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Current Cancer Drug Targets, 2007, 7, 541-558 541

Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel

Treatment Approaches
E.D. Warlick* and B.D. Smith

Hematologic Malignancies Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins 1650 Orleans Street, room 246
Baltimore, MD 21231, USA
Abstract: Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal disorders of hematopoietic progenitors manifest by
cytopenias, bleeding, infection, and potential for progression to acute myelogenous leukemia. The wide spectrum of clinical
manifestations, including variability in illness severity and potential for progression, suggest that myelodysplastic syndromes encompass
a multitude of disorders, likely involving numerous pathologic pathways. In fact, it is the effort to understand the underlying biology of
these syndromes that has led to recent advances in treatment approaches, including the FDA approval of three new agents (5-azacitidine,
decitabine, and lenalidomide) for the treatment of MDS. This review will present data supporting each of the current pathophysiologic
pathways implicated in the development and progression of MDS; summarize the emerging clinical paradigms for treating patients with
MDS; and offer insights into several novel approaches attempting to improve treatment options for future MDS patients.
Keywords: Myelodysplastic syndrome, pathophysiology, differentiation therapy, epigenetic therapy, bone marrow transplantation,

INTRODUCTION cohorts [12-14]. Additionally, altered immune surveillance

Myelodysplastic syndromes (MDS) are a complex and potentially creates an environment where the transformation to acute
heterogeneous group of bone marrow failure disorders characterized leukemia becomes possible [15]. The pathophysiology of low and
by ineffective hematopoiesis. This dysfunctional blood cell high grade MDS is slowly being incorporated into the evolving
production is manifest by peripheral cytopenias, marked morphologic classification hierarchies as well as treatment paradigms.
dysplasia, and cellular dysfunction resulting in an increased risk of
infection and need for transfusions in most MDS patients. In the CLASSIFICATION SYSTEMS
general population, the incidence of MDS is approximately 2-10 Throughout the years, various classification systems have been
cases per 100,000 people with the incidence rising to approximately developed to describe myelodysplastic syndromes. There is no clear
50 cases per 100,000 people over age 70 [1]. The median age at best schema, yet the numerous revisions and expansions based on
presentation approaches 70 with a slight male predominance of the ongoing understanding of MDS pathophysiology and clinical
unknown clinical significance. Traditionally, MDS is characterized as outcomes are notable improvements.
either primary (idiopathic) or secondary with exposure to benzene
[2], occupational chemicals [3], or prior treatment with radiation [4] FAB Morphologic Classification
or chemotherapy agents [5] well documented secondary causes.
Additional data implicates exposure to tobacco [6], excessive alcohol The initial FAB (French-American British) system was
[7], viral infections [8], or autoimmune disorders [9] as potential developed by an international group of clinicians and pathologists in
associations with MDS. the mid 1970s, refined in 1982, and primarily used cellular
morphology to define the MDS subgroups focusing on bone marrow
Alterations in many individual biologic pathways have been blast percentage, the presence or absence of monocytosis, and the
implicated in MDS pathophysiology. However, the generally presence or absence of ringed sideroblasts. These morphologic
accepted primary hypothesizes involves an initial deleterious genetic findings, aligned with important prognostic outcomes, were
event within a hematopoietic stem cell, subsequent development of eventually divided into four groups:1) Lower-risk MDS (RA and
excessive cytokines/inflammatory response leading to a pro- RARS) with a median survival of 4-5 years and low risk of AML
apoptotic/proliferative state, and resultant peripheral cytopenias transformation; 2) Intermediate-risk MDS (RAEB) with a median
despite a hypercellular bone marrow. The presence of detectable survival close to 1 year; 3) Higher-risk MDS (RAEBt) with a median
cytogenetic abnormalities in approximately 40-70% of patients with survival measured in months and a very high risk of AML
primary MDS and over 80% with secondary MDS [10] as well as the transformation; and 4) CMML associated with a wildly variable risk
validated prognostic value of cytogenetic data in MDS supports the [16,17]. The FAB classification served as the first framework to
theory of an incident genetic event. Specifically, good prognostic systematically identify and describe the different clinical entities of
cytogenetic groups (5q minus syndrome or deletion of the long arm MDS. However, the FAB system was limited by lack of cytogenetic
of chromosome 20 (20q)) are typically associated with more indolent and molecular information now commonly available, and did not
MDS that requires less intensive therapy while poor prognostic adequately accommodate hypoplastic MDS, MDS with
cytogenetic groups (loss of chromosome 5 or 7 or complex myelofibrosis, and other overlap syndromes [18, 19].
abnormalities) have a more aggressive course and are often poorly
responsive even to aggressive treatments [11]. The variable response
WHO Classification
to treatment and course of disease correlating with cytogenetic
findings suggests likely differential behavior of the MDS clone: More recently, in 1999, the World Health Organization (WHO)
differentiation arrest and a pro-apoptotic cytokine state in low risk proposed a newer classification system attempting to address some of
cytogenetic cohorts versus a state of proliferative advantage, possibly the limitations of the FAB system [20]. The main goal of this schema
due to underlying genomic instability or via altered gene expression was to formally incorporate biologic data, specifically cytogenetic
silencing of DNA repair or tumor suppressor genes, in high risk and molecular findings, clinical outcomes, and number of dysplastic
lineages involved, in order to better separate subgroups and delineate
syndromes within the previous FAB classification. Notably, the
*Address correspondence to this author at the Hematologic Malignancies Sidney Kimmel WHO classification recognized the unique 5q- syndrome and
Comprehensive Cancer Center at Johns Hopkins 1650 Orleans Street, room 246 CMML within their own categories, lowered the blast percentage
Baltimore, MD 21231, USA; Tel: (410) 614-5068; Fax: (410) 614-7437; E-mail: defining AML to 20% and eliminated the RAEBt category, assigned

1568-0096/07 $50.00+.00 2007 Bentham Science Publishers Ltd.

542 Current Cancer Drug Targets, 2007, Vol. 7, No. 6 Warlick and Smith

patients with characteristic AML-associated chromosomal from the observational case control studies involving benzene, an
abnormalities to AML regardless of blast percentage, and used the aromatic hydrocarbon and organic solvent derived from petroleum-
percentage of marrow blasts to divide RAEB into two groups noting refining, used in many occupational compounds [25]. The
that patients with >10% blasts had a shorter survival and increased association, first described in Turkish shoe workers who developed
transformation to acute leukemia compared to patients with <10% bone marrow failure/pancytopenia states, [26] lead to further
[20]. The WHO system also distinguished MDS patients with <5% prospective cohort studies involving 74,828 benzene exposed subjects
marrow blasts between those with multilineage dysplasia (worse in China and revealed a significantly increased relative risk of MDS
outcome) and those with erythroid-only dysplasia (better outcome), development approaching infinity [2]. The potential mechanisms of
and added an unclassifiable MDS category [19-21]. Although the MDS development in benzene-exposed individuals have been
WHO classification system built on the FAB foundation by including described in two contexts: genotoxic and non-genotoxic. Genotoxic
important biologic and clinical data, there remained some obvious mechanisms are characterized by the generation of oxygen free
shortcomings such as the MDS-unclassifiable category and radicals from benzene metabolites with subsequent DNA damage and
controversies such as the elimination of RAEBt [18]. These concerns apoptosis [27, 28]. Support for this mechanism includes the findings
epitomize the larger problem that MDS is truly a pleomorphic of chromosomal abnormalities (trisomy (+9), deletions (-5 or -7) and
grab bag term for multiple disorders that offer significant translocations [t (8, 21)]), oncogene mutations, and somatic mutations
challenges to both physicians treating patients as well as scientists in benzene-exposed MDS patients [29-31]. Additionally, as
studying these disorders. increasing somatic mutations may occur with aging, exposure to
benzene and other directly genotoxic agents could lead to more
IPSS Prognostic Classification significant damage that progresses to clonal expansion and MDS
[31]. Suggested non-genotoxic mechanisms include alteration of the
In 1997, Peter Greenberg and colleagues proposed a plan to
bone marrow microenvironment and immune function through
combine known prognostic variables with outcomes data from seven
reduced immunoglobulin and complement levels [31].
large, risk-based studies in an effort to determine the most important
variables for assigning prognosis to MDS patients. The International Radiation and prior chemotherapy are other well documented
Prognostic Scoring System (IPSS) emerged from the analysis of this exposures that can lead to the development of MDS [24, 23, 31].
data from nearly 900 MDS patients and represents the best effort to Specifically, chemotherapy-associated MDS has been associated with
date for prediction of prognosis and outcome. The variables most treatment using Topoisomerase II inhibitors, anthracyclines, and
predictive of prognosis included percentage bone marrow blasts, alkylating agents. MDS from exposure to Topoisomerase II inhibitors
cytogenetic abnormalities, and number of peripheral cytopenias. and anthracyclines typically has an early onset within 1-3 years and
Subsequent IPSS score calculation then assigns patients to one of four causes balanced genetic alterations typically involving 11q23 (Mixed
risk groups: Low, Intermediate-1 (INT-1), Intermediate-2 (INT-2), Lineage leukemia, MLL gene) [5] while exposure to alkylating agents
and High risk with decreasing survival and increasing risk of AML results in a later onset within 5-10 years and yields unbalanced
progression as the score increases [22]. Like each of the classification chromosomal alterations often involving chromosomes 5 and 7 [10,
schemas, the IPSS also has limitations including failure to offer 32]. With regard to radiation, epidemiologic studies of atomic bomb
prognostic points for treatment-related MDS (t-MDS) or CMML, and survivors have illustrated the connection between previous radiation
lack of scoring for most of the cytogenetic abnormalities commonly exposure and leukemia/MDS development, [33] and have
found in MDS. These limitations aside, the IPSS remains a characterized the importance of exposure dose and duration [34].
paramount tool in predicting prognosis, categorizing patients for Specific effects and chromosomal abnormalities, additionally, seem
studies, and analyzing treatment outcomes. In combination with the to be similar to those seen with exposure to alkylating agents [4].
other classification systems, it represents the most quantitative With a median age of newly diagnosed MDS patients nearing 70,
assignment of MDS risk available. the importance of aging in MDS is clear, yet the specific role it plays
biologically remains under investigation [1]. It is theorized that aging
THEORIES IN MDS PATHOPHYSIOLOGY itself may produce increased genetic mutations and alterations that
Better understanding of the underlying MDS biology is crucial result in MDS. Comparing bone marrow from normal controls and
for the development of better treatments for individual patients. It is older patients is one approach to highlighting potential similarities
commonly accepted that MDS develops through a multi-step process and differences that could explain the increased incidence of MDS in
encompassing changes within the hematopoietic stem cell, the bone the elderly. Ogawa et al. evaluated the bone marrows of 100 normal
marrow microenvironment, and the complex interactions between the controls of a variety of ages [35] and found increased apoptosis and
two [1, 15, 18, 23, 24]. Below we survey specific theories and decreased cellularity in patients of advanced age [36] with apoptosis
pathways implicated in the pathogenesis and progression of MDS levels similar in degree to MDS patients. Other studies describing
divided into five major categories: 1) cellular damage related to toxic MDS marrows detail a skew in specific TNF-alpha receptor
environmental exposures and cellular aging; 2) genetic alterations expression leading to increased rates of apoptosis comparable to that
including loss or gain of function due to both cytogenetic and seen in normal elderly marrows. While the increased apoptosis in
epigenetic abnormalities (Table I); 3) changes in the bone marrow both normal elderly marrows and MDS patients may have distinct
microenvironment; 4) dysregulation of the immune system; and 5) biologic causes, the finding may also suggest a reason for the
altered cell cycle regulation and blocked differentiation. (Theories preponderance of increased MDS in the elderly [37].
Summarized in Table II) Another biologic link between aging, stem cell damage, and
cancers such as MDS includes the study of telomeres and telomerase
Cellular Damage: Toxic Environmental Exposures and Cellular activity. Telomeres are simple tandem repeats at the ends of
Aging chromosomes in somatic cells that shorten with age and are also
found to be shortened in many cancers [38-40]. The shortening is
The epidemiology of MDS has offered pivotal links between
theorized to result from incomplete DNA replication leading to
various environmental exposures, aging, and the development of
genomic instability, subsequent chromosomal abnormalities, and
disease, namely the accumulation of DNA damage. Numerous
eventual mutations impacting disease progression once a certain
environmental exposures have been associated with the development
threshold is breeched. Telomerase is the enzyme required for the
of MDS including tobacco [6] and alcohol use [7], infections [8], or
replication of telomeres, and although not typically found in most
auto-immune disorders [9]; however, the classic example linking an
somatic cells, has been found in over 85% of primary malignancies
environmental toxin exposure to MDS development is highlighted
[41]. Telomerase may not be required for initiation of malignancy but
Myelodysplastic Syndromes Current Cancer Drug Targets, 2007, Vol. 7, No. 6 543

