. Proposed model for genetic progression of MDS to AML.
Hematology 2000
primarily characterized by stepwise gains and losses of
specific chromosomal regions (particularly chromosome
3p-, 3q-, 5q-, 7q-, 12p-, -17, -18, 20q11-12, +8). Such
gross chromosomal changes are ultimately accompanied
by sub-microscopic DNA mutations of genes such as p53,
FLT3, or RAS, methylation of specific gene promoters,
and in some cases by the reciprocal translocations and
inversions more frequently associated with AML. This
model of step-wise genetic progression for MDS and re-
lated AML is strikingly reminiscent of those proposed
for human solid tumors, such as colon cancer. Three lines
of evidence support this model and the existence of a
genetic predisposition to MDS: 1) the occurrence of AML
and MDS in families with inherited defects in DNA re-
pair or neurofibromatosis-type I33-37; 2) genetic mapping
studies in the rare families with “familial” MDS and
AML38-41; and 3) studies of the association of various
genetic polymorphisms with AML and MDS.42-48
An inherited genetic predisposition to MDS
Support for an inherited predisposition to MDS and re-
lated AML has long been evident from studies of inher-
ited constitutional genetic defects (such as Schwachman-
Diamond syndrome, the defective DNA repair of Fanconi
anemia, or deregulation of the RAS signal transduction
pathway in neurofibromatosis-type 1) that are present in
a large proportion of children who develop MDS and
AML.33-37 Indeed, recent studies indicate that up to 30%
of children affected by MDS and related myeloprolifera-
tive disorders have an inherited constitutional genetic
113
disorder.34 The original studies by Shannon and col-
leagues35,36 of the genetic basis of familial MDS with chro-
mosome 7q abnormalities (the “monosomy 7 syndrome”)
are important in that they first revealed that abnormali-
ties of chromosome 7q were not the “primary” cause of
the syndrome; indeed, these investigators concluded that
the predisposition locus mapped to some other as yet
unidentified chromosomal location. Thus, the foundation
was laid for the putative existence of genetic loci that
could “predispose” to chromosomal instability, second-
ary loss of specific chromosomal regions (such as 5q,
7q, and 20q), and the ultimate development of MDS and
AML in adults and children. This original hypothesis was
recently supported the findings of Gilliland and colleagues
who determined the genetic basis of familial platelet dis-
order with leukemia (FPD/AML), an autosomal-domi-
nant congenital thrombocytopenia characterized by plate-
let aggregation abnormalities.38-39 Affected individuals in
the seven pedigrees studied to date all have a striking
propensity to develop MDS, AML, and more rarely,
chronic myelogenous leukemia (CML). Interestingly, the
MDS and AML cases that develop in these pedigrees have
the cytogenetic abnormalities classically associated with
MDS, particularly abnormalities of chromosomes 5q and
7q and complex abnormalities. After mapping the FDP/
AML predisposition locus to chromosome 21q22 in 1998,
Gilliland and colleagues went on to determine that the
causative gene for this disorder was CBFA2 (AML1),
the gene whose function is most frequently disrupted in
the acute leukemias by various reciprocal translocations
and inversions, including the t(8;21), inv(16), t(3;21), and
t(12;21).49 Heterogeneous point mutations and small de-
letions of a single AML1 allele were found in these dif-
ferent pedigrees.39 Despite this molecular heterogeneity,
each mutation characteristic of each pedigree affected the
DNA-binding domain of one AML1 allele, particularly
targeting the two arginine residues at positions 166 and
201 that bind to DNA. The change of arginine to
glutamine resulted in a loss of DNA-binding activity.38
These data thus support the hypothesis that AML1 may
surprisingly function as a tumor suppressor gene and that
loss of one AML1 allele (hemizygous loss) is sufficient
to initiate tumorigenesis and establish a neoplastic clone
in affected individuals. This loss of function of a single
AML1 allele appears to also confer a susceptibility to
the acquisition of secondary mutations and the gain and/
or loss of the chromosomal regions frequently associ-
ated with AML and MDS. This discovery has led to a
particularly attractive model for MDS/AML whereby
AML1 mutations predispose to chromosome instability
leading to the eventual loss of chromosomes 5q, 7q; such
models are currently being developed in mice in which
the mutated AML1 allele has been introduced (Downing
and Gilliland, personal communication). These pivotal
114
studies also further cement a genetic and etiologic link
between MDS and AML (and even CML). Not unexpect-
edly, a low percentage of sporadic AML, ALL, and CML
cases (5–8%) have recently been reported to have simi-
lar AML1 mutations50; whether such AML1 mutations
can be observed in primary “sporadic” MDS cases is
currently under investigation. Whether AML and MDS
cases with AML1 mutations are indeed “sporadic” or rep-
resent AML and MDS cases that have arisen in individu-
als with inherited AML1 mutations is as yet unknown.
Given the functional role and association of CBF
(map-
ping to chromosome 16q22) with AML1 in normal and
neoplastic hematopoiesis,51 it is tempting to further specu-
late that CBF
might be the causative gene for the sec-
ond predisposition locus in AML and MDS in those fa-
milial cases where the predisposition has been mapped
to chromosome 16q21-23.2.40
Models for the development of sporadic MDS:
Cumulative environmental exposures in genetically
predisposed individuals
While genetic and familial mapping studies have clearly
demonstrated that mutations in a specific gene, such as
AML1, NF1, or genes mediating DNA repair, can pre-
dispose to the acquisition of secondary cytogenetic ab-
normalities and MDS, it is likely that such inherited ge-
netic mutations will account for only a minority of MDS
cases. How the majority of “sporadic” MDS cases arise
is as yet undetermined. However, epidemiologic case-
control studies of MDS (and related AML) have demon-
strated associations between MDS and smoking, expo-
sure to chemical compounds (particularly petroleum prod-
ucts and diesel derivatives, exhausts, organic solvents,
fertilizers, and nitro-organic explosives), semi-metals
(arsenic and thallium), stone dusts (such as silica), and
cereal dusts.52-53 In light of these epidemiologic studies, it is
interesting that evidence is increasing for a complex ge-
netic predisposition to MDS involving naturally occurring
DNA polymorphisms in genes that mediate DNA repair
and metabolize environmental carcinogens.42-48 These stud-
ies are leading to a model, also diagrammed in Figure 1,
in which MDS arises as a result of cumulative environ-
mental exposures in genetically predisposed individuals.
In this case, the genetic predisposition is a more com-
plex genetic trait: a constellation of genetic variants in
critical polymorphic genes. The initial attempts to dis-
sect this complex genetic predisposition have focused on
the association of MDS with naturally occurring poly-
morphisms in genes that mediate carcinogen metabo-
lism.42-48 Following initial reports of the association of a
non-functioning 609C➝T polymorphic allele of the
NAD(P)H:Quinone Oxidoreductase (NQO1) gene that
plays a critical role in detoxifying benzene metabolites
with an increased incidence of hematologic malignan-
American Society of Hematology
cies in Chinese workers exposed to benzene,43 several
groups have attempted to determine the incidence of this
polymorphism in primary and secondary leukemia
cases.44,45 Larson and colleagues first reported an in-
creased frequency of the NQ01 609C➝T polymorphism
in patients with therapy-related AML, particularly in AML
patients with abnormalities involving chromosomes 5 and
7, 88% of whom were homozygous for the non-func-
tional allele.44 Interestingly, studies of de novo AML in
children45 and adults (C.L. Willman et al, manuscript in
preparation and M.A. Smith et al, personal communica-
tion) have failed to demonstrate an association of this
NQO1 polymorphism with abnormalities of chromosome
5 and 7, but have instead demonstrated strong associa-
tions with balanced translocations and inversions, par-
ticularly involving MLL and chromosome 11q23. While
it is tempting to speculate that the NQO1 609C➝T poly-
morphism could predispose to the development of MDS,
no such studies focusing on MDS cases have been re-
ported; our own limited studies of 120 primary MDS cases
have failed to reveal such an association. Similar com-
plexities have arisen in studies of the association of MDS
and polymorphisms in the glutathione S-transferases
(GST) that mediate exposure to cytotoxic and genotoxic
agents, specifically the “null” variant allele GST theta 1
(GSTT1).46-48 Chen and colleagues initially reported that
the frequency of the GSTT1 null genotype was higher
among MDS cases than controls.46 However, Fenaux and
colleagues47 and other groups48 did not confirm these ini-
tial observations and actually reported that the incidence
of the GSTT1 null genotype tended to be higher in unex-
posed MDS patients and controls. Thus, while the hy-
pothesis and model that MDS arises due to cumulative
environmental exposures in genetically predisposed in-
dividuals is indeed attractive, these studies of natural
human genetic variation and disease association are only
in their infancy. Moreover, it is likely that true genetic
risk will not be simply determined through studies of one
gene, but through the constellation of risk-producing and
risk-protecting alleles present in each individual. Thus,
it will ultimately be necessary to study polymorphic vari-
ants in many human genes in a large number of affected
individuals and controls and carefully monitor environ-
mental exposures in order to dissect what is likely to be a
very complex genetic predisposition.
Cloning and identification of genes disrupted by the
recurrent cytogenetic abnormalities associated with MDS
The identification of potential “initiating” genetic lesions
in MDS and related AML patients has lead to the hy-
pothesis that the cytogenetic abnormalities traditionally
associated with MDS (involving chromosomes 7q, 5q,
20q11-12, trisomy 8, 12p, and 3q) are “secondary” ge-
netic events. However, these secondary cytogenetic ab-
Hematology 2000
normalities are likely no less critical for disease progres-
sion, and identification of the gene(s) involved in these
regions remains very important. Unfortunately, despite
years of mapping and definition of minimally deleted
chromosomal regions on chromosomes 5, 7, and 20, no
investigator has yet succeeded in identifying the “single”
tumor suppressor gene that is responsible for MDS and
AML on any of these chromosomes. Recent detailed cy-
togenetic and molecular mapping studies reveal that re-
arrangements and deletions involving these chromosomes
are very complex and that multiple distinct regions may
contribute to the disease phenotype or progression: at least
two different regions are implicated on chromosome 7q
(7q22 and 7q32-34) and more than four different regions
may be involved on chromosome 5q (5q11, 5q13-q21,
5q31, and distal 5q33-35).54-61 One issue with many map-
ping studies is that in most instances little attention was
paid to “phenotype” rather than “genotype.” In other
words, patient samples were selected for molecular stud-
ies based on the presence of a specific cytogenetic ab-
normality (such as a 5q- or a 7q- with or without addi-
