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10.1146/annurev.med.56.082103.104704

Annu. Rev. Med. 2005. 56:1–16

doi: 10.1146/annurev.med.56.082103.104704
Copyright

c 2005 by Annual Reviews. All rights reserved

MYELODYSPLASTIC SYNDROME
Wolf-K. Hofmann1 and H. Phillip Koeffler2
1
Department of Hematology and Oncology and Transfusion Medicine, University Hospital
“Benjamin Franklin”, 12200 Berlin, Germany; email: W.K.Hofmann@charite.de
2
Division of Hematology and Oncology, Cedars Sinai Medical Center, UCLA School
of Medicine, Los Angeles, California 90048
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Key Words classification, clinical features, diagnosis, molecular alterations,

treatment
■ Abstract During the past 15 years, important progress has been made in the
understanding of the biology and prognosis of myelodysplastic syndrome (MDS).
MDS is a clonal disorder characterized by ineffective hematopoiesis, which can lead
to either fatal cytopenias or acute myelogenous leukemia (AML). Risk-adapted treat-
ment strategies were established because of the high median age (60–75 years) of
the MDS patients and the individual history of the disease (number of cytopenias,
cytogenetic changes, transfusion requirements). Allogeneic bone marrow transplanta-
tion currently offers the only potentially curative treatment, but this form of therapy
is not available for the typical MDS patient, who is >60 years of age. Therapy with
erythropoietin and G-CSF has improved the quality of life of selected patients. The
development of small molecules directed against specific molecular targets with min-
imal adverse effects is the hope for the future. Innovative uses of immunomodulatory
agents and the optimizing of cytotoxic treatment should continue to help in the treatment
of MDS.

CLASSIFICATION
Myelodysplastic syndrome (MDS) is a clonal disorder characterized initially by in-
effective hematopoiesis and subsequently by frequent development of acute myel-
ogenous leukemia (AML). Peripheral blood cytopenias in combination with a
hypercellular bone marrow exhibiting dysplastic changes are the hallmark of
MDS. In 1982, the French-American-British Cooperative Group classified five
subentities of MDS (1): refractory anemia, refractory anemia with excess of blasts
(RAEB), refractory anemia with excess of blasts in transformation (RAEB-T),
refractory anemia with ringed sideroblasts (RARS), and chronic myelomonocytic
leukemia (CMML). This classification based on morphological criteria was re-
cently revised, resulting in the World Health Organization (WHO) classification
(2–6) (Table 1). Because of the better prognosis of patients with an isolated cy-
togenetic aberration at 5q, the WHO classification includes the 5q– syndrome as
0066-4219/05/0218-0001$14.00 1
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∗
TABLE 1 World Health Organization classification of myelodysplastic syndromes

Category Peripheral blood Bone marrow

RA Anemia Blasts <5%

Blasts <1% Ringed sid. <15%
Mono <1000/mm3
RARS Anemia Blasts <5%
Blasts <1% Ringed sid. ≥15%
Mono <1000/mm3
RCMD Cytopenias (bi- or pancytopenia) Dysplasia ≥10% of cells
Blasts <1% Blasts <5%
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Mono <1000/mm3 Ringed sid. <15%

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RCMD-RS Cytopenias (bi- or pancytopenia) Dysplasia ≥10% of cells

Blasts <1% Blasts <5%
Mono <1000/mm3 Ringed sid. ≥15%
RAEB-I Cytopenias Multilineage dysplasia
Blasts <5% Blasts 5%–9%
Mono <1000/mm3
RAEB-II Cytopenias Multilineage dysplasia
Blasts 5%–19% Blasts 10%–19%
Mono <1000/mm3 Auer rods ±
Auer rods ±
MDS–U Cytopenias Unilineage dysplasia
Blasts <1% Blasts <5%
MDS, isolated Anemia Blasts <5%
del(5q) Blasts <5% Isolated del(5q)
Platelets normal or increased Normal or increased mega.
∗
Abbreviations: RA, refractory anemia; RARS, RA with ringed sideroblasts; RCMD, refractory cytopenia with
multilineage dysplasia; RCMD–RS, RCMD with ringed sideroblasts; RAEB, RA with excess blasts; MDS–U,
myelodysplastic syndrome unclassifiable; Mono, monocytes; Sid., sideroblasts; mega., megakaryocytes.

a separate entity. The initial chromosomal aberration, the age of the patient, and
the number and severity of the cytopenias are important to evaluate the prognosis
of MDS, as summarized in the International Prognostic Scoring System, IPSS (7)
(Table 2). The median survival of MDS patients according to this classification
ranges from 6 years for low-risk to 6 months for high-risk patients.