Table I. Cytogenetic Abnormalities in MDS

Classic Clinical or
Chromosomal Incidence Associations: Exposures / Morphologic Prognostic Impact Research
Alteration (Approximate) Other Disorders

- 5q alone/5q syndrome = - 5q CDS: genes for

Chromosome 5 - 10-20% de novo MDS -Chemical Exposure Clinical: good/low risk of AML cell cycle & cellular
Abnormalities cases transformation [47, 50, cytokine receptors
-Chemotherapy [49] -5q Minus Syndrome =
51] - No specific gene loss
- Tx-related in 40% of cases macrocytic anemia, nl
[31] platelet count, female - Complex / other abn of yet identified [52-57]
predominance [50] 5 / t-MDS = poor
Morphologic: - Isolated 20q = good - CDS (20q11.2-q12)
Deletion 20q - 5% de novo MDS cases Polycythemia Vera [58] Dyserythropoiesis [58] outcomes contains numerous
Clinical: - 20q del + complex = tumor suppressor genes
- Tx-related in 7% of cases
poor outcome [22] [11, 58, 60, 61]
[11] ! freq. in low-risk dz,
longer survival: low - No specific gene loss
progression to AML [59] yet identified

Associated w/ not diagnostic - Numerous cancers Favorable prognosis if

Loss of Y of MDS [58] - Normal Aging population isolated abn [22]
[11, 58]
- Monosomy 7
Chromosome 7 -5% de novo MDS cases Associated w/ AML, MDS, Poor risk dz w/ high uniformly bad
abnormalities NF-1, Fanconis anemia, progression to AML [63, regardless of dz
- Tx-related in 55% of cases
[11] Downs Syndrome [62] 58] - CDS (7q22 and 7q32-
33) found but often full
7 loss so difficult to
study [64, 62]
- Often tx related = poor - Loss of p53 function
17p Syndrome - 5% of MDS cases [58] Morphologic: prognosis - Due to point mutation
- Tx-related in 33% of cases Dysgranulopoiesis, pseudo- - Often seen w/ other abn in p53 at 17p13 in 70%
[65] pelger huet cells, (5 and 7) = poorer pts [58]
hypogranularity [48] prognosis [11, 58, 65]
- AML/MDS - Isolated = Intermediate -High incidence in
Trisomy 8 - 10-15% of MDS cases [58] - Linked to Benzene Morphologic: Prognosis [22] MDS but not sufficient
exposure - Not specifically linked for leukemogenesis
- Sole abn. in 10% of cases MDS with monocytic
with FAB class/ AML alone [49]
[49] - Solid Tumors: Breast, component [58]
Colon, Sarcoma [66] progression [11]

-EVI-1 gene (3q26)

3q Abnormalities -2% of MDS cases [58] Morphologic: alterations:
- Typically tx-related [58] Abn megakaryocytic - Interference w/ 3q26
development transcription linked w/
differentiation: may
Retained platelet count interfere w/ GATA-1,
differentiation) [58]
- 10-20% of de novo MDS Only partial correlation
Complex Cytogenetics cases w/ outcome: poor
- Tx-related in 90% [67] prognosis [67]

Oncogene/Tumor Frequency of
Suppressor Abnormality in MDS Specifics of Abnormality Prognostic Implications Research
Suppressor Function
Abnormalities Patients
MLL fusion products Clinical: - MLL Amplification:
11q23/MLL Gene involved in numerous cell - 5% of MDS cases [58] Typically later stage dz, Assoc. w/ other abn: role in oncogenic
Abnormality functions: precise oncogenic high AML transformation, Complex, 5 and 7 [69] changes
- often tx-related [32]
mechanism still poorly shorter survival -Gain of function via
understood [68] HOX9A expression
found [70]
- Forms numerous fusion
protein pairs - absent in de novo
MDS [71]
Ras Family of genes encoding -Paquette Study of 220 -N-ras mutations assoc. -Study showing 70% of
GTP-binding proteins: role MDS Pts 9% w/ n-ras - Point Mutations [73] w/ shorter survival and pts w/ mutation
in signal transduction mutations [72] increased progression to progressed to AML w/i
AML [72] 2 yrs compared to
control [72]
p53 Control of DNA replication - In 69% of pts w/ 17p -In t-MDS often found w/ -Resistance to chemo:
repair: crucial for deletion [75] chromosome 5 abn and shorter survival: Shorter
maintaining genome [74] - ! p53 mutations in 17p + complex cytogenetics [65] time to leukemia
complex cytogenetics [76] - Not usually assoc. w/ development [76, 77]
chromosome 7 abn [32]
Legend: MDS = Myelodysplastic Syndrome; Tx = treatment; Nl = normal; AML = Acute Myelogenous Leukemia; t-MDS = treatment related MDS; CDS = Commonly Deleted Segment; w/ = with; Freq. = frequency;
Del = deletion; Abn = abnormality; NF-1 = neurofibromatosis 1; Dz = Disease; FAB = French American British; Assoc. = Associated; MLL = multi-lineage leukemia; Pts = patients; w/i - within
544 Current Cancer Drug Targets, 2007, Vol. 7, No. 6 Warlick and Smith