tional cytogenetic abnormalities) without regard to the
specific form of disease or mode of disease presentation
(primary MDS, secondary AML, de novo AML, or t-
AML/MDS). Both cytogenetic and molecular genetic
studies are not only revealing the tremendous heteroge-
neity in different breakpoints but also the need to focus
on a pure genotype and phenotype for mapping studies.
Very detailed cytogenetic studies by Pederson in 1996
revealed that while chromosome region 5q31 was deleted
in all patients with MDS, other chromosome 5 regions
were deleted more often than 5q31 in AML patients; the
chromosome 5q13-q21 region was particularly involved
in the genetic progression of RA to RAEB and 5q22-
5q33 for further progression to AML.61 Recent studies
by Westbrook and colleagues have focused on a single
AML patient with a very small deletion in the 5q31 re-
gion. In this patient, the D5S500-D5S594 region was
identified to be the minimal deletion interval, and this
interval was shown to contain nine transcriptional units
with five unknown expressed sequence tags (ESTs) and
the genes CDC25, HSPA9, EGR1, and CTNNA1.58 While
all of these sequences are interesting candidates and are
expressed in hematopoietic cells, none has yet been iden-
tified as “critical” for disease. It also remains possible
that loss of more than one gene in this region, as well as
the other distinct regions on chromosome 5, could actu-
ally be responsible for the disease phenotype. Boultwood
and colleagues56,57 have focused on the identification of
the gene(s) deleted in MDS patients who have the iso-
lated “5q- syndrome,” a clinically distinct form of RA
associated with more indolent disease and a lower rate of
progression to AML, chronic macrocytic anemia, throm-
bocytosis, and dysplastic megakaryocytes. Interestingly,
115
the region on chromosome 5 specifically associated with
this disease presentation appears to be more distal to 5q31;
novel transcriptional units have also been recently iden-
tified in this distinct region.57
In light of the complexity of this cytogenetic and mo-
lecular data, it is attractive to hypothesize that in MDS,
an initiating abnormality gives rise to genome instability
leading to the deletion and rearrangement of particularly
susceptible chromosomal regions, such as those on chro-
mosome 5q and 7q. Cytogenetic studies have revealed
the continued instability of these regions during disease
progression in individual patients.62 While it may be that
loss of function of a single gene in each of these rela-
tively large regions is responsible for disease progres-
sion, more recent studies have given more credence to
the possibility that hemizygous loss of the function of
several genes in each of these regions could contribute to
the disease phenotype.
Molecular mutations and genome methylation in MDS
In addition to the complex cytogenetic abnormalities seen
in MDS, several molecular defects have also been re-
ported. Studies of MDS in children, with or without Neu-
rofibromatosis-type 1, have provided evidence that ab-
normalities in the RAS signal transduction pathway co-
operate with a loss of genes on chromosome 7 to pro-
mote myeloid leukemogenesis.63 In adults with MDS,
disease progression has been associated with the muta-
tions in genes such as RAS, p53, and FLT364-67 and with
progressive methylation and transcriptional inactivation
of critical cell cycle regulatory genes such as p15INK4b
that normally function to inhibit cyclin-dependent kinase
activity at the G1 phase of the cell cycle.68-69 MDS pa-
tients have also been shown to have defective activation
of signal transduction pathways, particularly involving
STAT5, in response to erythropoietin,70 which may ac-
count in part for the defective erythropoiesis and persis-
tent anemia. These molecular abnormali-
ties associated with MDS all further con-
tribute to an escape from normal cell cycle
regulation, a disruption of the faithful
maintenance of DNA integrity and repair
leading to continued genetic instability,
and the altered activation of various sig-
nal transduction pathways.
Figure 2. MDS—An altered marrow microenvironment.
Cytokines, adhesion defects, angiogenesis, accelerated apoptosis, adhesion
dependence of proliferation and survival.
116
Biologic Features of MDS
An abnormal marrow microenvironment:
Cytokines, adhesion, apoptosis
While there is strong evidence supporting the view that
MDS arises from an intrinsic or acquired genetic defect
in hematopoietic stem cells leading to clonal expansion
of a stem cell population, it is also clear that other epige-
netic abnormalities such as aberrant cytokine production,
altered stem cell adhesion, or an abnormal marrow mi-
croenvironment contribute to the biology of the disease
and may provide important therapeutic targets (Figure
2). While studies reporting aberrant cytokine expression
profiles in MDS patients have been criticized for their
lack of controls, lack of a suitable ex vivo system to study
the true clonogenic hematopoietic stem cell and marrow
stromal cell interactions, and the failure to precisely iden-
tify the cellular origin of particular cytokines, abnormali-
ties and elevations in tumor necrosis factor- (TNF),
transforming growth factor-
(TGF
), and interleukin-
1
(IL-1
) have all been reported.2 In particular, an over-
abundance of IL-1
and a relative lack of its antagonist
IL-1
(ra) have been hypothesized to support the clonal
expansion of aberrant hematopoietic stem cells.2
Several recent studies have revealed that in its early
stages, MDS is characterized by accelerated apoptosis of
hematopoietic progenitor cells.71-72 While some contro-
versy remains, most studies of MDS samples using vari-
ous techniques have demonstrated a lowered apoptotic
threshold of marrow CD34+ cells to TNF-, interferon-
 (IFN-), and anti-FAS antibodies.70,71 Excessive apopto-
sis is an attractive explanation for how a clonal expan-
sion of marrow progenitor cells could result in ineffec-
tive hematopoiesis and marrow failure. However, how
such accelerated apoptosis is initiated or acquired is not
yet understood. Apoptosis may be triggered in cells by
intrinsic DNA damage or in cells that have an abnormal
American Society of Hematology
growth factor milieu; both mechanisms could contribute
to the accelerated apoptosis observed in MDS. Another
biologic mechanism that can induce apoptosis is a lack
of appropriate adhesive interactions between cells and
their stromal support (Figure 2). In the case of MDS,
perturbed adhesive interactions between clonogenic he-
matopoietic stem cells and the underlying marrow stroma
or endothelium could clearly trigger excessive apopto-
sis. The migration, retention, and survival of hematopoi-
etic stem cells in the marrow microenvironment is con-
trolled by critical adhesion receptors including CD34,
CD44, selectins, and integrins;
1 integrins play a par-
ticularly critical role in this process and virtually all he-
matopoietic stem cells express high levels of 4, 5, 6,
and
1 integrins.73-74 Unfortunately, this is a relatively
unexplored area of MDS and is worthy of continued in-
vestigation. Interestingly, while MDS is characterized by
excessive apoptosis, further genetic progression in this
disease and the transition to AML appears to be associ-
ated with a loss of functional apoptosis, though additional
studies documenting this progressive change in individual
patients with disease progression are clearly necessary.
Summary and Future Scientific Questions
Exciting scientific studies have provided phenomenal
insights into the striking biologic and genetic heteroge-
neity of MDS and related AML. As these scientific stud-
ies lead to the further refinement of genetic models for
the development of MDS, we may gain new insights that
will ultimately lead to the design of more effective pre-
vention strategies and therapeutic regimens. Our ongo-
ing attempts to improve our knowledge, classification,
and therapy of MDS and AML would be best served by
appreciating that these disorders are linked clonal dis-
eases and represent stages in the progressive transforma-
tion of clonal neoplastic hematopoietic stem cells. Par-
ticularly fruitful areas for future investigation include the
application of genomic and proteomic technologies to
understand alterations in the global patterns of gene ex-
pression and protein function in MDS and the alterations
in these patterns during the variable progression of MDS
to AML, studies of global genome methylation and aber-
rant methylation in the development of MDS, continued
studies of the complex genetic predisposition to MDS
and how such genetic predispositions and environmental
exposures contribute to disease etiology and pathogen-
esis, studies of the adhesive interactions of hematopoi-
etic stem cells and their underlying stroma and how these
interactions are perturbed in MDS, and the role of neo-
angiogenesis in the development of MDS.
Hematology 2000
II. IMMUNE MECHANISMS AND MODULATION IN MDS
A. John Barrett, M.D., FACP,* and Yogen
Saunthararajah*
Despite improvements in the supportive care of patients
with MDS with transfusions and antibiotics, nearly 50%
of patients die before transformation to acute leukemia
from complications of thrombocytopenic bleeding or in-
fection. Treatment of the marrow failure alone should
therefore bring survival advantages to a significant pro-
portion of patients with MDS. To improve the treatment
of the cytopenia associated with MDS requires an under-
standing of the pathophysiology of the disease. It is well
accepted that MDS is a clonal stem cell disorder, charac-
terized by cytopenia, progressive de-differentiation of
myeloid lineages and ultimately unregulated blast pro-
liferation. Recent research reveals a further dimension to
this pathophysiology, with extrinsic immunological and
microenvironmental factors compounding the intrinsic
stem cell defect and contributing to the pancytopenia and
possibly to leukemic progression. In this section, patho-
physiological findings in MDS that underpin experimental
trials of immune suppression, cytokine regulation and
inhibition of angiogenesis are reviewed.
Dysplasia, Apoptosis and Cytokines
Dysplasia of erythroid, granulocytic and megakaryocytic
lineages are the diagnostic hallmarks of MDS. Despite
increased proliferation of the marrow, there is an increased
rate of programmed cell death. Indeed some of the dys-
plastic appearance may be explained by apoptotic
changes.1,2 Kinetically the apoptosis prevails over the in-
creased proliferation, causing the peripheral cytopenia.3,4
Cytokines derived from unselected marrow mononuclear
cells are believed to be extrinsic factors predisposing to
apoptosis in MDS. 5-10 In MDS many studies link
overexpression of TNF- to cell death.7,11,12 TNF- pro-
duced by MDS mononuclear cells is inhibitory to both
normal and MDS colony growth indicating that residual
normal hematopoiesis can also be blocked in MDS.7,8
IFN-, IL-1, and TGF-
4,13 as well as undefined factors
produced by stromal cells have also been implicated in
causing apoptosis14 but their role in causing marrow fail-
ure is not well established. The identification of TNF-
as a key cytokine in cell death regulation and the increased
susceptibility of MDS cells to TNF- is the basis for sev-
eral clinical trials of TNF- inhibitors.4
*Hematology Branch, National Heart, Lung and Blood Institute,
National Institutes of Health, 9000 Rockville Pike, Bldg. 10 Room
7C103, Bethesda MD 20892-0003
117
Immune Dysfunction in MDS
Hamblin and others have pointed out an association of