Secondary MDS
Secondary MDS is a term that we use to emphasize that the MDS results from expo-
sure to a mutagen. This could occur as a consequence of therapy for another disease
(treatment-related MDS) or exposure to a toxic material, such as benzene. MDS has
been described following therapy of malignancies (e.g., Hodgkin’s disease, non-
Hodgkin lymphomas, multiple myeloma), including autologous transplantation
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MYELODYSPLASTIC SYNDROMES 3

TABLE 2 International prognostic scoring system for myelodysplastic syndromes

Score Bone marrow Cytopenias

valuea blasts (%) Karyotype (lineages affected)

0 <5 Normal, sole: –Y, del 5q, del 20q 0 to 1

0.5 5–10 Others 2 to 3
1.0 Complexb and/or
chromosome 7 anomalies
1.5 11–20
2.0 21–30
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a
The prognostic score is determined by the sum of the single scoring values. The risk groups are determined as
follows (brackets: median survival): Low = 0 points (5.7 years); Intermediate–1 = 0.5–1.0 points (3.5 years);
Intermediate–2 = 1.5–2.0 points (1.2 years); High ≥2.5 points (6 months).
b
≥3 chromosomal abnormalities.

(8–10). Alkylating chemotherapy most frequently is implicated as the causative

class of agents (11). The highest incidence of secondary MDS/AML occurs 3–
8 years after treatment of the antecedent malignancy (12).
After therapy with DNA topoisomerase II inhibitors, secondary MDS/AML
develops within a period of about 2–3 years (12). Recently, several single reports
have indicated that the NUP98 gene on chromosome 11p15 is one of the targets for
chromosomal translocations in patients with therapy-related MDS after exposure
to poly-chemotherapy including topoisomerase II inhibitors (13).

5q– Syndrome
This clinically distinct entity involves a deletion of the long arm of chromosome
5 and is characterized by a female preponderance, thrombocytosis, prominent
megaloblastoid erythroid hyperplasia in the bone marrow, and megakaryocytes
that are unusually large (often >30 µm in diameter) and often have a single,
eccentric, round nucleus (14). Interestingly, the rate of leukemic transformation
in individuals with 5q– syndrome is only 25% after an observation period of
15 years, as compared to about 40% in patients with a normal karyotype (7).
The underlying molecular targets in 5q– syndrome are still unknown. The criti-
cal segment may be at chromosome 5q31 (15, 16). The human GRAF (GTPase
regulator associated with focal adhesion kinase) gene located in this region can
fuse to the MLL (mixed lineage leukemia) gene, disrupting both alleles (17), but
the significance of this gene in the 5q– syndrome is unclear. Also, the loss of one
allele on 5q (haploinsufficiency) could contribute to the 5q– abnormality, similar
to what occurs in the familial platelet disorder with predisposition to AML (see
below).
In striking contrast to this syndrome is the loss of chromosome 5 or
5q– in therapy-related MDS, which presages an almost inevitable leukemic
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transformation. This may be associated with loss of regions of 5q other than the
region lost in the 5q– syndrome.

Hypoplastic MDS
Usually, patients with MDS have a hypercellular bone marrow. In ∼10% of cases,
peripheral blood cytopenia is associated with a hypoplastic bone marrow. In such
cases distinguishing MDS from aplastic anemia may be difficult, but the presence
of cytogenetic changes can help to identify malignant clonal cells, supporting the
diagnosis of MDS. The pathophysiology of hypoplastic MDS is not known; autore-
active and clonal-involved T-cells are believed to suppress normal hematopoietic
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to immunosuppressive agents.