\may be important in tumor propagation [42]. Interestingly, Identifying alterations of single nucleotide polymorphism (SNPs)
telomerase activity is found in cell populations with high renewal arrays have also been used to help investigators study and explain the
requirements such as hematopoietic stem cells [43]. In MDS, studies heterogeneity of MDS. Moreover, this technique has led to insights
evaluating telomeres and telomerase activity show loss of the typical on genetic predispositions for these diseases. SNPs are the most
correlation between telomere length and age: specifically, decreasing common form of genetic variation between individuals, and recent
telomere length with increasing age [44]. Further studies have found reports have investigated the possibility that genetic polymorphisms
an association between shortened telomeres and abnormal in genes required for proliferation and differentiation may play a role
cytogenetics, where progressively shortening telomeres correlated in MDS development. Specifically, a GLU785Lys polymorphism in
with worsening IPSS risk group [44]. Telomerase activity has also the G-CSF receptor was described and demonstrated functional
been assessed in MDS: high levels of activity have not commonly alterations in growth factor responsiveness in high risk MDS patients
been found. The culmination of this data may suggest that the suggesting a potential role in MDS pathophysiology [83]. It is likely
hematopoietic stem cells in MDS patients have insufficient that further investigations will reveal pathways impacted by these
telomerase to adequately restore cellular telomeres to their normal subtle changes in gene expression. SNP techniques have also looked
lengths subsequently resulting in increased genetic instability [44]. at the possibility that polymorphisms create a genetic predisposition
to MDS. Based on evidence of defective DNA mismatch repair
Gain or Loss of Gene Expression: Cytogenetic and Epigenetic enzymes in patients with t-MDS and mitochondrial/genetic instability
Alterations in patients with primary MDS [84], obvious implicated pathways
could include those involving metabolic activation or detoxification
One of the common end results of exposure to environmental
enzymes. Utilizing both specific and non-specific probes,
toxins is DNA damage and the loss or alteration of gene expression.
polymorphisms in detoxification enzymes such as glutathione S-
Yet, chromosomal abnormalities are often detected in MDS that are
transferase [85] as well as in quinone oxidoreductase have been
not associated with such exposures. In addition, newer techniques,
found, where the presence of NQO1 quinone oxidoreductase
including comparative genomic hybridization (CGH) and single
polymorphisms correlated with an increased risk of benzene-related
nucleotide polymorphisms (SNP) arrays, now allow the detection of
and treatment-related MDS [86, 87]. Additional investigation has also
even microscopic deletions of genes and continue to fuel the
shown microsatellite instability (MSI) in treatment-related MDS, a
understanding of MDS and its pathophysiology. Finally, it is now
hallmark of defective DNA mismatch repair [88].
clear that epigenetic gene silencing plays a role in loss or gain of gene
expression even when the DNA sequence is completely intact. In addition to these structural alternations in DNA, another
mechanism for altered gene expression leading to gain or loss of
Clonal cytogenetic abnormalities (Table I) are found in 30-70%
function involves the silencing of genes through epigenetic
of patients with primary myelodysplastic syndrome and in over 80%
modifications. The two most intensely studied alterations include
of treatment-related MDS and remain the most important individual
DNA methylation and histone acetylation. Both of these genetic
prognostic tool [11, 45-47]. The majority of the chromosomal
alterations can affect chromatin packing and create a DNA / histone
abnormalities in primary MDS involve unbalanced losses: entire
complex that is not able to be transcribed. The result is silencing of
chromosomal loss or point mutations [11, 45]. Consequently, it is
the noted gene despite its non-mutated presence. Although any gene
easy to invoke such abnormalities resulting in the loss or inactivation
can be affected by these epigenetic phenomena, many of the genes
of a critical tumor suppressor protein; however, efforts to determine a
implicated in cancer development involve tumor suppression, cell
culprit gene or cluster of genes have been much more difficult.
cycle control, cell death, cell growth, and differentiation. The
Characteristic chromosomal abnormalities in MDS include alterations
silencing of gene expression secondary to DNA methylation is
of chromosomes 5, 7, 8, 11, 17, 20 and Y or complex karyotypes
responsible for a variety of normal, physiologic functions including
involving multiple abnormalities within individual clonal populations
X-chromosome inactivation, facilitation of DNA imprinting, and
[45, 46]. Several of these abnormalities are shared with AML (e.g.,
protection against insertion of viral DNA into the genome [89]. DNA
deletions of chromosomes 5 or 7, trisomy 8, and complex
methyltransferase is the key enzyme that methylates CpG islands in
cytogenetics), while others appear almost exclusively in AML (e.g., t
the promoter region of genes leading to hypermethylation and
(15; 17), t (8; 21), and inversion 16) [22]. Although specific
silencing of gene transcription [90]. Many cancers appear to have
cytogenetic abnormalities within MDS do not typically correlate with
extensive regional hypermethylation as well as aberrant gene
WHO or FAB classifications, it is now clear that there are
expression leading researchers to explore the role of
characteristic syndromes within MDS, namely 5q- and 17p-
hypermethylation in tumor development and progression: AML and
syndromes [47, 48] that have unique clinical and prognostic
MDS lead the way in being the best studied diseases. There are
outcomes. Additionally, evidence suggests a correlation with
numerous genes that are implicated in MDS/AML pathophysiology
increasing frequency of cytogenetic abnormalities and severity of
with p15INK4B being one of the most studied. Specifically,
hypermethylation of p15INK4B, a known tumor suppressor and cell
The traditional cytogenetic alterations noted above are typically cycle regulatory gene, has been associated with progression of MDS
evaluated using conventional cytogenetic (CC) techniques that to AML [91, 92]. Functionally, CDK4 and CDK6 allow cell cycle
require adequate metaphase chromosomes for analysis. The progression from G1 to S phase. p15INK4B can act as a tumor
development of newer techniques has allowed investigators to suppressor and inhibit cell cycle progression by inhibiting the
uncover more subtle genetic alterations that help to reveal further function of CDK4 and 6. Hypermethylation of p15INK4B prevents
components of MDS pathophysiology. this suppressive function and allows uncontrolled progression
Comparative genomic hybridization (CGH) is a useful tool that through the cell cycle and resultant uncontrolled proliferation [93].
can uncover genomic imbalances without the requirement for quality p15INK4B hypermethylation has been seen in up to 50% of patients
mitoses or dividing cells. Specifically, it allows for detection of with MDS; specifically in higher risk MDS, where the uncontrolled
changes in chromosome copy number by hybridization techniques proliferation has shown increased progression to AML and portends a
between normal and tumor cells [78]. Studies comparing information worse prognosis [92, 94, 95]. Hypermethylation of the calcitonin
obtained through CC, FISH analysis, and CGH, showed close gene has also been described and can be found in 65% of MDS cases.
correlation between the three techniques with CGH providing Its presence spans all morphologic subtypes and is commonly found
additional information on the abnormalities identified by CC as well in patients with normal cytogenetics [96]. Numerous studies now
as uncovering unbalanced genetic alterations not described by CC suggest that hypermethylation of the calcitonin gene may be an
[79, 80]. CGH continues to add valuable information to many important marker of transformation from MDS to AML [97-99].
common cytogenetic findings [81, 82].
Myelodysplastic Syndromes Current Cancer Drug Targets, 2007, Vol. 7, No. 6 545

Other commonly reported hypermethylated genes in implicated in and definition of the cells from which they originate (macrophages,
MDS include E-Cadherin (CDH1), HIC1, and ER [94]. fibroblasts, or other) remain unanswered questions [114-117].
Similarly, conformational alterations of the DNA histone In addition to TNF-alphas impact on apoptosis in MDS,
complex also play an important role in the abnormal gene silencing abnormalities in FAS and bcl-2 pathways have also been implicated.
seen in many cancers. Acetylation of lysine residues on the N- FAS is a transmembrane receptor belonging to the same superfamily
terminus of core histones creates an open and readily transcribable as the TNF-alpha receptor and its stimulation follows a similar path to
chromatin structure while deacetylation creates a tightly coiled and apoptosis that terminates with caspase cascade stimulation and
non-transcribable chromatin structure [100]. Acetylation status can degradation of death substrates [14]. Abnormal FAS-signaling has
also alter transcription factors (GATA-1), nuclear import proteins, also been implicated in other bone marrow failure states such as
signal transduction proteins, DNA repair enzymes, heat shock aplastic anemia as well as in other malignancies with specific studies
proteins, and numerous other cellular proteins [101-106]. The in MDS illustrating increased FAS expression and apoptosis in low-
epigenetic modulation of these proteins leads to altered expression of risk disease and decreased FAS expression in high-risk disease.
pro-apoptotic and cell cycle proteins (ex. FAS/FAS ligand, Bcl2, p53, Interestingly, although increased FAS expression has been seen, no
caspases, Bax, and p21WAF1/Cip1) [106] and can result in multiple statistically significant correlation between FAS expression and
cellular effects including growth arrest in G1 or G2/M, degree of apoptosis has been shown [118]. Thus, while increased
differentiation, and preferential apoptosis of cancer cells [100, 107]. apoptosis is an important component in MDS pathophysiology and is
seen more in early stage disease, the mechanism for which this occurs
Altered Bone Marrow Microenvironment: Apoptosis, is not explained by one pathway alone and may involve FAS
Cytokines and Angiogenesis signaling either via direct or indirect pathways [14, 118, 119]. While
the TNF-alpha and FAS signaling has supported the increased rates of
The bone marrow microenvironment has also been implicated in
apoptosis in early stage disease, decreased apoptosis rates have also
the development and progression of MDS with numerous studies
been implicated in the progression from MDS to AML and has been
showing altered cytokine milieu and apoptosis rates as well as
documented to occur via alterations in anti-apoptotic bcl-2 and bcl-x
changes in vascular microdensity. These alterations produce a
expression [14].
common pathway of increased apoptosis of early, CD34+ progenitors
in early-stage MDS and a relative reversal of this ratio in later-stage Changes in vascular microdensity are another component of the
disease. As MDS progresses towards AML, these pathways become marrow environment identified as contributing to the development
less well defined and additional factors, including proliferative and sustenance of MDS clones [120]. Originally a focus of research
genetic events, may play a more important role [12-14]. Each of these in solid tumors, increased angiogenesis also appears to play a role in
processes may offer scientists numerous targets upon which to focus hematologic malignancies. In solid tumors new blood vessels are
new therapies. formed to sustain growth of the tumor by supplying blood and
nutrients. The role of angiogenesis in hematologic malignancies is
Bone marrow samples from MDS patients traditionally reveal a
slowly being unveiled, and early findings suggest not only its
hypercellular marrow in the context of increased cytokines, such as
importance but also its varied character among different cancers. New
TNF-alpha and IFN-gamma, and persistent peripheral cytopenias.
blood vessel growth can drive cytokine production, but may also be a
Interestingly, data support both increased and decreased programmed
byproduct of excessive cytokines. As described above, the milieu in
cell death within MDS marrows, yet careful analysis suggests that
MDS provides many cytokines capable of influencing new vessel
increased apoptosis is more often associated with early stage MDS
growth. In addition to increased TNF-alpha and INF-gamma in the
(RA/RARS) while decreased apoptosis is more characteristic of
marrow of MDS patients, varying levels of angiogenic factors
advanced disease (RAEB2/AML) [13, 14]. Cytokine dynamics offer
including VEGF (vascular endothelial growth factor), bFGF
one explanation for such cycles of altered apoptosis within the
(fibroblast growth factor), angiogenin, HGF (hepatic growth factor),
malignant clones. Elevations of TNF-alpha and IFN-gamma are
EGF (epidermal growth factor), and TGF-beta (transforming growth
consistently described in the MDS bone marrow microenvironment
factor) have been noted in the plasma of MDS patients. These
[37, 108, 109] with additional reports suggesting TGF-beta elevations
findings, coupled with direct evidence of increased microvascular
as well [110, 111] highlighting the important role cytokines play in
density (MVD) on marrow biopsies, support the development of early
MDS pathogenesis and maintenance. The role of increased TNF-
blood vessels in MDS [120-123]. Both plasma VEGF levels and
alpha has been well studied in its involvement in promoting apoptosis
increased MVD correlate with advanced MDS FAB class [124-126]
in MDS, particularly early stage disease [14, 37, 108]. TNF-alpha
and imply that increased VEGF may drive increased MVD eventually
promotes apoptosis by engaging with the tumor necrosis factor
stimulating MDS progression to AML.
receptor I and II (TNFRI or TNFRII) and via TNFRI mediates
programmed cell death by direct binding with TNF Receptor 1
associated protein with a death domain (TRADD), subsequent Immune System Dysregulation
indirect binding with FAS-associated protein with a death domain Dysregulated immunity has been implicated in the development
(FADD), and eventual activation of the caspase cascade. TNF-alpha of all cancers, including MDS [127], but direct evidence in MDS has
can also interact with TNFRII, which lacks a death domain, but been difficult to uncover. The successful use of immunosuppressive
interacts directly with TNF receptor-associated factor 2 (TRAF-2), therapies (i.e., cyclosporine-A, anti-thymocyte globulin), the
activating NF-!B and JNK, and ultimately promoting anti-apoptotic potentially curative role of allogeneic stem cell transplant, and the
effects [37, 112, 113]. The ratio of these receptors impacts the rates of more recent data showing improved peripheral cytopenias and
apoptosis in MDS with increased TNFRI documented in low-risk elimination of certain common cytogenetic abnormalities with
disease and increased TNFRII in high risk disease illustrating, again, immunomodulatory agents (i.e., thalidomide and lenalidomide)
the inverse correlation between rates of apoptosis and potential for highlight the role immune dysregulation plays in the development of
proliferation and disease progression [37]. MDS. Changes in both B and T cell dynamics have been implicated
Raza et al. have suggested that increased levels of TNF-alpha in MDS development. Studies have substantiated an autoimmune-
have a dual impact on MDS development through contrary type T cell attack in MDS pathogenesis. Specific in vitro work by
stimulatory and inhibitory effects: stimulation of primitive progenitor Smith et al. investigated the possibility of auto-reactive T cells and
cells, yielding the classic hypercellularity of MDS, while exertion of noted the presence of inhibitory T cells in patients with MDS [128]
apoptotic influence on more mature cells, correlating with the with subsequent clinical studies showing in vivo success using anti T-
peripheral cytopenias [111]. The etiology of these cytokine alterations cell therapies (anti-thymocyte globulin (ATG) [129] and
cyclosporine-A (CSA)) [130]. Investigation revealed an abnormal T
546 Current Cancer Drug Targets, 2007, Vol. 7, No. 6 Warlick and Smith