MDS with an autoimmune process, noting the occurrence
of autoantibody production, and monoclonal gammopathy
in some patients with MDS.15 The occasional finding of
T cell clonality in MDS has been interpreted as evidence
of T cell involvement in the stem cell disorder16; how-
ever, more recent evidence suggests that clonal T cell
expansion is a feature of autoimmunity: we have observed
a high frequency of T cell receptor (TCR) V-
repertoire
skewing in MDS patients indicating the presence of a
persisting clonally-expanded T cell population, charac-
teristic of an autoimmune process. Interestingly, it is not
uncommon to find MDS in association with T-cell large
granular lymphocyte (T-LGL) leukemia, a condition char-
acterized by oligoclonal or clonal T cell expansions aris-
ing in a background of autoimmune disease.17 MDS also
shares some of the features of acquired aplastic anemia
(AA), a disease with an established autoimmune pedi-
gree.18 Both in AA and MDS, plasma TNF- and IFN-
levels are high and T cell-mediated myelosuppression
occurs.19 Three groups studying MDS identified T cells
inhibitory to autologous granulocyte20, 21 or erythroid22
colony growth. These observations strongly suggest that,
as in AA, an autoimmune T cell-mediated myelosuppres-
sion contributes to the cytopenia of MDS. The use of
immunosuppressive treatment to restore marrow func-
tion in patients with AA has been the stimulus to con-
sider similar immunosuppressive treatment in MDS.23-
25,32
Evidence for immune-based myelosuppression in
MDS is summarized in Table 2.
Marrow Microenvironment and Angiogenesis
In MDS the marrow shows a non-homogeneous distri-
bution of cell types, seen as islands of pure erythroid cells,
granulocytes, megakaryocytes26 or blast cells termed “ab-
normally localized immature precursors” (ALIPS).27 This
appearance may reflect an underlying abnormality in the
marrow stroma. In MDS, vascular endothelial growth
factor (VEGF) is strongly expressed especially in mega-
Table 2. Evidence for an immune-mediated suppression of
the marrow in myelodysplastic syndrome (MDS).
• T cells inhibit MDS CFU-E
• CD8+ cells inhibit CFU-GM
• Immunosuppressive agents improve cytopenia in MDS and
eliminate autosuppressive T cells
• T cells are activated in MDS
• T cells show a skewed T cell receptor V-
repertoire
• HLA DR15 over representation in MDS and aplastic anemia
Abbreviations: CFU-E, colony-forming units-erythroid; CFU-GM,
colony-forming units-granulocyte/macrophage
118
karyocytes, and investigators have found an increased
density of blood vessels and an association of increasing
marrow vascularity with leukemic transformation.28,29
This is the basis for using angiogenesis inhibitors to cor-
rect abnormalities in MDS and possibly to retard disease
progression.
A Model of Pathophysiological Changes of MDS
A hypothetical model of MDS pathophysiology and the
role of experimental treatments is presented in Figure
3.1 Transformation of normal stem cells induces danger
signals or antigenic change and hence an autoimmune T
cell response directed against the marrow. Both MDS and
normal marrow cells at various stages of differentiation
are directly inhibited by CD8+ CTL causing varying de-
grees of stem cell failure. The MDS cells may be rela-
tively resistant to this immune attack than normal stem
cells, and consequently the abnormal immune environ-
ment may provide selective pressure in favor of the ab-
normal cells.2 T cell expansions are clonal and can be-
come autonomous in some individuals as illustrated by
the coincidence of MDS with T cell LGL.3 The persist-
ing autoimmune attack results in chronic overproduction
of pro-apoptotic cytokines, especially TNF-. This af-
fects cells differentiated at or beyond the CD34+ stage
of differentiation and may contribute to a dysplastic mor-
phology and increased apoptosis in the marrow. Despite
the increased cell proliferation in MDS, the marrow fails
to export sufficient cells into the blood because intramed-
ullary apoptosis mechanism prevails over proliferation.
Increased TNF- levels lead to changes in the MDS cells:
increased FAS, downregulation of Fap-1, and an increase
in caspases causing apoptosis. Non-hematopoietic cells
in the marrow microenvironment contribute to the pro-
cess in two ways: (1) stromal cells induce apoptosis by a
non TNF-dependent mechanism; (2) VEGF production
by the MDS cells may stimulate angiogenesis that could
favor disease progression by altering the microenviron-
ment to favor unregulated cell growth.
Experimental Treatments for MDS
Previous research in MDS has focused on increasing
marrow cell proliferation and differentiation by growth
factors and differentiating agents. Perhaps because of the
importance of inhibitory factors extrinsic to the MDS stem
cell itself, these treatment approaches have produced only
partial beneficial effects.
The results of experimental treatments that affect
extrinsic mechanisms of cytopenia and disease progres-
sion in MDS are outlined below.
It is important to recognize that MDS represents a
diversity of subtypes with different degrees of severity
of cytopenia and different rates of progression to leuke-
mia. Determining if a novel treatment has altered the natu-
American Society of Hematology
Figure 3. Mechanism of action of immune modulators in MDS.
Abbreviations: TNF, tumor necrosis factor; LGL, large granular lymphocytes; ATG, antithymocyte globulin
ral disease progression requires a knowledge of the rate
of progression and survival probability of MDS subtypes
with comparable prognostic features. Currently the IPSS
provides the most widely accepted yardstick to measure
disease progression and survival.30 Numerical changes
in cell counts are frequently used to describe responses
to cytopenia. However, even the finding of a 50% in-
crease in neutrophils or platelets is only of clinical rel-
evance if treatment raised the count from a level associ-
ated with a high risk of infection or bleeding to a safe
level. Furthermore, only sustained responses, not peak
counts achieved, correlate with prolonged clinical ben-
efit. Reliable end-points of major clinical significance
are independence from transfusion of blood and plate-
lets and a recovery of neutrophils from below 500 to
> 1000/mm3.
Hematology 2000
Immunosuppressive Treatments
Prednisone
Bagby et al reported in 1980 that prednisone alone im-
proved low blood counts in a minority of patients with
MDS and that the response could be predicted in vitro by
enhancement of granulocyte macrophage colony-form-
ing units (CFU-GM) growth.31 However, although ste-
roids have frequently been used in treatment, low response
rates and increased risk fo infection make corticoster-
oids unattractive agents in MDS.
Antithymocyte globulin
Because of the similarity of hypoplastic MDS to SAA,
antithymocyte globulin (ATG) has been used occasion-
ally to treat hypoplastic MDS with severe cytopenia. A
summary of case reports and small series reveals hema-
tological responses in 8/13 hypoplastic MDS patients.23,24
Based on these reports, unpublished observations, and
the hypothesis that a T cell-mediated process may cause
119
pancytopenia, we evaluated ATG as immunosuppressive
treatment to improve marrow function in MDS.25 This
study, now completed, involved 61 patients. Study entry
criteria were red cell or platelet transfusion-dependence
and no concurrent treatment with immunosuppressives,
chemotherapy or growth factors. Thirty-seven had refrac-
tory anemia (RA), 12 had RA with excess of blasts
(RAEB) and 10 RA with ring-sideroblasts (RARS). Mar-
row cellularity varied from hypo- to hyper-cellular. Most
patients (75%) had failed previous treatment with single
or multiple agents, including cyclosporine, amifostine,
and growth factors. The interval between diagnosis and
entry to the study was 3–300 months, with a median of
24 months. Twenty-three cases had hypoplastic MDS,
seven had the PNH abnormality by flow cytometry, and
23 had karyotypic abnormalities characteristic of MDS.
Patients received ATG at 40 mg/kg/day for 4 days and
were periodically evaluated for 38 (range 20–58) months.
The main criterion for response was independence from
the requirement for red cell transfusions. Twenty-one
(33%) patients became red cell transfusion-independent
within 8 months of treatment (median 75 days). Transfu-
sion-independence was maintained in 76% of respond-
ing patients for a median of 32 months (range 20–58).
Twenty-three of 41 (56%) severely thrombocytopenic
patients had sustained platelet count increases between
25,000–290,000/µl and 18/41 (44%) severely neutropenic
patients achieved sustained neutrophil counts > 1000/µl.
At last follow-up 39 patients were alive with an actuarial
survival of 64% at a median of 34 (range 18–72) months.
Of the 21 responders, 20 survived and one died follow-
ing progression to AML (Figure 4). In the others no sig-
nificant alteration in the bone marrow appearance or cel-
Figure 4. Survival of 61 patients with myelodysplastic syndrome given
antithymocyte globulin (ATG) treatment.
120
lularity was observed and cytogenetic abnormalities,
present in four, persisted after treatment. Three relapsed
with transfusion-dependence but one regained red cell
transfusion-independence after a second course of ATG.
Of the 40 non-responders 21 died, 15 from cytopenia and
7 from progression to AML.
Factors Predicting a Response to Immunosuppression
In a multivariate analysis of 82 RA, RARS or RAEB
patients treated with either ATG alone or cyclosporine
alone, younger age, shorter duration of red cell transfu-
sion dependence and the presence of HLA DRB1 15 pre-
dicted a response to immunosuppression. In other words,
to maximize the probability of response to immunosup-
pression, patients should be treated sooner rather than
later and this strategy appears to be particularly appro-
priate and effective in RA or RAEB patients who are
young and/or have HLA DRB1 15. Pretreatment vari-
ables associated with a response to immunosuppression
are summarized in Table 3. Responses were associated
with a significant survival benefit at 4 years (95% versus
38% for non-responders, p = 0.006). In the subset of 41/
61 patients with INT-1 IPSS given ATG, responders had
100% survival at 3 years and no disease progression ver-
sus 45% survival (p < 0.0004) and 51% probability of
disease progression in non-responders (p = 0.02). Since
we previously found correlation between response to ATG
treatment and normalization of the T cell repertoire, we
studied 15 patients with MDS who received immuno-
suppression for biological markers of response. Abnor-
malities in the TCR V
repertoire were common and
occurred both in responders and non-responders, render-
ing V
analysis of no prognostic value.
Cyclosporine
Jonasova and co-workers reported a
high rate of hematological responses
following cyclosporine treatment in
MDS. Sixteen patients with RA and one
with RAEB were given standard doses
of cyclosporine for 5–31 months. Sub-
stantial hematological responses were
observed,32 mostly occurring around 3
months. Transfusion independence was
achieved in all 12 patients requiring red
cells before cyclosporine administra-
tion, and significant increases in leuco-
cyte and platelet counts also occurred.
Responses occurred in RAEB as well
as RA patients and in hyper- or normo-
cellular MDS as well as in hypoplastic
MDS (6/8 and 7/9 responders respec-
tively). Of six patients with abnormal
karyotype, three responded (all were
American Society of Hematology
Table 3. Pretreatment variables correlating with a response to immunosuppression.