CLINICAL FEATURES
MDS occurs primarily in the elderly population, with a median age between 60
and 75 years and a surprisingly high incidence of about 15–50 cases per 100,000
individuals over the age of 70 per year (18, 19). Despite this predominance of
elderly patients, MDS occasionally occurs in younger individuals and even in
children. In recent years, the incidence of MDS appears to be rising, perhaps
partly owing to increased diagnostic awareness. The sex distribution is balanced
(18), despite earlier reports that indicated a male preponderance. The exception is
CMML, which has a clear male preponderance (20).
Fatigue and exertional dyspnea may develop over a prolonged period, often
exceeding 6–12 months. These symptoms may be misinterpreted as either cardiac
failure or pulmonary disease, particularly in elderly patients. Approximately half
of the individuals are asymptomatic at the time of initial diagnosis and are usually
diagnosed after a routine blood count. Progressive hematopoietic failure leading
to anemia, thrombocytopenia, and leukopenia, either alone or in any combination,
is the dominant finding in MDS. Anemia is an almost universal characteristic at
the time of initial diagnosis; more than 80% of patients present with a hemoglobin
concentration below 10 g/dl. The reticulocyte count usually is reduced.
The peripheral blood leukocyte count is low in ∼25%–30% of individuals with
MDS, but because the blast cells replace more of the bone marrow, 40% of RAEB
cases and 80% of RAEB-T cases can have leukopenia. Granulocytes may exhibit a
reduced segmentation and either diminished or absent granulation. Approximately
one third of the individuals have recurrent infections. These occur not only because
of granulocytopenia but also as a result of defects of neutrophil function, including
impaired chemotaxis and reduced phagocytic activity.
Signs of bleeding, mainly petechiae, gingival bleeding, or hematoma following
trivial injuries, are surprisingly uncommon, given the frequency of thrombocy-
topenia. Fewer than 10% of patients will present initially with serious bleeding,
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MYELODYSPLASTIC SYNDROMES 5

e.g., gastrointestinal hemorrhage, macrohematuria, or retinal or central nervous

system hemorrhage.

CYTOGENETICS AND MOLECULAR ALTERATIONS

The cytogenetic changes found in MDS are not unique to the disease. Both struc-
tural and numerical cytogenetic changes may occur (reviewed in References 21
and 22). The most frequent chromosomal abnormalities in MDS involve deletions
of chromosomes 5, 7, 11, 12, and 20 and/or trisomy 8 (Table 3). The incidence
of chromosomal abnormalities is about 30%–50% in primary MDS and 80% in
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mutagen-related MDS. The latter often features complex changes that frequently
involve deletions of chromosomes 5 and/or 7. Translocations are rare in MDS.
MDS-related chromosomal deletions imply alterations in tumor suppressor genes
or DNA repair genes. Usually these changes require two hits: mutation of the target
gene and loss of the second allele through deletion, duplication, or recombination.
The underlying causes of primary MDS are still being defined. Analysis of
cytogenetic abnormalities, G6PD isoenzymes, restriction-linked polymorphisms,
and X-linked DNA polymorphisms of the androgen receptor have shown that MDS
is a clonal abnormality of the hematopoietic stem cell characterized by defective
maturation and, in advanced stages, uncontrolled proliferation (23). Lymphocytes
are probably not involved in the clonal hematopoiesis in MDS (24), but precursors
of erythrocytes, platelets, neutrophils, monocytes, eosinophils, and basophils are
members of the abnormal clone. Figure 1 proposes a multistep pathogenesis of
MDS. After initial damage of the progenitor cell by a toxin or spontaneous mu-
tation, several additional alterations may affect these cells, providing them with a
growth advantage. These alterations can influence expression of cell cycle-related
genes, transcription factors, and tumor suppressor genes.