cell repertoire and T cell-mediated inhibition of bone marrow CFU- more pluripotent stem cell of origin. Specifically, Whites group
GM [131] as a potential mechanism to the response to ATG. Further showed the presence of deletion 20q in Epstein Barr Virus (EBV)
characterization of the T cell repertoire in MDS patients demonstrated immortalized lymphoid cell lines derived from an MDS patient [137]
T cell expansion with recurrent patterns of V-Beta and J region while Nilssons group has shown interesting findings with both 5q
skewing suggestive of unknown chronic antigenic stimulation [127] deletion and Trisomy 8 [138, 139]. Specific studies with 5q deletion
while other studies identified high percentages of cytotoxic T cells documented its presence in the majority of pluripotent (CD34+,
(CD8+, CD28-, CD57+) [132]. In aggregate, these findings indicate CD38-) stem cells with both myeloid and lymphoid differentiation;
an activated immune environment [133]. however, transfer of this cell population to SCID mice showed
Irregularities in B cell function have also been implicated in MDS inability to reconstitute hematopoiesis indicating absence of 5q in the
based upon epidemiologic data revealing increased frequency of most primitive progenitors [138]. Interestingly, in cases with both
autoimmune disorders and immune-mediated complications in these Trisomy 8 and del 5q, it was evident that Trisomy 8 was a secondary
patients [134, 135]. Studies evaluating this correlation revealed the genetic event potentially explaining the discrepancy by suggesting
presence of either clinical or serologic manifestation of auto- that the additional Trisomy 8 event developed in the progeny of the
immunity in 10-12% of MDS patients with a higher prevalence in CD34+CD38- del 5q containing stem cells [139]. The quest to
younger patients, those with treatment-related MDS, or those with document the potential clonality of B cells involved in MDS
cytogenetic abnormalities [135, 134]. Just as T cell repertoire pathogenesis has led to the deeper discovery that different cytogenetic
skewing has been noted, clonality of B cells within MDS is also abnormalities may originate in different cells of origin in MDS which
under investigation. The presence or absence of such clonality may could have substantial implications on treatment strategies.
lend insight to the cell of disease origin. Using cytogenetic
abnormalities as a marker to trace lineage, various progenitor and Cell Cycle Dysregulation, Abnormal Differentiation, and
terminally differentiated populations in MDS samples have been Transcription Factor Alterations
studied with seemingly discrepant findings. Using Trisomy 8 as the Abnormal differentiation and growth represents the most
tracing abnormality in their MDS samples, Saitohs group found the dominant morphologic feature of MDS. Although there has been an
additional 8th chromosome in granulocytes, monocytes, and exhaustive analysis of cellular signaling pathways in an effort to
erythroblasts but not in lymphocytes in the BM or in B, T, or NK define the main problems with differentiation, our best understanding
cells of the peripheral blood. Additional analysis found Trisomy 8 in of this problem is linked to studies of the cell cycle: the cells ability
the level of the CFU-GEMM stem cell (CD34+, CD33+) but not in to initiate normal cellular division, speed of the cell cycle, and
the pluripotent stem cells (CD34+, Thy1+) indicating absence of B regulation of cell cycle checkpoints. The speed of the cycle plays an
cell clonality and instead a myeloid progenitor as the neoplastic clone important role in assuring balanced homeostasis between self-renewal
[136]. Other groups have shown the presence of specific cytogenetic and progenitor expansion with natural aging and cellular death of
abnormalities in both myeloid and lymphoid lineages indicting a each cell type required to maintain an adequate blood supply [140].

Transplant Candidate?

Yes NO


AlloBMT# Growth Factors** DMTIs

Lenalidomide if 5q-


** If EPO level <500 consider

# Controversies in BMT for MDS: Approaches to Consider Erythropoietin. Consider addition of G-CSF
if no response to erythropoietin alone
Timing of transplantation:
Low/INT-1: Delay BMT until progression but prior to ! Improved response rates seen in
hypoplastic MDS, PNH clone, HLA-DR15
leukemic transformation positivity
INT-2/High: Proceed towards BMT from diagnosis
@ 5-azacitidine or decitabine
Treatment Pre-BMT:
Low/INT-1: Consider BMT as 1o Therapy + Participation in clinical trials encouraged
INT-2/High: Consider alternative 1o Therapy piror to BMT

Fig. (1). Hopkins approach to MDS treatment.

Myelodysplastic Syndromes Current Cancer Drug Targets, 2007, Vol. 7, No. 6 547

Detailed molecular work has shown characteristic lineage micronenvironmental, and common transcription factor alterations.
specific cell cycle changes required for normal differentiation: 1) up- The GATA transcription factor family (GATA-1, 2, and 3) is of
regulation of cdc2 and cyclin A in erythroid lines; 2) induction of interest with alterations implicated in MDS pathogenesis. Normal
cyclin D1 and p15 in myeloid lines; and 3) selective upregulation of GATA-1 is involved in control of erythroid cells, megakaryocytes,
cyclin D3 and induction of p21 in megakaryocyte differentiation eosinophils, and mast cells while GATA-2 is expressed in more
[141]. Alterations in any of these normal differentiation pathways immature progenitors including hematopoietic stem cells [142].
could thus lead to maturation arrests. Specific blocks in Abnormalities or increased levels of GATA-1 have previously been
differentiation in MDS and AML have been linked to abnormalities described to affect cell cycle regulation [143], proliferation,
such as constitutive activation of CDK inhibitor p16 leading to differentiation, and regulation of apoptosis [144] of both erythroid
G0/G1 arrest and subsequent maturation arrest [141]. Additionally, and megakaryocytic progenitors. Studies show that normal GATA-2
cell cycle specific changes, such as alterations to the CDK inhibitor expression is increased in hematopoietic stem cells and its expression
and tumor suppressor p15INK4B, have been closely linked to inhibits terminal differentiation thus playing more of a role in
uncontrolled cell cycling and proliferation leading to progression proliferation and self-renewal capacity of the stem cells [145].
from MDS to AML [93]. Consequently, imbalances of GATA-1 and GATA-2 could skew the
Resultant aberrant cell cycle function in MDS has been the progenitor population contributing to abnormal differentiation [146],
common final pathway for a number of genetic, epigenetic, the development of MDS [147], and in the setting of an additional
genetic hit may contribute to the progression to acute leukemia [142].