Significant Significant
Correlation in Correlation in
Univariate Multivariate
Analysis Analysis
Favorable Factors (p < 0.05) (p < 0.05) Odds in Multivariate Predictive Model

Younger age yes yes 2X less likely to respond with each 5 year increase in age
Shorter duration of red cell transfusion yes yes 1.5X less likely to respond with each 3 month increase
dependence (RCTD) in RCTD
Positive for HLA DRB1 15 yes yes 9.9X more likely to respond if HLA DRB1 15 positive
Decreased cellularity of bone marrow yes no
Increased number of cytopenias yes no
< 5% marrow blasts yes no
Normal cytogenetics yes no
PNH present by flow yes no
Low IPSS score no no

Table 4. Ongoing trials of immunosuppression in myelodysplastic syndromes.

Site Type of Immunosuppression Study Design

Hanover, Germany rATG single arm (n > 20, ongoing)

Basel, Switzerland
London, United Kingdom
Houston, USA
Scandinavian MDS Group
Multicenter, USA
Bethesda, USA
rATG +CSA randomized, multicenter (new)
rATG single arm (n = 30, stopped)
hATG, vs. hATG+CSA vs. hATG+fludarabine randomized (n = 21, ongoing)
hATG +CSA single arm (n = 13, ongoing)
rATG, supportive care randomized, multicenter (new)
hATG +CSA single arm (new)

Abbreviations: rATG, rabbit antithymocyte globuline; hATG, horse antithymocyte globulin

5q-). These clinical studies provide further strong evi-
dence to support an immune mechanism of marrow sup-
pression in patients with MDS.
New trials of immunosuppressive agents in MDS
Based on these preliminary findings, several trials evalu-
ating immunosuppressive treatment for MDS are under-
way in the US and in Europe (Table 4). Collectively these
studies should better define the potential benefit for im-
munosuppression by comparing ATG treatment with a
control arm of conventionally supported patients. Pro-
spective randomized trials will evaluate the relative ef-
fects of different ATG types and different immunosup-
pressive combinations in improving marrow function and
prolonging survival.
Cytokine inhibition
Amifostine is a phosphorylated organic thiol that is me-
tabolized to intermediates with antioxidant activity. The
drug has two actions: (1) It protects cells from oxidative
stress after exposure to cytokines including TNF-; (2)
it suppresses inflammatory cytokine release. Since
amifostine reduces apoptotic marrow cell death follow-
ing chemotherapy it may also reduce apoptosis in MDS.33
Indeed, incubation of MDS marrow cells with amifostine
was found to improve colony growth.34 In a study reported
by List et al, 35 15 of 18 patients with MDS given
amifostine had single or multilineage hematological re-
sponses. These results were recently updated for 75 pa-
tients; there were 40% platelet responses, 24% ANC re-
sponses and 20% with > 50% reduction in need for trans-
fusions.36 There are ongoing, not yet reported studies on
the use of amifostine in combination with growth factors
and chemotherapeutic agents that should provide more
information about the usefulness of amifostine.
Pentoxifylline
The observation that the three pro-inflammatory cyto-
kines TNF-, TGF-
and IL-1
are implicated in the in-
creased apoptosis of MDS4 led Raza et al to treat MDS
patients with pentoxifylline (PTX), a xanthine derivative
known to interfere with the lipid-signalling pathway used
by these cytokines.37 Ciprofloxacin was added because it
reduced the hepatic degradation of PTX, and dexametha-