TABLE 3 Most frequent chromosomal aberrations in MDS

patients (frequency of chromosomal aberration is given in
∗
brackets)

Numerical Translocations Deletions

+8 (19%) inv 3 (7%) del 5q (27%)

–7 (15%) t(1;7) (2%) del 11q (7%)
+21 (7%) t(1;3) (1%) del 12q (5%)
–5 (7%) t(3;3) (1%) del 20q (5%)
t(6;9) (<1%) del 7q (4%)
t(5;12) (<1%) del 13q (2%)
∗
Symbols: –, loss of chromosome; +, additional chromosome; inv, inversion; t,
translocation; del, deletion.
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Figure 1 Multistep pathogenesis in MDS. The initial genetic insult to the hematopoi-
etic stem cell can be caused by chemicals, radiation, cytotoxic drugs, or random en-
dogenous mutations. The accumulation of several alterations that may affect cell cycle
control, transcription, or tumor suppressors results in the expansion of the MDS clone.
The progression to leukemia probably does not depend on the order of occurrence of
genetic alterations but depends on which genes are altered. The final step, leukemic
transformation, may be enhanced by alteration of additional genes, including tumor
suppressor genes, and/or by hypermethylation of critical targets. The later stage of
leukemogenesis is associated with decreased apoptosis.

Recent studies have suggested that microarray analyses can provide sufficient
data to detect genes or gene patterns associated with alterations of specific cellular
pathways or signal cascades in MDS (25). The prediction of prognosis or risk type
of MDS from gene expression data is a long way from practice (26, 27), but it may
have a strong impact in the future on classification and risk definition in MDS.

TREATMENT
Patients with MDS are mainly older individuals suffering from accompanying
diseases. Therefore, various strategies have been used to treat patients with MDS.
Rather than to offer a cure, the main therapeutic goals in patients with MDS
are often to improve hematopoiesis and to ensure an age-related quality of life.
Low-intensity therapies, defined as treatments that permit outpatient management,
are often directed at patients with low-risk MDS (IPSS low and intermediate-1).
Such strategies are not necessarily associated with either improved survival or
progression-free survival.
Patients with high-risk MDS (IPSS intermediate-2 and high) need high-intensity
therapies (aggressive antileukemic chemotherapy and/or stem cell transplantation)
to eliminate the expanded clonal cells and to induce hematological responses.
Because of the high median age of patients with MDS, only about one third of
high-risk MDS patients can receive intensive cytotoxic treatment. For patients
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MYELODYSPLASTIC SYNDROMES 7

who do not qualify for intensive therapy, experimental treatments to suppress,

differentiate, or eradicate the malignant clone are under investigation.

Supportive Care
Supportive care generally is the mainstay of therapy. Patients should be treated
with erythrocytes for symptomatic anemia. To reduce the risk of iron overload
in patients who receive >10 erythrocyte transfusions per year, therapy with an
iron chelator should be used, e.g., by bolus subcutaneous administration (28). An
optimal hemoglobin level is not known, but usually symptoms such as fatigue and
dyspnea occur if the hemoglobin level drops below 8 g/dl, prompting erythrocyte
transfusions. Individuals with a history of coronary heart disease have to be trans-
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fused more aggressively. To minimize the risk of myocardial infarction in these

patients, the hemoglobin level should be 10 g/dl or greater.
Platelet transfusions are restricted to bleeding complications because repeated
platelet transfusions are associated with alloimmunization, which results in refrac-
toriness to donor platelets. In cases of refractoriness to either pooled or single-donor
platelet transfusions, administration of antifibrinolytic agents or vasopressin may
stop minor bleeding, such as from the nose or gingiva.
In the event of documented infections, as well as in the case of fever of unknown
origin, antibiotics must be given early. The danger of sepsis from common infec-
tions is greater in neutropenic patients than in normal individuals, and intravenous
antibiotics are often necessary.

Allogeneic Transplantation
Allogeneic bone marrow transplantation (BMT) or peripheral blood progenitor cell
transplantation (PBPCT) is a curative therapy for MDS. The results of allogeneic
transplantation vary considerably depending on the subtype of disease and other
clinical factors (29). The overall long-term disease-free survival is 60% for IPSS
low, 40% for IPSS intermediate-2, and 20% for IPSS high individuals (30–32).
Several important factors can improve the outcome after allogeneic transplantation
(33), including age (increased survival in patients aged <37 years), low number
of cytopenias (<2 is associated with good prognosis after allotransplantation),
low IPSS, matched sibling donor, short disease duration (<3–6 months), bone
marrow blast cells <5%, and the achievement of complete remission (CR) before
transplantation (Table 4). The non-relapse mortality (NRM) after 3 y in this set-
ting ranges from 12% to 30% for both sibling and unrelated matched transplants,
but it is up to 50% in unrelated HLA-nonidentical transplants. This considerable
therapy-associated mortality is related to a high incidence of graft-versus-host dis-
ease (GVHD), which is often associated with severe bacterial or fungal infections
including disseminated aspergillosis (32).
“Mini-transplantation” may be an alternative treatment option in MDS pa-
tients aged >60 years (34). These individuals receive partial hematopoietic and
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TABLE 4 Prognostic parameters that affect outcome after