Table II. Theories of Pathophysiology involved in MDS Development

Theories of Current Directed Therapies,

Pathophysiology involved Potential Targets/Components Involved Overall Result of Abnormality Potential Directed Therapies,
in MDS Development and Investigatory Treatments for MDS

Aging Increased BM apoptosis Decreased hematopoietic stem cell pool
! Smoking ! Direct Toxicity to hematopoietic stem
! Radiation cells
! Benzene ! Genotoxic: O2 free radicals, DNA
! Viral Infections
Environmental Exposures ! Non-Genotoxic: Immune
! Chemotherapy
alterations) and altered BM
! Potential decreased telomerase and ! Impaired ability to renew stem cell pool
Telomere Abnormalities subsequent telomere shortening ! Genetic Instability
Genetic Alterations
Common Abnormalities: ! Abnormalities: typically unbalanced ! Lenalidomide:* 5q- syndrome
! 5q- ! 20q- genetic loss ! Ph III Lenalidomide in del 5q- pts @
! Y- ! Trisomy 8 ! Numerous theories of tumor suppressor NCT00179621
Cytogenetic Abnormalities ! 7q-/Monosomy7 ! 17p Syndrome
! Multi-Hit progression from low risk
! 11q23 ! 3q
! P53 mutations ! Ras mutations
! Genetic Instability
! Complex Cytogenetics
! Hypermethylation: ! Methylation and acetylation ! DNA Methyltransferase Inhibitors: (DMTIs)#
! Calcitonin gene abnormalities lead to silencing of ! 5 Azacitidine*
genes important in cell cycle,
! p15INK4B ! Ph I Aza maintenance post AlloBMT
differentiation, apoptosis,
! ER @ NCT00350818
! E-Cadherin ! Decitabine*
! Acetylation Alterations: ! Ph I/II Decitabine + Tretinoin @
! Cell cycle components: p21WAF1
! Ph II Decitabine post Aza failure @
! Alteration of differentiation and
Epigenetic Modulation apoptotic machinery
! Histone Deacetylase Inhibitors (HDIs)
! Alterations of angiogenesis
! Ph I MS-275 + Aza @ NCT00101179

! Ph II Aza,VPA, ATRA @NCT00339196

! Ph II Aza vs. VPA vs. Ara-C @

! Ph II Decitabine +/- VPA @ NCT00414310

! Ph II MGCD0103 @ NCT00374296

! Ph I Vorinistat + Ara-C + VP-16 @

! Comparative Genomic Hybridization: ! Dysfunction of enzymes required for
! Single Nucleotide Polymorphisms detoxification, DNA mismatch repair,
(SNPs): or differentiation
Microscopic Genetic ! NQO1
! Glutathione S-transferase

! G-CSF Receptor

! Microsatellite instability
548 Current Cancer Drug Targets, 2007, Vol. 7, No. 6 Warlick and Smith

(Table II). Contd..

Theories of Current Directed Therapies,

Pathophysiology involved Potential Targets/Components Involved Overall Result of Abnormality Potential Directed Therapies,
in MDS Development and Investigatory Treatments for MDS

Altered Bone Marrow

! Upregulation of: ! Alteration of growth, differentiation, Anti-TNF-" Trials:
! TNF-" angiogenesis ! Ph I/II Aza + Etanercept: INT-2 / High Risk @
! IFN-gamma ! Immune modulation NCT00118287
Altered Bone Marrow ! TGF-Beta ! Ph II ATG + Etanercept: low / INT-1 @
Microenvironment NCT00217386
! IL-1B
Cytokines ! Ph II Infliximab: Low / INT-1 @ NCT00074074
! IL-6
! SCIO-469 Open Label Study: Inhibitor of
! Il-11
p38MAPK (TNF-"/other cytokine/Fas blocker)
@ NCT00113893
Increased TNF-! levels: ! Increased apoptosis and proliferation in Anti-TNF-" Trials: direct blockage see above
!Increased Apoptosis: Low Risk MDS early stage MDS leading to ! Bortezamib @ NCT00440076 (indirect NFkB
hypercellular marrow with peripheral inhibitor: implicated in TNF-" production)
! Binding to TNFRI
oligomerization TRADD/FAD
association -- activation of ! Decreased apoptosis and increased
Arsenic Trials: (Target TNF-", increase
Caspase cascade -- increased proliferation in later stage MDS
susceptibility to apoptosis, suppress VEG-F, induce
apoptosis leading to progression to AML
differentiation via p21/p27 activation)
! Decreased Apoptosis: High Risk MDS ! Ph II Arsenic Trioxide @ NCT00225992
! Binding to TNFRII -- TRAF-2 ! Ph I/II Arsenic+ Ara-C @ NCT00195104
interaction -- activation of NFkB
! Ph II Arsenic + Gemtuzimab @NCT00274781
apoptosis inhibition
Alterations in Apoptosis via ! Ph I/II Aza + Arsenic @ NCT00234000
FAS: Increased Apoptosis
! Increased FAS binds to FAS-Ligand --
trimerization -- activation of FADD -- FAS Target:
association with Caspase 8 -- ! See above SCIO-469 trial ( FAS blocker)
triggering protease/caspase cascade BCL-2 Target: Ph II BCL- 2 inhibitor GX15-
cleaving DNA repair proteins 070MS @ NCT00413114
BCL-2 alterations: Oncogene Targets:
! Oncogene Interactions: ! Ph I Sorafenib (Sorafenib: raf kinase/VEGF
! Inhibits c-myc: required for inhibitor) @ NCT00217646
progression from G1/S ! Ph III Lonafarnib vs Placebo (farnesyl
! Interacts with Raf-1 transferase inhibitor: inhibits RAS) @
! Interacts with Ras NCT00109538

! Increased VEG-F ! Increased Microvessel Density (MVD): ! Ph II Vatalanib (anti-angiogenesis/ VEGF

! Possible Increase: role in pathogenesis not clearly inhibitor) @ NCT000072475
Increased Angiogenesis elucidated but associated with ! See above Sorafenib trial (VEGF inhibitor)
! gFGF and EGF
progression to AML
! Angiogenin ! See Arsenic Trioxide Trials

! T cell Expansion ! Increased T cells leading to potential IMIDs:

! Skewed V# and J regions attack on hematopoietic stem cells ! Ph I Bortezomib + Thalidomide* @
! Increased Cytotoxic T cells CD8+, ! Etiology: Possible chronic antigenic NCT00271804
CD28-, CD57+ stimulation ! Ph I Lenolidamide* + Aza @
! B cell alterations NCT00326846
! Clonal B cell expansion/connection Other Immune Modulation:
with increased frequency of ! Ph III ATG + CSA vs. Best Supportive Care @
Immune Dysregulation autoimmune phenomena in MDS NCT00004208
! Ph I/II Campath +CSA @ NCT00217594
! WT-1/PR-1 Peptide Vaccine + GM-CSF @
! K562/GM-CSF Vaccine @NCT00361296
! Alloreactive NK Infusion + AlloBMT : Ph I/II
@ NCT00402558 and Ph II @ NCT00303667
! Cytoxan + DLI @ NCT00356928
! Cell Cycle Maturation arrest: Ex: p16 alt. ! Impaired maturation ! Ph II Calcitriol + Dex @ NCT00030069
Abnormal Differentiation ! Altered Proliferation: Ex. p15INK4B ! Cytopenias Growth Factors + Differentiating Agents:
! Transcription Factors alt: GATA-1/GATA-2 ! Progression to leukemia ! Ph II Bexarotene+GM-CSF@NCT00425477

Legend: *-FDA-Approved for MDS; @- clinical trials from; # = Numerous epigenetic trial combinations active: representative sample included.

BM = bone marrow; DMTIs = DNA Methyltransferase inhibitors; HDIs = Histone deacetylase inhibitors, MDS = myelodysplastic syndrome; AML = acute myelogenous leukemia; ER = Estrogen receptor; Aza =5-
Azacitidine; Ph = Phase; VPA = valproic acid; ATRA= all-trans retinoic acid; CSA = cyclosporine A; gFGF = fibroblast growth factor; EGF = epidermal growth factor; ATG = anti-thymocyte globulin; NK = natural
killer; AlloBMT = allogeneic bone marrow transplant; DLI = donor lymphocyte infusion; dex = decadron; GM-CSF = granulocyte macrophage colony stimulating factor; alt = alterations

Given the complexity of the cell cycle control in hematopoiesis, STANDARD TREATMENT FOR MDS
alterations of any key component could lead to abnormal Until the recent past, treatment for MDS was limited to best
differentiation and the potential for MDS. supportive care (growth factors and transfusion support) for the
Myelodysplastic Syndromes Current Cancer Drug Targets, 2007, Vol. 7, No. 6 549

Table III. Modified IWG Response Criteria

Response Category Response Criteria ( must last minimum of 4 weeks)

Complete Remission BM: < 5% blasts with normal trilineage maturation

Any persistent dysplasia
Hgb> 11g/dl
Neutrophils > 1 X 109/L
Blasts 0%
Partial Remission If abnormal before treatment, all CR criteria except:
BM blasts decreased by >50% but still greater than 5%
Marrow CR BM: < 5% blasts and greater than 50% decrease over pre-treatment
PB: HI responses will be described in addition to marrow CR
Stable Disease PR not achieved but no progression for >8 weeks
Failure Death or disease progression
Relapse post CR/PR 1+ of the following:
Recurrence of pre-treatment BM blast %
> 50% Decrease from greatest response in neutrophils or platelets
Hgb reduced by greater than 1.5 g/dl or transfusion dependence
Cytogenetic Response Complete: Resolution of all cytogenetic abnormalities
Partial: 50%+ reduction of cytogenetic abnormality
Disease Progression For patients with:
1) < 5% BM blasts: > 50% increase in blasts to >5%
2) 5-10% BM blasts: > 50% increase in blasts to >10%
3) 10-20% BM blasts: > 50% increase in blasts to >20%
4) 20-30% BM blasts: > 50% increase in blasts to >30%
Any of:
1) 50%+ decrease in maximum neutrophil or platelet response
2) Hgb reduction by > 2g/dl
3) Transfusion Dependence
Survival Endpoints:
OS: Death by any cause
EFS: Treatment failure or death by any cause
PFS: progressive disease or death from MDS
DFS: time to relapse
Cause-specific death: any death related to MDS
Hematologic Improvement Responses must be sustained for at least 8 weeks:
(HI) Erythroid Responses (pre-treatment <11 gm/dl):
Hgb increase by > 1.5 g/dl
Reduced PRBC transfusions by at least 4 per 8 week period compared to pre-treatment transfusion requirements (only those
given for Hgb < 9 g/dl counted)
Platelet Responses (pre-treatment < 100 X 109 /L)
Absolute increase of > 30 X 109 /L for pts starting with > 20 X 109/L
Increase from < 20 X 109/L to > 20 X 109/L by > 100%
Neutrophil Response (pre-treatment < 1 X 109/L)
> 100% increase and final count > 0.5 X 109/L
Progression or relapse after HI:
At least one of the following:
50%+ decrease from maximum response in neutrophils or platelets
Hgb reduction by > 1.5 g/dl
Transfusion dependence
Legend: BM = Bone marrow; PB = peripheral blood; g/dl = grams per deciliter; CR = Complete Remission; PR = Partial Remission; HI = Hematologic Response; Hgb = Hemoglobin; OS = Overall Survival; EFS =
Event-free survival; PFS = Progression Free Survival; DFS = Disease-Free Survival
Adapted from [148]