Hematology 2000 121

sone was used to further downregulate TNF- produc-
tion by reducing translation of TNF- mRNA. Eighteen
of 43 patients had hematopoietic responses that corre-
lated with a reduction in blood levels of TNF-. In a sub-
sequent study a four-drug combination of amifostine,
pentoxyfylline, ciprofloxacin and dexamethasone was
used to optimize the anti-cytokine effect.38 Of 29 evalu-
able patients given this combination (evaluable because
they survived 12 or more weeks), 22 (76%) showed par-
tial responses, 19 with improvement in neutrophils, 11
with a reduction in transfusion requirement or a rise in
hemoglobin, and 7 with improvements in platelet counts.
However, these improvements were not sustained or sta-
tistically significant at 24 weeks and are similar to those
reported for amifostine alone. There were no complete
responses or conversions to transfusion independence.
In contrast, in a study of 14 patients given PTX and
ciproflovacin, Neumatis et al found a trend to lower TNF-
 levels with treatment but failed to demonstrate a hema-
tological response in any patient.39
Soluble TNF- receptor (Enbrel)
Excessive amounts of soluble receptor can effectively
block the function of TNF- by competitive binding. In
a recent report the soluble receptor Enbrel was reported
to be well tolerated and to reduce plasma TNF- con-
centrations. However, clinical responses were modest.40
Thalidomide
Thalidomide is an immunosuppressive drug. It switches
T helper cells from a Th1 to a Th2 cytokine profile, in-
hibiting production of TNF-.41 It selectively inhibits
TNF- production by monocytes.42 The drug has also
been found to strongly inhibit angiogenesis in animal
experiments and in in vitro cultures of human cells.43,44
Thalidomide has produced surprisingly substantial re-
sponses in patients with myeloma, possibly because of
its effects on marrow angiogenesis. Both the immuno-
suppression and the angiogenesis inhibition of thalido-
mide might be beneficial in MDS. Raza and colleagues
have recently completed a study of thalidomide in 83
patients with MDS.45 The drug was started at a dose of
100 mg daily and increased to a maximum, when toler-
ated, of 400 mg daily. Despite this approach, 26 patients
stopped treatment within 12 weeks because of intoler-
ance. Twenty-one of the 57 patients who continued treat-
ment responded, 15 showing an erythroid, 13 a platelet
and 7 a neutrophil response, with a median time to re-
sponse of 10 weeks. By intention-to-treat analysis, 37%
of patients became responders. Of note, eight patients of
the erythroid responders became transfusion-independent.
There was no evidence that thalidomide favorably or
unfavorably affected disease progression, but follow-up
was short. Patients most likely to respond to thalidomide
122
had fewer blast cells in the marrow. These findings sug-
gest that thalidomide can improve marrow function in
some patients with MDS.
Future directions
We still know very little about the interaction of the im-
mune system, the marrow microenvironment and the
MDS stem cell. The antigens evoking the T cell response
are unknown and the mechanism of T cell-mediated my-
elosuppression is not defined. The etiology of MDS re-
mains unclear. Similarities between MDS and AA, in-
cluding the response to immunosuppressive treatment,
raise questions about the relationship between AA and
MD.20 Are they different diseases sharing a common au-
toimmune pathology or are they two ends of a spectrum
of a marrow failure syndrome differing only in their ten-
dency to evolve to acute leukemia? Provocatively, it has
been proposed that the abnormal cytokine milieu in AA
is the initiator of genetic instability in the aplastic stem
cell leading to clonal evolution and leukemia.46 Also, this
abnormal milieu may act as selective pressure in favor of
the abnormal MDS clone. In these scenarios immune
modulation at an early stage of clonal evolution might be
expected to maintain disease stability. Finally the rela-
tionship between the MDS stem cell and the marrow
microenvironment deserves further study. In this regard
it will be important to determine whether thalidomide
exerts its beneficial effect through inhibition of angio-
genesis as well as through immunosuppression.
III. THERAPEUTIC ADVANCES IN MDS
Eva Hellström-Lindberg, M.D., Ph.D.*
Increased biological understanding of different subtypes
of MDS has resulted in new therapeutic alternatives for
groups of patients in whom, hitherto, only conservative
treatment was available. Achievements in the techniques
for stem cell transplantation (SCT) have made it possible
to cure an increasing, but still small proportion of the
patients. Allogeneic SCT results for patients in older age
groups are constantly improving, which will increase the
proportion of MDS patients eligible for this treatment. A
large phase II trial suggests that a proportion of patients
with high-risk MDS with complete remission after high-
dose chemotherapy may benefit from consolidation with
autologous stem cell transplantation. Growth factors may
support hemoglobin levels and neutrophil counts in sub-
groups of patients, but is an ineffective and expensive
treatment for others, which encourages the development
of decision models for this type of treatment. While eryth-
* Department of Medicine, Division of Hematology, Karolinska
Institutet, Huddinge University Hospital, S-141 86 Stockholm,
Sweden
American Society of Hematology
ropoietin (Epo) as monotherapy has shown efficacy
mainly in RA patients with low serum Epo-levels, the
combination of G-CSF + Epo may induce long-lasting
normalization of hemoglobin levels, in particular in pa-
tients with RARS. For RA, again, new therapeutic ap-
proaches, such as ATG (reviewed in Section II), seem
promising. Low-dose chemotherapy may improve periph-
eral blood counts, but has previously been shown not to
improve long-term outcome. Two DNA-hypomethylating
agents, 5-azacytidine and 2,5-deoxycytidine may how-
ever change the role of low-dose chemotherapy, since 5-
azacytidine has been shown to prolong time to leukemic
transformation or death, compared to untreated patients.
The IPSS scoring system is at present the most use-
ful tool to predict long-term outcome in cohorts of un-
treated patients and should be included as a variable in
studies describing the effects of different treatment ap-
proaches.1 A new MDS classification has recently been
proposed, but its capacity to improve the clinical charac-
terization and management of MDS patients is under
debate.2
Allogeneic Transplantation
Allogeneic bone marrow transplantation (allo-BMT) is a
curative therapeutic option for younger patients with MDS
(Table 5). The outcome of treatment is highly dependent
on the selection of patients, and it is therefore difficult to
evaluate the effect of different conditioning regimens and
other treatment approaches. In a recent review from Fred
Hutchinson Cancer Research Center, the results of allo-
geneic BMT in 251 patients with MDS were reported.3
The overall median disease-free survival (DFS) was 40%
after a median follow-up of 6 years. Important predictors
for long-term survival were age, morphology and cyto-
genetics. While patients below 20 years of age (i.e. pedi-
atric MDS and young secondary MDS) showed a DFS of
Table 5. Large or new allogeneic stem cell transplantation studies in myelodysplastic syndromes.
Author (Year)Ref. Age Donor Outcome
No. pts (period) M (range) Related/VUD DFS
Appelbaum (1998)3 38 (1-66) 59% / 28% 40% at 6y
251 (1981-96) (60% < 20y,
20% > 50y)
Nevill (1998)4 40 (15-55) 38/22 29% at 7y
60 (1986-96)
de Witte (2000)5 not given 885/198 36% at 3 y36% (all)
1378 (1997) 25% (VUD)
Deeg (2000)6 59 (55-66) 36/6 42% at 3y
50 (1989-98)*
*Two patients transplanted 1978 and 1983
Abbreviations: DFS, disease-free survival; RA, refractory anemia; VUD, volunteer unrelated donor; IPSS, International Scoring System for
Evaluating Prognosis
Hematology 2000
almost 60%, DFS in patients > 50 years of age was be-
low 20%, mostly due to high transplant-related mortal-
ity. Increasing disease duration before transplant signifi-
cantly increased the risk for non-relapse mortality but
did not influence disease-free survival. A Canadian study
reported the outcome of 60 adult patients with MDS.4
The 7-year event-free survival was 29% for all patients,
> 60% for patients with RA/RARS, 20% for patients with
> 5% blasts, and 6% for patients in the poor cytogenetic
subgroup. An update of the EBMT experience of SCT in
1378 patients with MDS has recently been published.5
Estimated DFS and relapse risk at 3 years were both 36%
for 885 patients transplanted with stem cells from matched
siblings. DFS and relapse rate in RA/RARS was 55%
and 13%, respectively, while the corresponding figures
for more advanced MDS was 28% and 43%. DFS in pa-
tients with advanced MDS treated to CR was 44%. This
analysis did not indicate a significantly better DFS in
patients transplanted < 1 year from diagnosis.
Recently, Deeg et al reported results on 50 MDS
patients, aged 55–66, receiving allogeneic BMT with stem
cells from matched siblings (36), unrelated volunteers
(6), HLA-nonidentical family members (4), and identi-
cal twins (4).6 The Kaplan-Meier (KM) estimate of re-
lapse-free survival at 3 years was 39% for all patients
and 47% for patients with primary MDS transplanted with
stem cells from an HLA-identical sibling. As in previous
studies, cytogenetic risk group and IPSS score were
highly predictive for the outcome of treatment. More-
over, conditioning regimen with cyclophosphamide +
targeted busulfan showed an advantage compared to other
conditioning regimens. The study shows that results in
selected groups of older patients are beginning to im-
prove.
Although the results from allogeneic SCT for MDS
seem to improve over time, the outcome for patients with
Relapse Comments
18% Age, IPSS highly predictive for DFS
42% 6% DFS in poor cytogenetic risk group
Relapse rate in patients with >5% blasts 42–43%,
in MDS-AML 49%
19% DFS in RA, 53%. In high cytogenetic risk group 21%
123
MDS is still worse than for those with other myeloid di-
agnoses, mostly due to a high transplant-related mortal-
ity and relapse rate. Future studies will need to focus on
optimizing pre-treatment schedules, conditioning regi-
mens and post-transplant immune-modulation. Case re-
ports have shown an effect of donor lymphocyte infu-
sion also in MDS.7 Slavin reported one patient with MDS
who entered complete remission after non-myeloablative
stem cell transplantation,8 and approximately 60 patients
with MDS and secondary leukemia have been included