allogeneic stem cell transplantation in patients with MDS
(adapted from Reference 33)

Favorable Unfavorable

Younger age Age >60 years

HLA-matched sibling donor
Good performance status
Early-stage disease
Disease of short duration
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Mismatched donor
Poor performance status
Advanced or secondary MDS
Prolonged course of disease

immune ablation, and the transplantation results in a chimerism to encourage a

graft-versus-MDS/AML effect. This approach is still investigational.
The use of peripheral blood progenitor cells for transplantation is associated
with a rapid hematopoietic recovery. This significantly reduces the number of
days of fever, as well as the need for parenteral antibiotics, antifungal therapy, and
transfusion of erythrocytes and/or platelets. Total duration of hospitalization is also
decreased, compared with that of a historical matched bone marrow transplantation
group (35).

Autologous Transplantation
The high toxicity of allogeneic transplantation and the advanced age of most pa-
tients have prompted many investigators to evaluate the feasibility of autologous
transplants in high-risk MDS. Early results of PBPCT indicate that survival rates,
but not disease-free survival, may approach those of allogeneic transplantation
because of the low mortality associated with the autotransplant itself (36). A ret-
rospective analysis of 79 patients autografted for MDS showed an overall survival
of 39% and a disease-free survival of 34% at 2 years (37, 38).

Hematopoietic Growth Factors

Eighty-five percent of MDS patients have elevated serum erythropoietin levels.
Despite this fact, the rationale to treat MDS patients with recombinant erythro-
poietin (Epo) is the possibility that pharmaceutical doses may enhance the de-
fective proliferation and differentiation of the erythroid precursors. In ∼25% of
low-risk MDS patients receiving Epo, erythrocyte mass increases and/or transfu-
sion requirements are reduced. Factors associated with response to Epo include
serum Epo level below 200 U/L, absence of transfusion requirement, and ab-
sence of ringed sideroblasts (39). Long-term Epo responders have been described
(40).
Interestingly, the combination of Epo with either granulocyte-colony stimulat-
ing factor or granulocyte macrophage-colony stimulating factor (G- or GM-CSF)
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MYELODYSPLASTIC SYNDROMES 9

has a synergistic effect in patients with MDS (41–46). In particular, RARS pa-
tients who have almost no response to Epo have a 40% response rate (increased
erythrocyte mass) if they receive the combination of Epo and G-CSF. The clinical
role for thrombopoietin in MDS patients with low platelet counts (<20,000/µl)
must be further defined by careful, controlled clinical trials that evaluate bleed-
ing events, side effects, and particularly the risk of development of neutralizing
antibodies.

Demethylating Agents
Many genes have regions in their promoter (CpG islands) that can be methylated at
the 5 position of cytosine, which silences expression of these genes. Theoretically,
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demethylation of methylated genes that are important in differentiation and/or

apoptosis could have clinical applications. For example, p15INK4b, a cell cycle
brake, is frequently methylated in MDS but not in normal myeloid cells (47).
Both 5-azacytidine (Azacitidine; VidazaTM, Pharmion Corp., Boulder, CO) and
5-aza 2 -deoxycytidine (Decitabine, SuperGen, Inc., Dublin, CA) reduce DNA
methyltransferase activity and therefore can cause DNA hypomethylation (48, 49).
Whereas Azacitidine is incorporated mostly into mRNA and tRNA, Decitabine is
incorporated solely into DNA, possibly accounting for the somewhat different
toxicity profile of these two drugs.
Initial pilot trials with low-dose Azacitidine (50) and low-dose Decitabine (51)
provided encouraging results. A multicenter study of Azacitidine (52) confirmed its
efficacy. Recently, results of a multicenter phase II trial with low-dose intravenous
5-aza 2 -deoxycytidine (45 mg/m2 for 3 days every 6 weeks) were reported for
66 mostly elderly patients with advanced MDS (IPSS: 24% intermediate-1, 38%
intermediate-2, 38% high) (53). The overall hematologic response rate was 49%,
which included a response of 64% for high-risk individuals. The actuarial median
response duration was 31 weeks, with a response duration of 39 weeks and 36
weeks for patients who reached a PR or CR, respectively.