majority of patients and allogeneic stem cell transplant for the small approach to MDS patients. Unfortunately, these criteria of concern
minority of patients eligible for the procedure. Of these treatments, are common in the MDS population. Traditionally, supportive care
only transplant offered an approach that changed the natural history has taken the form of close blood count monitoring, blood product
of the disease and offered a cure. More recently, newer agents, such transfusions, systemically administered lineage-directed growth
as azacitidine and decitabine, have been FDA approved to treat MDS factors, and often prophylactic antibiotics with the sole intent of
based on their impact on the natural history of disease through improving marrow function and minimizing the impact of the bone
decreasing the rate of transformation from MDS to AML. Formal marrow failure on the patients lives. While somewhat effective, each
evaluation of response to treatment has been described by of these approaches is relatively limited. Close monitoring of blood
International Working Group (IWG) criteria, which has recently been counts requires a compliant and diligent patient and takes time each
modified and described in Table III [148]. We review current week for testing and follow-up. Use of transfusions is ultimately
standard treatments (Table IV), describe future directions and novel limited by the development of alloimmunization and the resultant
treatment approaches, and conclude with a treatment algorithm for antibodies that effectively reduce the impact of both red cell and
MDS patients (Fig. (1)). platelet transfusions. Myeloid growth factors are generally only
recommended in patients plagued by recurrent neutropenic fevers,
severe systemic infections, or in combination with erythropoietin.
Supportive Care
Erythropoietin is generally considered the most effective supportive
Based on concerns of poor tolerance to traditional cytotoxic approach yet yields an overall response of approximately 16% as a
agents in patients with advanced age, poor performance status, or single agent [149, 150] and up to 36-50% in combination with G-CSF
medical co-morbidities, supportive care has been the longstanding
550 Current Cancer Drug Targets, 2007, Vol. 7, No. 6 Warlick and Smith

[150-154]. Prolonged administration may yield higher responses with reports recommending allogeneic BMT for young patients with low
Terpos et al. showing response rates approximating 50% in patients grade, early stage disease, these data provide an updated perspective
with a low blast percentage [155]. Responders are typically limited to and would suggest that in young, low risk and INT-1 IPSS MDS
patients with significant anemia, transfusion independence, and low patients, transplant should be delayed until IPSS progression or
endogenous EPO levels [155, 149]. Newer studies using darbepoetin progression of cytogenetic abnormalities.
in MDS patients have reported erythroid response rates ranging from Most patients will not be considered medical candidates for
26% in previous erythropoietin failures [156] to rates as high as 71% myeloablative preparative regimens, and many of those who are
[157]. Interestingly, new reports have highlighted adverse outcomes candidates will not have a matched sibling donor. Strategies have
in patients receiving high doses of erythropoietin or darbepoetin to evolved to make allogeneic treatments more broadly available by
achieve a hemoglobin level greater than 12. While tumor progression developing approaches that adjust for each of the limiting factors.
and decreased survival were the adverse outcomes in head and neck Reduced intensity conditioning (RIC) and non-myeloablative
and breast cancer patients respectively, general adverse events regimens have successfully minimized the preparative regimen
included increased venous and arterial thrombosis, strokes, toxicities to make older patients and those with mild to moderate end-
myocardial infarction, and congestive heart failure. Given the organ dysfunction eligible. Graft manipulation methods have focused
increased concern, the FDA has altered its safety information to on decreasing the rates and severity of the most lethal complication of
recommend using the lowest dose of the agent needed to decrease allogeneic transplants, graft versus host disease. In addition,
transfusion requirements, increasing the hemoglobin gradually, and alternative stem cell sources, including the use of cord blood stem
not exceeding a hemoglobin level of 12mg/dl.1 While these studies cells and haploidentical stem cells, have been developed to expand
prompt caution in the extended use of erythropoietin growth factors the donor pool.
in MDS patients, reaching a hemoglobin level greater than 12 is
unusual, and consequently the degree to which these findings will Recent retrospective analysis of 993 MDS patients undergoing
affect this patient population is yet to be determined. allogeneic transplant comparing myeloablative and reduced intensity
conditioning (RIC) regimens showed improvements in favor of RIC
Allogeneic Stem Cell Transplantation in terms of non-relapse mortality at 3 years (22% vs. 32%) and rates
of acute GVHD (43% vs. 58%); however, these improvements
Allogeneic stem cell transplant, the only known curative were offset by a higher rate of relapse at 3 years (45% vs. 27%) [161].
treatment option for MDS patients, lies at the other treatment Not surprisingly, relapse rates were higher in individual risk groups
extreme. Unfortunately, several factors limit its application for most of older age (>50 years), poor risk cytogenetics, and in those
patients and include advanced age, poor performance status, limited undergoing transplant greater than 6 month from diagnosis.
access to an HLA matched sibling or matched un-related donor Interestingly, the overall survival and progression free survival rates
(MUD), and significant potential for treatment related morbidity and were not statistically different between the two groups with 3 year OS
mortality. Despite these problems, allogeneic transplants are of 41% and 45% in RIC and myeloablative regimens respectively and
commonly recommended for younger patients. Transplant outcomes a 3 year PFS of 33% and 39% [161]. Reduced intensity regimens, or
for more than 452 MDS patients conducted and reported by the non-myeloablative regiments, have thus been successful with regards
IBMTR from 1989 through 1997 were recently presented. The to decreasing transplant-related toxicity in terms of end organ
median age of the group undergoing the transplant was 38 years with toxicity; however, this proposed benefit has been offset by the higher
an overall disease free survival of 53% at 1 year and 40% at 3 years incidence of relapse, mixed chimerism, and similar or higher rates of
and cumulative incidences of relapse of 17% at 1 year and 23% at 3 GVHD [162-165]. One proposed mechanism for the increased
years [158]. The most important predictor of survival was the blast relapse, or decreased graft versus leukemia effect, is the loss of direct
percentage prior to transplant with increased relapse correlating with cytoreduction and increased occurrence of mixed chimerism from
increasing blast percentage and higher IPSS scores. Transplant- reduced intensity preparative regimens [162]. Despite the fact that
related mortality was 32% at 1 year and 37% at 3 years. Generally, RIC regimens allow for use of alloBMT in the older MDS
most data cite improved transplant outcomes in patients treated both population, several reports now suggest the importance of preparative
early in their disease course and with low level disease [158]. regimen dose intensity for allogeneic BMT in MDS, particularly due
Alternative reports indicate that some pause should be taken when to its ability to control active disease [162-165]. Unfortunately, better
making decisions regarding allogeneic BMT in younger or low risk disease control with intensity comes at the expense of increased
MDS patients. Kuendgen et al. reported their series following over mortality, particularly in elderly patients. Given these issues, an
200 untreated MDS patients younger than 50 years of age in an alternative method of transplant maintaining conditioning intensity
attempt to establish a more accurate natural history of disease and while decreasing treatment related toxicity and adequately dealing
compared their outcomes to a registry of over 2000 MDS patients with relapse is needed. The use of T cell depleted allografts following
older than 50. In IPSS low risk or INT-1 disease, untreated patients a myeloablative preparative regimen could reduce the toxicity of
less than 50 years of age had an overall survival nearing 80% (median alloBMT while maintaining dose intensity; however, the success of
still not reached at 360 months) compared to an overall survival less TCD has also been limited due to increased relapse [166, 158]
than 20% with a median of 45 months in the untreated older cohort suggesting that in such settings additional post-BMT interventions are
[159]. In IPSS INT-2 or high risk disease, there appeared to be no needed.
difference in survival between the two age groups thus indicating that
age was an important predictor for survival particularly in IPSS early Efforts are also underway to expand the potential source of
stage disease, while treatment more a predictor of outcome in donors for MDS patients requiring bone marrow transplantation by
advanced stage disease. The study also evaluated outcomes using alternative stem cell sources such as cord blood and
comparing treatment versus best supportive care and showed no haploidentical transplants. A recent analysis of 22 MDS patients
improvement in survival in low risk and INT-1 disease but superior undergoing unrelated cord blood transplants showed a four year
outcomes in treated INT-2 and high risk IPSS disease [159]. disease free survival of 76% with relatively low severe acute GVHD
Additionally, Cutler et al. contributed to decision analysis for use of and a moderate degree of extensive stage chronic GVHD [167]
alloBMT in MDS patients and showed improved outcomes when showing feasibility of this alternative source of bone marrow for
transplant was delayed from diagnosis but completed prior to patients without a suitable matched unrelated donor. Additionally,
leukemic transformation in low risk MDS [160]. With previous recent studies with haploidentical donors have shown similar
outcomes to fully-matched transplants in terms of GVHD and
morbidity and mortality in myeloid malignancies with only advanced
1 acute leukemia associated with higher rates of relapse and mortality 3/1/2007 report: FDA Warnings Regarding High Dose
Erythropoietin Products.
Myelodysplastic Syndromes Current Cancer Drug Targets, 2007, Vol. 7, No. 6 551