in the protocols from Jerusalem, Seattle and NIH (Shimon
Slavin, Rainer Storb, Ghulam Mufti, and John Barrett,
personal communication), and at the Huddinge transplan-
tation unit. Complete remissions lasting for 1–2 years
have been observed, which encourages further investiga-
tions.
Autologous Stem Cell Transplantation for MDS
Conventional high-dose chemotherapy for MDS may lead
to complete remission, but only to cure in extremely rare
cases. For patients without a suitable donor, or with age
and medical conditions making allogeneic stem cell trans-
plantation unsuitable, alternative methods to maintain CR
and obtain cure need to be developed. The presence of
polyclonal peripheral blood stem cells after high-dose
chemotherapy constitutes the theoretical basis for autolo-
gous stem cell transplantation,9,10 and several European
groups have evaluated the effect of ABMT/APSCT in
high-risk MDS.11,12 Encouraged by early findings that
DFS seemed to enter a plateau phase approximately 3
years after transplantation, more studies have followed.
The EBMT and EORTC working groups have conducted
a large phase II trial, in which 184 evaluable patients with
high-risk MDS and AML following MDS were given
induction therapy to obtain CR. In CR, patients with a
histocompatible sibling donor were candidates for allo-
geneic transplantation, while the remaining patients were
planned for autologous stem cell transplantation after
consolidation therapy and stem cell harvest (Th. de Witte
et al, submitted). The complete remission rate was 54%,
with a median remission duration of 12 months, and DFS
was 29% at 4 years. Thirty-five of 57 patients without a
donor received APSCT in first CR, and 13 of these (37%)
were in continuous complete remission at follow-up. The
benefit of APSCT compared to conventional high-dose
chemotherapy was also supported by a study in which
184 patients from the EORTC-EBMT trials were com-
pared with 216 patients from M.D. Anderson Cancer
Research Center receiving only combined chemo-
therapy.13 Preliminary results indicate a possible benefit
of using autologous transplantation as post-remission
consolidation, since the survival curve of the transplanted
patients showed a plateau, while that of the chemotherapy-
treated patients continued to decline. An ongoing study
124
within the EORTC-EBMT working group compares the
effect of APSCT with the effect of a second consolida-
tion with high-dose cytosine arabinoside. Careful stud-
ies of residual clonality in responding patients will serve
as a tool to predict the usefulness of this treatment in
individual patients. Although the relapse rate after APSCT
is higher than for de novo AML, the results suggest that
there is a subset of patients with MDS that may be cured
by intensive chemotherapy in combination with stem cell
support.
Intensive Chemotherapy
The results of AML-type induction regimens in high-risk
MDS have improved during recent years, but are still
poorer than for de novo AML. Estey et al compared 158
patients with MDS with a cohort of patients with AML.14
The CR rates were comparable in the MDS and AML
groups (62–66%), but patients with RAEB showed sig-
nificantly shorter event-free survival (EFS) than both
those with RAEB-t and AML. Poor prognostic karyo-
type, length of MDS phase and age predicted for a poorer
outcome to treatment. A French group compared high-
dose chemotherapy given with or without quinine.15 In
patients expressing P-glycoprotein (PGP) the response
rate to chemotherapy + quinine was 52% compared to
only 18% in those treated with chemotherapy only, indi-
cating that one important reason for the lower CR rates
in MDS is functional drug resistance. Bernasconi et al
randomized 105 patients to chemotherapy, with or with-
out G-CSF.16 The G-CSF-treated group showed a better
response rate (74% vs 52%, p < 0.05), but no effect on
long-term survival could be observed unless an allo-BMT
was given. In another study, 112 patients with RAEB-t,
MDS-AML and secondary AML (median age 58 years,
range 22–75) were treated with intensive chemotherapy
in combination with G-CSF.17 Overall response rate was
62%, but median duration of response was only 8 months.
DFS was 15% at 28 months. The CR rate was higher in
patients < 60 years (68% vs 55%), and patients who ob-
tained CR showed a DFS of 25% at 36 months. Outcome
was better compared with a previous trial in which pa-
tients were treated with the same chemotherapy, but with-
out G-CSF.
Topotecan, a topoisomerase I inhibitor, has been used
as single therapy in high-risk MDS. In a cohort of 47
patients with RAEB/RAEB-t and CMML, the CR rate
was 28%, with a response rate in previously untreated
patients of 31–38%.18 Toxicity, however, was significant
with 19% of patients dying during induction treatment.
In a recent review by Estey, the effects of topotecan, alone
and in combination with cytosine arabinoside (ara-C),
was compared with the effect of ara-C in other combina-
tions, such as the FLAG regimen.19 In RAEB/RAEB-t,
but not in CMML, ara-C seemed to add to the effect of
American Society of Hematology
topotecan as single therapy. Ara-C + topotecan did not
show any overall benefit compared to high-dose ara-C
alone, but in patients with high-risk (5/7) chromosomal
aberrations the combination of ara-C + topotecan showed
better results than both topotecan alone, high-dose ara-
C, and the FLAG regimen. None of these differences
translated into a difference in survival.
Thus, high-dose results are slowly improving over
time but long-term survival is still very poor for the ma-
jority of patients. It is, however, important to continue to
aim for better response rates, since CR is the starting point
for curative approaches.
Low-Dose Chemotherapy
Non-curative treatments must aim at improving quality
of life and reducing morbidity, but they may also carry
hope for improved survival and reduced risk of leukemic
transformation. Low-dose chemotherapy may improve
peripheral blood values and reduce blast counts, and can
be an effective and inexpensive alternative for certain
patients with MDS.
The drug that has been most extensively used in low
doses is ara-C. Low-dose ara-C may induce complete or
partial remissions in approximately 30% of patients with
RAEB, RAEB-t and MDS-AML.20,21 However, the only
prospective randomized phase III trial comparing low-
dose ara-C with supportive care failed to show a differ-
ence in survival between the two alternatives.22 More-
over, side effects (mainly bone marrow hypoplasia and
pancytopenia) can be pronounced, with therapy-related
deaths having a frequency of 7–19%.20 The addition of
growth factors, mostly GM-CSF, to ara-C has not been
successful.23 Based upon a large phase II trial, pretreat-
ment bone marrow cellularity, chromosome aberrations
and ringed sideroblasts were used to formulate a predic-
tive model for the use of low-dose ara-C in MDS and
MDS-AML.21 This model identified patient groups with
a > 50% probability of response and those with no re-
sponse to treatment.
Melphalan
Two recently published studies have reported the effects
of low-dose melphalan (2 mg/day until progression/tox-
icity or response) in patients with high-risk MDS. In the
first study, 8 of 21 patients with RAEB or RAEB-t (38%)
achieved a complete (7) or partial (1) response with a
median survival of 27 months for CR patients and 6.5
months for the rest.24 No severe side effects were ob-
served in any patients. Recently, these results were con-
firmed by a European group,25 who reported a response
rate of 40% and suggested a better response in patients
with hypocellular MDS. The difference from other low-
dose regimens seems to be that melphalan relatively fre-
quently causes improvement without preceding cytope-
Hematology 2000
nia. Other advantages are the extremely low cost of the
drug and its simple administration.
5-azacytidine and 5–aza-2´-deoxycytidine
Several trials have investigated the effect of low doses of
two DNA hypomethylating pyrimidine analogues, 5-
azacytidine (5-aza) and 5-aza-2´-deoxycytidine (DAC),
in high-risk MDS. In spite of the similar structure of these
drugs, their clinical effects differ in several ways. In phase
II studies, treatment with 5-aza led to improved periph-
eral blood values and reduction of bone marrow blasts in
49–54% of the patients.26 Inspired by this relatively high
response rate and moderate toxicity, 5-aza was evaluated
by CALGB in a large randomised phase III study in which
5-aza, given subcutaneously 7/28 days, was studied
against observation in a cross-over model.27 The overall
response rate was 63% (6% CR, 10% PR, 47% improved).
This is not better than for other chemotherapeutic com-
pounds, but the median time to leukemic transformation
or death was 22 months in the 5-aza arm versus 12 months
for those on supportive care (p = 0.003). Median sur-
vival for 5-aza and observation was 18 and 14 months,
respectively (p = 0.1). Moreover, treatment-related mor-
tality was low, quality of life was enhanced in respond-
ing patients, and toxic side effects few.28 This promising
study suggests that 5-aza may alter the natural course of
MDS. However, confirmatory studies are warranted.
DAC, given intravenously, has been evaluated in two
pilot trials and a large recently published multi-center
phase II trial, in which primary endpoints were response
rate and toxicity.29 The overall response rate was 49%,
with 64% response in patients with an IPSS high-risk
score. The actuarial median survival time from start of
therapy was 15 months. Myelosuppression was common,
and 7% therapy-related deaths were reported. Noticeable
was the rapid and distinct platelet response, which oc-
curred after the first course in the responding patients.
Compared to 5-aza, DAC seems to be more efficient in
inducing CR, it has more severe toxicity, and has not yet
been investigated in a trial with survival as endpoint. It
is, however, likely that both 5-aza and DAC will add to
the arsenal of clinically useful therapies for MDS.
Growth factor treatment
The bone marrow of patients with RA and RARS is
mainly characterized by ineffective hematopoiesis. This
is paralleled by reduced clonogenic growth in vitro, and
the presence of an increased proportion of apoptotic bone
marrow precursors.30-32 Recent studies suggest that the
underlying mechanisms behind apoptosis in MDS may
differ between the subtypes of MDS.33,34 Colony culture
studies of myelodysplastic bone marrow have shown that
the impaired erythroid growth may respond to Epo alone,
but that it may be further improved if Epo is combined
125
Table 6. Larger studies on erythropoietin (Epo) alone or Epo in combination with G-CSF.