Immunosuppressive Agents
Immunosuppressive therapy has been proposed for the past 15 years as a treatment
option for MDS to reverse bone marrow failure by inhibiting intramedullary se-
cretion of proapoptotic cytokines. In a pilot study, 42 transfusion-dependent MDS
patients received antithymocyte globuline (ATG, 40 mg/kg/d for 4 days) (54, 55).
Remarkedly, erythrocyte transfusion independence occurred in 16 individuals, and
platelets increased in 14 of them. Three individuals with refractory anemia had a
complete remission. The response rate was 64% in the low-risk individuals and
33% in those with high-risk MDS. The median response duration was 10 months,
ranging from 3 to 38 months. A recently published update of this nonrandomized,
single-treatment study (56) reported an overall frequency of transfusion indepen-
dence of 34% in a total of 61 patients with MDS. Parameters to predict a good
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response to ATG treatment are low IPSS and a short history of erythrocyte trans-
fusions (57).
Several small studies used cyclosporin A (CSA) for MDS patients (58–60) with
variable results. A predictive marker for a good response may be the expression
of the HLA-DRB1∗ 1501 allele (61). Of a total of 10 patients studied, 6 patients
responded to CSA, all of whom had the 1501 allele. Four patients did not show
any response and did not have this human leukocyte antigen. It remains unclear
how ATG and/or CSA improves hematopoiesis in MDS, and why many months of
therapy are needed before a response occurs. Several multicenter trials using ATG
and/or CSA for MDS are ongoing.
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Intensive Cytotoxic Treatment

At the present time, long-term benefit for individuals with MDS can be achieved
only by eradication of the abnormal clone and restoration of normal hematopoiesis.
Recent studies in which intensive cytotoxic treatment was administered to younger
individuals with high-risk MDS have produced remission rates ranging from 22%
to 79%. As a consequence of the further improved supportive care in patients
receiving intensive cytotoxic treatment, the remission rate achieved in high-risk
MDS patients is comparable with those for patients with de novo AML. On the
other hand, in a recently published study that evaluated intensive chemotherapy
alone compared to chemotherapy followed by transplantation in a total of 269
patients with high-risk MDS, neither the chemotherapy nor the transplantation
showed a clear benefit (62).
The decision whether to pursue aggressive treatment should include stratifica-
tion according to the patient’s risk factors using the IPSS (7). The use of hematopoi-
etic growth factors permits more patients to receive intensive cytotoxic treatment.
Nevertheless, the duration of remission often is short, usually about 12 months (63).
Long-term remissions are associated with restoration of polyclonal hematopoiesis
(64), and the achievement of a partial remission after induction therapy may be of
clinical benefit for high-risk patients.

Arsenic Trioxide (As2O3)

Arsenic compounds have been used therapeutically for at least a millennium in
China. In the West, arsenic in the form of “Fowler’s solution” was used in the
middle of the nineteenth century to treat fever of unknown orign. Most recently,
As2O3 has produced very good response in acute promyelocytic leukemia (65–67).
Clinical studies to evaluate As2O3 in MDS are under way (68).