[168]. Efforts continue to expand the potential alternative donor bone marrow blast percentage and those with a normal blast count
source and improve upon outcomes. had a greater than 50% response rate while those with > 10% blasts
Targeting Epigenetic Changes (RAEB I or II) had only a 6% response rate [178, 179]. Additional
studies with various HDIs such as MS-275, valproic acid, and SAHA
Within the past 3 years, options for the medical management of are ongoing.
MDS has evolved from the limited supportive care approach of
careful count monitoring, transfusions, and growth factors to now Use of IMIDS as Immune Therapy
having 3 FDA-approved agents indicated for the treatment of patients
with MDS. This progress has led to enthusiasm among physicians Cyclosporine and ATG were among the first immunomodulatory
and their patients and families. However, the availability of these agents used in the treatment of MDS and showed partial success in
drugs has raised many important questions including how to best use producing transfusion independence [129, 130]. The mechanism of
each of the drugs including when to initiate therapy, which agent to action of these agents remained unclear, but investigators identified a
use, and how to best administer each of the drugs. There is also small subset of patients, typically RA patients with less than 5%
intensive ongoing investigation to better understand the mechanism blasts, with the following associations that responded with transfusion
of action of each of the drugs. independence: HLA-DR15 or HLA-DR2 association, younger age,
and shorter duration of red cell transfusion dependence [180]. Efforts
The data supporting the close relationship between epigenetic to study agents that had immunomodulatory impact in MDS were
modifications and the biology of MDS grows almost daily. undertaken and thalidomide emerged as having mild clinical activity
Importantly, 5-azacitidine and decitabine, two newly FDA approved with very interesting potential mechanisms of action, including: 1)
DNA methyltransferase inhibitors, are clinically effective in high risk immunomodulatory effects related to a shift of T cell response from
MDS and appear to work at least in part, by reversing these Th1 to a Th2 [181], partial T cell activation via alteration of
epigenetic changes. The agents cause demethylation of commonly secondary T cell signals, and increased NK cell number and cellular
involved promoter regions by incorporation into DNA as nucleoside lytic activity [182]; 2) anti-angiogenic properties through possible
analogues resulting in inhibition of the methyltransferase activity mechanisms such as nitric oxide inhibition and blockage of
responsible for maintaining these hyper-methylated regions [169]. A endothelial cell migration [183], inhibition of VEG-F and bFGF
phase III CALGB trial comparing 5-azacitidine versus best [120], inhibition of TNF-alpha-induced upregulation of cell adhesion
supportive care showed an overall response rate of 60% (7% CR, 16 markers, [184] and additional TNF-alpha independent mechanisms
% PR, and 37% improved) compared to only 5% in the supportive [185]; 3) alterations of the bone marrow microenvironment through
care only arm [170]. The responses also appeared to confer a survival the impact of cytokines and augmentation of stromal cell growth
advantage and a decrease in the risk of AML transformation (21 [120]; 4) alterations of apoptosis [182, 186]; and 5) alterations of
months versus 13 months) in the 5-azacitidine treated group [170]. adhesion molecule expression [187, 182].
Retrospective analysis of several 5-azacitidine trials done in the
CALGB (trials 8421, 8921, and 9221) incorporated the new IWG Early studies of thalidomides effectiveness in patients with MDS
[171] response criteria (Table III) and confirmed its effectiveness but reported 31% hematologic responses after twelve weeks of therapy
showed lower complete response rates (10-17%) and increased [188]. Subsequent studies revealed response rates from minimal to
hematologic responses (23-26%) with most responses being seen by nearly 50% with partial success inducing transfusion independence
the sixth cycle [171]. seen in a subset of patients [189-192]. Unfortunately, the side effect
profile of hypotension, neuropathy, constipation, and drowsiness
Similar response data also exists for a second, FDA-approve makes the drug poorly tolerated, especially in elderly patients [190].
DNA methyltransferase inhibitor, decitabine. Early studies with Consequently, based on the clinical activity of thalidomide, newer
varying treatment schedules showed hematopoietic responses nearing analogues have been developed to try to minimize side effects.
50% [172, 173] and lead to further Phase III trials randomizing Lenalidomide is the only currently clinically available thalidomide
patients to decitabine versus best supportive care. In this Phase III analogue for treatment of patients with MDS. It is reported to share
study, the decitabine treatment resulted in a complete response rate of many of the same mechanisms of action with thalidomide; however,
9%, a hematologic improvement rate of 13%, and median response lenalidomide has not shown the same effect on endothelial cell
duration of 10 months [174]. Although no survival benefit was seen, proliferation [193-195]. Given the better toxicity profile and similar
most patients became transfusion independent and there was a trend mechanism of action, clinical investigation by List et al. began with
towards a delay to AML transformation or death [174]. Retrospective early phase I/II trials showing extraordinary clinical response
subset review suggested that responses were associated with specifically in a subset of MDS patients who either hadnt responded
cytogenetic complete remissions in 35% of patients [174]. More to EPO therapy or had high endogenous levels, had low risk IPSS, or
recent studies have focused on improving dosing schedules of had cytogenetic abnormalities involving chromosome 5 [196]. The
decitabine (namely lower dosing over increased days) for higher risk study boasted a 56% overall hematologic response rate across all
MDS patients and show higher CR rates (21-30%) and overall cytogenetic abnormalities; in predominantly low risk IPSS, with 63%
responses of up to 73% noting a median of 3 cycles needed to obtain of previously transfusion-dependant patients achieving transfusion
CR [175]. independence. Median time to hematologic response ranged from 9 to
Chromatin remodeling via histone acetylation status is a second 11.5 weeks depending on the dose of lenalidomide. Hematologic
epigenetic target [176] with histone deacetylase inhibitors (HDIs) effects, primarily erythroid, were the most notable in patients with
another group of agents used to modify epigenetic changes. deletion 5q31. Additionally, complete cytogenetic responses were
Acetylation of lysine residues on the N-terminus of core histones seen in 50% with a median time to response of 8 weeks. Toxicities
creates an open and readily transcribable chromatin structure. HDIs included significant neutropenia and thrombocytopenia in greater
function to reverse the gene silencing caused by deacetylation and than half the patients [196]. Further larger scale trials are ongoing to
maintain the histones in an acetylated and transcribable state [100] study the effects of lenalidomide in specific subsets of MDS and have
and exist as several different classes of drugs including hydroximates substantiated the early success [197]. Additionally, trials investigating
(trichostatin A and SAHA), cyclic peptides (cyclic tetrapeptides), the combination of lenalidomide with other agents are ongoing.
aliphatic acids (phenylbutyrate and valproic acid), and benzamides
(MS-275) [177]. A variety of clinical trials have shown both single NEW THERAPEUTIC APPROACHES UNDER DEVELOP-
agent clinical and biologic activity. For example, the use of valproic MENT FOR MDS
acid either alone or in combination with all-trans-retinoic acid
(ATRA) in MDS patients has shown an overall hematologic response The incredibly complex pathophysiology intrinsic to MDS
rate of 24%. Interestingly, response rate correlated inversely with provides many targets and fertile ground for investigators to develop
552 Current Cancer Drug Targets, 2007, Vol. 7, No. 6 Warlick and Smith

Table IV. Standard Treatments for MDS

Treatment Categories Drugs Dose Expected Response Studies
Growth Factors Erythropoietin Standard Starting Dose: Overall HR: 16% [149] Hellstrom-Linberg
150 IU/kg SQ 3 times weekly RR by certain characteristics: et al. Meta-
(Micromedix) Trans. Indep. vs. Dep. (44% vs. 10%) analysis [149]
vs. Mode using FAB group (RARS vs. other)
40,000-60,000 IU 2-3 times a + Epo level + trans. status predicts
week for 2-3 months (NCCN response to EPO
Guidelines) MDS (not RARS) + Trans. Indep. RR
RARS + EPO>200U/l RR=0%
Prolonged EPO administration Overall RR: 45% Terpos et al. [155]
(minimum 26 weeks) using 150 Better RR if:
IU/kg 3 times weekly dose low blast %
Good Cytogenetics
Darbepoetin ** under 300mcg SQ weekly then 300mcg Tx for 12 wks: ER: 71% Mannone et al.
investigation for SQ q2weeks maintenance 8/13 patients previous EPO non- [157]
MDS responders
Transition from EPO to Dar: Tx. Naive Patients: Patton et al. [156]
Darbepoetin dose 200mcg Epo: MR 35%
q2weeks Dar: MR 46%
Prev EPO:
Epo: MR 17%
Dar: MR 26%
Erythropoietin + G- Varied Schedules Results:
CSF EPO 5000-10,000 IU/day SQ + G- Overall ER: 38% Hellstrom-Lindberg
CSF 30-75-150mcg/day SQ et al. [198]
EPO 300U/kg 3 times weekly for ER: 50% Remacha et al. [152]
8 weeks + G-CSF 1mcg/kg/day
G-CSF 1mcg/kg daily X 2 weeks Combined treatment: Negrin et al.[153]
then EPO 300U /Kg per day for Neutrophil response 96% and ER 48%
minimum 8 weeks combined then After G-CSF Cessation:
G-CSF stopped All neutrophil responses lost and 8/55
continued ER
Review of studies Kasper et al. [154]
Epigenetic Modulators 5-Azacitidine 75mg/m2 SQ qd X 7 days q4 weeks Response Typically Seen after 4 cycles: Silverman et al.
DNA Methyltransferase Phase III CALGB: [170]
Inhibitors OR: 60%
(DMTIs) CR: 7% + PR: 16% + Improved: 37%
CALGB Reanalysis: Silverman et al.
CR: 10-17% [171]
HR: 23-26%
Majority of Responses seen by 6th cycle
Decitabine 15mg/m2 IV q8hours times 3 days q6 Phase III Trial: Kantarjian et al.
wks OR: 30% [174]
CR: 9% + PR: 8% + HR: 13%
All responders gained trans. indep.
Majority of Responders: cytogenetic

Alternative Treatment Schedules: Total Overall Response: 73% Kantarjian et al.