Inclusion Erythroid Favorable Variables/

Author Year Treatment No. Pts. Criteria Response Comments

Hellstrom-Lindberg40 1995 Epo 205 Various, all 16%* S-Epo < 200 U/L
meta-analysis studies since 1995 (8% RARS) RA/RAEB, no transfusions
Rose41 1995 Epo 116 Hb < 80 g/L, 28%** S-Epo < 100 U/L, RA
phase II S-Epo < 500 U/L (18% red. transf)
Italian Study Group42 1998 Epo / placebo 87 Hb < 90 g/L 37% vs 11%** Response significant in RA
phase III Blasts < 10% (p = 0.007) and in non-transfused pts
Negrin44 1996 Epo + G-CSF 55 Hb < 100 g/L 48%**, duration S-Epo
phase II median 10 mo.
Hellstrom-Lindberg45 1998 Epo + G-CSF 71 Hb < 100 g/L 38%*, duration S-Epo, transfusion need
phase II 24 months
Remacha47 1999 Epo + G-CSF 32 Hb < 100 g/L 50%** Predictive model (Figure 5)
phase II S-Epo < 250 U/L
Mantovani49 2000 Epo + G-CSF 33 Blasts < 20% 61%* (12 weeks) 50% response after 2 years
80% (36 weeks)