Future Experimental Approaches

Farnesyl transferase inhibitors showed in vivo efficacy in the treatment of pa-
tients with AML, conceivably by inhibiting the Ras pathway. The role of these
agents in the treatment of high-risk MDS patients who are not qualified to receive
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MYELODYSPLASTIC SYNDROMES 11

intensive treatment is not yet established, but they may be a future option
(69).
The bone marrow of individuals with MDS contains an abnormally high num-
ber of blood vessels (70, 71). This has encouraged the investigation of inhibitors
of angiogenesis, such as SU5416 and thalidomide, and of inhibitors of vascu-
lar endothelial growth factor (VEGF) for individuals with either AML or MDS.
Thalidomide was initially developed as a “sleeping pill,” but it was found to
have activity in the treatment of patients with multiple myeloma. In MDS, treat-
ment with thalidomide as a single agent (72) resulted in 30%–40% of MDS pa-
tients showing a hematopoietic response, usually improved erythropoiesis. Further
studies of antiangiogenetic drugs, including the new thalidomide analogue CC-
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5013 (RevimidTM; Celgene, Warren, NJ) which may have immunomodulatory

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efficacy in patients with 5q– syndrome (A. List, personal communication), and
anti-TNFα therapeutics are ongoing. Ultimately, we will define the genetic lesion
of the patient and have in our armamentarium a therapy specific for that molecular
abnormality.

Overall Treatment Approach in MDS

The treatment decision should take into consideration the patient’s disease risk
according to IPSS, age, and performance status. Based on these factors, possible
treatment strategies are as follows:

1. Individuals up to the (biological) age of ∼55–60 years are candidates for al-
logeneic transplantation from an HLA-matched (sibling or unrelated) donor.
The patients should be carefully informed about the risks of the allogeneic
stem cell transplantation. The alternative treatment options (see below)
should be discussed.
2. Patients with IPSS low or intermediate-1 MDS who have no HLA-identical
donor, or are older than 60 years and have good clinical performance, should
receive either supportive care or, when necessary, a trial of erythropoietin. For
nonresponders to erythropoietin, the combination therapy of erythropoietin
with G-CSF may be effective. Alternatively, immunosuppressive therapy
or other experimental approaches should be considered. As their disease
progresses, various therapies might be evaluated in the context of an ongoing
clinical study.
3. Patients with IPSS high or intermediate-2 MDS, older than 60 years and
having a good clinical performance, are candidates for intensive cytotoxic
therapy, followed by consolidation therapy and perhaps autologous trans-
plantation.
4. Individuals who are elderly and/or in poor clinical condition should re-
ceive supportive care. If possible and desired by the patient, investigational,
outpatient-based therapy (e.g., demethylating drugs or thalidomide) should
be offered.
 2 Dec 2004 7:12 AR AR236-ME56-01.tex AR236-ME56-01.sgm
12 HOFMANN
KOEFFLER
The Annual Review of Medicine is online at http://med.annualreviews.org
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December 9, 2004 15:2 Annual Reviews AR236-FM

Annual Review of Medicine

Volume 56, 2005

CONTENTS
MYELODYSPLASTIC SYNDROME, Wolf-K. Hofmann and H. Phillip Koeffler 1
G PROTEIN POLYMORPHISMS IN HYPERTENSION, ATHEROSCLEROSIS,
Annu. Rev. Med. 2005.56:1-16. Downloaded from arjournals.annualreviews.org
by "UNIV. OF WISCONSIN, MADISON" on 03/11/05. For personal use only.