Dose: 100mg/m2 CR: 34% + PR: 1% + Marrow CR: 11% + [175]
Marrow CR + HI: 14% + HI: 13%

CR % per dosing schedule:

20mg/m2 IV qd X 5d 20mg/m2 IV: 39%
20mg/m2 SQ qd X 5d 20mg/m2 SQ: 21%
10mg/m2 IV qd X 10d 10mg/ms IV: 24%
Bone Marrow Transplant Standard Per specific regimens 3 yr DFS: 40% IBMTR Data/
Myeloablative 3 yr Relapse Rate: 23% Sierra et al. [158]
Conditioning 3 yr TRM: 37%
Reduced Intensity Per specific Regimens 3 yr PFS: 33% Martino et al.
Conditioning 3 yr Relapse Rates: 45% [161]
3 year NRM: 22%
T Cell Depletion Per specific regimen Entire Group: Mattijssen et al.
(TCD) 2 yr DFS: 39% [166]
2 yr Relapse: 34%
RA Pts:
DFS: 73%
Relapse: 11%
Advanced MDS: (in CRI)
DFS: 42%
Relapse: 34%
IBMTR Data: TCD Sierra et al. [158]
Relative Risk of TRM: 0.6
Relative Risk of Relapse: 1.8
Immunotherapy Thalidomide 100mg titrated to 400mg/day for 12 wks ER: 31% Raza et al. [188]
Survey of studies Varied Response: Numerous Studies
0 50% [189-192]
Lenalidomide 10mg po qday ER: 54% List et al. [196]

10mg/day for 21 days ER: 65%

Improved Response:
Low IPSS/FAB class and highest in del5q-83%
Legend: Trans. = Transfusion; Indep. = Independence; Dep.= Dependence; kg = kilogram; mcg = microgram; OR = Overall response; MR = Major Response; Epo = Erythropoietin; CR = Complete response; ER =
Erythroid Response; Dar = Darbepoetin; PR = Partial response; RARS = Refractory Anemia w/ Ringed Sideroblasts; HR = Hematologic Response; RR = Response Rate; mg/m2 = milligrams per meters squared; CALGB
= The Cancer and Leukemia Group B; NRM = Non-relapse mortality; TRM = Treatment-related mortality; DFS = Disease Free Survival; PFS = Progression Free Survival; Pts = patients, TCD = T Cell Depletion.

new treatment approaches. A very well done recent review captured epigenetics, immune modulation, and differentiation-based
many of these approaches [199]. We focus our new therapeutic approaches.
discussion on three areas under development at our own institution:
Myelodysplastic Syndromes Current Cancer Drug Targets, 2007, Vol. 7, No. 6 553

Epigenetic Treatments Expanding Targets Differentiation Therapy Combinations that Improve

Epigenetic modulation through a combination of DMTIs and Responses
HDIs seemed to be a logical approach noting the responses seen with The outstanding success of ATRA in the treatment of acute
these individual classes of agents. A pilot study combining promyelocytic leukemia (APL) is proof of the principle that
phenylbutyrate (HDI) with 5-azacitidine showed that both complete differentiation therapy has potential to be an important therapy [203].
and partial remissions could be achieved in nearly half of the MDS MDS has also been the target of attempts at utilizing differentiation
and AML patients and showed a strong association between the therapy with the use of agents such as interferon, polar planar
clinical responses and changes in hypermethylation and expression of compounds, homoharringtonine, 5-azacitidine, ara-c, butyrates,
p15 [200]. The clinical responses were supported with findings from amifostine, retinoids, vitamin D derivatives, growth factors, and/or
a second pilot study of the same combination [201]. Gore et al. combinations of the above drugs [204]. Each of these agents has
combined MS-275 (HDI) with 5-azacitidine (DMTI) in a follow-up shown glimpses of differentiating activity, including single agent
pilot study recently presented in abstract form at ASH 20062. Thirty interferon [205-209], demethylating agents [170, 171, 173, 174],
one patients (13 MDS, 4CMMol, and 14 AML 4 of which had multi- vitamin D derivatives [210-212], and retinoids in combination with
lineage dysplasia) were treated with the combination. Azacitidine was other compounds [179, 213, 214].
given in 3 different doses subcutaneously for 10 days and MS-275 Interestingly, each of these agents appears to have differing
was given orally in 4 different doses on day 3 and 10 of a 28 day mechanisms of action raising the question of how pharmacologic
cycle. The treatment regimen was based on in vitro studies illustrating differentiating agents actually work. In vitro studies have shown that
the optimal timing for reversal of epigenetic silencing. Of patients lineage-specific growth factors can enhance the activity of many
with MDS or AML w/ MLD, 50% responded with a median time to pharmacologic differentiation agents noted above in both AML and
best hematologic response of 4 cycles. Of the entire cohort, 6 clinical MDS cell lines and primary bone marrow cells [215-217]. Further
responses were seen in the 20 patients with cytogenetic abnormalities investigation noted that this synergy only occurred with cytostatic
and included 4 with complete cytogenetic responses. Best cytogenetic doses of the pharmacologic differentiating agents. This supported the
responses were seen in a median of 4 cycles. Correlative studies hypothesis that pharmacologic differentiating agents functioned
showed increased H3 or H4 acetylation after 5 azacitidine alone in primarily through inhibition of cell cycle and could preferentially
30% of patients with increase in H3 and H4 acetylation after augment the differentiating capacity of growth factors indicating that
combination therapy in 25/29 and 28/29 patients respectively. Gores the agents were not sufficient in and of themselves for terminal
study provided additional excitement for the successful combination differentiation of malignant cells [217]. Matsuis group went on to
of DMTIs and HDIs in treating MDS and AML w/ MDL and show that growth factors were actually required for substantial in
prompted the current ECOG randomized trial comparing MS-275 + vitro differentiation [215-217]. While growth factors alone are
5-azacitidine to 5-azacitidine alone. sufficient to induce differentiation, their use as single agents is limited
due to their pleiotropic effects of stimulating proliferation and
Immune Strategies Immune System Modulation through enhancing survival via inhibition of apoptosis [218, 219]. Thus, in
Vaccines theory, preferential enhancement of self-renewal and survival could
Vaccine strategies have been employed in many solid tumor cause tumor progression while selective induction of differentiation
malignancies and more recently, hematologic malignancies. Despite could exhaust the neoplastic clone. This hypothesis was recently
the enthusiasm from many clinical immunologists, there is little tested in a phase I study with the differentiating agent bryostatin in
published clinical efficacy data for these approaches to date. Some combination with GM-CSF at the Sidney Kimmel Cancer Center at
strategies are based on targeting tumor antigens preferentially Johns Hopkins. Bryostatin, a protein kinase C agonist, was
expressed by the cancer cells. Specifically in MDS and AML, much administered via continuous infusion in a dose escalation fashion.
of the vaccines work has been based on overexpressed antigens (WT- Smith and colleagues3 found that Bryostatin, in conjunction with
1, survivin, and proteinase 3). A peptide vaccine against WT-1 was GM-CSF, had remarkable clinical activity with 1 poor risk AML
developed and studied in a phase I trial in Japan [202]. The study patient achieving a CR following a single course of the combination
treated 12 patients with AML and considered 7 responders based on a therapy and a second MDS patient having a morphologic CR and
decrease in WT-1 serum levels following the vaccines. Of interest, 2 partial cytogenetics response following 2 cycles. Unfortunately,
MDS patients receiving the vaccine became markedly cytopenic. further development was limited due to an intolerable side effect
Based on concerns that the vaccine may in fact be targeting both profile at clinically active doses. Future directions that build upon
normal and MDS stem cells, no further patients with MDS were these principles include agents with in vitro activity in combination
enrolled [202]. However, this may be the stronger piece of correlative with growth factors including the HDI, MS-275, and novel retinoids,
data supporting the activity of such approaches. Currently at the like bexarotene.
Sidney Kimmel Cancer Center at Johns Hopkins, we have created a
pilot study evaluating the use of an institutionally-developed, SUMMARY
K562/GM-CSF secreting vaccine in patients with MDS. Given that
K562 expresses a number of defined myeloid antigens, such as WT- The myelodysplastic syndromes are an incredibly complex
1, proteinase 3, and survivin, found overexpressed in MDS as well as spectrum of hematopoietic stem cell disorders. Their range of severity
other myeloid malignancies, it has the potential to generate specific along with variations in response to multiple treatment approaches
anti-tumor responses to these antigens. Open to 15 MDS patients, our suggests that the pathophysiology underpinning these disorders is just
trial will evaluate treatment success based on clinical parameters as complex. We are only beginning to unravel the biology of MDS.
including resolution of cytogenetic abnormalities or improvement of This review hopes to not only provide a broad introduction to the
transfusion requirements with additional investigation of immune complex pathways involved in the development and progression of
correlates. these disorders but also to intrigue and challenge both basic and
clinical scientists to continue to work towards unlocking the
mysteries of MDS.

Gore, S. D.; Jiemjit, A.; Silverman, L. B.; Aucott, T.; Baylin, S.; Carraway, H.;
Dauses, T.; Fandy, T.; Herman, J.; Karp, J.; Licht, J. D.; Murgo, A. J.; Odchimar-
Reissig, R.; Smith, B. D.; Zwiebel, J. A.; Sugar, E. Combined Smith, B. D.; Matsui, W.; Gladstone, D. E.; Karp, J.; Gore, S.; Huff, C. A.; Vala, M.;
Methyltransferase/Histone Deacetylase Inhibition with 5-Azacitidine and MS-275 in Baker, S.; Zhao, M.; Piantadosi, S.; Jones, R. J. Differentiation Therapy for Poor Risk
Patients with MDS, CMMoL and AML: Clinical Response, Histone Acetylation and Myeloid Malignancies: Results of a Dose Finding Study of Bryostatin-1 (BRYO) +
DNA Damage. Blood (ASH Annual Meeting Abstracts) 2006, 108, 517. GM-CSF. Blood (ASH Annual Meeting Abstracts) 2005, 106, 2792.
554 Current Cancer Drug Targets, 2007, Vol. 7, No. 6 Warlick and Smith

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Received: November 08, 2006 Revised: April 03, 2007 Accepted: April 09, 2007