* The definition of response required a total stop in transfusion need in transfusion-dependent patients.
** The definition of response required a 50% reduction in transfusion need in transfusion-dependent patients.
Abbreviations: S-Epo, serum Epo level; G-CSF, granulocyte colony-stimulating factor

with other growth factors.35 The ineffective hematopoie-
sis and cytopenia in RA, RARS and RAEB with < 10%
blasts is considered to respond poorly to chemotherapy,
and a number of clinical trials have therefore addressed
the use of growth factors in these subtypes (Table 6).
GM-CSF and G-CSF
GM-CSF and G-CSF are both effective in increasing pe-
ripheral neutrophil counts in MDS. In a preliminary re-
ported clinical phase III trial, patients were randomised
to either GM-CSF or observation.36,37 Granulocyte counts
were significantly increased, while hemoglobin levels,
survival, and the incidence of leukemic transformation
were not affected. G-CSF, used in phase II studies, showed
similar effects on neutrophil counts, and favorable long-
term results with maintained response for up to 16 months
were reported.38 A randomized study between G-CSF and
observation showed a significant G-CSF-induced increase
in neutrophil counts but no effect on hemoglobin lev-
els.39 After correction for risk factors, survival or evolu-
tion to AML was not significantly influenced by treat-
ment. Both these randomised studies showed that G-CSF,
as well as GM-CSF, had an overall negative effect on
platelet counts. Thus, there is at present no evidence that
supports the use of G-CSF and GM-CSF as single therapy
in MDS.
Erythropoietin
Erythropoietin (Epo) may improve the anemia in MDS.
All 17 studies (205 patients) published before 1995 were
included in a meta-analysis, which showed an overall
response rate of 16%.40 Information about FAB group,
transfusion need and serum Epo levels (S-Epo) were use-
ful to characterize groups of patients with different out-
comes to treatment. Patients with RARS responded sig-
nificantly less well to treatment than the other subgroups
(8% versus 21% in non-RARS). The response rates in
patients with S-Epo below or above 200 U/l, were 21%
and 10%, respectively, and 10% in patients with pretreat-
ment transfusion need. Rose et al treated 116 patients
with Epo.41 The response rate was 28%, S-Epo levels <
100 U/l predicited for a better response, and patients with
RA had a better response than those with RARS (39%
versus 17.5%). The Italian cooperative group performed
a placebo-controlled randomized study, which showed
that Epo significantly improved hemoglobin levels in
MDS. However, the response was significant only in pa-
tients with RA and in patients who did not need transfu-
sion before treatment.42 Finally, Hast et al reported a se-
ries of 18 patients responding to Epo, who continued on
maintenance treatment and showed a median response
duration of 15 months. The dose of Epo could be safely
reduced or withdrawn, since the majority of patients who
then relapsed with anemia responded well to reintroduc-
tion of Epo or to an increase of the dose.43
Erythropoietin in combination with other
growth factors
Several clinical trials have studied the combination of
Epo and G-CSF, GM-CSF or IL-3. The response rate to
Epo + G-CSF has been shown to be around 40% in MDS
patients with < 10% bone marrow blasts, i.e. twice as
much as for Epo alone. A large US phase II study and the
trials within the Scandinavian MDS Group have demon-
strated evidence of a clear synergistic effect between the
drugs in vivo.44,45 The US study showed that 50% of the

126 American Society of Hematology

patients with a response lost it when G-CSF was with-
drawn and regained it when G-CSF was reintroduced,
and the Scandinavian study showed that addition of G-
CSF could induce erythroid responses in Epo-resistant
patients. The synergistic effect was most pronounced in
patients with RARS, since this subgroup responded
poorly to Epo alone and showed the best response to the
combination (around 50%). A study of predictive factors
for a response to treatment identified S-Epo and the level
of pre-treatment transfusion need as significant variables
and these were combined in a predictive model for treat-
ment with G-CSF + Epo (Figure 5).46 The value of this
model was later confirmed in independent patient mate-
rial from a Spanish study,47 and in a third prospective
study within the Scandinavian MDS Group (data not re-
ported). This study included 52 evaluable patients from
the high (n = 31) and the intermediate (n = 21) predictive
groups (for explanation, see Figure 5). The response rate
was 61.3% in group 1 and 14.3% in group 2 (p = 0.004),
and no other pre-treatment variables improved the model.
Quality of life (QLQ 30) improved in patients with a re-
sponse to treatment (p < 0.05 for fatigue and global QOL).
A simplified and clinically useful decision model will be
developed based on these results. While waiting for the
results of ongoing prospective randomized studies, we
designed a case-control study in which 135 patients
treated with G-CSF + Epo were compared with control
cases from the data base generated by the International
MDS Risk Analysis Workshop (also used to create the
IPSS score). The median duration of response to G-CSF
+ Epo (defined as transfusion independence or normal
hemoglobin levels) was 10 months (range 0–72+) in the
whole group and 25 months in patients with RARS.
Lastly, a recently published study showed a response rate
of 61% in a cohort of 33 patients with MDS.48 A signifi-
> of MDS, in new therapeutic approaches
Figure 5. Predictive model for treatment with G-CSF + erythropoietin for the
anemia of myelodysplastic syndrome (MDS).
Hematology 2000
cant number of patients showed late responses (12–36
weeks after start of treatment).
These studies indicate a central role for G-CSF in
the treatment of RARS, but the mechanism has not yet
been clarified. Histopathological studies have shown that
patients who respond to treatment have a significant re-
duction of apoptotic cells in the bone marrow. Thus, it
seems likely that growth factors affect one of the major
pathogenetic mechanisms in MDS, ineffective hemato-
poiesis.32 Recent laboratory studies49 have shown that the
erythroid apoptosis in RARS is initiated at the CD34+ level,
is mediated by increase caspase activity, but not by endog-
enous stimulation of the Fas receptor, and can be signifi-
cantly reduced by G-CSF incubation of CD34+ cells.
GM-CSF and EPO have also been used in combina-
tion as treatment for MDS.50-52 One pilot study showed
that the combination could induce erythroid responses in
patients not responding to Epo alone. A phase II trial us-
ing GM-CSF + Epo resulted in an erythroid response rate
of 34.6%, but the authors questioned whether a synergis-
tic effect in vivo was obvious. Finally, a randomized phase
II trial showed that GM-CSF + Epo was more effective
in reducing transfusion need than GM-CSF + placebo, in
patients with S-Epo < 500 U/l. Thus, there is some evi-
dence that the combination of GM-CSF + Epo may also
offer an advantage over Epo alone, but the experience is
more limited than with to G-CSF + Epo, and GM-CSF
has more side effects. Lastly, Epo has been combined
with IL-3, but in spite of promising in vitro data, clinical
results have not encouraged a continued development of
this treatment.53
Concluding Remarks
To improve treatment for patients with MDS, better tools
will be required to define the underlying pathogenetic
mechanisms in individual patients. It is
thus important to estimate the risk for leu-
kemic transformation, the degree of inef-
fective hematopoiesis, signs of immune-
mediated myelosuppression, and overall
prognosis including age and performance
status, before making a therapeutic deci-
sion. Recent therapeutic advances have
made it clear that new biological informa-
tion in combination with statistically de-
veloped predictive models may help us to
better select patients for different thera-
peutic options and to develop new treat-
ment modalities. The future thus lies in
developing new insights into the biology
and well-conducted clinical trials, and in
the search for better tools to use existing
therapeutic options.
127
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