AND DIABETES, Winfried Siffert 17

POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDERS,
Stephen Gottschalk, Cliona M. Rooney, and Helen E. Heslop 29
METABOLIC SYNDROME: A CLINICAL AND MOLECULAR PERSPECTIVE,
David E. Moller and Keith D. Kaufman 45
NEW ANTICOAGULANT THERAPY, Lori-Ann Linkins and Jeffrey I. Weitz 63
ENDOTHELIAL PROGENITOR CELLS, Aarif Y. Khakoo and Toren Finkel 79
AROMATASE INHIBITORS: RATIONALE AND USE IN BREAST CANCER,
Cynthia Osborne and Debu Tripathy 103
ANDROPAUSE: IS ANDROGEN REPLACEMENT THERAPY INDICATED
FOR THE AGING MALE?, Rabih A. Hijazi and Glenn R. Cunningham 117
SURGICAL THERAPY FOR METASTATIC DISEASE TO THE LIVER,
David J. Bentrem, Ronald P. DeMatteo, and Leslie H. Blumgart 139
NEW STRATEGIES IN THE TREATMENT OF THE THALASSEMIAS,
Stanley L. Schrier and Emanuele Angelucci 157
NEW CONCEPTS IN VON WILLEBRAND DISEASE, J. Evan Sadler 173
GENETICS OF LONGEVITY AND AGING, Jan Vijg and Yousin Suh 193
PROGRESS TOWARD AN HIV VACCINE, Norman L. Letvin 213
THERAPEUTIC INTERVENTION AND TARGETS FOR SEPSIS, Todd W. Rice
and Gordon R. Bernard 225
MANAGEMENT OF PERIPHERAL VASCULAR DISEASE, I. Baumgartner,
R. Schainfeld, and L. Graziani 249
ROLE OF MAGNETIC RESONANCE IMAGING AND IMMUNOTHERAPY IN
TREATING MULTIPLE SCLEROSIS, Jingwu Zhang and George Hutton 273
DEFINITION AND CLINICAL IMPORTANCE OF HAPLOTYPES,
Dana C. Crawford and Deborah A. Nickerson 303
APPROACHES TO THERAPY OF PRION DISEASES, Charles Weissmann
and Adriano Aguzzi 321

v
P1: JRX
December 9, 2004 15:2 Annual Reviews AR236-FM

vi CONTENTS

ENDOMETRIOSIS: NEW GENETIC APPROACHES AND THERAPY,

David H. Barlow and Stephen Kennedy 345
SEVERE ACUTE RESPIRATORY SYNDROME (SARS): A YEAR IN
REVIEW, Danuta M. Skowronski, Caroline Astell, Robert C. Brunham,
Donald E. Low, Martin Petric, Rachel L. Roper, Pierre J. Talbot,
Theresa Tam, and Lorne Babiuk 357
GENE-ENVIRONMENT INTERACTIONS IN ASTHMA AND OTHER
RESPIRATORY DISEASES, Steven R. Kleeberger and David Peden 383
THE SILENT REVOLUTION: RNA INTERFERENCE AS BASIC BIOLOGY,
RESEARCH TOOL, AND THERAPEUTIC, Derek M. Dykxhoorn
Annu. Rev. Med. 2005.56:1-16. Downloaded from arjournals.annualreviews.org

and Judy Lieberman 401

by "UNIV. OF WISCONSIN, MADISON" on 03/11/05. For personal use only.

MANAGEMENT OF ADULT IDIOPATHIC THROMBOCYTOPENIC PURPURA,

Douglas B. Cines and Robert McMillan 425
MONOGENIC OBESITY IN HUMANS, I. Sadaf Farooqi
and Stephen O’Rahilly 443
APPLICATION OF MICROBIAL GENOMIC SCIENCE TO ADVANCED
THERAPEUTICS, Claire M. Fraser and Rino Rappuoli 459
ATRIAL FIBRILLATION: MODERN CONCEPTS AND MANAGEMENT,
Ashish Agarwal, Meghan York, Bharat K. Kantharia,
and Michael Ezekowitz 475
DNA REPAIR DEFECTS IN STEM CELL FUNCTION AND AGING,
Youngji Park and Stanton L. Gerson 495
HEMATOPOIETIC STEM AND PROGENITOR CELLS: CLINICAL AND
PRECLINICAL REGENERATION OF THE HEMATOLYMPHOID SYSTEM,
Judith A. Shizuru, Robert S. Negrin, and Irving L. Weissman 509
INHERITED SUSCEPTIBILITY TO COLORECTAL CANCER, Peter T. Rowley 539
APTAMERS: AN EMERGING CLASS OF THERAPEUTICS,
Shahid M. Nimjee, Christopher P. Rusconi, and Bruce A. Sullenger 555
GENE THERAPY FOR SEVERE COMBINED IMMUNODEFICIENCY,
Marina Cavazzana-Calvo, Chantal Lagresle, Salima Hacein-Bey-Abina,
and Alain Fischer 585

INDEXES
Subject Index 603
Cumulative Index of Contributing Authors, Volumes 52–56 637
Cumulative Index of Chapter Titles, Volumes 52–56 640
ERRATA
An online log of corrections to Annual Review of Medicine
chapters may be found at http://med.annualreviews.org/errata.shtml